U.S. patent application number 17/542262 was filed with the patent office on 2022-03-24 for aerosol tyrosine kinase inhibitor compounds and uses thereof.
The applicant listed for this patent is AVALYN PHARMA INC.. Invention is credited to Mark William Surber.
Application Number | 20220087937 17/542262 |
Document ID | / |
Family ID | 1000006010402 |
Filed Date | 2022-03-24 |
United States Patent
Application |
20220087937 |
Kind Code |
A1 |
Surber; Mark William |
March 24, 2022 |
AEROSOL TYROSINE KINASE INHIBITOR COMPOUNDS AND USES THEREOF
Abstract
Disclosed herein are formulations of imatinib or a
phenylaminopyrimidine derivative compound for aerosolization and
use of such formulations for inhaled aerosol administration of
imatinib or a phenylaminopyrimidine derivative compound for the
prevention or treatment of various fibrotic, carcinogenic, vascular
and viral infectious diseases, including diseases associated with
the lung, heart, kidney, liver, eye, central nervous system and
surgical sites. In some embodiments, formulations and delivery
options described herein allow for efficacious local delivery of
imatinib or a phenylaminopyrimidine derivative compound or salt
thereof. Compositions include all formulations, kits, and device
combinations described herein. Methods include inhalation
procedures, indications and manufacturing processes for production
and use of the compositions described. Also included are methods
for identifying compounds and indications that may benefit by
reformulation and inhalation administration.
Inventors: |
Surber; Mark William; (San
Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AVALYN PHARMA INC. |
Seattle |
WA |
US |
|
|
Family ID: |
1000006010402 |
Appl. No.: |
17/542262 |
Filed: |
December 3, 2021 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14449066 |
Jul 31, 2014 |
|
|
|
17542262 |
|
|
|
|
61948461 |
Mar 5, 2014 |
|
|
|
61860721 |
Jul 31, 2013 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/12 20130101;
A61K 31/506 20130101; A61K 9/008 20130101; A61K 9/0078 20130101;
A61K 47/02 20130101; A61K 9/14 20130101; A61K 9/0075 20130101 |
International
Class: |
A61K 9/14 20060101
A61K009/14; A61K 9/00 20060101 A61K009/00; A61K 47/02 20060101
A61K047/02; A61K 47/12 20060101 A61K047/12; A61K 31/506 20060101
A61K031/506 |
Claims
1. An aqueous solution for nebulized inhalation administration
comprising: water; nintedanib or a salt thereof at a concentration
from about 0.001 mg/mL to about 200 mg/mL; wherein the osmolality
of the aqueous solution is from about 50 mOsmol/kg to about 2000
mOsmol/kg.
Description
PRIORITY CLAIM
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/449,066, filed Jul. 31, 2014, which claims
benefit of U.S. Provisional Application No. 61/948,461, filed Mar.
5, 2014, and U.S. Provisional Application 61/860,721, filed Jul.
31, 2013, all entitled AEROSOL TYROSINE KINASE INHIBITOR COMPOUNDS
AND USES THEREOF. The Provisional Applications and the Copending
Non-provisional Application are hereby incorporated by reference in
their entireties and expressly claimed.
FIELD OF THE INVENTION
[0002] The present invention relates in its several embodiments to
liquid, dry powder and metered-dose formulations for therapeutic
inhaled delivery of phenylaminopyrimidine derivative compositions
such as imatinib and other kinase inhibitor compounds to desired
anatomical sites, for treatment and/or prophylaxis of a variety of
pulmonary, neurologic, cardiovascular and solid organ disease
conditions.
BACKGROUND OF THE INVENTION
[0003] Despite development of a number of promising therapies, a
number pulmonary diseases such as interstitial lung disease (ILD;
and sub-class diseases therein) cancer and many viral infectious
disease remain unmet clinical needs. Through inhalation, target
organ dose, pharmacokinetic profile and safety profile can be
improved to increase efficacy, safety and reduce patient
resistance. Additionally, a number of extrapulmonary diseases may
also benefit from inhaled delivery or other direct application to
the affected tissue. Described herein are compositions of imatinib,
phenylaminopyrimidine derivative and kinase inhibitor compounds
that are suitable for inhalation delivery to the lungs, central
nervous system and/or systemic compartment and methods of use.
SUMMARY
[0004] According to a certain embodiment of the present invention,
there is provided an imatinib or salt thereof,
phenylaminopyrimidine derivative or salt thereof, or kinase
inhibitor or salt thereof, or an imatinib, phenylaminopyrimidine
derivative or kinase inhibitor or salt thereof compound formulation
composition for oral pulmonary or intranasal inhalation delivery,
comprising formulations for aerosol administration of imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other kinase inhibitor or salt thereof, for the prevention or
treatment of various fibrotic diseases, including disease
associated with the lung, heart, kidney, liver, eye and central
nervous system, cancers, including those associated with the lung,
heart, kidney, liver, eye and central nervous system, and
hypertensive disease, including disease associated with the lung,
heart, kidney, liver and peripheral vasculature.
[0005] In some embodiments, the tyrosine kinase inhibitor or salt
thereof is a phenylaminopyrimidine derivative or salt thereof
compound. In some embodiments, the tyrosine kinase inhibitor or
salt thereof is imatinib or salt thereof. In some embodiments, a
salt of the tyrosine kinase inhibitor is used. In some embodiments,
a phosphate salt of the tyrosine kinase inhibitor is used.
[0006] In one aspect, described herein is an aqueous solution for
nebulized inhalation administration comprising: water; tyrosine
kinase inhibitor or salt thereof, at a concentration from about 0.1
mg/mL to about 100 mg/mL. In another aspect, described herein is an
aqueous solution for nebulized inhalation administration
comprising: water; tyrosine kinase inhibitor or salt thereof, at a
concentration from about 0.1 mg/mL to about 100 mg/mL; one or more
inorganic salts at a concentration of about 0.1% to about 1.0% to
adjust osmolality and provide a permeant ion; and optionally one or
more buffers to maintain the pH between about pH 4.0 to about pH
8.0. In some embodiments, the aqueous solution includes one more
inorganic salts selected from sodium chloride and magnesium. In
some embodiments, the aqueous solution includes sodium chloride. In
some embodiments, the aqueous solution includes magnesium chloride.
In some embodiments, the inorganic salt content of the aqueous
solution is from about 0.1% to about 1.0%. In some embodiments, the
inorganic salt content of the aqueous solution is from about 0.2%
to about 1.0%. In some embodiments, the inorganic salt content of
the aqueous solution is from about 0.3% to about 1.0%. In some
embodiments, the inorganic salt content of the aqueous solution is
from about 0.4% to about 1.0%. In some embodiments, the inorganic
salt content of the aqueous solution is from about 0.5% to about
1.0%. In some embodiments, the inorganic salt content of the
aqueous solution is from about 0.1% to about 0.9%. In some
embodiments, the inorganic salt content of the aqueous solution is
from about 0.1% to about 0.8%. In some embodiments, the inorganic
salt content of the aqueous solution is from about 0.1% to about
0.7%. In some embodiments, the inorganic salt content of the
aqueous solution is from about 0.1% to about 0.6%. In some
embodiments, the pH of the aqueous solution is from about pH 4.0 to
about pH 8.0. In some embodiments, the pH of the aqueous solution
is from about pH 5.0 to about pH 8.0. In some embodiments, the pH
of the aqueous solution is from about pH 4.0 to about pH 7.0. In
some embodiments, described herein is an aqueous solution for
nebulized inhalation administration comprising: water; tyrosine
kinase inhibitor or salt thereof, at a concentration from about
0.001 mg/mL to about 200 mg/mL; wherein the osmolality of the
aqueous solution is from about 50 mOsmol/kg to about 2000
mOsmol/kg. In some embodiments, tyrosine kinase inhibitor or salt
thereof, is at a concentration from about 0.001 mg/mL to about 200
mg/mL. In some embodiments, tyrosine kinase inhibitor or salt
thereof, is at a concentration from about 0.01 mg/mL to about 200
mg/mL. In some embodiments, tyrosine kinase inhibitor or salt
thereof, is at a concentration from about 0.01 mg/mL to about 150
mg/mL. In some embodiments, tyrosine kinase inhibitor or salt
thereof, is at a concentration from about 0.01 mg/mL to about 100
mg/mL. In some embodiments, tyrosine kinase inhibitor or salt
thereof, is at a concentration from about 0.01 mg/mL to about 50
mg/mL. In some embodiments, tyrosine kinase inhibitor or salt
thereof, is at a concentration from about 0.1 mg/mL to about 40
mg/mL. In some embodiments, tyrosine kinase inhibitor or salt
thereof, is at a concentration from about 0.1 mg/mL to about 200
mg/mL. In some embodiments, tyrosine kinase inhibitor or salt
thereof, is at a concentration from about 0.1 mg/mL to about 150
mg/mL. In some embodiments, tyrosine kinase inhibitor or salt
thereof, is at a concentration from about 0.1 mg/mL to about 100
mg/mL. In some embodiments, tyrosine kinase inhibitor or salt
thereof, is at a concentration from about 0.1 mg/mL to about 50
mg/mL. In some embodiments, tyrosine kinase inhibitor or salt
thereof, is at a concentration from about 0.1 mg/mL to about 40
mg/mL. In some embodiments, tyrosine kinase inhibitor or salt
thereof, is at a concentration from about 0.1 mg/mL to about 30
mg/mL. In some embodiments, tyrosine kinase inhibitor or salt
thereof, is at a concentration from about 0.1 mg/mL to about 20
mg/mL. In some embodiments, tyrosine kinase inhibitor or salt
thereof, is at a concentration from about 0.1 mg/mL to about 10
mg/mL. In some embodiments, the osmolality of the aqueous solution
is from about 50 mOsmol/kg to about 2000 mOsmol/kg. In some
embodiments, the osmolality of the aqueous solution is from about
100 mOsmol/kg to about 1000 mOsmol/kg. In some embodiments, the
osmolality of the aqueous solution is from about 100 mOsmol/kg to
about 750 mOsmol/kg, from about 100 mOsmol/kg to about 500
mOsmol/kg, from about 200 mOsmol/kg to about 2000 mOsmol/kg, from
about 200 mOsmol/kg to about 1000 mOsmol/kg, from about 200
mOsmol/kg to about 750 mOsmol/kg, or from about 200 mOsmol/kg to
about 500 mOsmol/kg. In some embodiments, the solution further
comprises one or more additional ingredients selected from
co-solvents, tonicity agents, sweeteners, surfactants, wetting
agents, chelating agents, anti-oxidants, inorganic salts, and
buffers. In some embodiments, the solution further comprises one or
more additional ingredients selected from taste masking
agents/sweeteners and inorganic salts. In some embodiments, the
tastemaking agent/sweetener is saccharin, or salt thereof. In some
embodiments, the aqueous solution includes one more buffers
selected from a citrate buffer and a phosphate buffer. In some
embodiments, the aqueous solution includes a phosphate buffer. In
some embodiments, the aqueous solution includes a citrate buffer.
In some embodiments, the aqueous solution includes a citrate buffer
or phosphate buffer; and sodium chloride, sodium bromide or
magnesium chloride. In some embodiments, the tyrosine kinase
inhibitor or salt thereof is a phenylaminopyrimidine derivative or
salt thereof compound. In some embodiments, the tyrosine kinase
inhibitor or salt thereof is imatinib or salt thereof. In some
embodiments, a salt of the tyrosine kinase inhibitor is used. In
some embodiments, a phosphate salt of the tyrosine kinase inhibitor
is used. In some embodiments, the tyrosine kinase inhibitor salt
will itself provide buffering capacity. In some embodiments,
described herein is from about 0.01 mL to about 6 mL of the aqueous
solution described herein. In some embodiments, described herein is
about 0.5 mL to about 6 mL of the aqueous solution described
herein.
[0007] In another aspect, described herein is an aqueous solution
for nebulized inhalation administration comprising: water; imatinib
or salt thereof, or a phenylaminopyrimidine derivative or salt
thereof compound, at a concentration from about 0.1 mg/mL to about
100 mg/mL. In another aspect, described herein is an aqueous
solution for nebulized inhalation administration comprising: water;
imatinib or salt thereof, or a phenylaminopyrimidine derivative or
salt thereof compound, at a concentration from about 0.1 mg/mL to
about 100 mg/mL; one or more inorganic salts at a concentration of
about 0.1% to about 1.0% to adjust osmolality and provide a
permeant ion; and optionally one or more buffers to maintain the pH
between about pH 4.0 to about pH 8.0. In some embodiments, the
aqueous solution includes one more inorganic salts selected from a
sodium chloride and magnesium chloride. In some embodiments, the
aqueous solution includes sodium chloride. In some embodiments, the
aqueous solution includes magnesium chloride. In some embodiments,
the inorganic salt content of the aqueous solution is from about
0.1% to about 1.0%. In some embodiments, the inorganic salt content
of the aqueous solution is from about 0.2% to about 1.0%. In some
embodiments, the inorganic salt content of the aqueous solution is
from about 0.3% to about 1.0%. In some embodiments, the inorganic
salt content of the aqueous solution is from about 0.4% to about
1.0%. In some embodiments, the inorganic salt content of the
aqueous solution is from about 0.5% to about 1.0%. In some
embodiments, the inorganic salt content of the aqueous solution is
from about 0.1% to about 0.9%. In some embodiments, the inorganic
salt content of the aqueous solution is from about 0.1% to about
0.8%. In some embodiments, the inorganic salt content of the
aqueous solution is from about 0.1% to about 0.7%. In some
embodiments, the inorganic salt content of the aqueous solution is
from about 0.1% to about 0.6%. In some embodiments, the pH of the
aqueous solution is from about pH 4.0 to about pH 8.0. In some
embodiments, the pH of the aqueous solution is from about pH 5.0 to
about pH 8.0. In some embodiments, the pH of the aqueous solution
is from about pH 4.0 to about pH 7.0. In some embodiments,
described herein is an aqueous solution for nebulized inhalation
administration comprising: water; imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof compound, at a
concentration from about 0.001 mg/mL to about 200 mg/mL; wherein
the osmolality of the aqueous solution is from about 50 mOsmol/kg
to about 2000 mOsmol/kg. In some embodiments, described herein is
an aqueous solution for nebulized inhalation administration
comprising: water; imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof compound, at a
concentration from about 0.1 mg/mL to about 100 mg/mL; wherein the
osmolality of the aqueous solution is from about 50 mOsmol/kg to
about 2000 mOsmol/kg. In some embodiments, imatinib or salt
thereof, or a phenylaminopyrimidine derivative or salt thereof
compound, is at a concentration from about 0.001 mg/mL to about 200
mg/mL. In some embodiments, imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof compound, is at a
concentration from about 0.01 mg/mL to about 200 mg/mL. In some
embodiments, imatinib or salt thereof, or a phenylaminopyrimidine
derivative or salt thereof compound, is at a concentration from
about 0.01 mg/mL to about 150 mg/mL. In some embodiments, imatinib
or salt thereof, or a phenylaminopyrimidine derivative or salt
thereof compound, is at a concentration from about 0.01 mg/mL to
about 100 mg/mL. In some embodiments, imatinib or salt thereof, or
a phenylaminopyrimidine derivative or salt thereof compound, is at
a concentration from about 0.01 mg/mL to about 50 mg/mL. In some
embodiments, imatinib or salt thereof, or a phenylaminopyrimidine
derivative or salt thereof compound, is at a concentration from
about 0.1 mg/mL to about 40 mg/mL. In some embodiments, imatinib or
salt thereof, or a phenylaminopyrimidine derivative or salt thereof
compound, is at a concentration from about 0.5 mg/mL to about 50
mg/mL. In some embodiments, imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof compound, is at a
concentration from about 1 mg/mL to about 50 mg/mL. In some
embodiments, imatinib or salt thereof, or a phenylaminopyrimidine
derivative or salt thereof compound, is at a concentration from
about 2 mg/mL to about 50 mg/mL. In some embodiments, imatinib or
salt thereof, or a phenylaminopyrimidine derivative or salt thereof
compound, is at a concentration from about 1 mg/mL to about 25
mg/mL. In some embodiments, imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof compound, is at a
concentration from about 2 mg/mL to about 50 mg/mL. In some
embodiments, imatinib or salt thereof, or a phenylaminopyrimidine
derivative or salt thereof compound, is at a concentration from
about 2 mg/mL to about 40 mg/mL. In some embodiments, imatinib or
salt thereof, or a phenylaminopyrimidine derivative or salt
thereof, is at a concentration from about 0.1 mg/mL to about 200
mg/mL. In some embodiments, imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof, is at a
concentration from about 0.1 mg/mL to about 150 mg/mL. In some
embodiments, imatinib or salt thereof, or a phenylaminopyrimidine
derivative or salt thereof, is at a concentration from about 0.1
mg/mL to about 100 mg/mL. In some embodiments, imatinib or salt
thereof, or a phenylaminopyrimidine derivative or salt thereof, is
at a concentration from about 0.1 mg/mL to about 50 mg/mL. In some
embodiments, imatinib or salt thereof, or a phenylaminopyrimidine
derivative or salt thereof, is at a concentration from about 0.1
mg/mL to about 40 mg/mL. In some embodiments, imatinib or salt
thereof, or a phenylaminopyrimidine derivative or salt thereof, is
at a concentration from about 0.1 mg/mL to about 30 mg/mL. In some
embodiments, imatinib or salt thereof, or a phenylaminopyrimidine
derivative or salt thereof, is at a concentration from about 0.1
mg/mL to about 20 mg/mL. In some embodiments, imatinib or salt
thereof, or a phenylaminopyrimidine derivative or salt thereof, is
at a concentration from about 0.1 mg/mL to about 10 mg/mL. In some
embodiments, the osmolality of the aqueous solution is from about
50 mOsmol/kg to about 2000 mOsmol/kg. In some embodiments, the
osmolality of the aqueous solution is from about 100 mOsmol/kg to
about 1000 mOsmol/kg. In some embodiments, the osmolality of the
aqueous solution is from about 100 mOsmol/kg to about 750
mOsmol/kg, from about 100 mOsmol/kg to about 500 mOsmol/kg, from
about 200 mOsmol/kg to about 2000 mOsmol/kg, from about 200
mOsmol/kg to about 1000 mOsmol/kg, from about 200 mOsmol/kg to
about 750 mOsmol/kg, or from about 200 mOsmol/kg to about 500
mOsmol/kg. In some embodiments, the solution further comprises one
or more additional ingredients selected from co-solvents, tonicity
agents, sweeteners, surfactants, wetting agents, chelating agents,
anti-oxidants, inorganic salts, and buffers. In some embodiments,
the solution further comprises one or more additional ingredients
selected from taste masking agents/sweeteners and inorganic salts.
In some embodiments, the tastemaking agent/sweetener is saccharin,
or salt thereof. In some embodiments, the aqueous solution includes
one more buffers selected from a citrate buffer and a phosphate
buffer. In some embodiments, the aqueous solution includes a
phosphate buffer. In some embodiments, the aqueous solution
includes a citrate buffer. In some embodiments, the aqueous
solution comprises water; imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof at a concentration from about
0.001 mg/mL to about 200 mg/mL; optionally a phosphate buffer that
maintains the pH of the solution from about pH 4.0 to about pH 8.0
or a citrate buffer that maintains the pH of the solution from
about pH 4.0 to about pH 7.0; optionally sodium saccharin at a
concentration of about 0.01 mM to about 10 mM; wherein the
osmolality of the of the aqueous solution is from about 50
mOsmol/kg to about 2000 mOsmol/kg. In some embodiments, the aqueous
solution comprises water; imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof at a concentration from about
0.001 mg/mL to about 200 mg/mL; optionally sodium saccharin at a
concentration of about 0.01 mM to about 10 mM; wherein the
osmolality of the of the aqueous solution is from about 50
mOsmol/kg to about 2000 mOsmol/kg. In some embodiments, the aqueous
solution comprises water; imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof at a concentration from about
0.001 mg/mL to about 200 mg/mL; optionally sodium chloride;
optionally sodium saccharin at a concentration of about 0.01 mM to
about 10 mM; wherein the osmolality of the of the aqueous solution
is from about 50 mOsmol/kg to about 2000 mOsmol/kg. In some
embodiments, a salt of imatinib or phenylaminopyrimidine derivative
is used. In some embodiments, a phosphate salt of imatinib or
phenylaminopyrimidine derivative is used. In some embodiments, the
imatinib salt, or a phenylaminopyrimidine derivative salt will
itself provide buffering capacity. In some embodiments, described
herein is from about 0.01 mL to about 6 mL of the aqueous solution
described herein. In some embodiments, described herein is from
about 0.5 mL to about 6 mL of the aqueous solution described
herein.
[0008] In some embodiments, the aqueous solution comprises: water;
a tyrosine kinase inhibitor or salt thereof at a concentration from
about 0.001 mg/mL to about 200 mg/mL; and optionally a phosphate
buffer that maintains the pH of the solution from about pH 4.0 to
about pH 8.0; wherein the osmolality of the aqueous solution is
from about 100 mOsmol/kg to about 1000 mOsmol/kg. In some
embodiments, the tyrosine kinase inhibitor or salt thereof is a
phenylaminopyrimidine derivative or salt thereof. In some
embodiments, the tyrosine kinase inhibitor or salt thereof is
imatinib or salt thereof.
[0009] In some embodiments, the aqueous solution comprises: water;
imatinib or salt thereof, or a phenylaminopyrimidine derivative or
salt thereof at a concentration from about 0.5 mg/mL to about 50
mg/mL; and optionally a phosphate buffer that maintains the pH of
the solution from about pH 4.0 to about pH 8.0; wherein the
osmolality of the aqueous solution is from about 100 mOsmol/kg to
about 1000 mOsmol/kg.
[0010] In some embodiments, the aqueous solution comprises: water;
a salt of imatinib, or a phenylaminopyrimidine derivative salt, at
an imatinib salt or phenylaminopyrimidine derivative salt
concentration from about 0.001 mg/mL to about 200 mg/mL wherein the
salt provides the buffering capacity that maintains the pH of the
solution from about pH 4.0 to about pH 8.0; wherein the osmolality
of the aqueous solution is from about 100 mOsmol/kg to about 1000
mOsmol/kg. In some embodiments, the aqueous solution comprises:
water; a phosphate salt of imatinib at a concentration from about
0.001 mg/mL to about 200 mg/mL wherein the salt provides the
buffering capacity that maintains the pH of the solution from about
pH 4.0 to about pH 8.0. In some embodiments, water is replaced with
saline.
[0011] In some embodiments, the aqueous solution for nebulized
inhalation administration described herein comprises: water;
tyrosine kinase inhibitor or salt thereof at a concentration from
about 0.001 mg/mL to about 200 mg/mL; sodium chloride from about
0.1% to about 1.0% to adjust osmolality and provide a permeant ion;
and optionally a phosphate buffer that maintains the pH of the
solution from about pH 4.0 to about pH 8.0. In some embodiments,
the aqueous solution for nebulized inhalation administration
described herein comprises: water; tyrosine kinase inhibitor or
salt thereof at a concentration from about 0.01 mg/mL to about 200
mg/mL; sodium chloride from about 0.1% to about 1.0% to adjust
osmolality and provide a permeant ion; and optionally a phosphate
buffer or a citrate buffer that maintains the pH of the solution
from about pH 4.0 to about pH 8.0. In some embodiments, the aqueous
solution for nebulized inhalation administration described herein
comprises: water; tyrosine kinase inhibitor or salt thereof at a
concentration from about 0.01 mg/mL to about 50 mg/mL; sodium
chloride from about 0.1% to about 1.0% to adjust osmolality and
provide a permeant ion; and optionally a phosphate buffer or a
citrate buffer that maintains the pH of the solution from about pH
4.0 to about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; tyrosine kinase inhibitor or salt thereof at a concentration
from about 0.01 mg/mL to about 10 mg/mL; sodium chloride from about
0.1% to about 1.0% to adjust osmolality and provide a permeant ion;
and optionally a phosphate buffer or a citrate buffer that
maintains the pH of the solution from about pH 4.0 to about pH 8.0.
In some embodiments, the aqueous solution for nebulized inhalation
administration described herein comprises: water; tyrosine kinase
inhibitor or salt thereof at a concentration from about 0.1 mg/mL
to about 200 mg/mL; sodium chloride from about 0.1% to about 1.0%
to adjust osmolality and provide a permeant ion; and optionally a
phosphate buffer or a citrate buffer that maintains the pH of the
solution from about pH 4.0 to about pH 8.0. In some embodiments,
the aqueous solution for nebulized inhalation administration
described herein comprises: water; tyrosine kinase inhibitor or
salt thereof compound at a concentration from about 0.1 mg/mL to
about 50 mg/mL; sodium chloride from about 0.1% to about 1.0% to
adjust osmolality and provide a permeant ion; and optionally a
phosphate buffer or a citrate buffer that maintains the pH of the
solution from about pH 4.0 to about pH 8.0. In some embodiments,
the aqueous solution for nebulized inhalation administration
described herein comprises: water; tyrosine kinase inhibitor or
salt thereof at a concentration from about 0.1 mg/mL to about 10
mg/mL; sodium chloride from about 0.1% to about 1.0% to adjust
osmolality and provide a permeant ion; and optionally a phosphate
buffer or a citrate buffer that maintains the pH of the solution
from about pH 4.0 to about pH 8.0. In some embodiments, the aqueous
solution for nebulized inhalation administration described herein
comprises: water; tyrosine kinase inhibitor or salt thereof at a
concentration from about 0.001 mg/mL to about 200 mg/mL; sodium
chloride from about 0.25% to about 1.0% to adjust osmolality and
provide a permeant ion; and optionally a phosphate buffer or a
citrate buffer that maintains the pH of the solution from about pH
4.0 to about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; tyrosine kinase inhibitor or salt thereof at a concentration
from about 0.001 mg/mL to about 200 mg/mL; sodium chloride from
about 0.5% to about 1.0% to adjust osmolality and provide a
permeant ion; and optionally a phosphate buffer or a citrate buffer
that maintains the pH of the solution from about pH 4.0 to about pH
8.0. In some embodiments, the aqueous solution for nebulized
inhalation administration described herein comprises: water;
tyrosine kinase inhibitor or salt thereof at a concentration from
about 0.001 mg/mL to about 200 mg/mL; sodium chloride from about
0.1% to about 0.9% to adjust osmolality and provide a permeant ion;
and optionally a phosphate buffer or a citrate buffer that
maintains the pH of the solution from about pH 4.0 to about pH 8.0.
In some embodiments, the aqueous solution for nebulized inhalation
administration described herein comprises: water; tyrosine kinase
inhibitor or salt thereof at a concentration from about 0.001 mg/mL
to about 200 mg/mL; sodium chloride from about 0.1% to about 0.8%
to adjust osmolality and provide a permeant ion; and optionally a
phosphate buffer or a citrate buffer that maintains the pH of the
solution from about pH 4.0 to about pH 8.0. In some embodiments,
the aqueous solution for nebulized inhalation administration
described herein comprises: water; tyrosine kinase inhibitor or
salt thereof compound at a concentration from about 0.001 mg/mL to
about 200 mg/mL; sodium chloride from about 0.1% to about 0.7% to
adjust osmolality and provide a permeant ion; and optionally a
phosphate buffer or a citrate buffer that maintains the pH of the
solution from about pH 4.0 to about pH 8.0. In some embodiments,
the aqueous solution for nebulized inhalation administration
described herein comprises: water; tyrosine kinase inhibitor or
salt thereof at a concentration from about 0.001 mg/mL to about 200
mg/mL; sodium chloride from about 0.1% to about 1.0% to adjust
osmolality and provide a permeant ion; and optionally a citrate
buffer that maintains the pH of the solution from about pH 4.0 to
about pH 7.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; tyrosine kinase inhibitor or salt thereof at a concentration
from about 0.001 mg/mL to about 200 mg/mL; sodium chloride from
about 0.1% to about 1.0% to adjust osmolality and provide a
permeant ion; and optionally a phosphate buffer that maintains the
pH of the solution from about pH 5.0 to about pH 8.0. In some
embodiments, the tyrosine kinase inhibitor or salt thereof is a
phenylaminopyrimidine derivative or salt thereof. In some
embodiments, the tyrosine kinase inhibitor or salt thereof is
imatinib or salt thereof.
[0012] In some embodiments, the aqueous solution for nebulized
inhalation administration described herein comprises: water;
imatinib or salt thereof, or a phenylaminopyrimidine derivative or
salt thereof at a concentration from about 0.5 mg/mL to about 50
mg/mL; sodium chloride from about 0.1% to about 1.0% to adjust
osmolality and provide a permeant ion; and optionally a phosphate
buffer that maintains the pH of the solution from about pH 4.0 to
about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, or a phenylaminopyrimidine
derivative or salt thereof at a concentration from about 0.5 mg/mL
to about 40 mg/mL; sodium chloride from about 0.1% to about 1.0% to
adjust osmolality and provide a permeant ion; and optionally a
phosphate buffer or a citrate buffer that maintains the pH of the
solution from about pH 4.0 to about pH 8.0. In some embodiments,
the aqueous solution for nebulized inhalation administration
described herein comprises: water; imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof at a concentration
from about 0.5 mg/mL to about 30 mg/mL; sodium chloride from about
0.1% to about 1.0% to adjust osmolality and provide a permeant ion;
and optionally a phosphate buffer or a citrate buffer that
maintains the pH of the solution from about pH 4.0 to about pH 8.0.
In some embodiments, the aqueous solution for nebulized inhalation
administration described herein comprises: water; imatinib or salt
thereof, or a phenylaminopyrimidine derivative or salt thereof at a
concentration from about 0.5 mg/mL to about 20 mg/mL; sodium
chloride from about 0.1% to about 1.0% to adjust osmolality and
provide a permeant ion; and optionally a phosphate buffer or a
citrate buffer that maintains the pH of the solution from about pH
4.0 to about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, or a phenylaminopyrimidine
derivative or salt thereof at a concentration from about 1.0 mg/mL
to about 50 mg/mL; sodium chloride from about 0.1% to about 1.0% to
adjust osmolality and provide a permeant ion; and optionally a
phosphate buffer or a citrate buffer that maintains the pH of the
solution from about pH 4.0 to about pH 8.0. In some embodiments,
the aqueous solution for nebulized inhalation administration
described herein comprises: water; imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof compound at a
concentration from about 2.0 mg/mL to about 50 mg/mL; sodium
chloride from about 0.1% to about 1.0% to adjust osmolality and
provide a permeant ion; and optionally a phosphate buffer or a
citrate buffer that maintains the pH of the solution from about pH
4.0 to about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, or a phenylaminopyrimidine
derivative or salt thereof at a concentration from about 5 mg/mL to
about 50 mg/mL; sodium chloride from about 0.1% to about 1.0% to
adjust osmolality and provide a permeant ion; and optionally a
phosphate buffer or a citrate buffer that maintains the pH of the
solution from about pH 4.0 to about pH 8.0. In some embodiments,
the aqueous solution for nebulized inhalation administration
described herein comprises: water; imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof at a concentration
from about 0.5 mg/mL to about 50 mg/mL; sodium chloride from about
0.25% to about 1.0% to adjust osmolality and provide a permeant
ion; and optionally a phosphate buffer or a citrate buffer that
maintains the pH of the solution from about pH 4.0 to about pH 8.0.
In some embodiments, the aqueous solution for nebulized inhalation
administration described herein comprises: water; imatinib or salt
thereof, or a phenylaminopyrimidine derivative or salt thereof at a
concentration from about 0.5 mg/mL to about 50 mg/mL; sodium
chloride from about 0.5% to about 1.0% to adjust osmolality and
provide a permeant ion; and optionally a phosphate buffer or a
citrate buffer that maintains the pH of the solution from about pH
4.0 to about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, or a phenylaminopyrimidine
derivative or salt thereof at a concentration from about 0.5 mg/mL
to about 50 mg/mL; sodium chloride from about 0.1% to about 0.9% to
adjust osmolality and provide a permeant ion; and optionally a
phosphate buffer or a citrate buffer that maintains the pH of the
solution from about pH 4.0 to about pH 8.0. In some embodiments,
the aqueous solution for nebulized inhalation administration
described herein comprises: water; imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof at a concentration
from about 0.5 mg/mL to about 50 mg/mL; sodium chloride from about
0.1% to about 0.8% to adjust osmolality and provide a permeant ion;
and optionally a phosphate buffer or a citrate buffer that
maintains the pH of the solution from about pH 4.0 to about pH 8.0.
In some embodiments, the aqueous solution for nebulized inhalation
administration described herein comprises: water; imatinib or salt
thereof, or a phenylaminopyrimidine derivative or salt thereof
compound at a concentration from about 0.5 mg/mL to about 50 mg/mL;
sodium chloride from about 0.1% to about 0.7% to adjust osmolality
and provide a permeant ion; and optionally a phosphate buffer or a
citrate buffer that maintains the pH of the solution from about pH
4.0 to about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, or a phenylaminopyrimidine
derivative or salt thereof at a concentration from about 0.5 mg/mL
to about 50 mg/mL; sodium chloride from about 0.1% to about 1.0% to
adjust osmolality and provide a permeant ion; and optionally a
citrate buffer that maintains the pH of the solution from about pH
4.0 to about pH 7.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, or a phenylaminopyrimidine
derivative or salt thereof at a concentration from about 0.5 mg/mL
to about 50 mg/mL; sodium chloride from about 0.1% to about 1.0% to
adjust osmolality and provide a permeant ion; and optionally a
phosphate buffer that maintains the pH of the solution from about
pH 5.0 to about pH 8.0.
[0013] In some embodiments, the aqueous solution for nebulized
inhalation administration described herein comprises: water;
imatinib salt thereof, or a phenylaminopyrimidine derivative salt
thereof at a concentration from about 0.001 mg/mL to about 200
mg/mL; sodium chloride from about 0.1% to about 1.0% to adjust
osmolality and provide a permeant ion; wherein the imatinib salt,
or a phenylaminopyrimidine derivative salt provides the buffering
capacity to maintain the pH of the solution from about pH 4.0 to
about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib salt thereof, or a phenylaminopyrimidine derivative
salt thereof at a concentration from about 0.01 mg/mL to about 200
mg/mL; sodium chloride from about 0.1% to about 1.0% to adjust
osmolality and provide a permeant ion; wherein the imatinib salt,
or phenylaminopyrimidine derivative salt provides the buffering
capacity to maintain the pH of the solution from about pH 4.0 to
about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib salt thereof, or a phenylaminopyrimidine derivative
salt thereof at a concentration from about 0.01 mg/mL to about 50
mg/mL; sodium chloride from about 0.1% to about 1.0% to adjust
osmolality and provide a permeant ion; wherein the imatinib salt,
or phenylaminopyrimidine derivative salt provides the buffering
capacity to maintain the pH of the solution from about pH 4.0 to
about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib salt thereof, or a phenylaminopyrimidine derivative
or salt thereof at a concentration from about 0.01 mg/mL to about
10 mg/mL; sodium chloride from about 0.1% to about 1.0% to adjust
osmolality and provide a permeant ion; wherein the imatinib salt,
or phenylaminopyrimidine derivative salt provides the buffering
capacity to maintain the pH of the solution from about pH 4.0 to
about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib salt thereof, or a phenylaminopyrimidine derivative
salt thereof at a concentration from about 0.1 mg/mL to about 200
mg/mL; sodium chloride from about 0.1% to about 1.0% to adjust
osmolality and provide a permeant ion; wherein the imatinib salt,
or phenylaminopyrimidine derivative salt provides the buffering
capacity to maintain the pH of the solution from about pH 4.0 to
about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib salt thereof, or a phenylaminopyrimidine derivative
salt thereof compound at a concentration from about 0.1 mg/mL to
about 50 mg/mL; sodium chloride from about 0.1% to about 1.0% to
adjust osmolality and provide a permeant ion; wherein the imatinib
salt, or phenylaminopyrimidine derivative salt provides the
buffering capacity to maintain the pH of the solution from about pH
4.0 to about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib salt thereof, or a phenylaminopyrimidine derivative
salt thereof at a concentration from about 0.1 mg/mL to about 10
mg/mL; sodium chloride from about 0.1% to about 1.0% to adjust
osmolality and provide a permeant ion; wherein the imatinib salt,
or phenylaminopyrimidine derivative salt provides the buffering
capacity to maintain the pH of the solution from about pH 4.0 to
about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib salt thereof, or a phenylaminopyrimidine derivative
salt thereof at a concentration from about 0.001 mg/mL to about 200
mg/mL; sodium chloride from about 0.25% to about 1.0% to adjust
osmolality and provide a permeant ion; wherein the imatinib salt,
or phenylaminopyrimidine derivative salt provides the buffering
capacity to maintain the pH of the solution from about pH 4.0 to
about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib salt thereof, or a phenylaminopyrimidine derivative
salt thereof at a concentration from about 0.001 mg/mL to about 200
mg/mL; sodium chloride from about 0.5% to about 1.0% to adjust
osmolality and provide a permeant ion; wherein the imatinib salt,
or phenylaminopyrimidine derivative salt provides the buffering
capacity to maintain the pH of the solution from about pH 4.0 to
about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib salt thereof, or a phenylaminopyrimidine derivative
salt thereof at a concentration from about 0.001 mg/mL to about 200
mg/mL; sodium chloride from about 0.1% to about 0.9% to adjust
osmolality and provide a permeant ion; wherein the imatinib salt,
or phenylaminopyrimidine derivative salt provides the buffering
capacity to maintain the pH of the solution from about pH 4.0 to
about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib salt thereof, or a phenylaminopyrimidine derivative
salt thereof at a concentration from about 0.001 mg/mL to about 200
mg/mL; sodium chloride from about 0.1% to about 0.8% to adjust
osmolality and provide a permeant ion; wherein the imatinib salt,
or phenylaminopyrimidine derivative salt provides the buffering
capacity to maintain the pH of the solution from about pH 4.0 to
about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib salt thereof, or a phenylaminopyrimidine derivative
salt thereof compound at a concentration from about 0.001 mg/mL to
about 200 mg/mL; sodium chloride from about 0.1% to about 0.7% to
adjust osmolality and provide a permeant ion; wherein the imatinib
salt, or phenylaminopyrimidine derivative salt provides the
buffering capacity to maintain the pH of the solution from about pH
4.0 to about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib salt thereof, or a phenylaminopyrimidine derivative
salt thereof at a concentration from about 0.001 mg/mL to about 200
mg/mL; sodium chloride from about 0.1% to about 1.0% to adjust
osmolality and provide a permeant ion; wherein the imatinib salt,
or phenylaminopyrimidine derivative salt providing buffering
capacity to maintain the pH of the solution from about pH 4.0 to
about pH 7.0 is citrate. In some embodiments, the aqueous solution
for nebulized inhalation administration described herein comprises:
water; imatinib salt thereof, a phenylaminopyrimidine derivative
salt thereof, or other tyrosine kinase inhibitor or salt thereof at
a concentration from about 0.001 mg/mL to about 200 mg/mL; sodium
chloride from about 0.1% to about 1.0% to adjust osmolality and
provide a permeant ion; wherein the imatinib salt, or
phenylaminopyrimidine derivative salt providing buffering capacity
to maintain the pH of the solution from about pH 4.0 to about pH
8.0 is phosphate.
[0014] In some embodiments, described herein is a unit dosage
adapted for use in a liquid nebulizer comprising from about 0.5 mL
to about 6 mL of an aqueous solution of imatinib or salt thereof,
or a phenylaminopyrimidine derivative or salt thereof, wherein the
concentration of imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof in the aqueous
solution is from about 0.1 mg/mL to about 100 mg/mL. In some
embodiments, described herein is a unit dosage adapted for use in a
liquid nebulizer comprising from about 0.01 mL to about 6 mL of an
aqueous solution of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, wherein the concentration of
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof in
the aqueous solution is from about 0.001 mg/mL to about 200 mg/mL.
In some embodiments, the aqueous solution further comprises one or
more additional ingredients selected from co-solvents, tonicity
agents, sweeteners, surfactants, wetting agents, chelating agents,
anti-oxidants, inorganic salts, and buffers; and the osmolality of
the aqueous solution is from about 50 mOsmol/kg to about 2000
mOsmol/kg. In some embodiments, the aqueous solution further
comprises: one or more inorganic salts selected from sodium
chloride and magnesium chloride; and one or both of a citrate
buffer or a phosphate buffer. In some embodiments, the aqueous
solution comprises: imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof dissolved in water
at a concentration from about 0.5 mg/mL to about 50 mg/mL;
optionally sodium chloride maintains the solution osmolality
between 200 and 800 mOsmo/kg; optionally phosphate buffer that
maintains the pH of the solutions between 5.0 and 8.0; optionally,
citrate buffer maintains the pH of the solution from about pH 4.0
to about pH 7.0; In some embodiments, the aqueous solution
comprises: imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof dissolved in water at a concentration from about 0.001
mg/mL to about 200 mg/mL; optionally sodium chloride maintains the
solution osmolality between 200 and 800 mOsmo/kg; optionally
phosphate buffer that maintains the pH of the solutions between 5.0
and 8.0; optionally, citrate buffer maintains the pH of the
solution from about pH 4.0 to about pH 7.0; optionally, the
imatinib salt, or a phenylaminopyrimidine derivative salt itself
maintains the pH of the solution from about pH 4.0 to about pH 8.0.
In some embodiments, the aqueous solution is as described
herein.
[0015] In some embodiments, described herein is a unit dosage
adapted for use in a liquid nebulizer comprising from about 0.01 mL
to about 6 mL of an aqueous solution of tyrosine kinase inhibitor
or salt thereof, wherein the concentration of tyrosine kinase
inhibitor or salt thereof in the aqueous solution is from about
0.001 mg/mL to about 200 mg/mL. In some embodiments, the aqueous
solution further comprises one or more additional ingredients
selected from co-solvents, tonicity agents, sweeteners,
surfactants, wetting agents, chelating agents, anti-oxidants,
inorganic salts, and buffers; and the osmolality of the aqueous
solution is from about 50 mOsmol/kg to about 2000 mOsmol/kg. In
some embodiments, the aqueous solution further comprises: one or
more inorganic salts selected from sodium chloride and magnesium
chloride; and one or both of a citrate buffer or a phosphate
buffer. In some embodiments, the aqueous solution comprises:
tyrosine kinase inhibitor or salt thereof dissolved in water at a
concentration from about 0.001 mg/mL to about 200 mg/mL; optionally
a sodium chloride maintains the solution osmolality between 200 and
800 mOsmo/kg; optionally phosphate buffer that maintains the pH of
the solutions between 5.0 and 8.0; optionally, citrate buffer
maintains the pH of the solution from about pH 4.0 to about pH 7.0;
optionally, the tyrosine kinase inhibitor salt itself maintains the
pH of the solution from about pH 4.0 to about pH 8.0. In some
embodiments, the aqueous solution is as described herein.
[0016] In some embodiments, described herein is a kit comprising: a
unit dosage of an aqueous solution of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, as described herein in a
container that is adapted for use in a liquid nebulizer.
[0017] In some embodiments, provided herein is an aqueous droplet
of imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
wherein the aqueous droplet has a diameter less than about 5.0
.mu.m. In some embodiments, the aqueous droplet was produced from a
liquid nebulizer and an aqueous solution of imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the aqueous solution of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, or other tyrosine kinase
inhibitor or salt thereof is as described herein. In some
embodiments, the aqueous solution has concentration of imatinib or
salt thereof, or a phenylaminopyrimidine derivative or salt thereof
from about 0.1 mg/mL and about 100 mg/mL and an osmolality from
about 50 mOsmol/kg to about 2000 mOsmol/kg. In some embodiments,
the aqueous solution has concentration of imatinib or salt thereof,
a phenylaminopyrimidine derivative or salt thereof, or other
tyrosine kinase inhibitor or salt thereof, from about 0.001 mg/mL
and about 200 mg/mL and an osmolality from about 50 mOsmol/kg to
about 2000 mOsmol/kg. In some embodiments, the aqueous droplet is
produced by a nebulizing an aqueous solution of imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, as described
herein with a nebulizer. In some embodiments, the nebulizer is a
liquid nebulizer. In some embodiments, the nebulizer is a high
efficiency liquid nebulizer.
[0018] In some embodiments, provided herein is an aqueous aerosol
comprising a plurality of aqueous droplets of imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, described
herein is an aqueous aerosol comprising a plurality of aqueous
droplets of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
wherein the plurality of aqueous droplets have a volumetric mean
diameter (VMD), mass median aerodynamic diameter (MMAD), and/or
mass median diameter (MMD) of less than about 5.0 .mu.m. In some
embodiments, the plurality of aqueous droplets was produced from a
liquid nebulizer and an aqueous solution of imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the aqueous solution has concentration of imatinib or
salt thereof, or a phenylaminopyrimidine derivative or salt thereof
compound from about 0.1 mg/mL and about 100 mg/mL and an osmolality
from about 50 mOsmol/kg to about 2000 mOsmol/kg. In some
embodiments, the aqueous solution has concentration of imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof compound from
about 0.001 mg/mL and about 200 mg/mL and an osmolality from about
50 mOsmol/kg to about 2000 mOsmol/kg. In some embodiments, at least
30% of the aqueous droplets in the aerosol have a diameter less
than about 5 .mu.m. In some embodiments, the aqueous aerosol is
produced by a nebulizing an aqueous solution of imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, or other tyrosine
kinase inhibitor or salt thereof as described herein with a
nebulizer. In some embodiments, the nebulizer is a liquid
nebulizer. In some embodiments, the nebulizer is a high efficiency
liquid nebulizer.
[0019] In some embodiments, the nebulizer used in any of the
methods described herein is a liquid nebulizer. In some
embodiments, the nebulizer used in any of the methods described
herein is a jet nebulizer, an ultrasonic nebulizer, a pulsating
membrane nebulizer, a nebulizer comprising a vibrating mesh or
plate with multiple apertures, or a nebulizer comprising a
vibration generator and an aqueous chamber. In some embodiments,
the nebulizer used in any of the methods described herein is a
nebulizer comprising a vibrating mesh or plate with multiple
apertures. In some embodiments, the liquid nebulizer: (i) achieves
lung deposition of at least 7% of the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, or other tyrosine kinase
inhibitor or salt thereof compound administered to the mammal; (ii)
provides a Geometric Standard Deviation (GSD) of emitted droplet
size distribution of the aqueous solution of about 1.0 .mu.m to
about 2.5 .mu.m; (iii) provides: a) a mass median aerodynamic
diameter (MMAD) of droplet size of the aqueous solution emitted
with the high efficiency liquid nebulizer of about 1 .mu.m to about
5 .mu.m; b) a volumetric mean diameter (VMD) of about 1 .mu.m to
about 5 .mu.m; and/or c) a mass median diameter (MMD) of about 1
.mu.m to about 5 .mu.m; (iv) provides a fine particle fraction
(FPF=%.ltoreq.5 microns) of droplets emitted from the liquid
nebulizer of at least about 30%; (v) provides an output rate of at
least 0.1 mL/min; and/or (vi) provides at least about 25% of the
aqueous solution to the mammal.
[0020] In some embodiments, the liquid nebulizer is characterized
as having at least two, at least three, at least four, at least
five, or all six of (i), (ii), (iii), (iv), (v), (vi). In some
embodiments, the liquid nebulizer: (i) achieves lung deposition of
at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at
least 10%, at least 12%, at least 14%, at least 16%, at least 18%,
at least 20%, at least 25%, at least 30%, at least 35%, at least
40% at least 45%, at least 50%, at least 55%, at least 60%, at
least 65%, at least 70%, at least 75%, or at least 80% of the
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
administered to the mammal. In some embodiments, the liquid
nebulizer: (ii) provides a Geometric Standard Deviation (GSD) of
emitted droplet size distribution of the aqueous solution of about
1.0 .mu.m to about 2.5 .mu.m, about 1.2 .mu.m to about 2.3 .mu.m,
about 1.4 .mu.m to about 2.1 .mu.m, or about 1.5 .mu.m to about 2.0
.mu.m. In some embodiments, the liquid nebulizer: (iii) provides a)
a mass median aerodynamic diameter (MMAD) of droplet size of the
aqueous solution emitted with the high efficiency liquid nebulizer
of about less than 5 .mu.m or about 1 .mu.m to about 5 .mu.m; b) a
volumetric mean diameter (VMD) of about less than 5 .mu.m or about
1 .mu.m to about 5 .mu.m; and/or c) a mass median diameter (MMD) of
about less than 5 .mu.m or about 1 .mu.m to about 5 .mu.m. In some
embodiments, the liquid nebulizer: (iv) provides a fine particle
fraction (FPF=%.ltoreq.5 microns) of droplets emitted from the
liquid nebulizer of at least about 30%, at least about 35%, at
least about 40%, at least about 45%, at least about 50%, at least
about 55%, at least about 60%, at least about 65%, at least about
70%, at least about 75%, at least about 80%, at least about 85%, or
at least about 90%. In some embodiments, the liquid nebulizer: (v)
provides an output rate of at least 0.1 mL/min, of at least 0.2
mL/min, of at least 0.3 mL/min, of at least 0.4 mL/min, of at least
0.5 mL/min, of at least 0.6 mL/min, of at least 0.7 mL/min, of at
least 0.8 mL/min, of at least 0.9 mL/min, of at least 1.0 mL/min,
or less than about 1.0 mL/min. In some embodiments, the liquid
nebulizer: (vi) provides at least about 25%, at least about 30%, at
least about 35%, at least about 40%, at least about 45%, at least
about 50%, at least about 55%, at least about 60%, at least about
65%, at least about 70%, at least about 75%, at least about 80%, at
least about 85%, or at least about 95%,of the aqueous solution to
the mammal. In some embodiments, the liquid nebulizer provides an
respirable delivered dose (RDD) of at least 5%, at least 6%, at
least 7%, at least 8%, at least 10%, at least 12%, at least 16%, at
least 20%, at least 24%, at least 28%, at least 32%, at least 36%,
at least 40%, at least 45%, at least 50%, at least 55%, at least
60%, at least 65%, at least 70%, at least 75%, at least 80%, at
least 85%, or at least 90%.
[0021] In some embodiments, described herein is a method for the
treatment of lung disease in a mammal comprising administering a
pharmaceutical composition comprising imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or tyrosine
kinase inhibitor or salt thereof compound by inhalation to the
mammal in need thereof. In some embodiments, the lung disease is
lung fibrosis, lung cancer, or pulmonary hypertension, and the
mammal is a human. In some embodiments, the pharmaceutical
composition comprising imatinib or salt thereof,
phenylaminopyrimidine derivative or salt thereof, or tyrosine
kinase inhibitor or salt thereof is administered with a nebulizer,
a metered dose inhaler, or a dry powder inhaler. In some
embodiments, the pharmaceutical composition comprising imatinib or
salt thereof, phenylaminopyrimidine derivative or salt thereof, or
tyrosine kinase inhibitor or salt thereof is an aqueous solution
and is administered to the mammal with a liquid nebulizer; wherein
the aqueous solution comprises water; imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, at a concentration from about
0.001 mg/mL to about 200 mg/mL; wherein the osmolality of the
aqueous solution is from about 50 mOsmol/kg to about 2000
mOsmol/kg. In some embodiments, the liquid nebulizer is a jet
nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer,
a nebulizer comprising a vibrating mesh or plate with multiple
apertures, or a nebulizer comprising a vibration generator and an
aqueous chamber. In some embodiments, the liquid nebulizer: (i)
achieves lung deposition of at least 7% of the imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof administered to the
mammal; (ii) provides a Geometric Standard Deviation (GSD) of
emitted droplet size distribution of the aqueous solution of about
1.0 .mu.m to about 2.5 .mu.m; (iii) provides: a) a mass median
aerodynamic diameter (MMAD) of droplet size of the aqueous solution
emitted with the high efficiency liquid nebulizer of about 1 .mu.m
to about 5 .mu.m; b) a volumetric mean diameter (VMD) of about 1
.mu.m to about 5 .mu.m; and/or c) a mass median diameter (MMD) of
about 1 .mu.m to about 5 .mu.m; (iv) provides a fine particle
fraction (FPF=%.ltoreq.5 microns) of droplets emitted from the
liquid nebulizer of at least about 30%; (v) provides an output rate
of at least 0.1 mL/min; and/or (vi) provides at least about 25% of
the aqueous solution to the mammal. In some embodiments, the liquid
nebulizer delivers from about 0.001 mg to about 200 mg of imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof
compound to the lungs of the mammal in less than about 20 minutes
with mass median diameter (MMAD) particles sizes from about 1 to
about 5 micron. In some embodiments, the pharmaceutical composition
comprises an aqueous solution of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or tyrosine
kinase inhibitor compound or salt thereof, wherein the
pharmaceutical composition is administered to the mammal with a
liquid nebulizer. In some embodiments, the pharmaceutical
composition comprises from about 0.1 mL to about 6 mL of an aqueous
solution comprising imatinib or salt thereof or a
phenylaminopyrimidine derivative compound or salt thereof, or
tyrosine kinase inhibitor compound or salt thereof, and optionally
one or more additional ingredients selected from co-solvents,
tonicity agents, sweeteners, surfactants, wetting agents, chelating
agents, anti-oxidants, inorganic salts, and buffers, wherein the
concentration of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or tyrosine kinase inhibitor compound
or salt thereof in the aqueous solution is from about 0.001 mg/mL
and about 200 mg/mL and the osmolality of the of the aqueous
solution is from about 50 mOsmol/kg to about 2000 mOsmol/kg. In
some embodiments, the aqueous solution comprises: water; imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor compound or salt
thereof at a concentration from about 0.001 mg/mL to about 200
mg/mL; optionally one or more inorganic salts selected from the
group consisting of sodium chloride, magnesium chloride, sodium
bromide, magnesium bromide, calcium chloride and calcium bromide,
wherein the total amount of the one or more inorganic salts is from
about 0.01% to about 2.0% by weight of the weight of aqueous
solution; optionally a phosphate buffer that maintains the pH of
the solution from about pH 5.0 to about pH 8.0, or citrate buffer
than maintains the pH of the solution from about 4.0 to about 7.0;
optionally sodium saccharin at a concentration of about 0.01 mM to
about 10 mM; wherein the osmolality of the aqueous solution is from
about 50 mOsmol/kg to about 2000 mOsmol/kg. In some embodiments,
the pharmaceutical composition comprises a dry powder composition
comprising imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof at a concentration of about 0.001% to about 100% by
weight of the weight of dry powder composition; optionally one of
more carrier agents selected from the group consisting of lactose
or mannitol at a concentration of about 0.001% to about 99.999% by
weight of the weight of dry powder composition; and optionally
sodium saccharin at a concentration of about 0.001% to about 0.1%
by weight of the weight of dry powder composition; wherein the
pharmaceutical composition is administered to the mammal with a dry
powder inhaler. In some embodiments, the dry powder inhaler
delivers from about 0.001 mg to about 200 mg of imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof to the lungs of the
mammal in less than about 10 breaths, wherein the mass median
diameter (MMAD) particles sizes are from about 1 to about 5 micron.
In some embodiments, the pharmaceutical composition comprises
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
wherein the total amount of imatinib or salt thereof,
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof is about 0.001% to about 10% by
volume of the volume of the pharmaceutical composition; one or more
propellants, wherein the total amount of the one or more
propellants is about 90% to about 99.999% by volume of the volume
of the pharmaceutical composition; optionally one of more
cosolvents selected from the group consisting of ethanol and
propylene glycol, wherein the total amount of the one or more
cosolvents is from about 0.01% to about 10% by volume of the volume
of the pharmaceutical composition; wherein the pharmaceutical
composition is administered to the mammal with a metered dose
inhaler. In some embodiments, the meter dose inhaler delivers from
about 0.001 mg to about 200 mg of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof to the lungs of the mammal in less
than about 10 breaths, wherein the mass median diameter (MMAD)
particles sizes are from about 1 to about 5 micron. In some
embodiments, the pharmaceutical composition comprising imatinib or
salt thereof, phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof is administered to
the mammal in need thereof by inhalation on a continuous dosing
schedule. In some embodiments, the pharmaceutical composition
comprising imatinib or salt thereof, phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof is administered once a week, twice a week, three times
a week, four times a weeks, five times a week, six times a week,
seven days a week, once a day, twice a day, three times a day, four
times a day, five times a day, or six times a day.
[0022] In some embodiments, described herein is a method for the
treatment of lung disease in a mammal comprising: administering to
mammal in need thereof an aqueous solution comprising imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof, with a liquid
nebulizer. In some embodiments, described herein is a method for
the treatment of lung disease in a mammal comprising: administering
to mammal in need thereof an aqueous solution comprising imatinib
or salt thereof, or a phenylaminopyrimidine derivative or salt
thereof with a liquid nebulizer; wherein the aqueous solution
comprises water; imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof at a concentration
from about 0.1 mg/mL to about 100 mg/mL; one or more inorganic
salts, wherein the osmolality of the aqueous solution is from about
50 mOsmol/kg to about 2000 mOsmol/kg; and one or more buffers
maintaining the solution pH between about 4.0 and 8.0. In some
embodiments, described herein is a method for the treatment of lung
disease in a mammal comprising: administering to mammal in need
thereof an aqueous solution comprising imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, with a liquid nebulizer; wherein
the aqueous solution comprises water; imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, at a concentration from about
0.001 mg/mL to about 200 mg/mL; one or more salts, wherein the
osmolality of the aqueous solution is from about 50 mOsmol/kg to
about 2000 mOsmol/kg; and one or more buffers maintaining the
solution pH between about 4.0 and 8.0. In some embodiments, the
aqueous solution for nebulized inhalation administration described
herein comprises: water; imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof at a concentration from about 0.01
mg/mL to about 200 mg/mL; sodium chloride from about 0.1% to about
1.0% to adjust osmolality and provide a permeant ion; and
optionally a phosphate buffer or a citrate buffer that maintains
the pH of the solution from about pH 4.0 to about pH 8.0. In some
embodiments, the aqueous solution for nebulized inhalation
administration described herein comprises: water; imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof at a concentration
from about 0.01 mg/mL to about 50 mg/mL; sodium chloride from about
0.1% to about 1.0% to adjust osmolality and provide a permeant ion;
and optionally a phosphate buffer or a citrate buffer that
maintains the pH of the solution from about pH 4.0 to about pH 8.0.
In some embodiments, the aqueous solution for nebulized inhalation
administration described herein comprises: water; imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof at a concentration
from about 0.01 mg/mL to about 10 mg/mL; sodium chloride from about
0.1% to about 1.0% to adjust osmolality and provide a permeant ion;
and optionally a phosphate buffer or a citrate buffer that
maintains the pH of the solution from about pH 4.0 to about pH 8.0.
In some embodiments, the aqueous solution for nebulized inhalation
administration described herein comprises: water; imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof at a concentration
from about 0.1 mg/mL to about 200 mg/mL; sodium chloride from about
0.1% to about 1.0% to adjust osmolality and provide a permeant ion;
and optionally a phosphate buffer or a citrate buffer that
maintains the pH of the solution from about pH 4.0 to about pH 8.0.
In some embodiments, the aqueous solution for nebulized inhalation
administration described herein comprises: water; imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound at a
concentration from about 0.1 mg/mL to about 50 mg/mL; sodium
chloride from about 0.1% to about 1.0% to adjust osmolality and
provide a permeant ion; and optionally a phosphate buffer or a
citrate buffer that maintains the pH of the solution from about pH
4.0 to about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt thereof
at a concentration from about 0.1 mg/mL to about 10 mg/mL; sodium
chloride from about 0.1% to about 1.0% to adjust osmolality and
provide a permeant ion; and optionally a phosphate buffer or a
citrate buffer that maintains the pH of the solution from about pH
4.0 to about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt thereof
at a concentration from about 0.001 mg/mL to about 200 mg/mL;
sodium chloride from about 0.25% to about 1.0% to adjust osmolality
and provide a permeant ion; and optionally a phosphate buffer or a
citrate buffer that maintains the pH of the solution from about pH
4.0 to about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt thereof
at a concentration from about 0.001 mg/mL to about 200 mg/mL;
sodium chloride from about 0.5% to about 1.0% to adjust osmolality
and provide a permeant ion; and optionally a phosphate buffer or a
citrate buffer that maintains the pH of the solution from about pH
4.0 to about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt thereof
at a concentration from about 0.001 mg/mL to about 200 mg/mL;
sodium chloride from about 0.1% to about 0.9% to adjust osmolality
and provide a permeant ion; and optionally a phosphate buffer or a
citrate buffer that maintains the pH of the solution from about pH
4.0 to about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt thereof
at a concentration from about 0.001 mg/mL to about 200 mg/mL;
sodium chloride from about 0.1% to about 0.8% to adjust osmolality
and provide a permeant ion; and optionally a phosphate buffer or a
citrate buffer that maintains the pH of the solution from about pH
4.0 to about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound at a concentration from about 0.001 mg/mL to about 200
mg/mL; sodium chloride from about 0.1% to about 0.7% to adjust
osmolality and provide a permeant ion; and optionally a phosphate
buffer or a citrate buffer that maintains the pH of the solution
from about pH 4.0 to about pH 8.0. In some embodiments, the aqueous
solution for nebulized inhalation administration described herein
comprises: water; imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof at a concentration from about 0.001 mg/mL to about 200
mg/mL; sodium chloride from about 0.1% to about 1.0% to adjust
osmolality and provide a permeant ion; and optionally a citrate
buffer that maintains the pH of the solution from about pH 4.0 to
about pH 7.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt thereof
at a concentration from about 0.001 mg/mL to about 200 mg/mL;
sodium chloride from about 0.1% to about 1.0% to adjust osmolality
and provide a permeant ion; and optionally a phosphate buffer that
maintains the pH of the solution from about pH 5.0 to about pH 8.0.
In some embodiments, the aqueous solution for nebulized inhalation
administration described herein comprises: water; imatinib salt
thereof, a phenylaminopyrimidine derivative salt thereof, or other
tyrosine kinase inhibitor or salt thereof at a concentration from
about 0.001 mg/mL to about 200 mg/mL; sodium chloride from about
0.1% to about 1.0% to adjust osmolality and provide a permeant ion;
wherein the salt providing buffering capacity to maintain the pH of
the solution from about pH 4.0 to about pH 7.0 is citrate. In some
embodiments, the aqueous solution for nebulized inhalation
administration described herein comprises: water; imatinib salt
thereof, a phenylaminopyrimidine derivative salt thereof, or other
tyrosine kinase inhibitor or salt thereof at a concentration from
about 0.001 mg/mL to about 200 mg/mL; sodium chloride from about
0.1% to about 1.0% to adjust osmolality and provide a permeant ion;
wherein the salt providing buffering capacity to maintain the pH of
the solution from about pH 4.0 to about pH 8.0 is phosphate.
In some embodiments, the aqueous solution for nebulized inhalation
administration described herein comprises: water; imatinib or salt
thereof, or a phenylaminopyrimidine derivative or salt thereof at a
concentration from about 0.5 mg/mL to about 30 mg/mL; sodium
chloride from about 0.1% to about 1.0% to adjust osmolality and
provide a permeant ion; and optionally a phosphate buffer or a
citrate buffer that maintains the pH of the solution from about pH
4.0 to about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt
thereof, or other tyrosine kinase inhibitor or salt thereof at a
concentration from about 0.001 mg/mL to about 200 mg/mL; sodium
chloride from about 0.1% to about 1.0% to adjust osmolality and
provide a permeant ion; and optionally a phosphate buffer or a
citrate buffer that maintains the pH of the solution from about pH
4.0 to about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, or a phenylaminopyrimidine
derivative or salt thereof at a concentration from about 0.5 mg/mL
to about 20 mg/mL; sodium chloride from about 0.1% to about 1.0% to
adjust osmolality and provide a permeant ion; and optionally a
phosphate buffer or a citrate buffer that maintains the pH of the
solution from about pH 4.0 to about pH 8.0. In some embodiments,
the aqueous solution for nebulized inhalation administration
described herein comprises: water; imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, or other tyrosine kinase
inhibitor or salt thereof at a concentration from about 0.01 mg/mL
to about 200 mg/mL; sodium chloride from about 0.1% to about 1.0%
to adjust osmolality and provide a permeant ion; and optionally a
phosphate buffer or a citrate buffer that maintains the pH of the
solution from about pH 4.0 to about pH 8.0. In some embodiments,
the aqueous solution for nebulized inhalation administration
described herein comprises: water; imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, or other tyrosine kinase
inhibitor or salt thereof at a concentration from about 0.01 mg/mL
to about 50 mg/mL; sodium chloride from about 0.1% to about 1.0% to
adjust osmolality and provide a permeant ion; and optionally a
phosphate buffer or a citrate buffer that maintains the pH of the
solution from about pH 4.0 to about pH 8.0. In some embodiments,
the aqueous solution for nebulized inhalation administration
described herein comprises: water; imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, at a concentration from about
0.01 mg/mL to about 50 mg/mL; sodium chloride from about 0.1% to
about 1.0% to adjust osmolality and provide a permeant ion; and
optionally a phosphate buffer or a citrate buffer that maintains
the pH of the solution from about pH 4.0 to about pH 8.0. In some
embodiments, the aqueous solution for nebulized inhalation
administration described herein comprises: water; imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, at a concentration
from about 0.01 mg/mL to about 10 mg/mL; sodium chloride from about
0.1% to about 1.0% to adjust osmolality and provide a permeant ion;
and optionally a phosphate buffer or a citrate buffer that
maintains the pH of the solution from about pH 4.0 to about pH 8.0.
In some embodiments, the aqueous solution for nebulized inhalation
administration described herein comprises: water; imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, at a concentration
from about 0.01 mg/mL to about 10 mg/mL; sodium chloride from about
0.1% to about 1.0% to adjust osmolality and provide a permeant ion;
and optionally a phosphate buffer or a citrate buffer that
maintains the pH of the solution from about pH 4.0 to about pH 8.0.
In some embodiments, the aqueous solution for nebulized inhalation
administration described herein comprises: water; imatinib or salt
thereof, or a phenylaminopyrimidine derivative or salt thereof at a
concentration from about 5 mg/mL to about 50 mg/mL; sodium chloride
from about 0.1% to about 1.0% to adjust osmolality and provide a
permeant ion; and optionally a phosphate buffer or a citrate buffer
that maintains the pH of the solution from about pH 4.0 to about pH
8.0. In some embodiments, the aqueous solution for nebulized
inhalation administration described herein comprises: water;
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
at a concentration from about 0.1 mg/mL to about 200 mg/mL; sodium
chloride from about 0.1% to about 1.0% to adjust osmolality and
provide a permeant ion; and optionally a phosphate buffer or a
citrate buffer that maintains the pH of the solution from about pH
4.0 to about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt thereof
at a concentration from about 0.1 mg/mL to about 50 mg/mL; sodium
chloride from about 0.1% to about 1.0% to adjust osmolality and
provide a permeant ion; and optionally a phosphate buffer or a
citrate buffer that maintains the pH of the solution from about pH
4.0 to about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt thereof
at a concentration from about 0.01 mg/mL to about 10 mg/mL; sodium
chloride from about 0.1% to about 1.0% to adjust osmolality and
provide a permeant ion; and optionally a phosphate buffer or a
citrate buffer that maintains the pH of the solution from about pH
4.0 to about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, or a phenylaminopyrimidine
derivative or salt thereof at a concentration from about 0.5 mg/mL
to about 50 mg/mL; sodium chloride from about 0.25% to about 1.0%
to adjust osmolality and provide a permeant ion; and optionally a
phosphate buffer or a citrate buffer that maintains the pH of the
solution from about pH 4.0 to about pH 8.0. In some embodiments,
the aqueous solution for nebulized inhalation administration
described herein comprises: water; imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, at a concentration from about
0.001 mg/mL to about 200 mg/mL; sodium chloride from about 0.25% to
about 1.0% to adjust osmolality and provide a permeant ion; and
optionally a phosphate buffer or a citrate buffer that maintains
the pH of the solution from about pH 4.0 to about pH 8.0. In some
embodiments, the aqueous solution for nebulized inhalation
administration described herein comprises: water; imatinib or salt
thereof, or a phenylaminopyrimidine derivative or salt thereof at a
concentration from about 0.5 mg/mL to about 50 mg/mL; sodium
chloride from about 0.5% to about 1.0% to adjust osmolality and
provide a permeant ion; and optionally a phosphate buffer or a
citrate buffer that maintains the pH of the solution from about pH
4.0 to about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt
thereof, at a concentration from about 0.001 mg/mL to about 200
mg/mL; sodium chloride from about 0.5% to about 1.0% to adjust
osmolality and provide a permeant ion; and optionally a phosphate
buffer or a citrate buffer that maintains the pH of the solution
from about pH 4.0 to about pH 8.0. In some embodiments, the aqueous
solution for nebulized inhalation administration described herein
comprises: water; imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof at a concentration
from about 0.5 mg/mL to about 50 mg/mL; sodium chloride from about
0.1% to about 0.9% to adjust osmolality and provide a permeant ion;
and optionally a phosphate buffer or a citrate buffer that
maintains the pH of the solution from about pH 4.0 to about pH 8.0.
In some embodiments, the aqueous solution for nebulized inhalation
administration described herein comprises: water; imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, at a concentration
from about 0.001 mg/mL to about 200 mg/mL; sodium chloride from
about 0.1% to about 0.9% to adjust osmolality and provide a
permeant ion; and optionally a phosphate buffer or a citrate buffer
that maintains the pH of the solution from about pH 4.0 to about pH
8.0. In some embodiments, the aqueous solution for nebulized
inhalation administration described herein comprises: water;
imatinib or salt thereof, or a phenylaminopyrimidine derivative or
salt thereof at a concentration from about 0.5 mg/mL to about 50
mg/mL; sodium chloride from about 0.1% to about 0.8% to adjust
osmolality and provide a permeant ion; and optionally a phosphate
buffer or a citrate buffer that maintains the pH of the solution
from about pH 4.0 to about pH 8.0. In some embodiments, the aqueous
solution for nebulized inhalation administration described herein
comprises: water; imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, at a concentration from about 0.001 mg/mL to about
200 mg/mL; sodium chloride from about 0.1% to about 0.8% to adjust
osmolality and provide a permeant ion; and optionally a phosphate
buffer or a citrate buffer that maintains the pH of the solution
from about pH 4.0 to about pH 8.0. In some embodiments, the aqueous
solution for nebulized inhalation administration described herein
comprises: water; imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof at a concentration
from about 0.5 mg/mL to about 50 mg/mL; sodium chloride from about
0.1% to about 0.7% to adjust osmolality and provide a permeant ion;
and optionally a phosphate buffer or a citrate buffer that
maintains the pH of the solution from about pH 4.0 to about pH 8.0.
In some embodiments, the aqueous solution for nebulized inhalation
administration described herein comprises: water; imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, at a concentration
from about 0.001 mg/mL to about 200 mg/mL; sodium chloride from
about 0.1% to about 0.7% to adjust osmolality and provide a
permeant ion; and optionally a phosphate buffer or a citrate buffer
that maintains the pH of the solution from about pH 4.0 to about pH
8.0. In some embodiments, the aqueous solution for nebulized
inhalation administration described herein comprises: water;
imatinib or salt thereof, or a phenylaminopyrimidine derivative or
salt thereof at a concentration from about 0.5 mg/mL to about 50
mg/mL; sodium chloride from about 0.1% to about 1.0% to adjust
osmolality and provide a permeant ion; and optionally a citrate
buffer that maintains the pH of the solution from about pH 4.0 to
about pH 7.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt
thereof, at a concentration from about 0.001 mg/mL to about 200
mg/mL; sodium chloride from about 0.1% to about 1.0% to adjust
osmolality and provide a permeant ion; and optionally a citrate
buffer that maintains the pH of the solution from about pH 4.0 to
about pH 7.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, or a phenylaminopyrimidine
derivative or salt thereof at a concentration from about 0.5 mg/mL
to about 50 mg/mL; sodium chloride from about 0.1% to about 1.0% to
adjust osmolality and provide a permeant ion; and optionally a
phosphate buffer that maintains the pH of the solution from about
pH 5.0 to about pH 8.0. In some embodiments, the aqueous solution
for nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt
thereof, at a concentration from about 0.001 mg/mL to about 200
mg/mL; sodium chloride from about 0.1% to about 1.0% to adjust
osmolality and provide a permeant ion; and optionally a phosphate
buffer that maintains the pH of the solution from about pH 5.0 to
about pH 8.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib salt thereof, a phenylaminopyrimidine derivative
salt thereof, or other tyrosine kinase inhibitor or salt thereof at
a concentration from about 0.001 mg/mL to about 200 mg/mL; sodium
chloride from about 0.1% to about 1.0% to adjust osmolality and
provide a permeant ion; wherein the salt providing buffering
capacity to maintain the pH of the solution from about pH 4.0 to
about pH 7.0 is citrate. In some embodiments, the aqueous solution
for nebulized inhalation administration described herein comprises:
water; imatinib salt thereof, a phenylaminopyrimidine derivative
salt thereof, or other tyrosine kinase inhibitor or salt thereof at
a concentration from about 0.001 mg/mL to about 200 mg/mL; sodium
chloride from about 0.1% to about 1.0% to adjust osmolality and
provide a permeant ion; wherein the salt providing buffering
capacity to maintain the pH of the solution from about pH 4.0 to
about pH 8.0 is phosphate. In some embodiments, the nebulizer is a
jet nebulizer, an ultrasonic nebulizer, a pulsating membrane
nebulizer, a nebulizer comprising a vibrating mesh or plate with
multiple apertures, or a nebulizer comprising a vibration generator
and an aqueous chamber. In some embodiments, the liquid nebulizer:
(i) achieves lung deposition of at least 7% of the imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, administered to
the mammal; (ii) provides a Geometric Standard Deviation (GSD) of
emitted droplet size distribution of the aqueous solution of about
1.0 [0023].mu.m to about 2.5 .mu.m; (iii) provides: a) a mass
median aerodynamic diameter (MMAD) of droplet size of the aqueous
solution emitted with the high efficiency liquid nebulizer of about
1 .mu.m to about 5 .mu.m; b) a volumetric mean diameter (VMD) of
about 1 .mu.m to about 5 .mu.m; and/or c) a mass median diameter
(MMD) of about 1 .mu.m to about 5 .mu.m; (iv) provides a fine
particle fraction (FPF=%.ltoreq.5 microns) of droplets emitted from
the liquid nebulizer of at least about 30%; (v) provides an output
rate of at least 0.1 mL/min; and/or (vi) provides at least about
25% of the aqueous solution to the mammal. In some embodiments, the
mammal is a human. In some embodiments, the lung disease is lung
fibrosis and the mammal is a human. In some embodiments, the lung
disease is idiopathic pulmonary fibrosis and the mammal is a human.
In some embodiments, the lung disease is pulmonary hypertension and
the mammal is a human. In some embodiments, the lung disease is
Type 1, 2, 3, 4 and 5 Pulmonary Hypertension and the mammal is a
human. In some embodiments, the lung disease is cancer and the
mammal is a human. In some embodiments, the lung cancer is small
cell lung cancer and the mammal is a human. In some embodiments,
the lung cancer is non-small cell lung cancer and the mammal is a
human. In some embodiments, the pulmonary cancer is large cell
carcinoma and the mammal is a human. In some embodiments, the
pulmonary cancer is mesothelioma and the mammal is a human. In some
embodiments, the pulmonary cancer is lung carcinoid tumors or
bronchial cardinoids and the mammal is a human. In some
embodiments, the pulmonary cancer is secondary lung cancer
resulting from metastatic disease and the mammal is a human. In
some embodiments, the pulmonary cancer is bronchioloalveolar
carcinoma and the mammal is a human. In some embodiments, the
pulmonary cancer may be sarcoma and the mammal is a human. In some
embodiments, the pulmonary cancer is may be a lymphoma and the
mammal is a human. In some embodiments, the liquid nebulizer
delivers from about 0.05 mg to about 600 mg of imatinib or salt
thereof, or a phenylaminopyrimidine derivative or salt thereof
compound to the lungs of the mammal in less than about 20 minutes
with mass median diameter (MMAD) particles sizes from about 1 to
about 5 micron. In some embodiments, the liquid nebulizer delivers
from about 0.01 mg to about 600 mg of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, compound to the lungs of the
mammal in less than about 20 minutes with
mass median diameter (MMAD) particles sizes from about 1 to about 5
micron.
[0024] In some embodiments, the lung tissue Cmax and/or AUC of
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
that is obtained after administration of a single inhaled dose to
the mammal is about the same or greater than the lung tissue Cmax
and/or AUC of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, that is obtained after a single dose of orally
administered dose of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, at a dose that is from about 80%
to about 120% of the inhaled dose; and/or the plasma Cmax and/or
AUC of imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt
thereof, that is obtained after administration of a single inhaled
dose to the mammal is less than the plasma Cmax and/or AUC of
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
that is obtained after a single dose of orally administered
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
at a dose that is from about 80% to about 120% of the inhaled dose.
In some embodiments, the lung tissue Cmax of imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, that is obtained
after administration of a single inhaled dose to the mammal is
greater than the lung tissue Cmax of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, that is obtained after a single
dose of orally administered imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, at a dose that is from about 80%
to about 120% of the inhaled dose. In some embodiments, the lung
tissue AUC of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, that is obtained after administration of a single
inhaled dose to the mammal is greater than the lung tissue AUC of
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
that is obtained after a single dose of orally administered
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
at a dose that is from about 80% to about 120% of the inhaled dose.
In some embodiments, the plasma Cmax of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, that is obtained after
administration of a single inhaled dose to the mammal is less than
the plasma Cmax of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, that is obtained after a single
dose of orally administered imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, at a dose that is from about 80%
to about 120% of the inhaled dose. In some embodiments, the plasma
AUC of imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof; or other tyrosine kinase inhibitor or salt
thereof, that is obtained after administration a single inhaled
dose to the mammal is less than the plasma AUC of imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, that is obtained
after a single dose of orally administered imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, compound at a dose
that is from about 80% to about 120% of the inhaled dose.
[0025] In some embodiments, the liquid nebulizer delivers from
about 0.1 mg to about 600 mg of imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof to the lungs of
the mammal in less than about 20 minutes with mass median diameter
(MMAD) particles sizes from about 1 to about 5 micron. In some
embodiments, the liquid nebulizer delivers from about 0.01 mg to
about 600 mg of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, to the lungs of the mammal in less than about 20
minutes with mass median diameter (MMAD) particles sizes from about
1 to about 5 micron.
[0026] In some embodiments, administration with the liquid
nebulizer does not include an initial dose-escalation period.
[0027] In some embodiments, described herein is a method of
reducing the risk of gastrointestinal (GI) adverse events in the
treatment of a human with imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, comprising: administering to the
human in need thereof a nebulized aqueous solution comprising
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
with a liquid nebulizer; wherein the aqueous solution comprises
water; imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt
thereof, at a concentration from about 0.001 mg/mL to about 200
mg/mL or at a concentration from about 0.1 mg/mL to about 100
mg/mL; one or more inorganic salts, wherein the osmolality of the
aqueous solution is from about 50 mOsmol/kg to about 2000
mOsmol/kg; and one or more buffers maintaining the solution pH
between about 4.0 and 8.0. In some embodiments, the aqueous
solution for nebulized inhalation administration described herein
comprises: water; imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, at a concentration from about 0.01 mg/mL to about 200
mg/mL or from about 0.5 mg/mL to about 40 mg/mL; sodium chloride
from about 0.1% to about 1.0% to adjust osmolality and provide a
permeant ion; and optionally a phosphate buffer or a citrate buffer
or the tyrosine kinase inhibitor salt itself maintains the pH of
the solution from about pH 4.0 to about pH 8.0. In some
embodiments, the aqueous solution for nebulized inhalation
administration described herein comprises: water; imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, at a concentration
from about 0.01 mg/mL to about 50 mg/mL or from about 0.5 mg/mL to
about 30 mg/mL; sodium chloride from about 0.1% to about 1.0% to
adjust osmolality and provide a permeant ion; and optionally a
phosphate buffer or a citrate buffer or the tyrosine kinase
inhibitor salt itself maintains the pH of the solution from about
pH 4.0 to about pH 8.0. In some embodiments, the aqueous solution
for nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt
thereof, at a concentration from about 0.01 mg/mL to about 10 mg/mL
or from about 0.5 mg/mL to about 20 mg/mL; sodium chloride from
about 0.1% to about 1.0% to adjust osmolality and provide a
permeant ion; and optionally a phosphate buffer or a citrate buffer
or the tyrosine kinase inhibitor salt itself maintains the pH of
the solution from about pH 4.0 to about pH 8.0. In some
embodiments, the aqueous solution for nebulized inhalation
administration described herein comprises: water; imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, at a concentration
from about 0.1 mg/mL to about 200 mg/mL or from about 1.0 mg/mL to
about 50 mg/mL; sodium chloride from about 0.1% to about 1.0% to
adjust osmolality and provide a permeant ion; and optionally a
phosphate buffer or a citrate buffer or the tyrosine kinase
inhibitor salt itself maintains the pH of the solution from about
pH 4.0 to about pH 8.0. In some embodiments, the aqueous solution
for nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt
thereof, at a concentration from about 0.1 mg/mL to about 50 mg/mL
or from about 2.0 mg/mL to about 50 mg/mL; sodium chloride from
about 0.1% to about 1.0% to adjust osmolality and provide a
permeant ion; and optionally a phosphate buffer or a citrate buffer
or the tyrosine kinase inhibitor salt itself maintains the pH of
the solution from about pH 4.0 to about pH 8.0. In some
embodiments, the aqueous solution for nebulized inhalation
administration described herein comprises: water; imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, at a concentration
from about 0.1 mg/mL to about 10 mg/mL or from about 5 mg/mL to
about 50 mg/mL; sodium chloride from about 0.1% to about 1.0% to
adjust osmolality and provide a permeant ion; and optionally a
phosphate buffer or a citrate buffer or the tyrosine kinase
inhibitor salt itself maintains the pH of the solution from about
pH 4.0 to about pH 8.0. In some embodiments, the aqueous solution
for nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt
thereof, at a concentration from about 0.001 mg/mL to about 200
mg/mL or from about 0.5 mg/mL to about 50 mg/mL; sodium chloride
from about 0.25% to about 1.0% to adjust osmolality and provide a
permeant ion; and optionally a phosphate buffer or a citrate buffer
or the tyrosine kinase inhibitor salt itself maintains the pH of
the solution from about pH 4.0 to about pH 8.0. In some
embodiments, the aqueous solution for nebulized inhalation
administration described herein comprises: water; imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, at a concentration
from about 0.001 mg/mL to about 200 mg/mL or from about 0.5 mg/mL
to about 50 mg/mL; sodium chloride from about 0.5% to about 1.0% to
adjust osmolality and provide a permeant ion; and optionally a
phosphate buffer or a citrate buffer or the tyrosine kinase
inhibitor salt itself maintains the pH of the solution from about
pH 4.0 to about pH 8.0. In some embodiments, the aqueous solution
for nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt
thereof, at a concentration from about 0.001 mg/mL to about 200
mg/mL or from about 0.5 mg/mL to about 50 mg/mL; sodium chloride
from about 0.1% to about 0.9% to adjust osmolality and provide a
permeant ion; and optionally a phosphate buffer or a citrate buffer
or the tyrosine kinase inhibitor salt itself maintains the pH of
the solution from about pH 4.0 to about pH 8.0. In some
embodiments, the aqueous solution for nebulized inhalation
administration described herein comprises: water; imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, at a concentration
from about 0.001 mg/mL to about 200 mg/mL or from about 0.5 mg/mL
to about 50 mg/mL; sodium chloride from about 0.1% to about 0.8% to
adjust osmolality and provide a permeant ion; and optionally a
phosphate buffer or a citrate buffer or the tyrosine kinase
inhibitor salt itself maintains the pH of the solution from about
pH 4.0 to about pH 8.0. In some embodiments, the aqueous solution
for nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt
thereof, at a concentration from about 0.001 mg/mL to about 200
mg/mL or from about 0.5 mg/mL to about 50 mg/mL; sodium chloride
from about 0.1% to about 0.7% to adjust osmolality and provide a
permeant ion; and optionally a phosphate buffer or a citrate buffer
or the tyrosine kinase inhibitor salt itself maintains the pH of
the solution from about pH 4.0 to about pH 8.0. In some
embodiments, the aqueous solution for nebulized inhalation
administration described herein comprises: water; imatinib or salt
thereof, or other tyrosine kinase inhibitor or salt thereof, a
phenylaminopyrimidine derivative or salt thereof at a concentration
from about 0.001 mg/mL to about 200 mg/mL or from about 0.5 mg/mL
to about 50 mg/mL; sodium chloride from about 0.1% to about 1.0% to
adjust osmolality and provide a permeant ion; and optionally a
citrate buffer that maintains the pH of the solution from about pH
4.0 to about pH 7.0. In some embodiments, the aqueous solution for
nebulized inhalation administration described herein comprises:
water; imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt
thereof, at a concentration from about 0.001 mg/mL to about 200
mg/mL or from about 0.5 mg/mL to about 50 mg/mL; sodium chloride
from about 0.1% to about 1.0% to adjust osmolality and provide a
permeant ion; and optionally a phosphate buffer that maintains the
pH of the solution from about pH 5.0 to about pH 8.0. In some
embodiments, the aqueous solution for nebulized inhalation
administration described herein comprises: water; imatinib or salt
thereof, or other tyrosine kinase inhibitor or salt thereof a
phenylaminopyrimidine derivative or salt thereof at a concentration
from about 0.001 mg/mL to about 200 mg/mL; sodium chloride from
about 0.1% to about 1.0% to adjust osmolality and provide a
permeant ion; wherein a citrate salt maintains the pH of the
solution from about pH 4.0 to about pH 7.0. In some embodiments,
the aqueous solution for nebulized inhalation administration
described herein comprises: water; imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof at a concentration from about
0.001 mg/mL to about 200 mg/mL; sodium chloride from about 0.1% to
about 1.0% to adjust osmolality and provide a permeant ion; wherein
the phosphate salt maintains the pH of the solution from about pH
5.0 to about pH 8.0. In some embodiments, the aqueous solution
comprises water; imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, compound, at a concentration from about 0.001 mg/mL
to about 200 mg/mL or from about 0.1 mg/mL to about 100 mg/mL; one
or more inorganic salts, wherein the osmolality of the aqueous
solution is from about 50 mOsmol/kg to about 2000 mOsmol/kg; and
one or more buffers maintaining the solution pH between about 4.0
and 8.0. In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, is administered to treat lung
disease in the human. In some embodiments, lung disease is
idiopathic pulmonary fibrosis. In other embodiments, lung disease
is cancer. In some embodiments, lung disease target is stroma
associated with lung cancer. In some embodiments, lung disease is
pulmonary hypertension.
[0028] In some embodiments, the liquid nebulizer delivers about 0.1
mg to about 600 mg of imatinib or phenylaminopyrimidine derivative
compound to the lungs in less than about 20 minutes with mass
median diameter (MMAD) particles sizes from about 1 to about 5
micron. In some embodiments, the liquid nebulizer delivers about
0.01 mg to about 600 mg of imatinib or phenylaminopyrimidine
derivative, or tyrosine kinase inhibitor compound to the lungs in
less than about 20 minutes with mass median diameter (MMAD)
particles sizes from about 1 to about 5 micron
[0029] In some embodiments, administration with the liquid
nebulizer does not include an initial dose-escalation period.
[0030] In some embodiments, about 0.5 mL to about 6 mL of the
aqueous solution is administered to the mammal with a liquid
nebulizer, the solution having a concentration of imatinib or salt
thereof, or a phenylaminopyrimidine derivative or salt thereof from
about 0.1 mg/mL to about 100 mg/mL and the osmolality of the
aqueous solution is from about 50 mOsmol/kg to about 2000
mOsmol/kg; and the liquid nebulizer is a nebulizer comprising a
vibrating mesh or plate with multiple apertures. In some
embodiments, about 0.01 mL to about 6 mL of the aqueous solution is
administered to the mammal with a liquid nebulizer, the solution
having a concentration of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, from about 0.001 mg/mL to about
200 mg/mL and the osmolality of the aqueous solution is from about
50 mOsmol/kg to about 2000 mOsmol/kg; and the liquid nebulizer is a
nebulizer comprising a vibrating mesh or plate with multiple
apertures.
[0031] In some embodiments, the liquid nebulizer delivers about 0.1
mg to about 600 mg of imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof to the lungs in
less than about 20 minutes with mass median diameter (MMAD)
particles sizes from about 1 to about 5 micron. In some
embodiments, the aqueous solution has a pH from about 4.0 to about
8.0 and an osmolality from about 50 mOsmol/kg to about 2000
mOsmol/kg. In some embodiments, the liquid nebulizer delivers about
0.01 mg to about 600 mg of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, to the lungs in less than about
20 minutes with mass median diameter (MMAD) particles sizes from
about 1 to about 5 micron. In some embodiments, the aqueous
solution has a pH from about 4.0 to about 8.0 and an osmolality
from about 50 mOsmol/kg to about 2000 mOsmol/kg.
[0032] In some embodiments, described herein is an inhalation
system for administration of imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof compound to the
respiratory tract of a human, the system comprising: (a) about 0.5
mL to about 6 mL of an aqueous solution of imatinib or salt
thereof, or a phenylaminopyrimidine derivative or salt thereof; and
(b) a high efficiency liquid nebulizer. In some embodiments,
described herein is an inhalation system for administration of
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
compound to the respiratory tract of a human, the system
comprising: (a) about 0.01 mL to about 6 mL of an aqueous solution
of imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof;
and (b) a high efficiency liquid nebulizer. In some embodiments,
the aqueous solution is any of the aqueous solutions described
herein. In some embodiments, the concentration of imatinib or salt
thereof, or a phenylaminopyrimidine derivative or salt thereof in
the aqueous solution is from about 0.1 mg/mL and about 100 mg/mL
and the osmolality of the aqueous solution is from about 200
mOsmol/kg to about 1000 mOsmol/kg. In some embodiments, the
concentration of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, in the aqueous solution is from about 0.001 mg/mL and
about 200 mg/mL and the osmolality of the aqueous solution is from
about 200 mOsmol/kg to about 1000 mOsmol/kg. In some embodiments,
the aqueous solution comprises: water; of imatinib or salt thereof,
or a phenylaminopyrimidine derivative or salt thereof at a
concentration from about 0.1 mg/mL to about 50 mg/mL; optionally a
phosphate buffer that maintains the pH of the solution from about
pH 5.0 to about pH 8.0. In some embodiments, the aqueous solution
comprises: water; of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, at a concentration from about
0.001 mg/mL to about 200 mg/mL; optionally a phosphate buffer that
maintains the pH of the solution from about pH 5.0 to about pH 8.0.
In some embodiments, the aqueous solution comprises: water;
imatinib or salt thereof, or a phenylaminopyrimidine derivative or
salt thereof at a concentration from about 0.1 mg/mL to about 50
mg/mL; optionally a citrate buffer that maintains the pH of the
solution from about pH 4.0 to about pH 7.0. In some embodiments,
the aqueous solution comprises: water; imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, at a concentration from about
0.001 mg/mL to about 200 mg/mL; optionally a citrate buffer that
maintains the pH of the solution from about pH 4.0 to about pH 7.0.
In some embodiments, the aqueous solution comprises: water; of
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
at a concentration from about 0.001 mg/mL to about 200 mg/mL;
wherein the phosphate salt maintains the pH of the solution from
about pH 4.0 to about pH 8.0. In some embodiments, the aqueous
solution comprises: water; imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, at a concentration from about
0.001 mg/mL to about 200 mg/mL; wherein the citrate salt maintains
the pH of the solution from about pH 4.0 to about pH 7.0. In some
embodiments, the aqueous solution is as described herein.
[0033] In one aspect, described herein is a method of achieving a
lung tissue Cmax of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound that is at least 1.5
times, at least 2 times, at least 3 times, at least 4 times, at
least 5 times, at least 6 times, at least 1.5 times, at least 1.5
times, at least 1.5 times, at least 1.5 times, at least 7 times, at
least 8 times, at least 9 times, at least 10 times, at least 1.5-20
times, at least 1.5-15 times, at least 1.5-10 times, at least 1.5-5
times, or at least 1.5-3 times times a Cmax of up to 600 mg of an
orally administered dosage of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, the method comprising nebulizing
an aqueous solution comprising imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, and administering the nebulized
aqueous solution to a human. In some embodiments, described herein
is a method of achieving a lung tissue Cmax of imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound that is at
least equivalent to or greater than a Cmax of up to 600 mg of an
orally administered dosage of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, the method comprising nebulizing
an aqueous solution comprising imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, and administering the nebulized
aqueous solution to a human.
[0034] In one aspect, described herein is a method of achieving a
lung tissue AUC.sub.0-24 of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, that is at least 1.5 times, at
least 2 times, at least 3 times, at least 4 times, at least 5
times, at least 6 times, at least 1.5 times, at least 1.5 times, at
least 1.5 times, at least 1.5 times, at least 7 times, at least 8
times, at least 9 times, at least 10 times, at least 1.5-20 times,
at least 1.5-15 times, at least 1.5-10 times, at least 1.5-5 times,
or at least 1.5-3 times times AUC.sub.0-24 of up to 600 mg of an
orally administered dosage of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, the method comprising nebulizing
an aqueous solution comprising imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound and administering the
nebulized aqueous solution to a human. In some embodiments,
described herein is a method of achieving a lung tissue
AUC.sub.0-24 of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound that is at least equivalent to or greater
than AUC.sub.0-24 of up to 600 mg of an orally administered dosage
of imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
the method comprising nebulizing an aqueous solution comprising
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
and administering the nebulized aqueous solution to a human.
[0035] In one aspect, described herein is a method of administering
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
to a human, comprising administering a nebulized aqueous solution
containing the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, wherein the lung tissue Cmax achieved with the
nebulized solution is at least 1.5 times, at least 2 times, at
least 3 times, at least 4 times, at least 5 times, at least 6
times, at least 1.5 times, at least 1.5 times, at least 1.5 times,
at least 1.5 times, at least 7 times, at least 8 times, at least 9
times, at least 10 times, at least 1.5-20 times, at least 1.5-15
times, at least 1.5-10 times, at least 1.5-5 times, or at least
1.5-3 times times the lung tissue Cmax achieved with an orally
administered imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, dosage that is from 80% to 120% of the dose amount of
imatinib that is administered by nebulization.
[0036] In one aspect, described herein is a method of administering
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
to a human, comprising administering a nebulized aqueous solution
containing the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, wherein the lung tissue Cmax achieved with the
nebulized solution is at least 1.5 times, at least 2 times, at
least 3 times, at least 4 times, at least 5 times, at least 6
times, at least 1.5 times, at least 1.5 times, at least 1.5 times,
at least 1.5 times, at least 7 times, at least 8 times, at least 9
times, at least 10 times, at least 1.5-20 times, at least 1.5-15
times, at least 1.5-10 times, at least 1.5-5 times, or at least
1.5-3 times times the lung tissue Cmax achieved with an orally
administered imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, dosage that is from 80% to 120% of the dosage of
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
in the nebulized aqueous solution of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, described
herein is a method of administering imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, to a human, comprising
administering a nebulized aqueous solution containing the imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof,
wherein the lung tissue Cmax achieved with the nebulized solution
is at least equivalent to or greater than the lung tissue Cmax
achieved with an orally administered imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, dosage that is from 80% to 120%
of the dosage of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, in the nebulized aqueous solution of imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof that is
administered.
[0037] In some embodiments, described herein is a method of
administering imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, to a human, comprising administering a nebulized
aqueous solution containing the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, wherein the plasma AUC.sub.0-24
achieved with the nebulized solution is less than the plasma
AUC.sub.0-24 achieved with an orally administered imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, dosage that is
from 80% to 120% of the dosage of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, in the nebulized aqueous solution
of imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
that is administered.
[0038] In one aspect, described herein is a method of administering
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
to a human, comprising administering a nebulized aqueous solution
containing the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, wherein the lung tissue AUC.sub.0-24 achieved with
the nebulized solution is at least 1.5 times, at least 2 times, at
least 3 times, at least 4 times, at least 5 times, at least 6
times, at least 1.5 times, at least 1.5 times, at least 1.5 times,
at least 1.5 times, at least 7 times, at least 8 times, at least 9
times, at least 10 times, at least 1.5-20 times, at least 1.5-15
times, at least 1.5-10 times, at least 1.5-5 times, or at least
1.5-3 times times the lung tissue AUC.sub.0-24 achieved with an
orally administered imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound dosage that is from 80%
to 120% of the dosage of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, in the nebulized aqueous solution
of imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof.
In some embodiments, described herein is a method of administering
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
to a human, comprising administering a nebulized aqueous solution
containing the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, wherein the lung tissue AUC.sub.0-24 achieved with
the nebulized solution is at least 1.5 times the lung tissue
AUC.sub.0-24 achieved with an orally administered imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, dosage that is
from 80% to 120% of the dosage of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, in the nebulized aqueous solution
of imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound.
[0039] In one aspect, provided herein is a method of improving the
pharmacokinetic profile obtained in a human following a single oral
dose administration of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the human
the imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
is administered to the human to treat lung disease. In some
embodiments, the lung disease is lung fibrosis. In some
embodiments, the lung disease is idiopathic pulmonary fibrosis. In
some embodiments, the single oral dose comprises up to about 600 mg
of imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof.
In some embodiments, the method of improving the pharmacokinetic
profile comprises the step of administering imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, by inhalation. In
some embodiments, the pharmacokinetic profile comprises the lung
tissue pharmacokinetic profile. In some embodiments, the
pharmacokinetic profile comprises the lung tissue pharmacokinetic
profile and/or plasma pharmacokinetic profile. In some embodiments,
the imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
is administered as an aqueous solution with a liquid nebulizer. In
some embodiments, the aqueous solution of imatinib or salt thereof,
a phenylaminopyrimidine derivative or salt thereof, or other
tyrosine kinase inhibitor or salt thereof, is as described herein.
In some embodiments, the method of improving the pharmacokinetic
profile further comprises a comparison of the pharmacokinetic
parameters following inhalation administration to the same
parameters obtained following oral administration. In some
embodiments, a prolonged improvement in pharmacokinetic profile is
obtained by repeated and frequent administrations of the aqueous
solution of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, as described herein by inhalation. In some
embodiments, repeated administration of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, by inhalation provides more
frequent direct lung exposure benefitting the human through repeat
high Cmax levels. In some embodiments, the inhaled imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, doses are
administered once a day, twice a day, three times a day, four time
a day, every other day, twice a week, three times a week, four
times a week, five times a week, six times a week, seven times a
week, or any combination thereof.
[0040] In some embodiments, described herein is a pharmaceutical
composition for pulmonary delivery, comprising a solution of
imatinib or salt thereof, or a phenylaminopyrimidine derivative or
salt thereof having a concentration greater than about 0.1 mg/mL,
having an osmolality greater than about 100 mOsmol/kg, and having a
pH greater than about 4.0. In some embodiments, described herein is
a pharmaceutical composition for pulmonary delivery, comprising a
solution of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, having a concentration greater than about 0.001
mg/mL, having an osmolality greater than about 100 mOsmol/kg, and
having a pH greater than about 4.0. In some embodiments, the
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
concentration is greater than about 0.01 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, concentration is greater than about 0.1 mg/mL. In
some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, concentration is greater than
about 0.5 mg/mL. In some embodiments, the imatinib or salt thereof,
a phenylaminopyrimidine derivative or salt thereof, or other
tyrosine kinase inhibitor or salt thereof concentration is greater
than about 1.0 mg/mL. In some embodiments, the imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, concentration is
greater than about 2.0 mg/mL. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof, concentration
is greater than about 4.0 mg/mL. In some embodiments, the imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof,
concentration is greater than about 8.0 mg/mL. In some embodiments,
the imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
concentration is greater than about 12.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, concentration is greater than about 20.0 mg/mL. In
some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, concentration is greater than
about 50.0 mg/mL. In some embodiments, the imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, concentration is
greater than about 100.0 mg/mL. In some embodiments, the imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof,
concentration is greater than about 200.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, solution has a permeant ion concentration from about
30 mM to about 300 mM. In some embodiments, the permeant ion is
chloride or bromide. In some embodiments, the imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, solution has a pH
from about 4.0 to about 8.0. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof, solution has an
osmolality from about 100 mOsmol/kg to about 1000 mOsmol/kg. In
some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, solution has an osmolality from
about 50 mOsmol/kg to about 2000 mOsmol/kg. In some embodiments,
the composition comprises a taste masking agent. In some
embodiments, the taste masking agent is selected from the group
consisting of lactose, sucrose, dextrose, saccharin, aspartame,
sucrulose, ascorbate and citrate. In some embodiments, the
composition comprises a mucolytic agent suitable for pulmonary
delivery. In some embodiments, the composition comprises a second
anti-fibrotic or anti-cancer or anti-infective agent suitable for
pulmonary delivery. In some embodiments, the method further
comprises administering a second anti-inflammatory agent suitable
for pulmonary delivery. In some embodiments, the composition
comprises a second anti-pulmonary hypertension agent suitable for
pulmonary delivery. In some embodiments, the composition may be
co-administered with a second anti-fibrotic or anti-cancer or
anti-infective agent suitable for pulmonary delivery. In some
embodiments, the composition co-administered a second
anti-inflammatory agent suitable for pulmonary delivery. In some
embodiments, the composition comprises a second anti-pulmonary
hypertension agent suitable for pulmonary delivery.
[0041] In some embodiments, described herein is a pharmaceutical
composition for pulmonary delivery, comprising a solution of
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
and a taste masking agent, wherein the solution has an osmolality
greater than about 100 mOsmol/kg, and a pH greater than about 4.0.
In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, concentration is greater than
about 0.001 mg/mL, having an osmolality greater than about 100
mOsmol/kg, and having a pH greater than about 4.0. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, concentration is greater than about 0.01 mg/mL. In
some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, concentration is greater than
about 0.1 mg/mL. In some embodiments, the imatinib or salt thereof,
a phenylaminopyrimidine derivative or salt thereof, or other
tyrosine kinase inhibitor or salt thereof, concentration is greater
than about 0.5 mg/mL. In some embodiments, the imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, concentration is
greater than about 1.0 mg/mL. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof, concentration
is greater than about 2.0 mg/mL. In some embodiments, the imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof,
concentration is greater than about 4.0 mg/mL. In some embodiments,
the imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
concentration is greater than about 8.0 mg/mL. In some embodiments,
the imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
concentration is greater than about 12.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, concentration is greater than about 16.0 mg/mL. In
some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, concentration is greater than
about 20.0 mg/mL. In some embodiments, the imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, concentration is
greater than about 50.0 mg/mL. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof, concentration
is greater than about 100.0 mg/mL. In some embodiments, the
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
concentration is greater than about 200.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, solution has a permeant ion concentration from about
30 mM to about 300 mM. In some embodiments, the permeant ion is
chloride or bromide. In some embodiments, the imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, solution has a pH
from about 4.0 to about 8.0. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof, solution has an
osmolality from about 100 mOsmol/kg to about 1000 mOsmol/kg. In
some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, solution has an osmolality from
about 50 mOsmol/kg to about 2000 mOsmol/kg. In some embodiments,
the composition comprises a taste masking agent. In some
embodiments, the taste masking agent is selected from the group
consisting of lactose, sucrose, dextrose, saccharin, aspartame,
sucrulose, ascorbate and citrate. In some embodiments, the
composition comprises a mucolytic agent suitable for pulmonary
delivery. In some embodiments, the composition comprises a second
anti-fibrotic or anti-cancer or anti-infective agent suitable for
pulmonary delivery. In some embodiments, the method further
comprises administering a second anti-inflammatory agent suitable
for pulmonary delivery. In some embodiments, the composition
comprises a second anti-pulmonary hypertension agent suitable for
pulmonary delivery. In some embodiments, the composition may be
co-administered with a second anti-fibrotic or anti-cancer or
anti-infective agent suitable for pulmonary delivery. In some
embodiments, the composition co-administered a second
anti-inflammatory agent suitable for pulmonary delivery. In some
embodiments, the composition comprises a second anti-pulmonary
hypertension agent suitable for pulmonary delivery.
[0042] In some embodiments, described herein is a sterile,
single-use container comprising from about 0.1 mL to about 20 mL of
a solution having an imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof concentration
greater than about 0.1 mg/mL, having an osmolality greater than
about 100 mOsmol/kg, and having a pH greater than about 4.0. In
some embodiments, described herein is a sterile, single-use
container comprising from about 0.01 mL to about 20 mL of a
solution having an imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, concentration greater than about
0.001 mg/mL, having an osmolality greater than about 200 mOsmol/kg,
and having a pH greater than about 4.0. In some embodiments, the
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
concentration is greater than about 0.001 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, concentration is greater than about 0.01 mg/mL. In
some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, concentration is greater than
about 0.1 mg/mL. In some embodiments, the imatinib or salt thereof,
a phenylaminopyrimidine derivative or salt thereof, or other
tyrosine kinase inhibitor or salt thereof, concentration is greater
than about 0.5 mg/mL. In some embodiments, the imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, concentration is
greater than about 1.0 mg/mL. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof, concentration
is greater than about 2.0 mg/mL. In some embodiments, the imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof,
concentration is greater than about 4.0 mg/mL. In some embodiments,
the imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
concentration is greater than about 8.0 mg/mL. In some embodiments,
the imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
concentration is greater than about 12.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, concentration is greater than about 16.0 mg/mL. In
some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, concentration is greater than
about 20.0 mg/mL. In some embodiments, the imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, concentration is
greater than about 50.0 mg/mL. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof concentration is
greater than about 100.0 mg/mL. In some embodiments, the imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof
concentration is greater than about 200.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, solution has a permeant ion concentration from about
30 mM to about 300 mM. In some embodiments, the permeant ion is
chloride or bromide. In some embodiments, the imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, solution has a pH
from about 4.0 to about 8.0. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof, solution has an
osmolality from about 100 mOsmol/kg to about 1000 mOsmol/kg. In
some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, solution has an osmolality from
about 50 mOsmol/kg to about 2000 mOsmol/kg. In some embodiments,
the container further comprises a taste masking agent. In some
embodiments, the taste masking agent is selected from the group
consisting of lactose, sucrose, dextrose, saccharin, aspartame,
sucrulose, ascorbate and citrate. In some embodiments, the
container further comprises a mucolytic agent suitable for
pulmonary delivery. In some embodiments, the container further
comprises a second anti-fibrotic or anti-cancer or anti-infective
agent suitable for pulmonary delivery. In some embodiments, the
method further comprises administering a second anti-inflammatory
agent suitable for pulmonary delivery. In some embodiments, the
composition comprises a second anti-pulmonary hypertension agent
suitable for pulmonary delivery. In some embodiments, the
composition may be co-administered with a second anti-fibrotic or
anti-cancer or anti-infective agent suitable for pulmonary
delivery. In some embodiments, the composition co-administered a
second anti-inflammatory agent suitable for pulmonary delivery. In
some embodiments, the composition comprises a second anti-pulmonary
hypertension agent suitable for pulmonary delivery.
In one aspect, described herein is a method to treat a pulmonary
disease comprising inhaling an aerosol generated from a solution
having an imatinib or salt thereof, or a phenylaminopyrimidine
derivative or salt thereof concentration greater than about 0.1
mg/mL, having an osmolality greater than about 100 mOsmol/kg, and
having a pH greater than about 4.0. In one aspect, described herein
is a method to treat a pulmonary disease comprising inhaling an
aerosol generated from a solution having an imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, concentration
greater than about 0.001 mg/mL, having an osmolality greater than
about 100 mOsmol/kg, and having a pH greater than about 4.0. In
some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, concentration is greater than
about 0.01 mg/mL. In some embodiments, the imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, concentration is
greater than about 0.5 mg/mL. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof, concentration
is greater than about 1.0 mg/mL. In some embodiments, the imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof,
concentration is greater than about 2.0 mg/mL. In some embodiments,
the imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
concentration is greater than about 4.0 mg/mL. In some embodiments,
the imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
concentration is greater than about 8.0 mg/mL. In some embodiments,
the imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
concentration is greater than about 12.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, concentration is greater than about 16.0 mg/mL. In
some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, concentration is greater than
about 20.0 mg/mL. In some embodiments, the imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, concentration is
greater than about 50.0 mg/mL. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof, concentration
is greater than about 100.0 mg/mL. In some embodiments, the
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
concentration is greater than about 200.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, solution has a permeant ion concentration from about
30 mM to about 300 mM. In some embodiments, the permeant ion is
chloride or bromide. In some embodiments, the imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, solution has a pH
from about 4.0 to about 8.0. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof, solution has an
osmolality from about 100 mOsmol/kg to about 1000 mOsmol/kg. In
some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, solution has an osmolality from
about 50 mOsmol/kg to about 2000 mOsmol/kg. In some embodiments,
the imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
solution has a taste masking agent. In some embodiments, the taste
masking agent is selected from the group consisting of lactose,
sucrose, dextrose, saccharin, aspartame, sucrulose, ascorbate and
citrate. In some embodiments, the method further comprises
administering a mucolytic agent suitable for pulmonary delivery. In
some embodiments, the method further comprises administering a
second anti-fibrotic or anti-cancer or anti-infective agent
suitable for pulmonary delivery. In some embodiments, the method
further comprises administering a second anti-inflammatory agent
suitable for pulmonary delivery. In some embodiments, the
composition comprises a second anti-pulmonary hypertension agent
suitable for pulmonary delivery. In some embodiments, the
composition may be co-administered with a second anti-fibrotic or
anti-cancer or anti-infective agent suitable for pulmonary
delivery. In some embodiments, the composition co-administered a
second anti-inflammatory agent suitable for pulmonary delivery. In
some embodiments, the composition comprises a second anti-pulmonary
hypertension agent suitable for pulmonary delivery. In some
embodiments, the pulmonary disease is interstitial lung disease. In
some embodiments, the interstitial lung disease is idiopathic
pulmonary fibrosis. In some embodiments, the interstitial lung
disease is radiation-therapy-induced pulmonary fibrosis. In some
embodiments, the pulmonary disease is chronic obstructive pulmonary
disease. In some embodiments, the pulmonary disease is chronic
bronchitis. In some embodiments, the pulmonary disease is cancer.
In some embodiments, the pulmonary cancer is small cell lung
cancer. In some embodiments, the pulmonary cancer is large cell
carcinoma. In some embodiments, the pulmonary cancer is
mesothelioma. In some embodiments, the pulmonary cancer is lung
carcinoid tumors or bronchial cardinoids. In some embodiments, the
pulmonary cancer is secondary lung cancer resulting from metastatic
disease. In some embodiments, the pulmonary cancer is non-small
cell lung cancer. In some embodiments, the pulmonary cancer is
bronchioloalveolar carcinoma. In some embodiments, the pulmonary
cancer may be sarcoma. In some embodiments, the pulmonary cancer is
may be a lymphoma. In some embodiments, the method further
comprises co-administering, administering sequentially, or
co-prescribing (such that medicines are requested by a prescribing
physician to be taken in some sequence as combination therapy to
treat the same disease) with agents targeting cancer. In some
embodiments, imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, are administered to target cancer-associated stroma
to reduce proliferation, invasion and metastisis of cancer cells,
enable anti-cancer agent penetration to cancer cells, and reduce
interstitial hypertension (whereby increasing anti-cancer agent
access to internal cancer cells. In some embodiments, the aerosol
comprises particles having a mean aerodynamic diameter from about 1
micron to about 5 microns. In some embodiments, the aerosol has a
mean particle size from about 1 microns to about 5 microns
volumetric mean diameter and a particle size geometric standard
deviation of less than or equal to 3 microns. In some embodiments,
the inhaling step delivers a dose of at least 5 mcg imatinib or
salt thereof, or a phenylaminopyrimidine derivative or salt
thereof. In some embodiments, the inhaling step delivers a dose of
at least 0.001 mg imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof. In some embodiments, the inhaling step delivers a
dose of at least 0.005 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 0.01 mg imatinib or salt thereof,
a phenylaminopyrimidine derivative or salt thereof, or other
tyrosine kinase inhibitor or salt thereof. In some embodiments, the
inhaling step delivers a dose of at least 0.05 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the inhaling step delivers a dose of at least 0.1 mg
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof.
In some embodiments, the inhaling step delivers a dose of at least
0.5 mg imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt
thereof. In some embodiments, the inhaling step delivers a dose of
at least 1.0 mg imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof. In some embodiments, the inhaling step delivers a
dose of at least 2.0 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 4.0 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 8 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 12 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 16 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 20 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 30 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 40 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 50 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 60 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 70 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 80 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 90 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 100 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 110 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 120 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 130 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 140 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 150 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 160 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 170 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 180 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 190 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 200 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 250 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step is performed in less than about 20 minutes. In some
embodiments, the inhaling step is performed in less than about 10
minutes. In some embodiments, the inhaling step is performed in
less than about 7.5 minutes. In some embodiments, the inhaling step
is performed in less than about 5 minutes. In some embodiments, the
inhaling step is performed in less than about 2.5 minutes. In some
embodiments, the inhaling step is performed in less than about 1.5
minutes. In some embodiments, the inhaling step is performed in
less than about 30 seconds. In some embodiments, the inhaling step
is performed in less than about 5 breaths. In some embodiments, the
inhaling step is performed in less than about 3 breaths. In some
embodiments, the inhaling step is performed in less than about 2
breaths. In some embodiments, the inhaling step is performed in
less than about 1 breaths.
[0044] In one aspect, described herein is a method to treat a
pulmonary disease comprising inhaling an aerosol generated from a
solution having an imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof concentration
greater than about 0.1 mg/mL, having an osmolality greater than
about 100 mOsmol/kg, and having a pH greater than about 4.0. In one
aspect, described herein is a method to treat a pulmonary disease
comprising inhaling an aerosol generated from a solution having an
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
concentration greater than about 0.001 mg/mL, having an osmolality
greater than about 100 mOsmol/kg, and having a pH greater than
about 4.0. In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, concentration is greater than
about 0.01 mg/mL. In some embodiments, the imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, concentration is
greater than about 0.1 mg/mL. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof, concentration
is greater than about 0.5 mg/mL. In some embodiments, the imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof,
concentration is greater than about 1.0 mg/mL. In some embodiments,
the imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
concentration is greater than about 2.0 mg/mL. In some embodiments,
the imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
concentration is greater than about 4.0 mg/mL. In some embodiments,
the imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
concentration is greater than about 8.0 mg/mL. In some embodiments,
the imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
concentration is greater than about 12.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, concentration is greater than about 16.0 mg/mL. In
some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, concentration is greater than
about 20.0 mg/mL. In some embodiments, the imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, concentration is
greater than about 50.0 mg/mL. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof, concentration
is greater than about 100.0 mg/mL. In some embodiments, the
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
solution has a permeant ion concentration from about 30 mM to about
300 mM. In some embodiments, the permeant ion is chloride or
bromide. In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, solution has a pH from about 4.0
to about 8.0. In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, solution has an osmolality from
about 100 mOsmol/kg to about 1000 mOsmol/kg. In some embodiments,
the imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
solution has an osmolality from about 50 mOsmol/kg to about 2000
mOsmol/kg. In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, solution has a taste masking
agent. In some embodiments, the taste masking agent is selected
from the group consisting of lactose, sucrose, dextrose, saccharin,
aspartame, sucrulose, ascorbate and citrate. In some embodiments,
the method further comprises administering a mucolytic agent
suitable for pulmonary delivery. In some embodiments, the method
further comprises administering a second anti-fibrotic or
anti-cancer or anti-infective agent suitable for pulmonary
delivery. In some embodiments, the method further comprises
administering a second anti-inflammatory agent suitable for
pulmonary delivery. In some embodiments, the composition comprises
a second anti-pulmonary hypertension agent suitable for pulmonary
delivery. In some embodiments, the composition may be
co-administered with a second anti-fibrotic or anti-cancer or
anti-infective agent suitable for pulmonary delivery. In some
embodiments, the composition co-administered a second
anti-inflammatory agent suitable for pulmonary delivery. In some
embodiments, the composition comprises a second anti-pulmonary
hypertension agent suitable for pulmonary delivery. In some
embodiments, the pulmonary disease is interstitial lung disease. In
some embodiments, the interstitial lung disease is idiopathic
pulmonary fibrosis. In some embodiments, the interstitial lung
disease is radiation-therapy-induced pulmonary fibrosis. In some
embodiments, the pulmonary disease is chronic obstructive pulmonary
disease. In some embodiments, the pulmonary disease is chronic
bronchitis. In some embodiments, the pulmonary disease is pulmonary
hypertension. In some embodiments, the pulmonary hypertension is
Type 1. In some embodiments, the pulmonary hypertension is Type 2.
In some embodiments, the pulmonary hypertension is Type 3. In some
embodiments, the pulmonary hypertension is Type 4. In some
embodiments, the pulmonary hypertension is Type 5. In some
embodiments, the pulmonary hypertension is secondary to pulmonary
fibrosis. In some embodiments, the method further comprises
co-administering, administering sequentially, or co-prescribing
(such that medicines are requested by a prescribing physician to be
taken in some sequence as combination therapy to treat the same
disease) with agents targeting pulmonary hypertension. In some
embodiments, the aerosol comprises particles having a mean
aerodynamic diameter from about 1 micron to about 5 microns. In
some embodiments, the aerosol has a mean particle size from about 1
microns to about 5 microns volumetric mean diameter and a particle
size geometric standard deviation of less than or equal to 3
microns. In some embodiments, the inhaling step delivers a dose of
at least 0.001 mg imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof. In some embodiments, the inhaling step delivers a
dose of at least 0.005 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 0.01 mg imatinib or salt thereof,
a phenylaminopyrimidine derivative or salt thereof, or other
tyrosine kinase inhibitor or salt thereof. In some embodiments, the
inhaling step delivers a dose of at least 0.05 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the inhaling step delivers a dose of at least 0.1 mg
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof.
In some embodiments, the inhaling step delivers a dose of at least
0.5 mg imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt
thereof. In some embodiments, the inhaling step delivers a dose of
at least 1.0 mg imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof. In some embodiments, the inhaling step delivers a
dose of at least 2.0 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 4.0 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 8 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 12 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 16 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 20 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 30 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 40 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 50 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 60 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 70 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 80 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 90 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 100 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 110 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 120 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 130 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 140 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 150 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 160 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 170 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 180 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 190 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 200 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof; or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 250 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step is performed in less than about 20 minutes. In some
embodiments, the inhaling step is performed in less than about 10
minutes. In some embodiments, the inhaling step is performed in
less than about 7.5 minutes. In some embodiments, the inhaling step
is performed in less than about 5 minutes. In some embodiments, the
inhaling step is performed in less than about 2.5 minutes. In some
embodiments, the inhaling step is performed in less than about 1.5
minutes. In some embodiments, the inhaling step is performed in
less than about 30 seconds. In some embodiments, the inhaling step
is performed in less than about 5 breaths. In some embodiments, the
inhaling step is performed in less than about 3 breaths. In some
embodiments, the inhaling step is performed in less than about 2
breaths. In some embodiments, the inhaling step is performed in
less than about 1 breaths.
[0045] In one aspect, described herein is a method to administer an
anti-fibrotic agent to lungs of a patient, comprising: introducing
in a nebulizer a solution having an imatinib or salt thereof; a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof concentration greater than about
0.001 mg/mL, having an osmolality greater than about 100 mOsmol/kg,
and having a pH greater than about 4.0. In some embodiments, the
imatinib or salt thereof; a phenylaminopyrimidine derivative or
salt thereof; or other tyrosine kinase inhibitor or salt thereof
concentration is greater than about 0.01 mg/mL. In some
embodiments, the imatinib or salt thereof; a phenylaminopyrimidine
derivative or salt thereof; or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 0.1 mg/mL. In some
embodiments, the imatinib or salt thereof; a phenylaminopyrimidine
derivative or salt thereof; or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 0.5 mg/mL. In some
embodiments, the imatinib or salt thereof; a phenylaminopyrimidine
derivative or salt thereof; or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 1.0 mg/mL. In some
embodiments, the imatinib or salt thereof; a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 2.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 4.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 8.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof concentration is greater than about 12.0
mg/mL. In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof concentration is greater than
about 16.0 mg/mL. In some embodiments, the imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof concentration is
greater than about 20.0 mg/mL. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof concentration is
greater than about 50.0 mg/mL. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof concentration is
greater than about 100.0 mg/mL. In some embodiments, the imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof, or
other tyrosine kinase inhibitor or salt thereof solution has a
permeant ion concentration from about 30 mM to about 300 mM. In
some embodiments, the permeant ion is chloride or bromide. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, solution has a pH from about 4.0 to about 8.0. In
some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, solution has an osmolality from
about 100 mOsmol/kg to about 1000 mOsmol/kg. In some embodiments,
the imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
solution has an osmolality from about 50 mOsmol/kg to about 2000
mOsmol/kg. In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, solution has a taste masking
agent. In some embodiments, the taste masking agent is selected
from the group consisting of lactose, sucrose, dextrose, saccharin,
aspartame, sucrulose, ascorbate and citrate. In some embodiments,
the method further comprises administering a mucolytic agent
suitable for pulmonary delivery. In some embodiments, the mucolytic
agent is inhaled separately from the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, solution. In some embodiments,
the method further comprises administering a second anti-fibrotic
or anti-cancer or anti-infective agent suitable for pulmonary
delivery. In some embodiments, the method further comprises
administering a second anti-inflammatory agent suitable for
pulmonary delivery. In some embodiments, the composition may be
co-administered with a second anti-fibrotic or anti-cancer or
anti-infective agent suitable for pulmonary delivery. In some
embodiments, the composition co-administered a second
anti-inflammatory agent suitable for pulmonary delivery.
[0046] In one aspect, described herein is a method to treat an
extrapulmonary disease target comprising inhaling an aerosol
generated from a solution having an imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof concentration greater than about
0.001 mg/mL, having an osmolality greater than about 100 mOsmol/kg,
and having a pH greater than about 4.0. In some embodiments, the
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
concentration is greater than about 0.01 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 0.1 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 0.5 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 1.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 2.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 4.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 8.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof concentration is greater than about 12.0
mg/mL. In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof concentration is greater than
about 16.0 mg/mL. In some embodiments, the imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof concentration is
greater than about 20.0 mg/mL. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof concentration is
greater than about 50.0 mg/mL. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof concentration is
greater than about 100.0 mg/mL. In some embodiments, the imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof
solution has a permeant ion concentration from about 30 mM to about
300 mM. In some embodiments, the permeant ion is chloride or
bromide. In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof solution has a pH from about 4.0
to about 8.0. In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof solution has an osmolality from
about 100 mOsmol/kg to about 1000 mOsmol/kg. In some embodiments,
the imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
solution has an osmolality from about 50 mOsmol/kg to about 2000
mOsmol/kg. In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof solution has a taste masking
agent. In some embodiments, the taste masking agent is selected
from the group consisting of lactose, sucrose, dextrose, saccharin,
aspartame, sucrulose, ascorbate and citrate. In some embodiments,
the method further comprises administering a mucolytic agent
suitable for pulmonary delivery. In some embodiments, the mucolytic
agent is inhaled separately from the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof solution. In some embodiments, the
method further comprises administering a second anti-fibrotic or
anti-cancer or anti-infective agent suitable for pulmonary
delivery. In some embodiments, the method further comprises
administering a second anti-inflammatory agent suitable for
pulmonary delivery. In some embodiments, the extrapulmonary disease
target is the heart. In some embodiments, the extrapulmonary
disease target is white blood cells. In some embodiments, the
extrapulmonary disease target is the bone marrow. In some
embodiments, the extrapulmonary disease target is the kidney. In
some embodiments, the extrapulmonary disease target is the liver.
In some embodiments, the extrapulmonary disease target is the
central nervous system. In some embodiments, the composition may be
co-administered with a second anti-fibrotic or anti-cancer or
anti-infective agent suitable for pulmonary delivery. In some
embodiments, the composition co-administered a second
anti-inflammatory agent suitable for pulmonary delivery.
[0047] In any of the methods described herein using an aerosol or
nebulizer to deliver an imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, compound to the lungs, the
aerosol comprises particles having a mean aerodynamic diameter from
about 1 micron to about 5 microns. In some embodiments, the aerosol
has a mean particle size from about 1 microns to about 5 microns
volumetric mean diameter and a particle size geometric standard
deviation of less than or equal to 3 microns. In some embodiments,
the inhaling step delivers a dose of at least 5 mcg imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the inhaling step delivers a dose of at least 0.001 mg
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof.
In some embodiments, the inhaling step delivers a dose of at least
0.005 mg imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof. In some embodiments, the inhaling step delivers a
dose of at least 0.01 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 0.05 mg imatinib or salt thereof,
a phenylaminopyrimidine derivative or salt thereof, or other
tyrosine kinase inhibitor or salt thereof. In some embodiments, the
inhaling step delivers a dose of at least 0.1 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the inhaling step delivers a dose of at least 0.5 mg
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof.
In some embodiments, the inhaling step delivers a dose of at least
1.0 mg imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt
thereof. In some embodiments, the inhaling step delivers a dose of
at least 2.0 mg imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof. In some embodiments, the inhaling step delivers a
dose of at least 4.0 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 8 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 12 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 16 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 20 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 30 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 40 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 50 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 60 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 70 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 80 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 90 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 100 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 110 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 120 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 130 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 140 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 150 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 160 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 170 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 180 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 190 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 200 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 250 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step is performed in less than about 20 minutes. In some
embodiments, the inhaling step is performed in less than about 10
minutes. In some embodiments, the inhaling step is performed in
less than about 7.5 minutes. In some embodiments, the inhaling step
is performed in less than about 5 minutes. In some embodiments, the
inhaling step is performed in less than about 2.5 minutes. In some
embodiments, the inhaling step is performed in less than about 1.5
minutes. In some embodiments, the inhaling step is performed in
less than about 30 seconds. In some embodiments, the inhaling step
is performed in less than about 5 breaths. In some embodiments, the
inhaling step is performed in less than about 3 breaths. In some
embodiments, the inhaling step is performed in less than about 2
breaths. In some embodiments, the inhaling step is performed in
less than about 1 breaths.
[0048] In one aspect, described herein is a method to treat a
neurologic disease comprising intranasal inhalation of an aerosol
generated from a solution having an imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof concentration greater than about
0.001 mg/mL, having an osmolality greater than about 100 mOsmol/kg,
and having a pH greater than about 4.0. In some embodiments, the
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
concentration is greater than about 0.01 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 0.1 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 0.5 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 1.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 2.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 4.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 8.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof concentration is greater than about 12.0
mg/mL. In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof concentration is greater than
about 16.0 mg/mL. In some embodiments, the imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof concentration is
greater than about 20.0 mg/mL. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof concentration is
greater than about 50.0 mg/mL. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof concentration is
greater than about 100.0 mg/mL. In some embodiments, the imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof
solution has a permeant ion concentration from about 30 mM to about
300 mM. In some embodiments, the permeant ion is chloride or
bromide. In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof solution has a pH from about 4.0
to about 8.0. In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof solution has an osmolality from
about 100 mOsmol/kg to about 1000 mOsmol/kg. In some embodiments,
the imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
solution has an osmolality from about 50 mOsmol/kg to about 2000
mOsmol/kg. In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof solution has a taste masking
agent. In some embodiments, the taste masking agent is selected
from the group consisting of lactose, sucrose, dextrose, saccharin,
aspartame, sucrulose, ascorbate and citrate. In some embodiments,
the method further comprises administering a mucolytic agent
suitable for pulmonary delivery. In some embodiments, the mucolytic
agent is inhaled separately from the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof solution.
[0049] In some embodiments, described herein is a method to
administer an anti-demylination agent to nasal cavity of a patient,
comprising: introducing in a nebulizer a a solution having an
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
concentration greater than about 0.001 mg/mL, having an osmolality
greater than about 100 mOsmol/kg, and having a pH greater than
about 4.0. In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof concentration is greater than
about 0.01 mg/mL. In some embodiments, the imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof concentration is
greater than about 0.1 mg/mL. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof concentration is
greater than about 0.5 mg/mL. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof concentration is
greater than about 1.0 mg/mL. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof concentration is
greater than about 2.0 mg/mL. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof concentration is
greater than about 4.0 mg/mL. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof concentration is
greater than about 8.0 mg/mL. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof
concentration is greater than about 12.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 16.0 mg/mL. In
some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof concentration is greater than
about 20.0 mg/mL. In some embodiments, the imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof concentration is
greater than about 50.0 mg/mL. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof concentration is
greater than about 100.0 mg/mL. In some embodiments, the imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof
solution has a permeant ion concentration from about 30 mM to about
300 mM. In some embodiments, the permeant ion is chloride or
bromide. In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof solution has a pH from about 4.0
to about 8.0. In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof solution has an osmolality from
about 100 mOsmol/kg to about 1000 mOsmol/kg. In some embodiments,
the imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
solution has an osmolality from about 50 mOsmol/kg to about 2000
mOsmol/kg. In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof solution has a taste masking
agent. In some embodiments, the taste masking agent is selected
from the group consisting of lactose, sucrose, dextrose, saccharin,
aspartame, sucrulose, ascorbate and citrate. In some embodiments,
the method further comprises administering a mucolytic agent
suitable for intranasal delivery. In some embodiments, the
mucolytic agent is inhaled separately from the imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, solution. In some
embodiments, the method further comprises administering a second
agent suitable for intranasal delivery. In some embodiments, the
composition may be co-administered with a second anti-fibrotic or
anti-cancer or anti-infective agent suitable for pulmonary
delivery. In some embodiments, the composition may be
co-administered with a second anti-fibrotic or anti-cancer or
anti-infective agent suitable for internasal delivery. In some
embodiments, the composition co-administered a second
anti-inflammatory agent suitable for pulmonary delivery. In some
embodiments, the composition co-administered a second
anti-inflammatory agent suitable for internasal delivery.
[0050] In any of the methods described herein involving introducing
in a nebulizer an imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof solution, the
method involves a step of opening a sterile single-use container
containing between about 0.5 mL to about 10 mL of a solution of
imatinib or salt thereof, or a phenylaminopyrimidine derivative or
salt thereof solution for introduction into a nebulizer.
[0051] In any of the methods described herein involving introducing
in a nebulizer an imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof solution, the method involves a step of opening a
sterile single-use container containing between about 0.01 mL to
about 10 mL of a solution of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, solution for introduction into a
nebulizer.
[0052] In any of the methods described herein involving a
nebulizer, the aerosol comprises particles having a mean
aerodynamic diameter from about 1 micron to about 5 microns. In
some embodiments, the aerosol has a mean particle size from about 1
microns to about 5 microns volumetric mean diameter and a particle
size geometric standard deviation of less than or equal to 3
microns. In some embodiments, the aerosol comprises particles
having a mean aerodynamic diameter from about 1 micron to about 20
microns. In some embodiments, the aerosol has a mean particle size
from about 1 microns to about 20 microns volumetric mean diameter
and a particle size geometric standard deviation of less than or
equal to 3 microns. In some embodiments, the inhaling step delivers
a dose of at least 5 mcg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 0.001 mg imatinib or salt thereof,
a phenylaminopyrimidine derivative or salt thereof, or other
tyrosine kinase inhibitor or salt thereof. In some embodiments, the
inhaling step delivers a dose of at least 0.005 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the inhaling step delivers a dose of at least 0.01 mg
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof.
In some embodiments, the inhaling step delivers a dose of at least
0.05 mg imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof. In some embodiments, the inhaling step delivers a
dose of at least 0.1 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 0.5 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 1.0 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 2.0 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 4.0 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 8 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 12 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 16 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 20 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 30 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 40 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 50 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 60 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 70 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 80 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 90 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 100 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 110 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 120 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 130 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 140 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 150 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 160 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 170 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 180 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 190 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 200 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 250 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step is performed in less than about 20 minutes. In some
embodiments, the inhaling step is performed in less than about 10
minutes. In some embodiments, the inhaling step is performed in
less than about 7.5 minutes. In some embodiments, the inhaling step
is performed in less than about 5 minutes. In some embodiments, the
inhaling step is performed in less than about 2.5 minutes. In some
embodiments, the inhaling step is performed in less than about 1.5
minutes. In some embodiments, the inhaling step is performed in
less than about 30 seconds. In some embodiments, the inhaling step
is performed in less than about 5 breaths. In some embodiments, the
inhaling step is performed in less than about 3 breaths. In some
embodiments, the inhaling step is performed in less than about 2
breaths. In some embodiments, the inhaling step is performed in
less than about 1 breaths.
[0053] In one aspect, provided herein is a kit comprising: a
pharmaceutical composition comprising an imatinib or salt thereof,
a phenylaminopyrimidine derivative or salt thereof, or other
tyrosine kinase inhibitor or salt thereof solution in a sterile
container, wherein the solution has an imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof concentration greater than about
0.001 mg/mL, having an osmolality greater than about 100 mOsmol/kg,
and having a pH greater than about 4.0. In some embodiments, the
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
concentration is greater than about 0.01 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 0.1 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 0.5 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 1.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 2.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 4.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 8.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof concentration is greater than about 12.0
mg/mL. In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof concentration is greater than
about 16.0 mg/mL. In some embodiments, the imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof concentration is
greater than about 20.0 mg/mL. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof concentration is
greater than about 50.0 mg/mL. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof concentration is
greater than about 100.0 mg/mL. In some embodiments, the imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof
solution has a permeant ion concentration from about 30 mM to about
300 mM. In some embodiments, the permeant ion is chloride or
bromide. In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof solution has a pH from about 4.0
to about 8.0. In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof solution has an osmolality from
about 100 mOsmol/kg to about 1000 mOsmol/kg. In some embodiments,
the imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
solution has an osmolality from about 50 mOsmol/kg to about 2000
mOsmol/kg. In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof solution has a taste masking
agent. In some embodiments, the taste masking agent is selected
from the group consisting of lactose, sucrose, dextrose, saccharin,
aspartame, sucrulose, ascorbate and citrate. In some embodiments,
the kit further comprises a mucolytic agent suitable for pulmonary
delivery. In some embodiments, the kit further comprises a second
anti-fibrotic or anti-cancer or anti-infective agent suitable for
pulmonary delivery. In some embodiments, the kit further comprises
a second anti-inflammatory agent suitable for pulmonary delivery.
In some embodiments, the composition may be co-administered with a
second anti-fibrotic or anti-cancer or anti-infective agent
suitable for pulmonary delivery. In some embodiments, the
composition co-administered a second anti-inflammatory agent
suitable for pulmonary delivery.
[0054] In another aspect, provided herein is a kit comprising: a
pharmaceutical composition comprising an imatinib or salt thereof,
a phenylaminopyrimidine derivative or salt thereof, or other
tyrosine kinase inhibitor or salt thereof, solution in a sterile
container, wherein the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, solution has a concentration
greater than about 0.001 mg/mL, an osmolality greater than about
100 mOsmol/kg, and a pH greater than about 4.0, and a nebulizer
adapted to aerosolize the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, solution for delivery to the
nasal cavity through intranasal inhalation.
[0055] In some embodiments, the solution has an imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof concentration
greater than about 0.1 mg/mL, having an osmolality greater than
about 100 mOsmol/kg, and having a pH greater than about 4.0. In
some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof concentration greater than about
0.001 mg/mL, having an osmolality greater than about 100 mOsmol/kg,
and having a pH greater than about 4.0. In some embodiments, the
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
concentration is greater than about 0.01 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 0.1 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 0.5 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 1.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 2.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 4.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is greater than about 8.0 mg/mL. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof concentration is greater than about 12.0
mg/mL. In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof concentration is greater than
about 16.0 mg/mL. In some embodiments, the imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof concentration is
greater than about 20.0 mg/mL. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof concentration is
greater than about 50.0 mg/mL. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof concentration is
greater than about 100.0 mg/mL. In some embodiments, the imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof
solution has a permeant ion concentration from about 30 mM to about
300 mM. In some embodiments, the permeant ion is chloride or
bromide. In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof solution has a pH from about 4.0
to about 8.0. In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof solution has an osmolality from
about 100 mOsmol/kg to about 1000 mOsmol/kg. In some embodiments,
the imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
solution has an osmolality from about 50 mOsmol/kg to about 2000
mOsmol/kg. In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof solution has a taste masking
agent. In some embodiments, the taste masking agent is selected
from the group consisting of lactose, sucrose, dextrose, saccharin,
aspartame, sucrulose, ascorbate and citrate. In some embodiments,
the kit further comprises a mucolytic agent suitable for intranasal
delivery. In some embodiments, the kit further comprises a second
anti-fibrotic or anti-cancer or anti-infective agent suitable for
intranasal delivery. In some embodiments, the kit further comprises
a second anti-inflammatory agent suitable for intranasal delivery.
In some embodiments, the composition may be co-administered with a
second anti-fibrotic or anti-cancer or anti-infective agent
suitable for pulmonary delivery. In some embodiments, the
composition co-administered a second anti-inflammatory agent
suitable for pulmonary delivery.
[0056] In one aspect, described herein is a method for treating
lung disease, comprising administering imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, to a middle to lower respiratory
tract of a subject having or suspected of having interstitial lung
disease through oral inhalation of an aerosol comprising imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof,
wherein the disease is selected from interstitial lung disease,
including idiopathic pulmonary fibrosis and radiation
therapy-induced fibrosis. In some embodiments, the subject is
identified as having interstitial lung disease. In some
embodiments, the subject is identified as having idiopathic
pulmonary fibrosis. In some embodiments, the subject is identified
as having radiation therapy-induced pulmonary fibrosis. In some
embodiments, the subject is a subject being mechanically
ventilated.
[0057] In one aspect, described herein is a method for treating
lung disease, comprising administering imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, to a middle to lower respiratory
tract of a subject having or suspected of having vascular lung
disease through oral inhalation of an aerosol comprising imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof,
wherein the disease is selected from vascular lung disease,
including pulmonary hypertension. In some embodiments, the subject
is identified as having vascular lung disease. In some embodiments,
the subject is identified as having pulmonary hypertension. In some
embodiments, the subject is identified as having portopulmonary
hypertension. In some embodiments, the subject is a subject being
mechanically ventilated.
[0058] In one aspect, described herein is a method for treating
lung disease, comprising administering imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, to a middle to lower respiratory
tract of a subject having or suspected of having pulmonary disease
through oral inhalation of an aerosol comprising imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, wherein the
pulmonary disease is cancer. In some embodiments, the pulmonary
cancer is small cell lung cancer. In some embodiments, the
pulmonary cancer is large cell carcinoma. In some embodiments, the
pulmonary cancer is mesothelioma. In some embodiments, the
pulmonary cancer is lung carcinoid tumors or bronchial cardinoids.
In some embodiments, the pulmonary cancer is secondary lung cancer
resulting from metastatic disease. In some embodiments, the
pulmonary cancer is non-small cell lung cancer. In some
embodiments, the pulmonary cancer is bronchioloalveolar carcinoma.
In some embodiments, the pulmonary cancer may be sarcoma. In some
embodiments, the pulmonary cancer is may be a lymphoma. In some
embodiments, the subject is a subject being mechanically
ventilated.
[0059] In one aspect, described herein is a method for treating
lung disease, comprising administering imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, to a middle to lower respiratory
tract of a subject having or suspected of having pulmonary disease
through oral inhalation of an aerosol comprising imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, wherein the
pulmonary disease is cancer. In some embodiments, the therapeutic
target for said pulmonary cancer is tumor stroma. In some
embodiments, the subject is a subject being mechanically
ventilated.
[0060] In one aspect, described herein is a method for treating
lung disease, comprising administering imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, to a middle to lower respiratory
tract of a subject having or suspected of having pulmonary disease
through oral inhalation of an aerosol comprising imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, wherein the
pulmonary disease is pulmonary hypertension. In some embodiments,
the subject is a subject being mechanically ventilated.
[0061] A method for treating extrapulmonary disease, comprising
administering imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, to a middle to lower respiratory tract of a subject
having or suspected of having extrapulmonary cancer through oral
inhalation of an aerosol comprising imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, for purposes of pulmonary
vascular absorption and delivery to extrapulmonary diseased
tissues, wherein the disease is selected from regional cancers
including leukemia and lymphoma. In some embodiments, the subject
is identified as having chronic myloid leukemia (CML). In some
embodiments, the subject is identified as having gastrointestinal
stromal tumors (GIST). In some embodiments, the subject is
identified as having relapsed or refractory Ph-positive Acute
lymphoblastic leukemia (ALL). In some embodiments, the subject is
identified as having myelodysplastic/myeloproliferative diseases
associated with platelet-derived growth factor receptor gene
re-arrangements. In some embodiments, the subject is identified as
having aggressive systemic mastocytosis (ASM) without or an unknown
D816V c-KIT mutation. In some embodiments, the subject is a subject
being mechanically ventilated. In some embodiments, the subject is
identified as having hypereosinophilic syndrome (HES) and/or
chronic eosinophilic leukemia (CEL) who have the
FIP1L1-PDGFR.alpha. fusion kinase (CHIC2 allele deletion) or
FIP1L1-PDGFR-alpha fusion kinase negative or unknown. In some
embodiments, the subject is identified as having unresectable,
recurrent and/or metastatic dermatofibrosarcoma protuberans.
[0062] A method for treating extrapulmonary disease, comprising
administering imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, to a middle to lower respiratory tract of a subject
having or suspected of having extrapulmonary fibrosis, inflammatory
and/or toxicity-related diseases through oral inhalation of an
aerosol comprising imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, for purposes of pulmonary
vascular absorption and delivery to extrapulmonary diseased
tissues, wherein the disease is selected from cardiac fibrosis,
kidney fibrosis, hepatic fibrosis, kidney toxicity and heart
toxicity. In some embodiments, the subject is identified as having
cardiac fibrosis. In some embodiments, the subject is identified as
having kidney fibrosis. In some embodiments, the subject is
identified as having hepatic fibrosis. In some embodiments, the
subject is identified as having kidney toxicity. In some
embodiments, the subject is identified as having heart toxicity. In
some embodiments, the subject is identified as having
atherosclerosis. In some embodiments, the subject is a subject
being mechanically ventilated.
[0063] A method for treating infectious disease, comprising
administering imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, to a middle to lower respiratory tract of a subject
having or suspected of having an infection through oral inhalation
of an aerosol comprising imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, for purposes of pulmonary
exposure and or pulmonary vascular absorption and delivery to
extrapulmonary diseased tissues, wherein the disease is selected
from viral infections. In some embodiments, the subject is
identified as having small pox. In some embodiments, the subject is
identified as having cytomegalovirus (CMV). In some embodiments,
the subject is identified as having varicella-zoster virus (VZV).
In some embodiments, the subject is identified as having human
immunodeficiency virus (HIV). In some embodiments, the subject is
identified as having herpes simplex virus (HSV). In some
embodiments, the subject is identified as having influenza virus.
In some embodiments, the subject is identified as having
polyomavirus BK (BKV). In some embodiments, the subject is
identified as having measles virus. In some embodiments, the
subject is identified as having mumps virus. In some embodiments,
the subject is identified as having rubella virus. In some
embodiments, the subject is identified as having polio virus. In
some embodiments, the subject is identified as having West Nile
Virus. In some embodiments, the subject is identified as having
Lyme disease. In some embodiments, the subject is identified as
having Subacute sclerosing panencephalitis. In some embodiments,
the subject is identified as having Progressive multifocal
leukoencephalopathy. In some embodiments, the subject is identified
as having meningitis. In some embodiments, the subject is
identified as having encephalitis. In some embodiments, the subject
is identified as having acute flaccid paralysis. In some
embodiments, the subject is identified as having polio virus. In
some embodiments, the subject is identified as having
poliomyelitis. In some embodiments, the subject is identified as
having Herpes simplex encephalitis. In some embodiments, the
subject is identified as having Enteroviral disease. In some
embodiments, the subject is identified as having lyme meningitis.
In some embodiments, the subject is identified as having Eastern
equine encephalitis. In some embodiments, the subject is identified
as having Western equine encephalitis. In some embodiments, the
subject is identified as having St. Louis encephalitis. In some
embodiments, the subject is identified as having rabies. In some
embodiments, the subject is identified as having La crosse
encephalitis. In some embodiments, the subject is identified as
having progressive rubella panencephalitis. In some embodiments,
the subject is identified as having varicella-zoster encephalitis.
In some embodiments, the subject is identified as having acute
measles encephalitis. In some embodiments, the subject is
identified as having mumps meningoencephalitis. In some
embodiments, the subject is a subject being mechanically
ventilated.
[0064] A method for treating infectious disease, comprising
administering imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof to the oral or nasal cavity of a subject having or
suspected of having neurologic infection through oral or intranasal
inhalation of an aerosol comprising imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, tyrosine kinase inhibitor or salt
thereof for purposes of pulmonary or nasal vascular absorption and
delivery to central nervous system, wherein the disease is selected
from viral infection. In some embodiments, the subject is
identified as having cytomegalovirus (CMV). In some embodiments,
the subject is identified as having varicella-zoster virus (VZV).
In some embodiments, the subject is identified as having human
immunodeficiency virus (HIV). In some embodiments, the subject is
identified as having herpes simplex virus (HSV). In some
embodiments, the subject is identified as having influenza virus.
In some embodiments, the subject is identified as having
polyomavirus BK (BKV). In some embodiments, the subject is
identified as having measles virus. In some embodiments, the
subject is identified as having mumps virus. In some embodiments,
the subject is identified as having rubella virus. In some
embodiments, the subject is identified as having polio virus. In
some embodiments, the subject is identified as having West Nile
Virus. In some embodiments, the subject is identified as having
Lyme disease. In some embodiments, the subject is identified as
having Subacute sclerosing panencephalitis. In some embodiments,
the subject is identified as having Progressive multifocal
leukoencephalopathy. In some embodiments, the subject is identified
as having meningitis. In some embodiments, the subject is
identified as having encephalitis. In some embodiments, the subject
is identified as having acute flaccid paralysis. In some
embodiments, the subject is identified as having polio virus. In
some embodiments, the subject is identified as having
poliomyelitis. In some embodiments, the subject is identified as
having Herpes simplex encephalitis. In some embodiments, the
subject is identified as having Enteroviral disease. In some
embodiments, the subject is identified as having lyme meningitis.
In some embodiments, the subject is identified as having Eastern
equine encephalitis. In some embodiments, the subject is identified
as having Western equine encephalitis. In some embodiments, the
subject is identified as having St. Louis encephalitis. In some
embodiments, the subject is identified as having rabies. In some
embodiments, the subject is identified as having La crosse
encephalitis. In some embodiments, the subject is identified as
having progressive rubella panencephalitis. In some embodiments,
the subject is identified as having varicella-zoster encephalitis.
In some embodiments, the subject is identified as having acute
measles encephalitis. In some embodiments, the subject is
identified as having mumps meningoencephalitis. In some
embodiments, the subject is a subject being mechanically
ventilated. In one aspect, described herein is a method for
treating neurologic disease, comprising administering imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof, to the oral or
nasal cavity of a subject having or suspected of having neurologic
disease through oral or intranasal inhalation of an aerosol
comprising imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, for purposes of pulmonary or nasal vascular
absorption and delivery to central nervous system, wherein the
disease is multiple sclerosis. In some embodiments, the subject is
identified as having multiple sclerosis. In some embodiments, the
subject is a subject being mechanically ventilated.
[0065] In one aspect, described herein is a method for treating
neurologic disease, comprising administering imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, to the oral or
nasal cavity of a subject having or suspected of having neurologic
disease through oral or intranasal inhalation of an aerosol
comprising imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, for purposes of pulmonary or nasal vascular
absorption and delivery to central nervous system, wherein the
disease is neurofibromatosis. In some embodiments, the subject is
identified as having neurofibromatosis type I. In some embodiments,
the subject is identified as having Alzheimer's disease. In some
embodiments, the subject is identified as having opiod tolerance.
In some embodiments, the subject is identified as having desmoid
tumor. In some embodiments, the subject is a subject being
mechanically ventilated.
[0066] In one aspect, described herein is a pharmaceutical
composition for pulmonary delivery, comprising a dry powder
containing imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, having a dosage content greater than about 1%. In
some embodiments, the dose content is at least 0.005 mg imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 0.01 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 0.05 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 0.1 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 0.5 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 1.0 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 2.0 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 4.0 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 8 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 12 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 16 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 20 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 30 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 40 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 50 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 60 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 70 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 80 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 90 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 100 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 110 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 120 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 130 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 140 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 150 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 160 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 170 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 180 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 190 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 200 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the content may be administered in one more doses. In
some embodiments, the powder may be delivered neat. In some
embodiments, the powder further comprises a carrier agent. In some
embodiments, the carrier agent is selected from the group
consisting of lactose.
[0067] Efficient drug delivery to the lungs through dry powder
inhalers (DPIs) is dependent on several factors including inhaler
device, formulation, and inhalation manoeuvre. Preparing ideal DPI
formulations requires control overall formulation characteristics
at particulate and bulk level to ensure the drug delivery to lower
airway regions. In DPI formulations, it is customary to blend
micronized drug particles (less than 5 micron in size) with larger
carrier particles to address flowability and dose variability
issues. The typical concentration of drug in drug-carrier DPI
formulations is low (e.g. 1 drug: 67.5 carrier), but can vary
depending on the aerosol dispersion properties of the formulation.
Therefore, during drug-carrier mixing, drug particles will
preferably adhere to the active binding sites (more adhesive areas)
on the carrier surface and expected to separate from carrier
surface upon inhalation. Drug re-dispersion is considered most
important for getting drug particles into deep lung airway regions.
Usually, only small amounts of drug reaches the lower airway
regions due to strong drug-carrier adhesion. Indeed, drug
re-dispersion is a function of balance between cohesive forces
(between the drug particles) and the adhesive forces (between drug
and carrier particles). In order to aerosolise drug particles,
patient inspiratory force should overcome drug-carrier adhesive
forces which are dependent on physicochemical properties of both
drug particles and carrier particles. Consequently, the
characteristics of carrier particles must be well-controlled in
terms of size, morphology, crystal form, surface energy, etc. It
has been reported that the differences in carrier particle size is
likely to have significant impact on DPI aerosolisation
performance. The presence of fine particles on carrier surface may
decrease the drug-carrier contact area and consequently
drug-carrier adhesion forces leading to improved DPI performance.
Better aerosolisation performance was observed when the carrier tap
density was higher, whereas no correlation was found between
carrier flowability and DPI performance. Carriers with reduced
dispersive surface energy produced higher fine particle fraction
(FPF) of the drug upon aerosolisation. Carrier particles with
higher elongation ratio or increased surface roughness showed
favorable inhalation properties.
[0068] In one aspect, described herein is a pharmaceutical
composition for pulmonary delivery, comprising a dry powder
containing imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof having a dosage content greater than about 1%. In yet
another aspect, described herein is a single-use container
comprising from about 0.01 mg to about 100 mg dry powder containing
imatinib or salt thereof, or a phenylaminopyrimidine derivative or
salt thereof having a dosage content greater than about 1%. In yet
another aspect, described herein is a single-use container
comprising from about 0.001 mg to about 200 mg dry powder
containing imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, having a dosage content greater than about 1%. In a
further aspect, described is a method to treat a pulmonary disease
comprising inhalation of a dry powder aerosol containing imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof, dosage
content greater than about 1%. In some embodiments, the dose
content is at least 0.005 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 0.01 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 0.05 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 0.1 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 0.5 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 1.0 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 2.0 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 4.0 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 8 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 12 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 16 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 20 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 30 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 40 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 50 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 60 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 70 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 80 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 90 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 100 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 110 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 120 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 130 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 140 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 150 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 160 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 170 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 180 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 190 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 200 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dry
powder further comprises a carrier agent. In some embodiments, the
carrier agent is lactose.
[0069] In one aspect, described herein is a method for treating
pulmonary disease, comprising administering imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, to a middle to
lower respiratory tract of a subject having or suspected of having
interstitial lung disease through oral inhalation of a dry powder
aerosol comprising imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, having a dosage content greater
than about 1%. In yet another aspect, described herein is a
single-use container comprising from about 0.01 mg to about 100 mg
dry powder containing imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof having dosage
content greater than about 1%. In yet another aspect, described
herein is a single-use container comprising from about 0.001 mg to
about 200 mg dry powder containing imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, having dosage content greater
than about 1%. In some embodiments, the pulmonary disease is
interstitial lung disease. In some embodiments, the interstitial
lung disease is idiopathic pulmonary fibrosis. In some embodiments,
the interstitial lung disease is radiation-therapy-induced
pulmonary fibrosis. In some embodiments, the pulmonary disease is
chronic bronchitis. In some embodiments, the dry powder aerosol
comprises particles having a mean aerodynamic diameter from about 1
micron to about 5 microns. In some embodiments, the aerosol has a
mean particle size from about 1 microns to about 5 microns
volumetric mean diameter and a particle size geometric standard
deviation of less than or equal to 3 microns. In some embodiments,
the dose content is at least 0.005 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 0.01 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 0.05 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 0.1 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 0.5 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 1.0 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 2.0 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 4.0 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 8 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 12 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 16 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 20 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 30 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 40 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 50 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 60 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 70 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 80 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 90 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 100 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 110 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 120 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 130 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 140 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 150 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 160 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 170 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 180 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 190 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the dose
content is at least 200 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step is performed in less than about 5 breaths. In some
embodiments, the inhaling step is performed in less than about 3
breaths. In some embodiments, the inhaling step is performed in
less than about 2 breaths. In some embodiments, the inhaling step
is performed in one breath.
In one aspect, provided herein is a method to administer an
anti-fibrotic agent to lungs of a subject, comprising: introducing
in a dry powder inhaler an imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, dry powder formulation having a
dosage content greater than about 1%. In yet another aspect,
provided herein is a method to treat an extrapulmonary disease
target comprising inhalation of a dry powder aerosol containing
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
dosage content greater than about 1%. In some embodiments, the
extrapulmonary disease target is the heart. In some embodiments,
the extrapulmonary disease target is the kidney. In some
embodiments, the extrapulmonary disease target is the liver. In
some embodiments, the extrapulmonary disease target is white blood
cells. In some embodiments, the extrapulmonary disease target is
bone marrow. In yet another aspect, provided herein is a method to
treat a neurologic disease comprising oral or intranasal inhalation
of a dry powder aerosol containing imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, dosage content greater than about
1%. In some embodiments, the neurologic disease is multiple
sclerosis. In yet another aspect, provided herein is a method to
administer an anti-demylination agent to nasal cavity of a subject,
comprising: introducing in a dry powder inhaler an imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, dry powder
formulation having a dosage content greater than about 1%. In some
embodiments, the dose content is at least 0.005 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 0.01 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 0.05 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 0.1 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 0.5 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 1.0 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 2.0 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 4.0 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 8 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 12 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 16 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 20 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 30 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 40 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 50 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 60 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 70 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 80 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 90 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 100 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 110 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 120 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 130 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 140 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 150 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 160 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 170 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 180 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 190 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 200 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dry powder comprises a carrier agent. In some
embodiments, the carrier agent is lactose. In some embodiments, the
aerosol comprises particles having a mean aerodynamic diameter from
about 1 micron to about 5 microns. In some embodiments, the aerosol
has a mean particle size from about 1 microns to about 5 microns
volumetric mean diameter and a particle size geometric standard
deviation of less than or equal to 3 microns. In some embodiments,
the aerosol comprises particles having a mean aerodynamic diameter
from about 1 micron to about 20 microns. In some embodiments, the
aerosol has a mean particle size from about 1 microns to about 20
microns volumetric mean diameter and a particle size geometric
standard deviation of less than or equal to 3 microns. In some
embodiments, the inhaling step delivers a dose of at least 0.001 mg
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof.
In some embodiments, the inhaling step delivers a dose of at least
0.005 mg imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof. In some embodiments, the inhaling step delivers a
dose of at least 0.01 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 0.05 mg imatinib or salt thereof,
a phenylaminopyrimidine derivative or salt thereof, or other
tyrosine kinase inhibitor or salt thereof. In some embodiments, the
inhaling step delivers a dose of at least 0.1 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the inhaling step delivers a dose of at least 0.5 mg
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof.
In some embodiments, the inhaling step delivers a dose of at least
1.0 mg imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt
thereof. In some embodiments, the inhaling step delivers a dose of
at least 2.0 mg imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof. In some embodiments, the inhaling step delivers a
dose of at least 4.0 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 8 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 12 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 16 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 20 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 30 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 40 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 50 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 60 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 70 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 80 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 90 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 100 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 110 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 120 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 130 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 140 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 150 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 160 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 170 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 180 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 190 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step delivers a dose of at least 200 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In some embodiments, the inhaling
step is performed in less than about 5 breaths. In some
embodiments, the inhaling step is performed in less than about 3
breaths. In some embodiments, the inhaling step is performed in
less than about 2 breaths. In some embodiments, the inhaling step
is performed in one breath. In some embodiments, the method further
comprises the step of opening a single-use dry powder container
holding between about 0.01 mg to about 100 mg dry powder
formulation containing imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof for introduction
into a dry powder inhaler. In some embodiments, the method further
comprises the step of opening a single-use dry powder container
holding between about 0.001 mg to about 200 mg dry powder
formulation containing imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof for introduction into a dry powder
inhaler.
[0071] In one aspect, described herein is a method for treating
lung disease, comprising administering imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, to a middle to lower respiratory
tract of a subject having or suspected of having vascular lung
disease through oral inhalation of a dry powder aerosol comprising
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
wherein the disease is selected from vascular lung disease,
including pulmonary hypertension. In some embodiments, the subject
is identified as having vascular lung disease. In some embodiments,
the subject is identified as having pulmonary hypertension. In some
embodiments, the subject is identified as having portopulmonary
hypertension. In some embodiments, the subject is a subject being
mechanically ventilated.
[0072] In one aspect, described herein is a method for treating
lung disease, comprising administering imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, to a middle to lower respiratory
tract of a subject having or suspected of having pulmonary disease
through oral inhalation of a dry powder aerosol comprising imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof,
wherein the pulmonary disease is cancer. In some embodiments, the
pulmonary cancer is small cell lung cancer. In some embodiments,
the pulmonary cancer is large cell carcinoma. In some embodiments,
the pulmonary cancer is mesothelioma. In some embodiments, the
pulmonary cancer is lung carcinoid tumors or bronchial cardinoids.
In some embodiments, the pulmonary cancer is secondary lung cancer
resulting from metastatic disease. In some embodiments, the
pulmonary cancer is non-small cell lung cancer. In some
embodiments, the pulmonary cancer is bronchioloalveolar carcinoma.
In some embodiments, the pulmonary cancer may be sarcoma. In some
embodiments, the pulmonary cancer is may be a lymphoma. In some
embodiments, the subject is a subject being mechanically
ventilated.
[0073] A method for treating extrapulmonary disease, comprising
administering imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, to a middle to lower respiratory tract of a subject
having or suspected of having extrapulmonary cancer through oral
inhalation of a dry powder aerosol comprising imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, for purposes of
pulmonary vascular absorption and delivery to extrapulmonary
diseased tissues, wherein the disease is selected from regional
cancers including leukemia and lymphoma. In some embodiments, the
subject is identified as having chronic myloid leukemia (CML). In
some embodiments, the subject is identified as having
gastrointestinal stromal tumors (GIST). In some embodiments, the
subject is identified as having relapsed or refractory Ph-positive
acute lymphoblastic leukemia (ALL). In some embodiments, the
subject is identified as having myelodysplastic/myeloproliferative
diseases associated with platelet-derived growth factor receptor
gene re-arrangements. In some embodiments, the subject is
identified as having aggressive systemic mastocytosis (ASM) without
or an unknown D816V c-KIT mutation. In some embodiments, the
subject is a subject being mechanically ventilated. In some
embodiments, the subject is identified as having hypereosinophilic
syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have
the FIP1L1-PDGFR.alpha. fusion kinase (CHIC2 allele deletion) or
FIP1L1-PDGFR-alpha fusion kinase negative or unknown. In some
embodiments, the subject is identified as having unresectable,
recurrent and/or metastatic dermatofibrosarcoma protuberans.
[0074] A method for treating extrapulmonary disease, comprising
administering imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, to a middle to lower respiratory tract of a subject
having or suspected of having extrapulmonary fibrosis, inflammatory
and/or toxicity-related diseases through oral inhalation of a dry
powder aerosol comprising imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, for purposes of pulmonary
vascular absorption and delivery to extrapulmonary diseased
tissues, wherein the disease is selected from cardiac fibrosis,
kidney fibrosis, hepatic fibrosis, kidney toxicity and heart
toxicity. In some embodiments, the subject is identified as having
cardiac fibrosis. In some embodiments, the subject is identified as
having kidney fibrosis. In some embodiments, the subject is
identified as having hepatic fibrosis. In some embodiments, the
subject is identified as having kidney toxicity. In some
embodiments, the subject is identified as having heart toxicity. In
some embodiments, the subject is identified as having
atherosclerosis. In some embodiments, the subject is a subject
being mechanically ventilated.
[0075] A method for treating infectious disease, comprising
administering imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, to a middle to lower respiratory tract of a subject
having or suspected of having an infection through oral inhalation
of a dry powder aerosol comprising imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, for purposes of pulmonary
exposure and or pulmonary vascular absorption and delivery to
extrapulmonary diseased tissues, wherein the disease is selected
from viral infections. In some embodiments, the subject is
identified as having small pox. In some embodiments, the subject is
identified as having cytomegalovirus (CMV). In some embodiments,
the subject is identified as having varicella-zoster virus (VZV).
In some embodiments, the subject is identified as having human
immunodeficiency virus (HIV). In some embodiments, the subject is
identified as having herpes simplex virus (HSV). In some
embodiments, the subject is identified as having influenza virus.
In some embodiments, the subject is identified as having
polyomavirus BK (BKV). In some embodiments, the subject is
identified as having measles virus. In some embodiments, the
subject is identified as having mumps virus. In some embodiments,
the subject is identified as having rubella virus. In some
embodiments, the subject is identified as having polio virus. In
some embodiments, the subject is identified as having West Nile
Virus. In some embodiments, the subject is identified as having
Lyme disease. In some embodiments, the subject is identified as
having Subacute sclerosing panencephalitis. In some embodiments,
the subject is identified as having Progressive multifocal
leukoencephalopathy. In some embodiments, the subject is identified
as having meningitis. In some embodiments, the subject is
identified as having encephalitis. In some embodiments, the subject
is identified as having acute flaccid paralysis. In some
embodiments, the subject is identified as having polio virus. In
some embodiments, the subject is identified as having
poliomyelitis. In some embodiments, the subject is identified as
having Herpes simplex encephalitis. In some embodiments, the
subject is identified as having Enteroviral disease. In some
embodiments, the subject is identified as having lyme meningitis.
In some embodiments, the subject is identified as having Eastern
equine encephalitis. In some embodiments, the subject is identified
as having Western equine encephalitis. In some embodiments, the
subject is identified as having St. Louis encephalitis. In some
embodiments, the subject is identified as having rabies. In some
embodiments, the subject is identified as having La crosse
encephalitis. In some embodiments, the subject is identified as
having progressive rubella panencephalitis. In some embodiments,
the subject is identified as having varicella-zoster encephalitis.
In some embodiments, the subject is identified as having acute
measles encephalitis. In some embodiments, the subject is
identified as having mumps meningoencephalitis. In some
embodiments, the subject is a subject being mechanically
ventilated.
[0076] A method for treating infectious disease, comprising
administering imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, to the oral or nasal cavity of a subject having or
suspected of having neurologic infection through oral or intranasal
inhalation of a dry powder aerosol comprising imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, for purposes of
pulmonary or nasal vascular absorption and delivery to central
nervous system, wherein the disease is selected from viral
infection. In some embodiments, the subject is identified as having
cytomegalovirus (CMV). In some embodiments, the subject is
identified as having varicella-zoster virus (VZV). In some
embodiments, the subject is identified as having human
immunodeficiency virus (HIV). In some embodiments, the subject is
identified as having herpes simplex virus (HSV). In some
embodiments, the subject is identified as having influenza virus.
In some embodiments, the subject is identified as having
polyomavirus BK (BKV). In some embodiments, the subject is
identified as having measles virus. In some embodiments, the
subject is identified as having mumps virus. In some embodiments,
the subject is identified as having rubella virus. In some
embodiments, the subject is identified as having polio virus. In
some embodiments, the subject is identified as having West Nile
Virus. In some embodiments, the subject is identified as having
Lyme disease. In some embodiments, the subject is identified as
having Subacute sclerosing panencephalitis. In some embodiments,
the subject is identified as having Progressive multifocal
leukoencephalopathy. In some embodiments, the subject is identified
as having meningitis. In some embodiments, the subject is
identified as having encephalitis. In some embodiments, the subject
is identified as having acute flaccid paralysis. In some
embodiments, the subject is identified as having polio virus. In
some embodiments, the subject is identified as having
poliomyelitis. In some embodiments, the subject is identified as
having Herpes simplex encephalitis. In some embodiments, the
subject is identified as having Enteroviral disease. In some
embodiments, the subject is identified as having lyme meningitis.
In some embodiments, the subject is identified as having Eastern
equine encephalitis. In some embodiments, the subject is identified
as having Western equine encephalitis. In some embodiments, the
subject is identified as having St. Louis encephalitis. In some
embodiments, the subject is identified as having rabies. In some
embodiments, the subject is identified as having La crosse
encephalitis. In some embodiments, the subject is identified as
having progressive rubella panencephalitis. In some embodiments,
the subject is identified as having varicella-zoster encephalitis.
In some embodiments, the subject is identified as having acute
measles encephalitis. In some embodiments, the subject is
identified as having mumps meningoencephalitis. In some
embodiments, the subject is a subject being mechanically
ventilated. In one aspect, described herein is a method for
treating neurologic disease, comprising administering imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof, to the oral or
nasal cavity of a subject having or suspected of having neurologic
disease through oral or intranasal inhalation of an aerosol
comprising imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, for purposes of pulmonary or nasal vascular
absorption and delivery to central nervous system, wherein the
disease is multiple sclerosis. In some embodiments, the subject is
identified as having multiple sclerosis. In some embodiments, the
subject is a subject being mechanically ventilated.
[0077] In one aspect, described herein is a method for treating
neurologic disease, comprising administering imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof to the oral or
nasal cavity of a subject having or suspected of having neurologic
disease through oral or intranasal inhalation of a dry powder
aerosol comprising imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, for purposes of pulmonary or
nasal vascular absorption and delivery to central nervous system,
wherein the disease is neurofibromatosis. In some embodiments, the
subject is identified as having neurofibromatosis type I. In some
embodiments, the subject is identified as having Alzheimer's
disease. In some embodiments, the subject is identified as having
opiod tolerance. In some embodiments, the subject is identified as
having desmoid tumor. In some embodiments, the subject is a subject
being mechanically ventilated.
[0078] In one aspect, described herein is a kit comprising: a
pharmaceutical composition comprising a dry powder imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, formulation in a
container, wherein the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, dosage content is greater than
about 1%; and a dry powder inhaler adapted to aerosolize the
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
dry powder formulation for delivery to the middle to lower
respiratory tract through oral inhalation. In another aspect,
described herein is a kit comprising: a pharmaceutical composition
comprising a dry powder imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, formulation in a container,
wherein the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, dosage content is greater than about 1%, and a dry
powder inhaler adapted to aerosolize the imatinib or salt thereof,
a phenylaminopyrimidine derivative or salt thereof, or other
tyrosine kinase inhibitor or salt thereof, dry powder formulation
for delivery to the nasal cavity through intranasal inhalation. In
some embodiments, the dose content is at least 0.005 mg imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 0.01 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 0.05 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 0.1 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 0.5 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 1.0 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 2.0 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 4.0 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 8 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 12 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 16 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 20 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 30 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 40 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 50 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 60 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 70 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 80 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 90 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 100 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 110 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 120 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 130 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 140 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 150 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 160 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 170 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 180 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 190 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the dose content is at least 200 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the powder further comprises a carrier agent. In some
embodiments, the carrier agent is lactose.
[0079] In one aspect, described herein is a method for treating
lung disease, comprising administering imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, to a middle to lower respiratory
tract of a subject having or suspected of having interstitial lung
disease through oral inhalation of an aerosol comprising imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof,
wherein the disease is selected from interstitial lung disease,
including idiopathic pulmonary fibrosis and radiation
therapy-induced fibrosis. In some embodiments, the subject is
identified as having interstitial lung disease. In some
embodiments, the subject is identified as having idiopathic
pulmonary fibrosis. In some embodiments, the subject is identified
as having radiation therapy-induced pulmonary fibrosis. In some
embodiments, the subject is identified as having chronic
bronchitis. In some embodiments, the subject is a subject being
mechanically ventilated.
[0080] In one aspect, described herein is a method for treating
extrapulmonary disease, comprising administering imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, to a middle to
lower respiratory tract of a subject having or suspected of having
extrapulmonary fibrosis, inflammatory and/or toxicity-related
diseases through oral inhalation of an aerosol comprising imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof, for
purposes of pulmonary vascular absorption and delivery to
extrapulmonary diseased tissues, wherein the disease is selected
from cardiac fibrosis, kidney fibrosis, hepatic fibrosis, kidney
toxicity and heart toxicity.
[0081] In some embodiments, the subject is identified as having
cardiac fibrosis. In some embodiments, the subject is identified as
having kidney fibrosis. In some embodiments, the subject is
identified as having hepatic fibrosis. In some embodiments, the
subject is identified as having kidney toxicity. In some
embodiments, the subject is identified as having heart toxicity. In
some embodiments, the subject is a subject being mechanically
ventilated.
[0082] In one aspect, described herein is a method for treating
neurologic disease, comprising administering imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof, to the nasal
cavity of a subject having or suspected of having neurologic
disease through intranasal inhalation of an aerosol comprising
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
for purposes of nasal vascular absorption and delivery to central
nervous system, wherein the disease is multiple sclerosis. In some
embodiments, the subject is identified as having multiple
sclerosis. In some embodiments, the subject is a subject being
mechanically ventilated.
[0083] In one aspect, described herein is a method of administering
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
to treat a patient, wherein the patient avoids abnormal liver
function exhibited by a grade 2 or higher abnormality following
oral administration in one or more biomarkers of liver function
after imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt
thereof, administration, comprising administering to said patient
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
at doses less than 600 mg per day. In some embodiments, "Grade 2
liver function abnormalities" include elevations in alanine
transaminase (ALT), aspartate transaminase (AST), alkaline
phosphatase (ALP), or gamma-glutamyl transferase (GGT) greater than
2.5-times and less than or equal to 5-times the upper limit of
normal (ULN). Grade 2 liver function abnormalities also include
elevations of bilirubin levels greater than 1.5-times and less than
or equal to 3-times the ULN. In some embodiments, the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof, is delivered to
the patient by oral inhalation or intranasal inhalation. In some
embodiments, said one or more biomarkers of liver function is
selected from the group consisting of alanine transaminase,
aspartate transaminase, bilirubin, and alkaline phosphatase. In
some embodiments, the method further comprises the step of
measuring one or more biomarkers of liver function. In some
embodiments, the blood Cmax following administration of imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof, is less than 10
mcg/mL. In some embodiments, the blood Cmax following
administration of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, is less than 5 mcg/mL. In some embodiments, the blood
Cmax following administration of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, is less than 2 mcg/mL. In some
embodiments, the blood Cmax following administration of imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof, is less than 1
mcg/mL. In some embodiments, the blood Cmax following
administration of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, is greater than 10 mcg/mL. In some embodiments, the
blood Cmax following administration of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, is greater than 0.5 mcg/mL. In
some embodiments, the blood Cmax following administration of
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof is
greater than 0.1 mcg/mL.
[0084] In one aspect, described herein is a method of administering
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
to treat a patient with pulmonary disease, extrapulmonary disease
and central nervous system disease, wherein the patient avoids
abnormal liver function exhibited by a grade 2 or higher
abnormality following oral administration in one or more biomarkers
of liver function after imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, administration, comprising
administering to said patient imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, at doses less than 600 mg per
day. In some embodiments, "Grade 2 liver function abnormalities"
include elevations in alanine transaminase (ALT), aspartate
transaminase (AST), alkaline phosphatase (ALP), or gamma-glutamyl
transferase (GGT) greater than 2.5-times and less than or equal to
5-times the upper limit of normal (ULN). Grade 2 liver function
abnormalities also include elevations of bilirubin levels greater
than 1.5-times and less than or equal to 3-times the ULN. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, is delivered to the patient by oral inhalation or
intranasal inhalation. In some embodiments, said one or more
biomarkers of liver function is selected from the group consisting
of alanine transaminase, aspartate transaminase, bilirubin, and
alkaline phosphatase. In some embodiments, the method further
comprises the step of measuring one or more biomarkers of liver
function. In some embodiments, the blood Cmax following
administration of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, is less than 5 mcg/mL. In some embodiments, the blood
Cmax following administration of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof is less than 2 mcg/mL. In some
embodiments, the blood Cmax following administration of imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof is less than 1
mcg/mL. In some embodiments, the blood Cmax following
administration of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof is less than 0.5 mcg/mL. In some embodiments, the
blood Cmax following administration of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof is less than 0.1 mcg/mL.
[0085] In one aspect, described herein is a method of administering
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
to treat a patient with cancer, wherein the patient avoids abnormal
liver function exhibited by a grade 2 or higher abnormality
following oral administration in one or more biomarkers of liver
function after imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, administration, comprising administering to said
patient imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, at doses less than 600 mg per day. In some
embodiments, "Grade 2 liver function abnormalities" include
elevations in alanine transaminase (ALT), aspartate transaminase
(AST), alkaline phosphatase (ALP), or gamma-glutamyl transferase
(GGT) greater than 2.5-times and less than or equal to 5-times the
upper limit of normal (ULN). Grade 2 liver function abnormalities
also include elevations of bilirubin levels greater than 1.5-times
and less than or equal to 3-times the ULN. In some embodiments, the
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
is delivered to the patient by oral inhalation or intranasal
inhalation. In some embodiments, said one or more biomarkers of
liver function is selected from the group consisting of alanine
transaminase, aspartate transaminase, bilirubin, and alkaline
phosphatase. In some embodiments, the method further comprises the
step of measuring one or more biomarkers of liver function. In some
embodiments, the blood Cmax following administration of imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof, is less than 5
mcg/mL. In some embodiments, the blood Cmax following
administration of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof is less than 2 mcg/mL. In some embodiments, the blood
Cmax following administration of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof is less than 1 mcg/mL. In some
embodiments, the blood Cmax following administration of imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof is less than 0.5
mcg/mL. In some embodiments, the blood Cmax following
administration of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof is less than 0.1 mcg/mL.
[0086] In one aspect, described herein is a method of administering
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
to treat a patient with a viral infection, wherein the patient
avoids abnormal liver function exhibited by a grade 2 or higher
abnormality following oral administration in one or more biomarkers
of liver function after imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, administration, comprising
administering to said patient imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, at doses less than 600 mg per
day. In some embodiments, "Grade 2 liver function abnormalities"
include elevations in alanine transaminase (ALT), aspartate
transaminase (AST), alkaline phosphatase (ALP), or gamma-glutamyl
transferase (GGT) greater than 2.5-times and less than or equal to
5-times the upper limit of normal (ULN). Grade 2 liver function
abnormalities also include elevations of bilirubin levels greater
than 1.5-times and less than or equal to 3-times the ULN. In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, is delivered to the patient by oral inhalation or
intranasal inhalation. In some embodiments, said one or more
biomarkers of liver function is selected from the group consisting
of alanine transaminase, aspartate transaminase, bilirubin, and
alkaline phosphatase. In some embodiments, the method further
comprises the step of measuring one or more biomarkers of liver
function. In some embodiments, the blood Cmax following
administration of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, is less than 5 mcg/mL. In some embodiments, the blood
Cmax following administration of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof is less than 2 mcg/mL. In some
embodiments, the blood Cmax following administration of imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof is less than 1
mcg/mL. In some embodiments, the blood Cmax following
administration of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof is less than 0.5 mcg/mL. In some embodiments, the
blood Cmax following administration of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof is less than 0.1 mcg/mL.
[0087] In one aspect, described herein is a method of administering
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
to treat a patient, wherein the patient avoids the incidence of
nausea, diarrhoea, headaches, leg aches/cramps, fluid retention,
visual disturbances, itchy rash, lowered resistance to infection,
bruising or bleeding, loss of appetite, weight gain, reduced number
of blood cells (neutropenia, thrombocytopenia, anemia), headache,
edema, congestive cardiac failure observed following oral
administration, comprising administering to said patient imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof, at
doses less than 600 mg per day. In some embodiments, the imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof is
delivered to the patient by oral inhalation or intranasal
inhalation. In some embodiments, the incidence of nausea,
diarrhoea, headaches, leg aches/cramps, fluid retention, visual
disturbances, itchy rash, lowered resistance to infection, bruising
or bleeding, loss of appetite, weight gain, reduced number of blood
cells (neutropenia, thrombocytopenia, anemia), headache, edema,
and/or congestive cardiac failure adverse events is less than about
10%. In some embodiments, the incidence of nausea, diarrhoea,
headaches, leg aches/cramps, fluid retention, visual disturbances,
itchy rash, lowered resistance to infection, bruising or bleeding,
loss of appetite, weight gain, reduced number of blood cells
(neutropenia, thrombocytopenia, anemia), headache, edema, and/or
congestive cardiac failure-related adverse events is less than
about 5%. In some embodiments, the incidence of nausea, diarrhoea,
headaches, leg aches/cramps, fluid retention, visual disturbances,
itchy rash, lowered resistance to infection, bruising or bleeding,
loss of appetite, weight gain, reduced number of blood cells
(neutropenia, thrombocytopenia, anemia), headache, edema, and/or
congestive cardiac failure-related adverse events is less than
about 1%. In some embodiments, the blood Cmax following
administration of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof, less than 5 mcg/mL. In some embodiments, the blood
Cmax following administration of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof is less than 2 mcg/mL. In some
embodiments, the blood Cmax following administration of imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof is less than 1
mcg/mL. In some embodiments, the blood Cmax following
administration of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof is less than 0.5 mcg/mL. In some embodiments, the
blood Cmax following administration of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof is less than 0.1 mcg/mL.
[0088] In one aspect, described herein is a method of administering
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
to treat a patient with resistance to tyrosine kinase inhibitor
therapy. Types of resistance include tyrosine kinase gene
amplification increasing the number of tyrosine kinase protein
copies, tyrosine kinase gene mutations altering the ability of the
tyrosine kinase inhibitor to bind the tyrosine kinase, and plasma
levels of alpha-glycoprotein (AGP). By example, it has been shown
that AGP binds imatinib at physiological concentrations in vitro
and in vivo, and blocks the ability of imatinib to inhibit kinase
activity in a dose-dependent manner. Finally, activation of
tyrosine kinase-independent pathways. Inhalation delivers imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof
directly to lung tissue. Such administration provides lung drug
levels not possible by oral administration. Further, by direct
inhalation lung delivery, adverse events associated with the
required high oral dose levels are reduced or avoided. Further,
direct inhalation lung delivery addresses three key issues
associated with resistance: 1. Direct lung delivery avoids AGP
absorption permitting maximum dosing to the pulmonary compartment;
2. Direct lung delivery administers higher lung doses than possible
by oral administration. This enables sufficient dosing to overcome
increases in tyrosine kinase copy number resulting from tyrosine
kinase gene amplification; 3. Direct lung delivery administers
higher lung doses than possible by oral administration, thus
applying therapeutic influence prior to tyrosine kinase mutation;
4. Direct lung delivery administers higher lung doses than possible
by oral administration, thus delivering a sufficient lung dose
necessary to overcome tyrosine kinase resistance; 5. Because direct
lung delivery requires smaller doses than oral administration to
accomplish superior therapeutic lung levels, the initially-achieved
superior lung dose is eliminated to levels below that sustained
following oral administration and thus projected to reduce or
eliminate mutant selective pressure. To this later point, the
frequency of both tyrosine kinase and non-tyrosine kinase pathway
compensatory mutations are reduced. 6. Because direct lung delivery
requires smaller doses than oral administration to accomplish
superior therapeutic lung levels, systemic exposure is reduced and
side effects common with the route and dose of oral delivery are
reduced or eliminated. In another embodiment, methods described to
avoid resistance in the pulmonary compartment may also reduce,
avoid or overcome resistance in extrapulmonary diseases. In some
embodiments, less than 600 mg per day of imatinib or salt thereof,
or a phenylaminopyrimidine derivative or salt thereof is delivered
to the patient by inhalation. In some embodiments, less than 400
mg, less than 300 mg, less 200 mg, less than 100 mg, less than 90
mg, less than 80 mg, less than 70 mg, less than 60 mg, less than 50
mg, less than 40 mg, less than 30 mg, less than 20 mg, less than 10
mg or less than 5 mg per day of imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof is delivered to
the patient by inhalation. In some embodiments, less than 200 mg
per day of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof is delivered to the patient by inhalation. In some
embodiments, less than 200 mg, less than 150 mg, less than 100 mg,
less than 50 mg, less than 20 mg, less than 16 mg, less than 12 mg,
less than 8 mg, less than 4 mg, less than 2 mg, less than 1 mg,
less than 0.5 mg, less than 0.1 mg, less than 0.05 mg, or less than
0.01 mg per day of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof is delivered to the patient by
inhalation. In some embodiments, imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof is delivered by
inhalation once per day, twice per day, three time a day, or four
time a day. In some embodiments, imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof is delivered by inhalation once
per day, twice per day, three times a day, four times a day, five
times a day, six times a day or greater than six times per day. In
some embodiments, imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof is delivered by inhalation daily, every other day,
every third day, every fourth day, every fifth day, every sixth day
or weekly, every other week, every third week or monthly.
[0089] In some embodiments, up to about 600 mg of imatinib or salt
thereof, or a phenylaminopyrimidine derivative or salt thereof is
delivered to the patient by inhalation per dose. In some
embodiments, about 0.01 mg to about 600 mg, about 0.05 mg to about
600 mg, about 0.1 mg to about 600 mg, about 0.5 mg to about 600 mg,
about 1 mg to about 600 mg, about 1 mg to about 400 mg, about 1 mg
to about 200 mg, about 1 mg to about 100 mg, about 1 mg to about 80
mg, about 1 mg to about 60 mg, about 1 mg to about 40 mg, about 1
mg to about 20 mg, about 1 mg to about 10 mg, about 2 mg to about
200 mg, about 4 mg to about 200 mg, about 4 mg to about 200 mg,
about 6 mg to about 200 mg, about 8 mg to about 200 mg, about 15 mg
to about 200 mg, about 20 mg to about 200 mg, about 25 mg to about
200 mg, about 30 mg to about 200 mg, about 40 mg to about 200 mg,
about 60 mg to about 200 mg, or about 80 mg to about 200 mg, of
imatinib or salt thereof, or a phenylaminopyrimidine derivative or
salt thereof is delivered to the patient by inhalation per dose. In
some embodiments, up to about 200 mg of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof is delivered to the patient by
inhalation per dose. In some embodiments, about 0.001 mg to about
200 mg, about 0.01 mg to about 200 mg, about 0.01 mg to about 150
mg, about 0.01 mg to about 100 mg, about 0.01 mg to about 50 mg,
about 0.01 mg to about 40 mg, about 0.01 mg to about 30 mg, about
0.01 mg to about 20 mg, about 0.01 mg to about 10 mg, about 0.1 mg
to about 200 mg, about 0.1 mg to about 150 mg, about 0.1 mg to
about 100 mg, about 0.1 mg to about 50 mg, about 0.1 mg to about 40
mg, about 0.1 mg to about 30 mg, about 0.1 mg to about 30 mg, about
0.1 mg to about 20 mg, about 0.1 mg to about 10 mg, about 1.0 mg to
about 200 mg, about 2.0 mg to about 200 mg, about 4.0 mg to about
200 mg, about 8.0 mg to about 200 mg, about 16.0 mg to about 200
mg, about 20 mg to about 200 mg, or about 50 mg to about 200 mg, of
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof is
delivered to the patient by inhalation per dose. In some
embodiments, imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof is delivered by inhalation once per day, twice per
day, three time a day, or four time a day. In some embodiments,
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof is
delivered by inhalation daily, every other day, every third day,
every fourth day, every fifth day, every sixth day or weekly, every
other week, every third week or monthly.
[0090] In one aspect, described herein is a pharmaceutical
composition comprising a therapeutically effective amount of an
inhaled agent, wherein the agent is imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof, wherein the agent
is in a particle less than 5 microns in mass mean aerodynamic
diameter or less than 10 microns volumetric mean diameter wherein
the composition, upon inhalation, delivers a dose to the lung
greater than about 0.0005 mg imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof compound per gram
or 1 micromole per kilogram of adult human lung tissue.
[0091] In one aspect, described herein is a pharmaceutical
composition comprising a therapeutically effective amount of an
inhaled agent, wherein the agent is imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, wherein the agent is in a
particle less than 5 microns in mass mean aerodynamic diameter or
less than 10 microns volumetric mean diameter wherein the
composition, upon inhalation, delivers a dose to the lung greater
than about 0.00000025 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound per gram or about 0.5
nanomole per kilogram of adult human lung tissue.
[0092] In one aspect, described herein is a pharmaceutical
composition for aerosol delivery to the lung, comprising a solution
where the active pharmaceutical ingredient is imatinib or salt
thereof, or a phenylaminopyrimidine derivative or salt thereof
concentration is between 0.01 mg/mL and 100 mg/mL in unit
increments of about 0.01 mg/mL composition. By example, about about
0.1 mg/mL, about 0.5 mg/mL, about 1 mg/mL, about 2 mg/mL, about 3
mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL,
about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 15 mg/mL, about
20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 30 mg/mL, about 35
mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 55
mg/mL, about 60 mg/mL, about 65 mg/mL, about 70 mg/mL, about 75
mg/mL, about 80 mg/mL, about 85 mg/mL. In some embodiments, the
composition is a stable, water-soluble formulation. In one aspect,
described herein is a pharmaceutical composition for aerosol
delivery to the lung, comprising a solution where the active
pharmaceutical ingredient is imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof concentration is between 0.001
mg/mL and 200 mg/mL in unit increments of about 0.001 mg/mL
composition. By example, about about 0.001 mg/mL, about 0.005
mg/mL, about 0.01 mg/mL, about 0.5 mg/mL, about 1.0 mg/mL, about 2
mg/mL, about 4 mg/mL, about 8 mg/mL, about 12 mg/mL, about 16
mg/mL, about 20 mg/mL, about 30 mg/mL, about 40 mg/mL, about 50
mg/mL, about 60 mg/mL, about 70 mg/mL, about 80 mg/mL, about 90
mg/mL, about 100 mg/mL, about 110 mg/mL, about 120 mg/mL, about 130
mg/mL, about 140 mg/mL, about 150 mg/mL, about 160 mg/mL, about 170
mg/mL, about 180 mg/mL, about 190 mg/mL, and about 200 mg/mL. In
some embodiments, the composition is a stable, water-soluble
formulation. In some embodiments, the osmolality is greater than
about 50 mOsmol/kg composition in unit increments of about 1
mOsmol/kg. By example, greater than about 50 mOsmol/kg, about 100
mOsmol/kg, about 150 mOsmol/kg, about 200 mOsmol/kg, about 250
mOsmol/kg, about 300 mOsmol/kg, about 350 mOsmol/kg, about 400
mOsmol/kg, about 450 mOsmol/kg, about 500 mOsmol/kg, about 550
mOsmol/kg, about 600 mOsmol/kg, about 650 mOsmol/kg, about 700
mOsmol/kg, about 750 mOsmol/kg, about 800 mOsmol/kg, about 850
mOsmol/kg, about 900 mOsmol/kg, about 950 mOsmol/kg, about 1000
mOsmol/kg, greater than about 1500 mOsmol/kg, or about 2000
mOsmol/kg. In some embodiments, the pH is greater than about 3.0 in
pH unit increments of about 0.1. By example, a pH of about 3, a pH
of about 3.5, a pH of about 4, a pH of about 4.5, a pH of about 5,
a pH of about 5.5, a pH of about 6, a pH of about 6.5, a pH of
about 7, a pH of about 7.5, a pH of about 8, a pH of about 8.5, a
pH of about 9, a pH of about 9.5, a pH of about 10 a pH of about
10.5, and a pH of about 11. In some embodiments, the pH is balanced
by the inclusion of an organic buffer selected from the group
consisting of citric acid, citrate, malic acid, malate, pyridine,
formic acid, formate, piperazine, succinic acid, succinate,
histidine, maleate, bis-tris, pyrophosphate, phosphoric acid,
phosphate, PIPES, ACES, MES, cacodylic acid, carbonic acid,
carbonate, ADA (N-(2-Acetamido)-2-iminodiacetic acid). In some
embodiments, the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof solution contains a permeant ion concentration. In
some embodiments, the permeant ion is selected from the group
consisting of bromine, chloride, and lithium. In some embodiments,
the permeant ion concentration is from about 30 mM to about 300 mM
in about 0.1 mM increments. By example, about 30 mM, about 40 mM,
about 50 mM, about 60 mM, about 70 mM, about 80 mM, about 90 mM,
about 100 mM, about 150 mM, about 200 mM, about 250 mM, and about
300 mM. In some embodiments, the composition further comprises a
taste masking agent. In some embodiments, the taste masking agent
is selected from the group consisting of lactose, sucrose,
dextrose, saccharin, aspartame, sucrulose, ascorbate, multivalent
cation and citrate. In some embodiments, the taste masking agent
concentration is from 0.01 mM to about 50 mM in about 0.01 mM
increments. In some embodiments, the taste masking agent
concentration is about 0.01 mM, about 0.05 mM, about 0.1 mM, about
0.2 mM, about 0.3 mM, about 0.4 mM, about 0.5 mM, about 0.6 mM,
about 0.7 mM, about 0.8 mM, about 0.9 mM, about 1 mM, about 2 mM,
about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8
mM, about 9 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM,
about 30 mM, about 35 mM, about 40 mM, about 45 mM, and about 50
mM.
[0093] In some embodiments, the formulations described herein are
filled into a primary package. In some embodiments, primary
packaging material is taken from the group consisting of glass or
plastic, wherein plastic materials may be selected from the group
consisting of low-density polyethylene (LDPE), high-density
polypropylene (HDPP), or high-density polyethylene (HDPE). In some
embodiments, the primary packaging consists of a vial, syringe or
ampoule. In some embodiments, the composition is protected from
light.
[0094] In some embodiments, the compositions described herein are
formulated under or to result in conditions of reduced oxygen. In
some embodiments, oxygen is reduced by sparging the formulation
diluent prior to addition of the active pharmaceutical ingredient.
Sparging gases may be selected from the group consisting of carbon
dioxide, argon or nitrogen. In some embodiments, oxygen is reduced
by sparging the formulation diluent after addition of the active
pharmaceutical ingredient. Sparging gases may be selected from the
group consisting of carbon dioxide, argon or nitrogen. In some
embodiments, oxygen exposure is reduced by replacing the ambient
gas headspace of the formulation container with an inert gas. Inert
gases may be selected from the group consisting of argon or
nitrogen.
[0095] In some embodiments, oxygen exposure is reduced by replacing
the ambient gas headspace of the primary packaging container with
an inert gas. Inert gases may be selected from the group consisting
of argon or nitrogen.
[0096] In some embodiments, oxygen exposure is reduced by inserting
the primary packaging into a gas-impermeable secondary packaging
container.
[0097] In some embodiments, oxygen exposure is reduced by replacing
the ambient gas headspace of the secondary packaging with an inert
gas. Inert gases may be selected from the group consisting of argon
or nitrogen.
[0098] In some embodiments, the aerosol for delivery to the lungs
of a mammal described herein contains a fine particle fraction
between 10 and 100% with increment units of 1%. By example, about
10%, about 15%, about 20%, about 25%, about 30%, about 35%, about
40%, about 45%, about 50%, about 55%, about 60%, about 65%, about
70%, about 75%, about 80%, about 85%, about 90%, about 95%, and
about 100%. In some embodiments, the fine particle dose is between
about 0.01 mg to about 600 mgs imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof. In some
embodiments, the fine particle dose is between about 0.001 mg to
about 200 mg imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof. By example, about 0.01 mg, about 0.05 mg, about 0.1
mg, about 0.5 mg, and about 1 mg in 0.01 mg increments. By further
example, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6
mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg,
about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg,
about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg,
about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg,
about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg,
about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200
mg in 0.1 mg increments. By example, about 0.001 mg, about 0.005
mg, about 0.01 mg, about 0.05 mg, about 0.1 mg, and about 0.5 mg in
0.001 mg increments. By further example, about about 1 mg, about 2
mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg,
about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg,
about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg,
about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg,
about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg,
about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg,
about 140 mg, about 160 mg, about 180 mg, and about 200 mg in 0.1
mg increments.
[0099] In some embodiments, the compositions further comprise a
mucolytic agent suitable for pulmonary delivery. In some
embodiments, the compositions further comprise a second
anti-fibrotic or anti-cancer or anti-infective or anti-infective
agent suitable for pulmonary delivery. In some embodiments, the
compositions further comprise a second anti-inflammatory agent
suitable for pulmonary delivery. In some embodiments, the
composition may be co-administered with a second anti-fibrotic or
anti-cancer or anti-infective agent suitable for pulmonary
delivery. In some embodiments, the composition co-administered a
second anti-inflammatory agent suitable for pulmonary delivery.
[0100] These and other aspects of the invention will be evident
upon reference to the following detailed description. All of the
U.S. patents, U.S. patent application publications, U.S. patent
applications, foreign patents, foreign patent applications and
non-patent publications referred to in this specification, are
incorporated herein by reference in their entirety, as if each was
incorporated individually. Aspects of the invention can be
modified, if necessary, to employ concepts of the various patents,
applications and publications to provide yet further embodiments of
the invention.
BRIEF DESCRIPTION OF THE FIGURES
[0101] FIG. 1. Lung tissue pharmacokinetics following intratracheal
aerosol delivery of imiatinib phosphate.
[0102] FIG. 2. X-ray powder diffraction (XRPD) pattern of
Crystalline Imatinib Fumarate Salt.
[0103] FIG. 3. X-ray powder diffraction (XRPD) pattern of
Crystalline Imatinib Hydrochloride Salt.
[0104] FIG. 4. X-ray powder diffraction (XRPD) pattern of
Crystalline Imatinib Phosphate Salt (Pattern 1).
[0105] FIG. 5. X-ray powder diffraction (XRPD) pattern of
Crystalline Imatinib Phosphate Salt (Pattern 2).
[0106] FIG. 6. X-ray powder diffraction (XRPD) pattern of
Crystalline Imatinib Phosphate Salt (Pattern 3).
DETAILED DESCRIPTION
[0107] A number of undesirable pulmonary diseases such as
interstitial lung disease (ILD; and sub-class diseases therein),
cancer (lung cancer; and sub-class diseases therein), fibrotic
indications of the lungs, kidney, heart and eye, viral infections
and diseases of the central nervous system are current areas of
unmet clinical need.
[0108] In fibrosis, scarring serves a valuable healing role
following injury. However, tissue may become progressively scarred
following more chronic and or repeated injuries resulting in
abnormal function. In the case of idiopathic pulmonary fibrosis
(IPF; and other subclasses of ILD), if a sufficient proportion of
the lung becomes scarred respiratory failure can occur. In any
case, progressive scarring may result from a recurrent series of
insults to different regions of the organ or a failure to halt the
repair process after the injury has healed. In such cases the
scarring process becomes uncontrolled and deregulated. In some
forms of fibrosing disease scarring remains localized to a limited
region, but in others it can affect a more diffuse and extensive
area resulting in direct or associated organ failure.
[0109] In epithelial injury, epithelial cells are triggered to
release several pro-fibrotic mediators, including the potent
fibroblast growth factors transforming growth factor-beta
(TGF-beta), tumor necrosis factor (TNF), platelet derived growth
factor (PDGF), endothelin, other cytokines, metalloproteinases and
the coagulation mediator tissue factor. Importantly, the triggered
epithelial cell becomes vulnerable to apoptosis, and together with
an apparent inability to restore the epithelial cell layer are the
most fundamental abnormalities in fibrotic disease.
[0110] In conditions such as diseases, physiological responses
characterized by control of pro-fibrotic factors with
phenylaminopyrimidine derivative, such as imatinib may be
beneficial to attenuate and/or reverse fibrosis, treat cancer,
infection or central nervous system disease. Therapeutic strategies
exploiting such phenylaminopyrimidine derivative and/or imatinib
effects in these and other indications are contemplated herein.
[0111] The mechanism of action for phenylaminopyrimidine
derivative, such as imatinib is the inhibition of specific tyrosine
kinases. Tyrosine kinases regulate many cellular processes,
including growth and survival, and deregulated activity of these
enzymes has been implicated in malignant transformation in various
neoplasms. Therefore, specific inhibitors of tyrosine kinases are
attractive therapeutic agents. BCR-ABL functions as a
constitutively activated tyrosine kinase and mutagenic analysis has
shown that this activity is essential for the transforming function
of the protein. Imatinib mesylate binds to the amino acids of the
BCR/ABL tyrosine kinase ATP binding site and stabilizes the
inactive, non-ATP-binding form of BCR/ABL, thereby preventing
tyrosine auto phosphorylation and, in turn, phosphorylation of its
substrates. This process ultimately results in "switching-off" the
downstream signaling pathways that promote leukemogenesis. An agent
that specifically blocked ABL tyrosine kinase activity would be an
ideal targeted therapy for CML. In addition to activity against
BCR/ABL, phenylaminopyrimidine derivative and imatinib have
activity against additional tyrosine kinases important in other
disease processes.
[0112] In chronic myeloid leukemia (CML), a BCR-ABL fusion gene,
which is the result of a reciprocal translocation between
chromosomes 9 and 22, cytogenetically visible as a shortened
chromosome 22 (Philadelphia [Ph] chromosome). It has been shown
that BCR-ABL is directly associated with the pathogenesis of CML,
and that constitutive tyrosine kinase activity is central to
BCR-ABL's capacity to transform hematopoietic cells in vitro and in
vivo. The activation of multiple signal transduction pathways in
BCR-ABL-transformed cells leads to increased proliferation, reduced
growth-factor dependence and apoptosis, and perturbed interaction
with extracellular matrix and stroma. It is thought that the
expression of BCR-ABL endows a pluripotent hematopoietic progenitor
cell and/or its progeny with a growth and survival advantage over
normal cells, which in time leads to the clinical manifestation of
CML. In response, imatinib was created as a BCR-ABL-specific
tyrosine kinase inhibitor.
[0113] Studies using purified enzymes showed that imatinib potently
inhibits all of the ABL tyrosine kinases. This includes cellular
ABL, viral ABL (v-ABL), and BCR-ABL. In contrast, the compound was
inactive against serine/threonine kinases, did not inhibit the
epidermal growth factor (EGF) receptor intracellular domain, and
showed weak or no inhibition of the kinase activity of the
receptors for vascular endothelial growth factor (VEGF-R1 and
VEGF-R2), fibroblast growth factor receptor 1 (FGF-R1), tyrosine
kinase with immunoglobulin and EGF homology-2 (TIE-2 [TEK]), c-MET,
and nonreceptor tyrosine kinases of the SRC family (FGR, LYN, and
LCK).
[0114] Kinase assay results were confirmed in cell lines where
imatinib was found to inhibit ABL kinase activity with 50%
inhibitory concentration (IC50) values ranging between 0.1 and 0.35
.mu.M. Numerous Ph+ cell lines derived from patients with CML or
acute lymphoblastic leukemia (ALL) were also tested. In most of
these lines, the IC50 values were also in the range of 0.1 to 0.5
.mu.M, indicating that the compound effectively penetrates the cell
membrane.
[0115] Consistent with its in vitro profile, imatinib inhibited
signaling of the ligand-activated platelet-derived growth factor
receptor (PDGFR), with an IC50 of 0.1 to 1 .mu.M. Furthermore, the
compound potently inhibited autophosphorylation of the KIT receptor
upon binding of its cognate ligand, stem-cell factor (SCF), and to
suppress KIT autophosphorylation in a cell line established from a
patient with a gastrointestinal stromal tumor (GIST) with an
activating Kit mutation.
[0116] Imatinib was tested for its antiproliferative activity
against a variety of cell lines expressing activated ABL proteins.
The in vitro IC50 for inhibition of proliferation generally
paralleled the IC50 values for inhibition of BCR-ABL kinase
activity seen in cellular assays. Exposure to imatinib led to
apoptotic cell death. Additional studies demonstrated activity in
fresh leukemic cells from patients with CML and Ph+ and selective
inhibition of colony formation by committed progenitor cells from
patients with CML.
[0117] Imatinib strongly inhibited proliferation of
v-sis-transformed BALB/c 3T3 mouse fibroblasts, which proliferate
autonomously due to autocrine PDGF production. Furthermore, the
compound dose-dependently suppressed PDGF-stimulated proliferation
of A10 rat aorta smooth muscle cells but did not affect
serum-induced growth. Cells expressing a TEL-PDGF receptor fusion
protein were also imatinib sensitive. The proliferative activities
of PDGF receptor (PDGFR) and other tyrosine kinases in IPF
pathogenesis led to in vivo and in vitro investigations assessing
imatinib as a potential inhibitor of lung fibrosis. Imatinib was
identified as a potent inhibitor of lung fibroblast-myofibroblast
transformation and proliferation as well as extracellular matrix
production through inhibition of PDFG and transforming growth
factor (TGF)-.beta. signaling. Additionally, In addition, imatinib
also inhibited fibrosis in bleomycin-induced models of lung
fibrosis. Interestingly, as a parallel mechanism, the ability of
imatinib to also interrupt TGF-.beta. signaling has also been
explored. It has been shown that TGF-.beta.-induced fibrosis is
mediated by activation of the Abelson (Abl) tyrosine kinase. In
these studies, fibroblasts responded to TGF-.beta. by stimulating
c-Abl kinase activity independently of Smad2/3 phosphorylation or
PDGFR activation. Moreover, inhibition of c-Abl by imatinib
prevented TGF-.beta.-induced extracellular matrix (ECM) gene
expression, morphologic transformation, and cell proliferation
independently of any effect on Smad signaling. Taken together,
treatment of idiopathic pulmonary fibrosis or other fibrotic
diseases with imatinib or phenylaminopyrimidine derivative may
exhibit a dual effect.
[0118] Imatinib was also found to inhibit stem cell factor
(SCF)-mediated growth of small-cell lung cancer cell lines. The
IC50 values for inhibition of KIT autophosphorylation and
proliferation were 0.1 and 0.3 .mu.M, respectively.
[0119] Because of the three known targets of imatinib (as Gleevec),
many potential cancers can be speculated to be good candidates for
clinical testing of this new drug. However, CML was selected as the
first indication for clinical testing. Clinically, CML is a chronic
disease that evolves through three successive stages, from the
chronic phase to the end stage of blast crisis that resembles acute
leukaemia. Overall, the median survival time of patients with newly
diagnosed CML is approximately 5-6 years with an interferon-based
treatment regimen. The first trial treated patients with oral doses
ranging from 25 to 1,000 mg per day, and no maximal tolerated dose
was identified, despite a trend for a higher frequency of Grade
III-IV adverse events at doses of 750 mg or higher. On the other
hand, a clear dose-response relationship with respect to efficacy
was described in patients with chronic-phase CML. At doses of 300
mg or higher, 98% of the patients achieved a complete
haematological response, and trough serum levels were above the
concentrations required for in vitro activity. Subsequently, a
mathematical modelling of the relationship between dose and
response, as measured by leukocyte counts after four weeks of
therapy, confirmed that oral doses of 400 mg and higher were
optimal in inducing a haematological response. From this study,
oral doses ranging from 400 mg (for chronic-phase patients) to 600
mg (for advanced-phase CML) were recommended.
[0120] The most frequently reported adverse events were mild
nausea, vomiting, edema and muscle cramps. However, rare but
serious adverse events, such as liver toxicity or fluid-retention
syndromes, were also reported. Neuropaenias and thrombopaenias were
more common in patients with advanced disease, which indicates that
haematological toxicity might be related more to an underlying
compromised bone-marrow reserve than to toxicity of the drug itself
through inhibition of c-KIT-driven haematopoiesis.
[0121] Even though the CML rate of haematological responses to
Gleevec is high, these responses are usually short lived, and most
patients will ultimately develop resistance and undergo disease
progression. A prerequisite to optimally develop strategies to
prevent or overcome this resistance is to get a good understanding
of the potential mechanisms of resistance in these patients.
Several potential mechanisms of resistance have been described.
These can be categorized into two main groups: tyrosine
kinase-dependent and tyrosine kinase-independent mechanisms.
[0122] The first mutation linked to imatinib resistance in a cohort
of relapsed patients was T334I. T334I involves the ATP-binding
pocket of BCR-ABL and impairs drug binding, but preserves ATP
binding. T334 makes a critical hydrogen bond with the drug, but
when this residue is replaced by the bulkier isoleucine side chain,
an aberrant narrower cleft results that clashes with the
phenylaminopyrimidine group of the drug and thereby sterically
blocks drug binding. Several other mutations have been identified
in closely juxtaposed residues (e.g., F378V, F336L, V308A). Still
more mutations emerged in the residues that constituted the
nucleotide-binding p-loop: E274K, E274V, Y272F, Y272H, G269E, and
Q271R/H. These mutations modified the flexibility of the p-loop,
destabilized the conformation required for imatinib binding, or
shifted the equilibrium of the kinase conformation to favor the
activated state, which naturally resists imatinib binding. This
dynamic balance is again influenced by a cluster of mutations
occurring in the activation loop itself, which presumably alter the
ability of the loop to flip into the "off" state (e.g., H415P,
H415R and L406M).
[0123] Additionally, drug-resistant variants have been mapped to
the linker region between the SH2 domain and the N lobe of the
kinase. This stretch of amino acids sits between the SH3 domain and
the N lobe of the SRC structure, where mutation within this stretch
or the complementary surface on the kinase domain activated both
the SRC and ABL kinases. Other mutations have been found in the
linker between the SH3 and SH2 domains, again activating the
kinase. Finally, imatinib-resistant mutations have been mapped to
the cap portion of the structure, the SH3-SH2 linker, and the
SH3-kinase domain interface, all regions important to ABL kinase
regulation. Together, it is postulated that ABL is autoinhibited
and that imatinib resistance was mechanistically coupled to kinase
activation. Hence, while imatinib trapped BCR-ABL in the inactive,
autoinhibited conformation, mutations linked to imatinib resistance
tended to activate the kinase, favoring adoption of the
autophosphorylated state that resists imatinib binding. Thus
BCR-ABL mutation can result in both steric and allosteric
mechanisms of drug resistance.
[0124] Imatinib-resistant mutations in c-KIT have also been found
in patients with gastrointestinal stromal tumors, systemic
mastocytosis and, in rare cases, with other hematological
malignancies. These mutations have been localized in three
different regions of the receptor: the juxtamembrane domain
(prevalent in gastrointestinal stromal tumors), the activation loop
of the catalytic domain (prevalent in systemic mastocytosis) and
the extracellular domain. Interestingly, imatinib is effective at
inhibiting KIT kinase activity only for mutations in the
juxtamembrane domain-coding region. Mutations affecting the
activation loop of KIT are resistant to imatinib.
[0125] Flt3 is the most commonly mutated gene in acute myelogenous
leukemia. In one third of these malignancies, internal tandem
duplication of the juxtamembrane coding domain of this gene have
been found, which correlates with adverse prognosis.
Imatinib-resistant mutations have also been detected in the
activation loop of FLT3, some of which appear homologous to those
in c-KIT.
[0126] The activity of Glivec in patients with newly diagnosed CML
is being further investigated by a large randomized Phase III study
to compare first-line therapy with Glivec against standard
interferon in combination with low-dose cytarabine. This study,
known as the `IRIS` study (International Randomized study of
Interferon versus STI571), has enrolled 1,106 patients. The results
of an interim analysis with a median follow-up of 14 months
indicate a better tolerability and a superior efficacy of
first-line Glivec compared with interferon and low-dose cytarabine
in terms of cytogenetic response, haematological response and, more
importantly, time to progression to accelerated phase or blast
crisis46.
[0127] Preclinical studies have shown that the combination of
Glivec with various anticancer agents might have synergistic
effects. Consequently, several Phase I/II studies are evaluating
the feasibility of combining Glivec with interferon, polyethylene
glycol (PEG)ylated interferon, cytarabine and other single-agent or
combination chemotherapy regimens, in patients with either
chronic-phase or advanced CML.
[0128] Tyrosine kinase-independent mechanisms include efflux and
protein binding. Alpha-1 glycoprotein (AGP) binds imatinib with
high affinity and blocks its biological activity (proliferation and
kinase activity). Drugs known to compete with imatinib for binding
to AGP, such as erythromycin displace (or prevent binding of)
imatinib from AGP and restore imatinib biological and therapeutic
activity. In addition to competing drugs for AGP binding, increased
imatinib dosing may also overcome this mechanism. Similar to AGP
binding, efflux mechanisms that expel imatinib from the cytoplasm
(thereby, limiting intracellular tyrosine kinase exposure) may also
be overcome with dose escalation. Unfortunately, increases in
imatinib oral dosing is hampered by side effects. It is
hypothesized that AGP binding and subsequent below-efficacy
circulating levels of imatinib provide sufficient resistant mutant
selective pressure to induce tyrosine kinase-dependent
mutations.
[0129] An additional tyrosine kinase-dependent resistance mechanism
is gene amplification, whereby increased copies of the tyrosine
kinase are produced. By example, it has been shown that increased
chromosomal copies of BCR-ABL (e.g., >14 copies) can grow in 1
.mu.m imatinib. This cell line could be selected only by exposing
cells to marginally active concentrations of imatinib (slightly
less than its IC50). When active concentrations (1 .mu.m) were used
from the beginning, all cells were killed and no selection was
possible. It is evident, therefore, that the exposure of leukemic
cells to marginally active imatinib concentrations, which probably
happens in tissues at present dosages, will favor such a
selection.
[0130] Important differences exist between this model and the
clinical situation. Basal human AGPs levels are 4-5 times higher
than murine ones; therefore, AGP levels can rise, after
inflammatory stimuli, up to 20-30-fold over basal values in mice,
and only 2-4-fold in humans. In addition, given the higher basal
values in humans, "normal" levels of AGP are theoretically
sufficient to bind most of the imatinib that is present in
patients' plasma (17)
[0131] In addition to various oncogenic forms of the BCR-ABL
tyrosine kinase, imatinib also inhibits the receptor for stem cell
factor (SCF) c-KIT, a member of the type III group of receptor
kinases. Preclinical studies have established that imatinib blocks
c-KIT autophosphorylation, as well as SCF-stimulated downstream
signalling events. In addition to treating gastrointestinal stromal
tumors (GISTs), imatinib may also be successful at treating
small-cell lung cancer (SCLC).
[0132] SCLC is one of the most aggressive and lethal cancers in
humans. It constitutes approximately 15%-25% of all cases of
primary lung cancers. Although standard combination cytotoxic
chemotherapy agents have shown antitumor activity with initial
responses seen in 70%-90% for both limited and extensive stages of
SCLC, long-term survival is low and most patients eventually
develop progressive disease. Autocrine or paracrine activation of
growth has been used to explain deregulated growth of SCLC. SCLC
tumors and cultured cell lines produce a wide variety of peptide
hormones and receptors that stimulate growth. High level of
expression of c-kit and its ligand (SCF) are been widely found in
SCLC tumors. The role of the c-kit autocrine loop in SCLC has been
well studied. This autocrine loop not only functions cooperatively
with other SCLC autocrine loops but, more importantly, seems to
confer a tumor survival advantage in SCLC. More importantly, in
vitro treatment with c-kit tyrosine kinase inhibitors reversed
apoptosis resistance to growth factor deprivation in H526 cells, a
SCLC cell line with co-expression of c-kit and SCF. The ensuing
growth inhibition was well correlated with the inhibition of c-kit
tyrosine phosphorylation.
[0133] It has been demonstrated that pretreatment of H526 cells
with imatinib inhibited SCF-mediated kit activation. Inhibition of
serum-dependent proliferation of multiple SCLC cell lines has been
established at an approximate IC50 of 5 .mu.mol/l. It was also
demonstrated that imatinib mesylate sufficiently blocked the signal
transduction cascade triggered by c-kit activation. A separate
study of SCLC cell lines documented a dose-dependent inhibition of
tyrosine phosphorylation and in vitro kinase activity (at 5 .mu.M)
of c-kit using imatinib.
[0134] With this success, imatinib was studied in SCLC tumor
patients. In an initial study, patients with either chemosensitive
relapsed SCLC or previously untreated extensive stage SCLC were
enrolled in a phase II trial using oral imatinib mesylate 600 mg
daily for up to 12 months. There was no observed antitumor activity
in this group of patients. However, the study was inconclusive, as
it was weakened by at least two limitations: only 21% of the
patients had c-kit positive tumors and 26% of the patients had
non-SCLC histology upon an unplanned post-hoc central pathology
review. With this a second study enrolled
immunohistochemistry-confirmed c-kit+SCLC patients administered 400
mg oral imatinib mesylate twice daily.
[0135] Study results demonstrated that in spite of selection of
cases, imatinib mesylate did not have clinical activity in
c-kit-expressing SCLC. The dosage selected was adequate based on
data extrapolated from earlier pharmacokinetic studies to achieve
the inhibitory concentration for SCLC identified in preclinical
studies. However, adverse events were significant. This observation
reinforces findings in trials of other tumor types of increased
toxicities of daily doses at or above 800 mg. Although toxicities
limited interpretation apparent treatment failure due to disease
progression accounted for the majority of patients.
[0136] A potential limitation of the study is the use of tumor
tissue obtained for initial diagnosis (prior to first-line
chemotherapy) in the immunohistochemistry analyses. It has been
reported that up to 50% of SCLC cases that were c-kit-positive at
the time of initial diagnosis were subsequently found to be
c-kit-negative using a post-chemotherapy relapse specimen [31].
Moreover, current immunohistochemistry techniques are constrained
to merely demonstrating c-kit expression, whereas most preclinical
data of imatinib activity in SCLC were in cell lines that
co-expressed its cognate ligand SCF. Another condition controlled
in the preclinical study of imatinib was serum deprivation, which
cannot be achieved in the clinical setting. However, in vitro serum
deprivation may have circumvented the presence of drug-absorbing
AGP. Thus, the clinical setting may have had below efficacious
circulating and bioavailable imatinib.
[0137] The third target of imtinig is the PDGF-receptor tyrosine
kinase. Cellular studies have shown potent inhibition of the two
structurally similar PDGF-.alpha. and PDGF-.beta. receptors
(PDGFR-.alpha. and PDGFR-.beta.), as well as blockade of
PDGF-mediated cellular events. PDGF is a connective-tissue-cell
mitogen with in vivo functions that include embryonal development,
wound healing and control of interstitial-fluid pressure in soft
connective tissue. There is increasing evidence that the PDGF
ligand-receptor system also has an important role in tumorigenesis.
Paracrine and/or autocrine activation of the PDGFR kinase has been
postulated in numerous malignancies, and the presence of PDGF
autocrine loops is most well documented in gliomas. Imatinib
inhibits in vitro and in vivo growth of cells with autocrine PDGF
signalling, including the formation of tumours. These inhibitory
effects were mediated predominantly through promotion of growth
arrest rather than apoptosis.
[0138] Autocrine PDGFR activation is also well documented in tumour
cells of dermatofibrosarcoma protuberans (DFSP), a highly
recurrent, infiltrative skin tumour that is characterized by a
chromosomal rearrangement involving chromosomes 17 and 22. The
resulting fusion-gene product collagen I, .alpha.1 polypeptide
(COL1A1)-PDGF-.beta. triggers the autocrine stimulation of the
PDGFR67. COL1A1-PDGF.beta.-transformed fibroblasts, as well as
primary DFSP and giant-cell fibrosarcoma cell cultures, were
inhibited by Glivec in vitro and in vivo. The main mechanism by
which imatinib affected DFSP tumour growth was through induction of
apoptosis.
[0139] Relatively little is known about the ligand-independent
activation of PDGFR. However, rearrangement of PDGFR.beta. has been
described in chronic myeloproliferative diseases. The best known of
these is the t(5;12) chromosomal translocation in chronic
myelomonocytic leukaemia (CMML), in which PDGFR.beta., which is
located on chromosome 5, is fused to the TEL gene on chromosome 12.
Transformation of haematopoietic cells occurs through
oligomerization of the TEL-PDGFR-.beta. fusion protein, which
causes ligand-independent constitutive activation of the PDGFR
kinase. Imatinib inhibited the growth of cells expressing
TEL-PDGFR.beta., and in transgenic mice that expressed the
TEL-PDGFR.beta., treatment with imatinib inhibited tumor formation
and prolonged survival of the animals. A remarkable haematological
and complete cytogenetic response has been observed in two patients
with chronic myeloproliferative disorders associated with a t(5;12)
translocation--one of them with a well-characterized TEL-PDGFR
fusion gene and the second with a rearranged PDGFR gene with an as
yet unidentified partner gene. Other exploratory clinical trials
have been carried out in gliomas and in prostate cancer.
[0140] It has been demonstrated that treatment with imatinib
inhibited the development of pulmonary fibrosis using a bleomycin
model in mice. It has been further demonstrated that imatinib has
antifibrotic effects in murine radiation-induced lung fibrosis.
Imatinib has also been reported to prevent fibrogenesis in the
liver and kidneys. These results suggest that imatinib serves as an
antifibrotic drug for various fibrotic diseases.
[0141] It was found that early treatment (from Days 0 to 15)
significantly prevented the development of pulmonary fibrosis in
the bleomycin model in mice, whereas late treatment (from Days 15
to 28) did not. It was also reported that early (from Days 0 to
21), but not late (from Days 22 to 35) treatment was effective in
inhibiting liver fibrosis using a bile duct ligation model. It was
later determined that AGP plays a pivotal role in the antifibrotic
effects of imatinib both in vitro and in vivo, and that the
coadministration of 14-membered ring macrolides was effective in
restoring late treatment effects of imatinib in bleomycin-induced
pulmonary fibrosis. It was also found that AGP was elevated in the
serum of patients with idiopathic pulmonary fibrosis. Results also
demonstrated that resistance to imatinib occurred in pulmonary
fibrosis, caused by a factor that was identified as AGP. More than
400 .mu.g/ml of AGP significantly reduced the imatinib-mediated
suppression of the growth of lung fibroblasts in vitro. In
addition, from 700 to 1,000 .mu.g/ml of AGP was detected in the
serum of bleomycin-treated mice, indicating the relevance in vivo
of the AGP-mediated suppression of imatinib in mice.
[0142] It was also found that addition of erythromycin or
clarithromycin to the culture of lung fibroblasts containing
imatinib and AGP reversed the suppressive influence of AGP on the
growth-inhibitory effects of imatinib. To abrogate the effects of
800 .mu.g/ml of AGP, more than 1 .mu.M erythromycin and 10 .mu.M
clarithromycin was required in vitro. It was also shown that
combined use of erythromycin or clarithromycin and imatinib
attenuated the bleomycin-induced pulmonary fibrosis in mice partly
via inhibiting the growth of fibroblasts even when both agents were
administered from Days 14.
[0143] Finally, it was demonstrated that the levels of AGP were
higher in patients with IPF than in healthy subjects. The
concentration of AGP in 12 of 25 patients with IPF (48%) was higher
than 1,000 .mu.g/ml, a level that was demonstrated to reverse the
antifibrotic effects of imatinib in vitro. Substantial differences
were found in the baseline levels of AGP between mice and humans
(<100 .mu.g/ml vs. 400-800 .mu.g/dl). However, the plasma
concentration of imatinib is also higher in humans than in mice.
Because the effects of imatinib appear to depend on the balance of
the concentrations of imatinib and AGP, resistance to imatinib
caused by AGP might occur in patients with IPF.
[0144] In a randomized placebo controlled clinical trial, 600 mg
oral imatinib mesylate was dosed daily for 96 weeks to subjects
with IPF. Dose de-escalation was permitted to 400 mg orally daily
to accommodate perceived drug toxicity. Unfortunately, there was no
benefit of imatinib regarding the primary outcome, time to disease
progression, and no benefit in secondary outcome parameters,
including D1CO, absolute change in FVC, and the distance walked
using a 6-minute walk test. Overall imatinib-related AEs were
common, and despite toxicity-driven, protocolized, blinded dose
reduction from 600 mg to 400 mg daily imatinib was associated with
a higher incidence of AE-related drop-outs (22%) compared with
placebo (10%). It was postulated by the investigators that the
results may be explained by circulating AGP.
[0145] The reason why AGP levels are high in patients with IPF
remains unclear. Because AGP is an acute-phase protein synthesized
in the liver, it is reasonable that its levels are elevated in
patients with inflammatory diseases. However, there was no
correlation between the levels of AGP and C-reactive protein in
patients with IPF at first diagnosis. Furthermore, the expression
of AGP in lung homogenates is enhanced in the late-phase fibrosis.
Although the precise biological roles of AGP in pulmonary fibrosis
have not been fully determined it has been reported that alveolar
macrophages and type II alveolar epithelial cells in fibrotic lungs
are able to produce AGP.
[0146] Imatinib has been most extensively studied in circulating
cancers (e.g., CML). However, its ability to penetrate tissue and
achieve effective concentrations has not been well characterized.
Coupling the possibility that imatinib penetrates tissues poorly
with circulating AGP absorption and efflux mechanisms, it is likely
that oral-delivered imatinib is not capable to achieve effective
levels in the lung and other solid tissues. Moreover, extended low
levels in the blood, coupled with a widely variable population
pharmacokinetic profile, lung and other solid tissue are likely
subjected to resistant mutant selective pressure. To address these
issues, direct pulmonary delivery by aerosol inhalation is proposed
to increase imatinib lung and tissues levels immediately downstream
of the pulmonary compartment (by limiting example the heart,
kidney, and central nervous system) which will improve tyrosine
kinase-directed efficacy, reduce or remove resistance mutant
selective pressure and improve the safety and tolerability profile
of imatinib.
[0147] For oral administration in the context of treatment of
pulmonary fibrosis high oral doses are required to achieve plasma
levels required for efficacious lung tissue exposure. However,
gastrointestinal side-effects and systemic toxicities have limited
the approved oral dose to a level restricted to the low end of the
efficacy and dose-response curve. In one embodiment, inhaled
tyrosine kinase inhibitor or salt thereof improves tyrosine kinase
inhibitor or salt thereof treatment effectiveness through increased
lung dose and improved compliance. In one embodiment, inhaled
imatinib or salt thereof, or a phenylaminopyrimidine derivative or
salt thereof improves imatinib or salt thereof, or
phenylaminopyrimidine derivative or salt thereof, treatment
effectiveness through increased lung dose and improved compliance.
In one embodiment, inhalation of a tyrosine kinase inhibitor or
salt thereof (e.g. with a nebulizer) delivers the tyrosine kinase
inhibitor or salt thereof directly to the lung and whole-body
dilution of the delivered dose is minimized. In one embodiment,
inhalation of imatinib or salt thereof, or a phenylaminopyrimidine
derivative or salt thereof (e.g. with a nebulizer) delivers
imatinib or salt thereof, or a phenylaminopyrimidine derivative or
salt thereof directly to the lung and whole-body dilution of the
delivered dose is minimized. In some embodiments, inhalation of
tyrosine kinase inhibitor or salt thereof reduces or eliminates GI
exposure and/or systemic toxicities that are common with oral
administration of the tyrosine kinase inhibitor or salt thereof. In
some embodiments, inhalation of imatinib or salt thereof reduces or
eliminates GI exposure and/or systemic toxicities that are common
with oral administration of imatinib or salt thereof. In some
embodiments, inhalation delivery of tyrosine kinase inhibitor or
salt thereof provided herein provides higher lung tissue levels of
tyrosine kinase inhibitor or salt thereof than is possible through
oral administration. In some embodiments, inhalation delivery of
imatinib or salt thereof, provided herein provides higher lung
tissue levels of imatinib or salt thereof, than is possible through
oral administration. In some embodiments, inhalation delivery of
tyrosine kinase inhibitor or salt thereof serves as an efficient
means of delivering tyrosine kinase inhibitor or salt thereof to
the systemic compartment. In some embodiments, inhalation delivery
of imatinib or salt thereof, or a phenylaminopyrimidine derivative
or salt thereof serves as an efficient means of delivering imatinib
or salt thereof, or a phenylaminopyrimidine derivative or salt
thereof to the systemic compartment. In some embodiments,
inhalation delivery of tyrosine kinase inhibitor or salt thereof
provides Cmax and AUC benefits over the oral route. In some
embodiments, inhalation delivery of imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof provides Cmax and
AUC benefits over the oral route. In some embodiments, inhalation
delivery of tyrosine kinase inhibitor or salt thereof provides Cmax
and AUC benefits over the oral route, wherein plasma re-circulated,
aerosol-delivered tyrosine kinase inhibitor or salt thereof
maintains these beneficial properties. In some embodiments,
inhalation delivery of imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof provides Cmax and
AUC benefits over the oral route, wherein plasma re-circulated,
aerosol-delivered imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof maintains these
beneficial properties. In some embodiments, the methods described
herein may be used to treat patients diagnosed with
mild-to-moderate IPF. In some embodiments, the methods described
herein may be used to treat patients diagnosed with mild-to-severe
IPF. In some embodiments, the methods described herein may be used
to treat patients diagnosed with mild-to-moderate IPF without the
need to initially dose-escalate the patient. In some embodiments,
the methods described herein may be used to treat patients
diagnosed with mild-to-severe IPF without the need to initially
dose-escalate the patient. In some embodiments, the methods
described herein may be used to treat patients diagnosed with
mild-to-moderate IPF without the need to monitor and dose-reduce or
stop therapy due to adverse events. In some embodiments, the
methods described herein may be used to treat patients diagnosed
with mild-to-severe IPF without the need to monitor and dose-reduce
or stop therapy due to adverse events. In some embodiments, the
methods described herein may be used to provide a prophylactic
therapy to patients diagnosed with mild-to-moderate IPF. In some
embodiments, the methods described herein may be used to provide a
prophylactic therapy to patients diagnosed with mild-to-severe IPF.
In some embodiments, the methods described herein may be used to
provide a prophylactic therapy to patients diagnosed with
mild-to-moderate IPF without the need to monitor and dose-reduce or
stop therapy due to adverse events. In some embodiments, the
methods described herein may be used to provide a prophylactic
therapy to patients diagnosed with mild-to-severe IPF without the
need to monitor and dose-reduce or stop therapy due to adverse
events. In some embodiments, the methods described herein may be
used to slow disease progression of patients diagnosed with
mild-to-moderate IPF without the need to initially dose-escalate
the patient. In some embodiments, the methods described herein may
be used to slow disease progression of patients diagnosed with
mild-to-severe IPF without the need to initially dose-escalate the
patient. In some embodiments, the methods described herein may be
used to slow disease progression of patients diagnosed with
mild-to-moderate IPF without the need to monitor and dose-reduce or
stop therapy due to adverse events. In some embodiments, the
methods described herein may be used to slow disease progression of
patients diagnosed with mild-to-severe IPF without the need to
monitor and dose-reduce or stop therapy due to adverse events. By
non-limiting example, clinical end points of IPF efficacy include
reduced decline in forced vital capacity (FVC), reduced decline in
distance walked over a six-minute interval (six-minute walk test;
6MWT), slowed decline in carbon monoxide diffusion capacity (DLCO),
improved progression-free survival (PFS), reduced mortality and
monitoring changes in biomarkers such as MMP7, CCL18 and KL6.
[0148] In some embodiments the methods described herein provide for
delivery of high concentration, readily bioavailable tyrosine
kinase inhibitor or salt thereof compound which in turn provides
improved efficacy over tyrosine kinase inhibitor or salt thereof
compound administered by the oral route or by inhalation of a
slow-dissolving or otherwise slowly bioavailable compound
formulation. In some embodiments, such slow-dissolving or otherwise
slowly bioavailable compound formulations for inhalation include,
but are not limited to a dry powder formulation, a liposomal
formulation, a nano-suspension formulation, or a micro-suspension
formulation. In some embodiments, the aqueous solutions of tyrosine
kinase inhibitor or salt thereof described and contemplated herein
for administration by inhalation are completely homogeneous and
soluble.
[0149] In some embodiments the methods described herein provide for
delivery of high concentration, readily bioavailable imatinib or
salt thereof, or a phenylaminopyrimidine derivative or salt thereof
compound which in turn provides improved efficacy over imatinib or
salt thereof, or a phenylaminopyrimidine derivative or salt thereof
compound administered by the oral route or by inhalation of a
slow-dissolving or otherwise slowly bioavailable compound
formulation. In some embodiments, such slow-dissolving or otherwise
slowly bioavailable compound formulations for inhalation include,
but are not limited to a dry powder formulation, a liposomal
formulation, a nano-suspension formulation, or a micro-suspension
formulation. In some embodiments, the aqueous solutions of imatinib
or salt thereof, or a phenylaminopyrimidine derivative or salt
thereof described and contemplated herein for administration by
inhalation are completely homogeneous and soluble.
[0150] In some embodiments, an obstacle to patient compliance with
oral imatinib therapy is GI intolerability. Imatinib blood levels
may also be important has they have been implicated in other
observed toxicities. Thus, factors contributing to increased blood
levels must be considered. For the oral route of administration,
toxicity and GI intolerability have limited the dose range from 400
mg or 600 mg once a day to 400 mg twice a day. The most common side
effects include nausea, diarrhoea, headaches, leg aches/cramps,
fluid retention, visual disturbances, itchy rash, lowered
resistance to infection, bruising or bleeding, loss of appetite,
weight gain, reduced number of blood cells (neutropenia,
thrombocytopenia, anemia), headache, and edema. Secondly, imatinib
mainly metabolised via the liver enzyme CYP3A4. Substances
influencing the activity of this enzyme change the plasma
concentration of the drug. An example of a drug that increases
imatinib activity and therefore side effects by blocking CYP3A4 is
ketoconazole. The same could be true of itraconazole,
clarithromycin, grapefruit juice, among others. Conversely, CYP3A4
inductors like rifampicin and St. John's Wort reduce the drug's
activity, risking therapy failure. Imatinib also acts as an
inhibitor of CYP3A4, 2C9 and 2D6, increasing the plasma
concentrations of a number of other drugs like simvastatin,
ciclosporin, pimozide, warfarin, metoprolol, and possibly
paracetamol. The drug also reduces plasma levels of levothyroxin
via an unknown mechanism. As with other immunosuppressants,
application of live vaccines is contraindicated because the
microorganisms in the vaccine could multiply and infect the
patient. Inactivated and toxoid vaccines do not hold this risk, but
may not be effective under imatinib therapy.
[0151] As many products effecting CYP enzymes are useful to
fibrosis patients, permitting their use would be beneficial. While
the oral route is already at the maximum permissible dose (which
provides only moderate efficacy), any inhibition of the enzymes
described above elevates imatinib blood levels and increases the
rate and severity of the toxic events described herein. In some
embodiments oral inhalation and intranasal inhalation delivery of
tyrosine kinase inhibitor or salt thereof can achieve effective
tissue levels with much less drug than that required by the oral
product, and in some embodiments result in blood levels are
significantly lower and consequences associated with CYP enzyme
inhibitory properties described herein are removed. In some
embodiments oral inhalation and intranasal inhalation delivery of
imatinib or salt thereof, or a phenylaminopyrimidine derivative or
salt thereof can achieve effective tissue levels with much less
drug than that required by the oral product, and in some
embodiments result in blood levels are significantly lower and
consequences associated with CYP enzyme inhibitory properties
described herein are removed. In some embodiments, use of these CYP
inhibitory enzyme products currently contraindicated with the oral
medicine may be administered with the tyrosine kinase inhibitor or
salt thereof. In some embodiments, use of these CYP inhibitory
enzyme products currently contraindicated with the oral medicine
may be administered with imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof.
[0152] In some embodiments, administration of imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound by
inhalation has reduced gastroinstestinal side-effects when compared
to oral administration. In some embodiments, the reduced
gastroinstestinal side-effects with administration by inhalation
avoids the need for initial dose-escalation. In some embodiments,
administration of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof by inhalation avoids or substantially avoids the
gastrointestinal tract and therefore effects observed with oral
administration of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound will be minimized or not present. In some
embodiments, the lack of food effects with administration by
inhalation will allow for full dose delivery.
[0153] In some embodiments, pharmaceutical compositions described
herein are used in the treatment of lung disease in mammal. In some
embodiments, the pharmaceutical compositions described herein are
administered to a mammal by oral inhalation or intranasal
inhalation methods for the purpose of treating lung disease in the
mammal. In some embodiments, lung disease includes, but is not
limited to, pulmonary fibrosis, idiopathic pulmonary fibrosis,
radiation induced fibrosis, silicosis, asbestos induced pulmonary
or pleural fibrosis, acute lung injury, acute respiratory distress
syndrome (ARDS), sarcoidosis, usual interstitial pneumonia (UIP),
cystic fibrosis, Chronic lymphocytic leukemia (CLL)-associated
fibrosis, Hamman-Rich syndrome, Caplan syndrome, coal worker's
pneumoconiosis, cryptogenic fibrosing alveolitis, obliterative
bronchiolitis, chronic bronchitis, emphysema, pneumonitis, Wegner's
granulamatosis, lung scleroderma, silicosis, interstitial lung
disease, asbestos induced pulmonary and/or pleural fibrosis. In
some embodiments, lung disease is lung fibrosis (i.e. pulmonary
fibrosis). In some embodiments, lung disease is idiopathic
pulmonary fibrosis. In some embodiments, lung disease in cancer or
infectious. In some embodiments, the extrapulmonary disease is
fibrosis, cancer or the result of an active or previous infection
or surgery.
[0154] Pulmonary Fibrosis
[0155] A method for treating or preventing progression of pulmonary
disease, comprising administering a tyrosine kinase inhibitor or
salt thereof to a middle to lower respiratory tract of a subject
having or suspected of having pulmonary disease through oral
inhalation of an aerosol comprising a tyrosine kinase inhibitor or
salt thereof. A method for treating or preventing progression of
pulmonary disease, comprising administering imatinib or salt
thereof, or a phenylaminopyrimidine derivative or salt thereof to a
middle to lower respiratory tract of a subject having or suspected
of having pulmonary disease through oral inhalation of an aerosol
comprising imatinib or salt thereof, or a phenylaminopyrimidine
derivative or salt thereof. In some embodiments, the pulmonary
disease is fibrosis. Pulmonary fibrosis may be treated with
tyrosine kinase inhibitors. In some embodiments, this may be
selected from a group of tyrosine kinases including SRC, BRC, ABL,
JAK2, FLT3, RET, TRK-A, FGFR1, FYN, Aurora B kinase, FGF, VEGF
receptor, IGF1R, KIT, PDGF receptor or combination thereof. In some
embodiments, pulmonary fibrosis includes interstitial pulmonary
fibrosis. In some embodiments, the subject is a subject being
mechanically ventilated. This group of disorders is characterized
by scarring of deep lung tissue, leading to shortness of breath and
loss of functional alveoli, thus limiting oxygen exchange.
Etiologies include inhalation of inorganic and organic dusts,
gases, fumes and vapors, use of medications, exposure to radiation,
and development of disorders such as hypersensitivity pneumonitis,
coal worker's pneumoconiosis, radiation, chemotherapy, transplant
rejection, silicosis, byssinosis and genetic factors.
[0156] IPF as described herein refers to "idiopathic pulmonary
fibrosis" and is in some embodiments a chronic disease that
manifests over several years and is characterized by scar tissue
within the lungs, in the absence of known provocation.
Exercise-induced breathlessness and chronic dry cough may be the
prominent symptoms. IPF belongs to a family of lung disorders known
as the interstitial lung diseases (ILD) or, more accurately, the
diffuse parenchymal lung diseases. Within this broad category of
diffuse lung diseases, IPF belongs to the subgroup known as
idiopathic interstitial pneumonia (IIP). There are seven distinct
IIPs, differentiated by specific clinical features and pathological
patterns. IPF is the most common form of IIP. It is associated with
the pathologic pattern known as usual interstitial pneumonia (UIP);
for that reason, IPF is often referred to as IPF/UIP. IPF is
usually fatal, with an average survival of approximately three
years from the time of diagnosis. There is no single test for
diagnosing pulmonary fibrosis; several different tests including
chest x-ray, pulmonary function test, exercise testing,
bronchoscopy and lung biopsy are used in conjunction with the
methods described herein.
[0157] Idiopathic pulmonary fibrosis (also known as cryptogenic
fibrosing alveolitis) is the most common form of interstitial lung
disease, and may be characterized by chronic progressive pulmonary
parenchymal fibrosis. It is a progressive clinical syndrome with
unknown etiology; the outcome is frequently fatal as no effective
therapy exists. In some embodiments, imatinib inhibits fibroblast
proliferation and differentiation related to collagen synthesis,
inhibits the production and activity of TGF-beta, reduces
production of fibronective and connective tissue growth factor,
inhibits TNF-alpha and I-CAM, increase production of IL-10, and/or
reduces levels of platelet-derived growth factor (PDGF) A and B in
belomycin-induced lung fibrosis. The imatinib methods and
compositions described herein may provide tolerability and
usefulness in patients with advanced idiopathic pulmonary fibrosis
and other lung diseases. In some embodiments, imatinib methods and
compositions described herein may provide tolerability and
usefulness in patients with mild to moderate idiopathic pulmonary
fibrosis. In some embodiments, increased patient survival, enhanced
vital capacity, reduced episodes of acute exacerbation (compared to
placebo), and/or slowed disease progression are observed following
imatinib treatment. In some embodiments inhaled delivery of
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
may be an effective means to prevent, manage or treat idiopathic
pulmonary fibrosis or other pulmonary fibrotic diseases.
[0158] The term "pulmonary fibrosis", includes all interstitial
lung disease associated with fibrosis. In some embodiments,
pulmonary fibrosis includes the term "idiopathic pulmonary
fibrosis" or "IPF". In some embodiments, pulmonary fibrosis, by
non-limiting example, may result from inhalation of inorganic and
organic dusts, gases, fumes and vapors, use of medications,
exposure to radiation or radiation therapy, and development of
disorders such as hypersensitivity pneumonitis, coal worker's
pneumoconiosis, chemotherapy, transplant rejection, silicosis,
byssinosis and genetic factors.
[0159] Exemplary fibrotic lung diseases for the treatment or
prevention using the methods described herein include, but are not
limited, idiopathic pulmonary fibrosis, pulmonary fibrosis
secondary to systemic inflammatory disease such as rheumatoid
arthritis, scleroderma, lupus, cryptogenic fibrosing alveolitis,
radiation induced fibrosis, sarcoidosis, scleroderma, chronic
asthma, silicosis, asbestos induced pulmonary or pleural fibrosis,
acute lung injury and acute respiratory distress (including
bacterial pneumonia induced, trauma induced, viral pneumonia
induced, ventilator induced, non-pulmonary sepsis induced, and
aspiration induced).
[0160] A method for treating or preventing progression of pulmonary
disease, comprising administering imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof to a middle to lower respiratory
tract of a subject having or suspected of having pulmonary disease
through oral inhalation of an aerosol comprising imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. In some
embodiments, the pulmonary disease is cancer. Several cancers may
be treated with tyrosine kinase inhibitors. In some embodiments,
these tyrosine kinases may be the result of fusion between the abl
(Albelson leukemia virus) proto-oncogene on chromosome 9 to the bcr
(breakpoint cluster region) gene on chromosome 22, resulting in the
production of an activated BCR-ABL protein tyrosine kinase. In some
embodiments, this may be selected from a group of tyrosine kinases
including SRC, BRC, ABL, JAK2, FLT3, RET, TRK-A, FGFR1, FYN, Aurora
B kinase, FGF, VEGF receptor, IGF1R, KIT, PDGF receptor or
combination thereof. In some embodiments, the pulmonary cancer is
small cell lung cancer. In some embodiments, the pulmonary cancer
is large cell carcinoma. In some embodiments, the pulmonary cancer
is mesothelioma. In some embodiments, the pulmonary cancer is lung
carcinoid tumors or bronchial cardinoids. In some embodiments, the
pulmonary cancer is secondary lung cancer resulting from metastatic
disease. In some embodiments, the pulmonary cancer is non-small
cell lung cancer. In some embodiments, the pulmonary cancer is
bronchioloalveolar carcinoma. In some embodiments, the pulmonary
cancer may be sarcoma. In some embodiments, the pulmonary cancer is
may be a lymphoma. In some embodiments, the subject is a subject
being mechanically ventilated.
[0161] A method for treating or preventing progression of an
extrapulmonary disease, comprising administering imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof to a middle to
lower respiratory tract of a subject having or suspected of having
extrapulmonary disease through oral inhalation of an aerosol
comprising imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof for purposes of pulmonary vascular absorption and
delivery to extrapulmonary diseased tissues. In some embodiments,
the extrapulmonary disease is cancer. Several cancers may be
treated with tyrosine kinase inhibitors. In some embodiments, these
tyrosine kinases may be the result of fusion between the abl
(Albelson leukemia virus) proto-oncogene on chromosome 9 to the bcr
(breakpoint cluster region) gene on chromosome 22, resulting in the
production of an activated BCR-ABL protein tyrosine kinase. In some
embodiments, this may be selected from a group of tyrosine kinases
including SRC, BRC, ABL, JAK2, FLT3, RET, TRK-A, FGFR1, FYN, Aurora
B kinase, FGF, VEGF receptor, IGF1R, KIT, PDGF receptor or
combination thereof. In some embodiments, this cancer is leukemia
or lymphoma. In some embodiments, the subject is identified as
having chronic myloid leukemia (CML). In some embodiments, the
subject is identified as having gastrointestinal stromal tumors
(GIST). In some embodiments, the subject is identified as having
relapsed or refractory Ph-positive Acute lymphoblastic leukemia
(ALL). In some embodiments, the subject is identified as having
myelodysplastic/myeloproliferative diseases associated with
platelet-derived growth factor receptor gene re-arrangements. In
some embodiments, the subject is identified as having aggressive
systemic mastocytosis (ASM) without or an unknown D816V c-KIT
mutation. In some embodiments, the subject is a subject being
mechanically ventilated. In some embodiments, the subject is
identified as having hypereosinophilic syndrome (HES) and/or
chronic eosinophilic leukemia (CEL) who have the
FIP1L1-PDGFR.alpha. fusion kinase (CHIC2 allele deletion) or
FIP1L1-PDGFR-alpha fusion kinase negative or unknown. In some
embodiments, the subject is identified as having unresectable,
recurrent and/or metastatic dermatofibrosarcoma protuberans.
[0162] A method for treating infectious disease, comprising
administering imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof to a middle to lower respiratory tract of a subject
having or suspected of having an infection through oral inhalation
of an aerosol comprising imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof for purposes of pulmonary exposure
and or pulmonary vascular absorption and delivery to extrapulmonary
diseased tissues, wherein the disease is selected from viral
infections. Several viral infections may be treated with tyrosine
kinase inhibitors. In some embodiments, these tyrosine kinases may
be selected from a group of tyrosine kinases including SRC, BRC,
ABL, JAK2, FLT3, RET, TRK-A, FGFR1, FYN, Aurora B kinase, FGF, VEGF
receptor, IGF1R, KIT, PDGF receptor or combination thereof. In some
embodiments, the subject is identified as having small pox. In some
embodiments, the subject is identified as having cytomegalovirus
(CMV). In some embodiments, the subject is identified as having
varicella-zoster virus (VZV). In some embodiments, the subject is
identified as having human immunodeficiency virus (HIV). In some
embodiments, the subject is identified as having herpes simplex
virus (HSV). In some embodiments, the subject is identified as
having influenza virus. In some embodiments, the subject is
identified as having polyomavirus BK (BKV). In some embodiments,
the subject is identified as having measles virus. In some
embodiments, the subject is identified as having mumps virus. In
some embodiments, the subject is identified as having rubella
virus. In some embodiments, the subject is identified as having
polio virus. In some embodiments, the subject is identified as
having West Nile Virus. In some embodiments, the subject is
identified as having Lyme disease. In some embodiments, the subject
is identified as having Subacute sclerosing panencephalitis. In
some embodiments, the subject is identified as having Progressive
multifocal leukoencephalopathy. In some embodiments, the subject is
identified as having meningitis. In some embodiments, the subject
is identified as having encephalitis. In some embodiments, the
subject is identified as having acute flaccid paralysis. In some
embodiments, the subject is identified as having polio virus. In
some embodiments, the subject is identified as having
poliomyelitis. In some embodiments, the subject is identified as
having Herpes simplex encephalitis. In some embodiments, the
subject is identified as having Enteroviral disease. In some
embodiments, the subject is identified as having lyme meningitis.
In some embodiments, the subject is identified as having Eastern
equine encephalitis. In some embodiments, the subject is identified
as having Western equine encephalitis. In some embodiments, the
subject is identified as having St. Louis encephalitis. In some
embodiments, the subject is identified as having rabies. In some
embodiments, the subject is identified as having La crosse
encephalitis. In some embodiments, the subject is identified as
having progressive rubella panencephalitis. In some embodiments,
the subject is identified as having varicella-zoster encephalitis.
In some embodiments, the subject is identified as having acute
measles encephalitis. In some embodiments, the subject is
identified as having mumps meningoencephalitis. In some
embodiments, the subject is a subject being mechanically
ventilated.
[0163] A method for treating infectious disease, comprising
administering imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof to the oral or nasal cavity of a subject having or
suspected of having neurologic infection through oral or intranasal
inhalation of an aerosol comprising imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof for purposes of pulmonary or nasal
vascular absorption and delivery to central nervous system, wherein
the disease is selected from viral infection. Several viral
infections may be treated with tyrosine kinase inhibitors. In some
embodiments, this may be selected from a group of tyrosine kinases
including SRC, BRC, ABL, JAK2, FLT3, RET, TRK-A, FGFR1, FYN, Aurora
B kinase, FGF, VEGF receptor, IGF1R, KIT, PDGF receptor or
combination thereof. In some embodiments, the subject is identified
as having cytomegalovirus (CMV). In some embodiments, the subject
is identified as having varicella-zoster virus (VZV). In some
embodiments, the subject is identified as having human
immunodeficiency virus (HIV). In some embodiments, the subject is
identified as having herpes simplex virus (HSV). In some
embodiments, the subject is identified as having influenza virus.
In some embodiments, the subject is identified as having
polyomavirus BK (BKV). In some embodiments, the subject is
identified as having measles virus. In some embodiments, the
subject is identified as having mumps virus. In some embodiments,
the subject is identified as having rubella virus. In some
embodiments, the subject is identified as having polio virus. In
some embodiments, the subject is identified as having West Nile
Virus. In some embodiments, the subject is identified as having
Lyme disease. In some embodiments, the subject is identified as
having Subacute sclerosing panencephalitis. In some embodiments,
the subject is identified as having Progressive multifocal
leukoencephalopathy. In some embodiments, the subject is identified
as having meningitis. In some embodiments, the subject is
identified as having encephalitis. In some embodiments, the subject
is identified as having acute flaccid paralysis. In some
embodiments, the subject is identified as having polio virus. In
some embodiments, the subject is identified as having
poliomyelitis. In some embodiments, the subject is identified as
having Herpes simplex encephalitis. In some embodiments, the
subject is identified as having Enteroviral disease. In some
embodiments, the subject is identified as having Lyme meningitis.
In some embodiments, the subject is identified as having Eastern
equine encephalitis. In some embodiments, the subject is identified
as having Western equine encephalitis. In some embodiments, the
subject is identified as having St. Louis encephalitis. In some
embodiments, the subject is identified as having rabies. In some
embodiments, the subject is identified as having La crosse
encephalitis. In some embodiments, the subject is identified as
having progressive rubella panencephalitis. In some embodiments,
the subject is identified as having varicella-zoster encephalitis.
In some embodiments, the subject is identified as having acute
measles encephalitis. In some embodiments, the subject is
identified as having mumps meningoencephalitis. In some
embodiments, the subject is a subject being mechanically
ventilated.
[0164] In one aspect, described herein is a method for treating
neurologic disease, comprising administering imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof to the oral or
nasal cavity of a subject having or suspected of having neurologic
disease through oral or intranasal inhalation of an aerosol
comprising imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof for purposes of pulmonary or nasal vascular absorption
and delivery to central nervous system, wherein the disease is
neurofibromatosis. In some embodiments, the subject is identified
as having neurofibromatosis type I. In some embodiments, the
subject is identified as having Alzheimer's disease. In some
embodiments, the subject is identified as having opiod tolerance.
In some embodiments, the subject is identified as having desmoid
tumor. In some embodiments, the subject is a subject being
mechanically ventilated.
[0165] Kidney Fibrosis
[0166] A method for treating or preventing progression of an
extrapulmonary disease, comprising administering imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof to a middle to
lower respiratory tract of a subject having or suspected of having
extrapulmonary disease through oral inhalation of an aerosol
comprising imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof for purposes of pulmonary vascular absorption and
delivery to extrapulmonary diseased tissues. In some embodiments,
the extrapulmonary disease is kidney fibrosis. Kidney fibrosis may
be treated with tyrosine kinase inhibitors. In some embodiments,
these tyrosine kinases may be the result of fusion between the abl
(Albelson leukemia virus) proto-oncogene on chromosome 9 to the bcr
(breakpoint cluster region) gene on chromosome 22, resulting in the
production of an activated BCR-ABL protein tyrosine kinase. In some
embodiments, this may be selected from a group of tyrosine kinases
including SRC, BRC, ABL, JAK2, FLT3, RET, TRK-A, FGFR1, FYN, Aurora
B kinase, FGF, VEGF receptor, IGF1R, KIT, PDGF receptor or
combination thereof. Kidney fibrosis may develop as a result of
chronic infection, obstruction of the ureter by calculi, malignant
hypertension, radiation therapy, transplant rejection, severe
diabetic conditions, or chronic exposure to heavy metals. In
addition, idiopathic glomerulosclerosis and renal interstitial
fibrosis have been reported in children and adults. Kidney fibrosis
correlates well with the overall loss of renal function. Studies
have shown that oral imatinib provides protective effect against
heavy metal challenge and fibrosis reversal following diabetic
challenge in rats. Additionally, the antifibrotic action of
imatinib in renal fibrosis following partial nephrectomy in rats
has also been shown. Moreover, clinical studies administering oral
imatinib have shown slowed renal function decline in focal
segmental glomeruloschlerosis patients. In some embodiments,
because the kidneys vasculature is immediately downstream of the
lung, inhaled delivery of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof may be an effective means to
prevent, manage or treat kidney fibrosis resulting from various
medical conditions or procedures without exposing the systemic
compartment to otherwise toxic drug levels associated with oral
administration.
[0167] The term "kidney fibrosis" by non-limiting example relates
to remodeling associated with or resulting chronic infection,
obstruction of the ureter by calculi, malignant hypertension,
radiation therapy, transplant rejection, severe diabetic conditions
or chronic exposure to heavy metals. In some embodiments, kidney
fibrosis correlates well with the overall loss of renal
function.
[0168] Heart and Kidney Toxicity
[0169] A method for treating or preventing progression of an
extrapulmonary disease, comprising administering imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof to a middle to
lower respiratory tract of a subject having or suspected of having
extrapulmonary disease through oral inhalation of an aerosol
comprising imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof for purposes of pulmonary vascular absorption and
delivery to extrapulmonary diseased tissues. In some embodiments,
the extrapulmonary disease is heart or kidney toxicity. Heart and
kidney toxicity may be treated with tyrosine kinase inhibitors. In
some embodiments, this may be selected from a group of tyrosine
kinases including SRC, BRC, ABL, JAK2, FLT3, RET, TRK-A, FGFR1,
FYN, Aurora B kinase, FGF, VEGF receptor, IGF1R, KIT, PDGF receptor
or combination thereof. Chemotherapeutic agents have toxic effects
upon multiple organ during therapy. By non-limiting example
doxorubicin has a broad spectrum of therapeutic activity against
various tumors. However, its clinical use is limited by its
undesirable systemic toxicity, especially in the heart and kidney.
Treatment with imatinib reduced the severity of doxorubicin-induced
toxicity as assessed by reduced mortality, diminished volume of
recovered fluid in the abdominal cavity, and severity of cardiac
and renal lesions at both the biochemical and morphological levels.
In some embodiments, because the heart and kidney vasculature are
immediately downstream of the lung, inhaled delivery of imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof may be an
effective means to prevent, manage or treat chemotherapy-induced
cardiac and/or renal inflammation without exposing the systemic
compartment to otherwise toxic drug levels associated with oral
administration. In some embodiments, inhaled delivery of imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof
compound is used in the treatment of heart toxicity and/or kidney
toxicity associated with chemotherapy or other therapeutic agents
in a human.
[0170] The term "heart toxicity" by non-limiting example may be
associated with or caused by exposure to chemotherapeutic agents
having toxic effects. By non-limiting example doxorubicin has a
broad spectrum of therapeutic activity against various tumors.
However, its clinical use is limited by its undesirable systemic
toxicity, especially in the heart and kidney.
[0171] The term "kidney toxicity" by non-limiting example may be
associated with or caused by exposure to chemotherapeutic agents
having toxic effects. By non-limiting example doxorubicin has a
broad spectrum of therapeutic activity against various tumors.
However, its clinical use is limited by its undesirable systemic
toxicity, especially in the heart and kidney.
[0172] Cardiac Fibrosis
[0173] A method for treating or preventing progression of an
extrapulmonary disease, comprising administering imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof to a middle to
lower respiratory tract of a subject having or suspected of having
extrapulmonary disease through oral inhalation of an aerosol
comprising imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof for purposes of pulmonary vascular absorption and
delivery to extrapulmonary diseased tissues. In some embodiments,
the extrapulmonary disease is cardiac fibrosis. Cardiac fibrosis
may be treated with tyrosine kinase inhibitors. In some
embodiments, this may be selected from a group of tyrosine kinases
including SRC, BRC, ABL, JAK2, FLT3, RET, TRK-A, FGFR1, FYN, Aurora
B kinase, FGF, VEGF receptor, IGF1R, KIT, PDGF receptor or
combination thereof. Cardiac remodeling as in chronic hypertension
involves myocyte hypertrophy as well as fibrosis, an increased and
non-uniform deposition of extracellular matrix proteins. The
extracellular matrix connects myocytes, aligns contractile
elements, prevents overextending and disruption of myocytes,
transmits force and provides tensile strength to prevent rupture.
Fibrosis occurs in many models of hypertension leading to an
increased diastolic stiffness, a reduction in cardiac function and
an increased risk of arrhythmias. If fibrosis rather than myocyte
hypertrophy is the critical factor in impaired cardiovascular
function, then reversal of cardiac fibrosis by itself may return
cardiac function towards normal. Since collagen deposition is a
dynamic process, appropriate pharmacological intervention could
selectively reverse existing fibrosis and prevent further fibrosis
and thereby improve function, even if the increased systolic blood
pressure was unchanged.
[0174] Treatment of DOCA-salt hypertensive rats with imatinib
reversed and prevented fibrosis. Suggesting that imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof therapy may be an
effective means to attenuate cardiac fibrosis associated with
chronic hypertension and also the functional impairment of the
heart in hypertensive humans. Moreover, the reversal of fibrosis
following imatinib treatment of streptozotocin-diabetic rats was
also shown (Miric et al., 2001). Together, and because the heart
vasculature are immediately downstream of the lung, inhaled
delivery of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof may be an effective means to prevent, manage or treat
cardiac fibrosis resulting from various medical conditions or
procedures, including by non-limiting example viral or bacterial
infection, surgery, Duchenne muscular dystrophy, radiation,
chemotherapy, and transplant rejection.
[0175] The term "cardiac fibrosis" by non-limiting example relates
to remodeling associated with or resulting from viral or bacterial
infection, surgery, Duchenne muscular dystrophy, radiation therapy,
chemotherapy, transplant rejection and chronic hypertension where
myocyte hypertrophy as well as fibrosis is involved and an
increased and non-uniform deposition of extracellular matrix
proteins occurs. Fibrosis occurs in many models of hypertension
leading to an increased diastolic stiffness, a reduction in cardiac
function, an increased risk of arrhythmias and impaired
cardiovascular function.
[0176] Hepatic Fibrosis
[0177] A method for treating or preventing progression of an
extrapulmonary disease, comprising administering imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof to a middle to
lower respiratory tract of a subject having or suspected of having
extrapulmonary disease through oral inhalation of an aerosol
comprising imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof for purposes of pulmonary vascular absorption and
delivery to extrapulmonary diseased tissues. In some embodiments,
the extrapulmonary disease is hepatic fibrosis. hepatic fibrosis
may be treated with tyrosine kinase inhibitors. In some
embodiments, this may be selected from a group of tyrosine kinases
including SRC, BRC, ABL, JAK2, FLT3, RET, TRK-A, FGFR1, FYN, Aurora
B kinase, FGF, VEGF receptor, IGF1R, KIT, PDGF receptor or
combination thereof. Hepatic fibrosis occurs consequence of severe
liver damage in patients with chronic liver disease, caused by
non-limiting example persistent viral hepatitis, alcohol overload
and autoimmune. Hepatic fibrosis involves an abnormal accumulation
of extracellular matrix components, particularly collagens. Hepatic
stellate cells are non-parenchymal liver cells residing in the
perisinusoidal space. These cells have been shown to be the major
cellular source of extracellular matrix in hepatic fibrosis.
Studies have shown that oral imatinib provides protective effect
against dimethylnitrosamine-induced hepatic fibrosis in preventing
weight loss, suppressed loss in liver weight, suppressed induction
of hepatic fibrosis determined by histological evaluation and
reduced hepatic hydroxyproline levels. Expression of mRNA for type
I collagen and transforming growth factor-beta in the liver were
also suppressed by imatinib treatment. Additionally, clinical
studies administering oral imatinib have shown decreased fibrosis
and improved quality of life in Hepatitis C viral-related liver
disease patients. Together, and because the liver vasculature is
downstream of the lung, these results suggest that inhaled delivery
of imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
may be an effective means to prevent, manage or treat hepatic
fibrosis resulting from various medical conditions or procedures
without exposing the systemic compartment to otherwise toxic drug
levels associated with oral administration.
[0178] The term "hepatic fibrosis" by non-limiting example may be
associated with or caused by severe liver damage in patients with
chronic liver disease, caused by non-limiting example persistent
viral hepatitis, alcohol overload and autoimmune diseases. Hepatic
fibrosis involves an abnormal accumulation of extracellular matrix
components, particularly collagens. Hepatic stellate cells are
non-parenchymal liver cells residing in the perisinusoidal
space.
[0179] Glaucoma Surgery Post-Operative Fibrosis
[0180] A method for treating or preventing progression of an
extrapulmonary disease, comprising administering imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof directly to the
diseased extrapulmonary tissue; either directly to the tissue prior
to completing the surgery and/or post-operatively. In some
embodiments, the extrapulmonary disease is post-operative fibrosis
following glaucoma surgery. Post-operative fibrosis may be treated
with tyrosine kinase inhibitors. In some embodiments, this may be
selected from a group of tyrosine kinases including SRC, BRC, ABL,
JAK2, FLT3, RET, TRK-A, FGFR1, FYN, Aurora B kinase, FGF, VEGF
receptor, IGF1R, KIT, PDGF receptor or combination thereof. The
success of glaucoma filtration surgery is dependent on the degree
of post-operative wound healing and the amount of scar tissue
formation. Bleb failure occurs as fibroblasts proliferate and
migrate toward the wound, eventually causing scarring and closure
of the fistula tract. This frequently leads to poor postoperative
intraocular pressure control with subsequent progressive optic
nerve damage. The use of adjunctive antifibrotic agents such as
5-fluorouracil and mitomycin C has significantly improved the
success rate of filtration surgery. However, because of their
nonspecific mechanisms of action, these agents can cause widespread
cell death and apoptosis, resulting in potentially
sight-threatening complications such as severe postoperative
hypotony, bleb leaks, and endophthalmitis. Thus, alternative
antifibrotic agents are needed. For this purpose, the anti-fibrotic
agent imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt thereof
may prove beneficial.
[0181] Cancer
[0182] Lung cancer mortality is high, and annual lung cancer deaths
equal prostate, breast, colon, and rectum cancers combined. Despite
the advancement in knowledge on molecular mechanisms and the
introduction of multiple new therapeutic lung cancer agents, the
dismal 5-year survival rate (11-15%) remains relatively unaltered.
This reflects the limited available knowledge on factors promoting
oncogenic transformation to and proliferation of malignant
cells.
[0183] Until recent years, the principal focus in cancer research
has mostly been the malignant cell itself. As a consequence, today,
there is a significant discrepancy between the vast knowledge about
cancer biology generated in experimental settings and the
translation of this knowledge into information that can be used in
clinical decision making. Understanding the nature of the tumor
environment today may be equally important for future cancer
therapies as understanding cancer genetics per se. Cancers are not
simply autonomous neoplastic cells but also composed of
fibroblasts, immune cells, endothelial cells, and specialized
mesenchymal cells. These different cell types in the stromal
environment can be recruited by malignant cells to support tumor
growth and facilitate metastatic dissemination.
[0184] Although the "seed and soil" hypothesis was presented more
than a century ago, we are now starting to comprehend the complex
crosstalk between the tumor cells (the "seeds") and the
tumor-growing microenvironment (the "soil"). We now know that tumor
growth is not determined only by malignant cells, because
interactions between cancer cells and the stromal compartment have
major impacts on cancer growth and progression. Aggressive
malignant cells are clever at exploiting the tumor
microenvironment: tumor cells can (1) reside in the stroma and
transform it, (2) alter the surrounding connective tissue, and (3)
modify the metabolism of resident cells, thus yielding a stroma,
which is permissive rather than defensive.
[0185] Beyond overcoming the microenvironmental control by the
host, key characteristics of cancer cells is their ability to
invade the tissue and metastasize distantly. For invasion and
metastasis, the concerted interactions between fibroblasts, immune
cells, and angiogenic cells and factors are essential.
[0186] The tumor stroma basically consists of (1) the nonmalignant
cells of the tumor such as CAFs, specialized mesenchymal cell types
distinctive to each tissue environment, innate and adaptive immune
cells, and vasculature with endothelial cells and pericytes and (2)
the extracellular matrix (ECM) consisting of structural proteins
(collagen and elastin), specialized proteins (fibrilin,
fibronectin, and elastin), and proteoglycans. Angiogenesis is
central for cancer cell growth and survival and has hitherto been
the most successful among stromal targets in anticancer therapy.
Initiation of angiogenesis requires matrix metalloproteinase (MMP)
induction leading to degradation of the basement membrane,
sprouting of endothelial cells, and regulation of pericyte
attachment. However, CAFs play an important role in synchronizing
these events through the expression of numerous ECM molecules and
growth factors, including transforming growth factor (TGF)-.beta.,
vascular endothelial growth factor (VEGF), and fibroblast growth
factor (FGF2).
[0187] The normal tissue stroma is essential for maintenance and
integrity of epithelial tissues and contains a multitude of cells
that collaborate to sustain normal tissue homeostasis. There is a
continuous and bilateral molecular crosstalk between normal
epithelial cells and cells of the stromal compartment, mediated
through direct cell-cell contacts or by secreted molecules. Thus,
minor changes in one compartment may cause dramatic alterations in
the whole system.
[0188] A similarity exists between stroma from wounds and tumors,
because both entities had active angiogenesis and numerous
proliferating fibroblasts secreting a complex ECM, all on a
background of fibrin deposition. Consequently, the tumor stroma has
been commonly referred to as activated or reactive stroma.
[0189] A genetic alteration during cancer development, leading to a
malignant cell, will consequently change the stromal host
compartment to establish a permissive and supportive environment
for the cancer cell. During early stages of tumor development and
invasion, the basement membrane is degraded, and the activated
stroma, containing fibroblasts, inflammatory infiltrates, and newly
formed capillaries, comes into direct contact with the tumor cells.
The basement membrane matrix also modifies cytokine interactions
between cancer cells and fibroblasts. These cancer-induced
alterations in the stroma will contribute to cancer invasion.
Animal studies have shown that both wounding and activated stroma
provides oncogenic signals to facilitate tumorigenesis. Although
normal stroma in most organs contains a minimal number of
fibroblasts in association with physiologic ECM, the activated
stroma is associated with more ECM-producing fibroblasts, enhanced
vascularity, and increased ECM production. This formation of a
specific tumor stroma type at sites of active tumor cell invasion
is considered an integral part of the tumor invasion and has been
termed as tumor stromatogenesis.
[0190] The expansion of the tumor stroma with a proliferation of
fibroblasts and dense deposition of ECM is termed a desmoplastic
reaction. It is secondary to malignant growth and can be separated
from alveolar collapse, which do not show neither activated
fibroblasts nor the dense collagen/ECM. Morphologically this is
termed desmoplasia and was initially conceived as a defense
mechanism to prevent tumor growth, but data have shown that in
established tumors, this process, quite oppositely, participates in
several aspects of tumor progression, such as angiogenesis,
migration, invasion, and metastasis. The latter studies show that
fibroblasts and tumor cells can enhance local tissue growth and
cancer progression through secreting ECM and degrading components
of ECM within the tumor stroma. This is in part related to the
release of substances sequestered in the ECM, such as VEGF, and
cleavage of products from ECM proteins as a response to secretion
of carcinoma-associated MMPs.
[0191] Profibrotic growth factors, released by cancer cells, such
as TGF-.beta., platelet-derived growth factor (PDGF), and FGF2
govern the volume and composition of the tumor stroma as they are
all key mediators of fibroblast activation and tissue fibrosis.
PDGF and FGF2 play significant roles in angiogenesis as well.
[0192] In tumors, activated fibroblasts are termed as peritumoral
fibroblasts or carcinoma-associated fibroblasts (CAFs). CAFs, like
activated fibroblasts, are highly heterogeneous and believed to
derive from the same sources as activated fibroblasts. The main
progenitor seems to be the locally residing fibroblast, but they
may also derive from pericytes and smooth muscle cells from the
vasculature, from bone marrow-derived mesenchymal cells, or by
epithelial or endothelial mesenchymal transition. The term CAF is
rather ambiguous because of the various origins from which these
cells are derived, as is the difference between activated
fibroblasts and CAFs. There are increasing evidence for epigenetic
and possibly genetic distinctions between CAFs and normal
fibroblasts. CAFs can be recognized by their expression of a-smooth
muscle actin, but due to heterogeneity .alpha.-smooth muscle actin
expression alone will not identify all CAFs. Hence, other used CAF
markers are fibroblast-specific protein 1, fibroblast activation
protein (FAP), and PDGF receptor (PDGFR) .alpha./.beta..
[0193] In response to tumor growth, fibroblasts are activated
mainly by TGF-.beta., chemokines such as monocyte chemotactic
protein 1, and ECM-degrading agents such as MMPs. Although normal
fibroblasts in several in vitro studies have demonstrated an
inhibitory effect on cancer progression, today, there is solid
evidence for a cancer-promoting role of CAFs. In breast carcinomas,
as much as 80% of stromal fibroblasts are considered to have this
activated phenotype (CAFs).
[0194] CAFs promote malignant growth, angiogenesis, invasion, and
metastasis. The roles of CAFS and their potential as targets for
cancer therapy have been studied in xenografts models, and evidence
from translational studies has revealed a prognostic significance
of CAFs in several carcinoma types.
[0195] In the setting of tumor growth, CAFs are activated and
highly synthetic, secreting, for example, collagen type I and IV,
extra domain A-fibronectin, heparin sulfate proteoglucans, secreted
protein acidic and rich in cysteine, tenascin-C, connective tissue
growth factors, MMPs, and plasminogen activators. In addition to
secreting growth factors and cytokines, which affect cell motility,
CAFs are an important source for ECM-degrading proteases such as
MMPs that play several important roles in tumorigenesis. Through
degradation of ECM, MMPs can, depending on substrate, promote tumor
growth, invasion, angiogenesis, recruitment of inflammatory cells,
and metastasis. Besides, a number of proinflammatory cytokines seem
to be activated by MMPs.
[0196] After injection of B16M melanoma cells in mice, the
formation of liver metastases was associated with an early
activation of stellate cells (fibroblast-like) in the liver, as
these seemed important for creating a metastatic niche and
promoting angiogenesis. MMPs have also been linked to tumor
angiogenesis in various in vivo models. CAFs, when coinjected into
mice, facilitated the invasiveness of otherwise noninvasive cancer
cells. Furthermore, xenografts containing CAFs apparently grow
faster than xenografts infused with normal fibroblasts.
[0197] At CAF recruitment and accumulation in the tumor stroma,
these cells will actively communicate with cancer cells, epithelial
cells, endothelial cells, pericytes, and inflammatory cells through
secretion of several growth factors, cytokines, and chemokines.
CAFs provide potent oncogenic molecules such as TGF-.beta. and
hepatocyte growth factor (HGF).
[0198] TGF-.beta. is a pleiotropic growth factor expressed by both
cancer and stromal cells. TGF-.beta. is, in the normal and
premalignant cells, a suppressor of tumorigenesis, but as cancer
cells progress, the antiproliferative effect is lost, and instead,
TGF-.beta. promotes tumorigenesis by inducing differentiation into
an invasive phenotype. TGF-.beta. may also instigate cancer
progression through escape from immunosurveillance, and increased
expression of TGF-.beta. correlate strongly with the accumulation
of fibrotic desmoplastic tissue and cancer progression. Recently, a
small molecule inhibitor of TGF-.beta. receptor type I was reported
to inhibit the production of connective tissue growth factor by
hepatocellular carcinoma (HCC) cells, resulting in reduced stromal
component of the HCCs. Inhibition of the TGF-.beta. receptor
aborted the crosstalk between HCCs and CAFs and consequently
avoided tumor proliferation, invasion, and metastasis. HGF belongs
to the plasminogen family and is tethered to ECM in a precursor
form. It binds to the high-affinity receptor c-met, and
overexpression or constant oncogenic c-Met signaling lead to
proliferation, invasion, and metastasis.
[0199] PDGFs are regulators of fibroblasts and pericytes and play
important roles in tumor progression. It is a chemotactic and
growth factor for mesenchymal and endothelial cells. It has a
limited autocrine role in tumor cell replication, but is a
potential player, in a paracrine fashion, and in tumor stroma
development. It induces the proliferation of activated fibroblasts
and possibly recruits CAFs indirectly by stimulation of TGF-.beta.
release from macrophages.
[0200] A tumor cannot develop without the parallel expansion of a
tumor stroma. Although we still do not comprehend the exact
mechanisms regulating fibroblast activation and their accumulation
in cancer, the available evidence points to the possibility that
the tumor stroma or CAFs may be candidate targets for cancer
treatment.
[0201] CAFs and MMPs have been considered two of the key regulators
of epithelial-derived tumors representing potential new targets for
integrative therapies, affecting both the transformed and
nontransformed components of the tumor environment. As commented
earlier, the experience with MMP inhibitors have so far been
unsuccessful. Evidence that CAFs are epigenetically and possibly
also genetically distinct from normal fibroblasts is beginning to
define these cells as potential targets for anticancer therapy.
FAP, expressed in more than 90% of epithelial carcinomas, emerged
early as a promising candidate for targeting CAFs, and the
potential therapeutic benefit of its inhibition was reviewed
recently. In preclinical studies, abrogation of FAP attenuates
tumor growth and significantly enhance tumor tissue uptake of
anticancer drugs. In a phase I study, where patients with
FAP-positive advanced carcinomas (colorectal cancer and NSCLC) were
treated with FAP-antibody, the antibody bound specifically to tumor
sites, but no objective responses were observed.
[0202] The consistent and repeated findings of cancer cells that
readily undergo invasion and metastasis in response to TGF-.beta.
have pointed to the need of novel anticancer agents targeting the
oncogenic activities of TGF-.beta.. A large number of
anti-TGF-.beta. antibodies and TGF-.beta.-receptor I kinases have
been tested preclinically during the past decade. Because of the
lack of success, targeting of the TGF-.beta. signaling system still
remains elusive. It should be noted that both protumoral and
antitumoral effects have been assigned to TGF-.beta., and the
multifunctional nature of TGF-.beta. apparently represents the
greatest barrier to effectively target this ligand, its receptor,
or downstream effectors.
[0203] Pulmonary Hypertension
[0204] Pulmonary arterial hypertension (PAH) is a life-threatening
disease characterized by a marked and sustained elevation of
pulmonary artery pressure. The disease results in right ventricular
failure and death. Current therapeutic approaches for the treatment
of chronic pulmonary hypertension mainly provide symptomatic
relief, as well as some improvement of prognosis. Although
postulated for all treatments, evidence for direct
antiproliferative effects of most approaches is missing. In
addition, the use of most of the currently applied agents is
hampered by either undesired side effects or inconvenient drug
administration routes. Pathological changes in hypertensive
pulmonary arteries include endothelial injury, proliferation, and
hypercontraction of vascular smooth muscle cells (SMCs).
[0205] The World Health Organization divides pulmonary hypertension
(PH) into five groups. These groups are organized based on the
cause of the condition and treatment options. In all groups, the
average pressure in the pulmonary arteries is 25 mmHg or higher.
The pressure in normal pulmonary arteries is 8-20 mmHg at rest.
(Note that group 1 is called pulmonary arterial hypertension (PAH)
and groups 2 through 5 are called pulmonary hypertension. However,
together all groups are called pulmonary hypertension.) Group 1
Pulmonary Arterial Hypertension includes PAH that has no known
cause; PAH that's inherited; PAH that's caused by drugs or toxins,
such as street drugs and certain diet medicines; PAH that's caused
by conditions such as: Connective tissue diseases, HIV infection,
Liver disease, Congenital heart disease. This is heart disease
that's present at birth, Sickle cell disease, Schistosomiasis. This
is an infection caused by a parasite. Schistosomiasis is one of the
most common causes of PAH in many parts of the world; and PAH that
is caused by conditions that affect the veins and small blood
vessels of the lungs. Group 2 Pulmonary Hypertension includes PH
with left heart disease. Conditions that affect the left side of
the heart, such as mitral valve disease or long-term high blood
pressure, can cause left heart disease and PH. Left heart disease
is likely the most common cause of PH. Group 3 Pulmonary
Hypertension includes PH associated with lung diseases, such as
COPD (chronic obstructive pulmonary disease) and interstitial lung
diseases. Interstitial lung diseases cause scarring of the lung
tissue. Group 3 also includes PH associated with sleep-related
breathing disorders, such as sleep apnea. Group 4 Pulmonary
Hypertension includes PH caused by blood clots in the lungs or
blood clotting disorders. Group 5 Pulmonary Hypertension includes
PH caused by various other diseases or conditions. Examples
include: Blood disorders, such as polycythemia vera and essential
thrombocythemia, Systemic disorders, such as sarcoidosis and
vasculitis. Systemic disorders involve many of the body's organs,
metabolic disorders, such as thyroid disease and glycogen storage
disease. (In glycogen storage disease, the body's cells don't use a
form of glucose properly.), and other conditions, such as tumors
that press on the pulmonary arteries and kidney disease.
[0206] Several growth factors have been implicated in the abnormal
proliferation and migration of SMCs, including PDGF, basic FGF
(bFGF), and EGF. In vitro studies established that PDGF acts as a
potent mitogen and chemoattractant for SMCs. Active PDGF is built
up by polypeptides (A and B chain) that form homo- or heterodimers
and stimulate .alpha. and .beta. cell surface receptors. Recently,
two additional PDGF genes were identified, encoding PDGF-C and
PDGF-D polypeptides. The PDGF receptors (PDGFRs) belong to a family
of transmembrane receptor tyrosine kinases (RTKs) and are supposed
to be held together by the bivalent PDGF ligands. This complex of
dimeric receptor and PDGF results in an autophosphorylation of the
RTK and an increase in kinase activity.
[0207] Both receptors activate the major signaling transduction
pathways, including Ras/MAPK, PI3K, and phospholipase C.gamma..
Recently, upregulation of both PDGFR.alpha. and PDGFR.beta. has
been shown in lambs with chronic intrauterine pulmonary
hypertension. Pulmonary PDGF-A or PDGF-B mRNA, however, did not
differ between pulmonary hypertensive and control animals. In lung
biopsies from patients with severe pulmonary arterial hypertension
(PAH), PDGF-A chain expression was significantly increased.
[0208] As altered PDGF signaling plays an important role in the
course of PAH, imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof may also have a positive effect on hemodynamics and
pulmonary vascular remodeling in PAH and serve as an
anti-remodeling therapy for this disease.
[0209] The present invention provides, in several embodiments as
herein disclosed, compositions and methods for imatinib and
phenylaminopyrimidine derivative compound formulations that offer
unprecedented advantages with respect to localized delivery of
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof in
a manner that permits both rapid and sustained availability of
therapeutically useful imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof levels to one or more desired
tissues.
[0210] In certain preferred embodiments, and as described in
greater detail below, delivery of the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound formulation is to the
respiratory tract tissues in mammalian subjects, for example, via
the respiratory airways to middle airways and/or pulmonary beds
(e.g., alveolar capillary beds) in human patients. According to
certain particularly preferred embodiments, delivery to these
regions of the lung may be achieved by inhalation therapy of an
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound formulation as described herein.
[0211] These and related embodiments will usefully provide
therapeutic and/or prophylactic benefit, by making therapeutically
effective imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof available to a desired tissue promptly upon
administration, while with the same administration event also
offering time periods of surprisingly sustained duration during
which locally delivered imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof is available for a prolonged
therapeutic effect.
[0212] The compositions and methods disclosed herein provide for
such rapid and sustained localized delivery of imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof to a wide variety
of tissues. Contemplated are embodiments for the treatment of
numerous clinically significant conditions including pulmonary
fibrosis, cancer, cystic fibrosis, cardiac fibrosis,
transplantation (e.g., lung, liver, kidney, heart, etc.), vascular
grafts, and/or other conditions such as infectious diseases for
which rapid and sustained bioavailable imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof therapy may be indicated.
[0213] Various embodiments thus provide compositions and methods
for optimal prophylactic and therapeutic activity in prevention and
treatment of pulmonary fibrosis in human and/or veterinary subjects
using aerosol administration, and through the delivery of
high-concentration (or dry formulation), sustained-release active
drug exposure directly to the affected tissue. Specifically, and in
certain preferred embodiments, concentrated doses are delivered of
an imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt
thereof.
[0214] Without wishing to be bound by theory, according to certain
of these and related embodiments as described in greater detail
herein, an imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof is provided in a formulation having components that
are selected to deliver an efficacious dose of imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof following
aerosolization of a liquid, dry powder or metered-dose formulation
providing rapid and sustained localized delivery of imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof to the site of
desired effect.
[0215] According to certain related embodiments, regulation of the
total amount of dissolved solutes in an imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound formulation is believed,
according to non-limiting theory, to result in aqueous imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof compound
formulations having therapeutically beneficial properties,
including the properties of nebulized liquid particles formed from
aqueous solutions of such formulations. Additionally, and as
disclosed herein, it has been discovered that within the parameters
provided herein as pertain to imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound concentration, pH, and
total solute concentration, tolerability of formulations at or near
the upper portion of the total solute concentration range can be
increased by inclusion of a taste-masking agent as provided
herein.
[0216] An unexpected observation is that exposure of inhaled
imatinib to the lung surface results in depletion of essential
lung-surface cations and increased propensity for acute toxicity.
The apparent mechanism for this depletion is imatinib's ability to
chelate ions such as iron(III) in a ratio of three imatinib
molecules per on iron(III) ion. Chelation of iron(III) occurs at
about one-half the chelation strength of EDTA. One method to
prevent lung-surface ion depletion is to formulation imatinib with
a multivalent ion. By non-limiting example, such multi-valent
cations may include iron(II), iron(III), calcium, magnesium, etc.
By non-limiting example, formulation of imatinib was found to
chelate magnesium at a ratio of two imatinib molecules to one
magnesium ion. Thus, formulation of between about two and ten
imatinib molecules with one magnesium molecule results in filling
or saturating the chelation capacity of imatinib and reduces
imatinib's to deplete lung-surface cations. Coupling this solution
with the need to adjust formulation osmolality and permeant ion
content, the salt form of multivalent ion may also be beneficial.
By non-limiting example, using magnesium chloride to formulate
imatinib reduces imatinib's ability to deplete essential
lung-surface cations, contributes to adjusting the formulations
osmolality and serves to provide the formulation a chloride
permeant ion. In certain such embodiments, for example, an imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof
compound formulation that comprises imatinib or salt thereof; or a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, alone or formulated with
excipients dissolved in a simple aqueous solution that may be
aerosolized and injected or inhaled to the nasal or pulmonary
compartment. Such a formulation may contain a multivalent cation
and/or be buffered to a pH from about 4.0 to about 11.0, more
preferably from about pH 4.0 to about pH 8.0, at a concentration of
at least 34 mcg/mL to about 463 mg/mL, and having a total
osmolality at least 100 mOsmol/kg to about 6000 mOsmol/kg, or 300
to about 5000 mOsmol/kg. Such a simple aqueous formulation may
further comprise a taste-masking agent thereby to become tolerable
for inhalation administration (i.e., to overcome undesirable taste
or irritative properties that would otherwise preclude effective
therapeutic administration). Hence and as described in greater
detail herein, regulation of formulation conditions with respect to
pH, buffer type, imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration, total osmolality and potential
taste-masking agent, provides certain therapeutic and other
advantages.
[0217] In certain such embodiments, for example, an imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof compound
formulation that comprises imatinib or salt thereof, or a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, in a dry powder formulation alone
or formulated with an excipient, such as a multivalent cation
providing improved stability and/or dispersion properties, such
that at least 0.1 mg to about 100 mg may be dispersed and injected
or inhaled to the nasal or pulmonary compartment. Hence and as
described in greater detail herein, regulation of formulation
conditions with respect to dispersion excipient, imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof stability
(including, by non-limiting example polymorph, amorphic content and
water content), imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof amount and potential taste-masking agent, provides
certain therapeutic and other advantages.
[0218] In certain such embodiments, for example, an imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof compound
formulation that comprises imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof in a pressurized meter-dose
inhaler configuration providing improved stability and/or aerosol
properties, such that at least 0.1 mg to about 100 mg may be
aerosolized and injected or inhaled to the nasal or pulmonary
compartment. Hence and as described in greater detail herein,
regulation of formulation conditions with respect to propellant,
suitable pressurized metered-dose inhaler canister, imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof stability
provides certain therapeutic and other advantages.
[0219] In certain preferred embodiments, an imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound
formulation or salts thereof may serve as prodrugs,
sustained-release or active substances in the presently disclosed
formulations and compositions and may be delivered, under
conditions and for a time sufficient to produce maximum
concentrations of sustained-release or active drug to the
respiratory tract (including pulmonary beds, nasal and sinus
cavities), and other non-oral topical compartments including, but
not limited to the skin, rectum, vagina, urethra, urinary bladder,
eye, and ear. As disclosed herein, certain particularly preferred
embodiments relate to administration, via oral and/or nasal
inhalation, of an imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound to the lower respiratory tract, in other
words, to the lungs or pulmonary compartment (e.g., respiratory
bronchioles, alveolar ducts, and/or alveoli), as may be effected by
such "pulmonary delivery" to provide effective amounts of the
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound to the pulmonary compartment and/or to other tissues and
organs as may be reached via the circulatory system subsequent to
such pulmonary delivery of the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound to the pulmonary
vasculature.
[0220] Because different drug products are known to have varying
efficacies depending on the dose, form, concentration and delivery
profile, certain presently disclosed embodiments provide specific
formulation and delivery parameters that produce anti-inflammatory,
anti-fibrotic, anti-demylination and/or tissue-remodeling results
that are prophylactic or therapeutically significant. These and
related embodiments thus include imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. As noted above, however, the
invention is not intended to be so limited and may relate,
according to particularly preferred embodiments, to imatinib or a
salt thereof. Other contemplated embodiments may relate to another
phenylaminopyrimidine derivative compound such as those disclosed
herein.
[0221] As a non-limiting example, in a preferred embodiment, a
phenylaminopyrimidine derivative compound as provided herein (e.g.,
imatinib) formulated to permit mist, gas-liquid suspension or
liquid nebulized, dry powder and/or metered-dose inhaled aerosol
administration to supply effective concentrations or amounts
conferring desired anti-inflammatory, anti-fibrotic or
tissue-remodeling benefits, for instance, to prevent, manage or
treat patients with pulmonary fibrosis.
[0222] Because different drug products are known to vary in
efficacy depending on the dose, form, concentration and delivery
profile, the presently disclosed embodiments provide specific
formulation and delivery parameters that produce protection against
and treatment for pulmonary fibrosis associated, by non-limiting
example with infection, radiation therapy, chemotherapy, inhalation
of environmental pollutants (e.g. dust, vapors, fumes, and
inorganic and organic fibers), hypersensitivities, silicosis,
byssinosis, genetic factors and transplant rejection.
[0223] These and related applications are also contemplated for use
in the diseased lung, sinus, nasal cavity, heart, kidney, liver,
nervous system and associated vasculature. The imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound
formulations and methods described herein may be used with
commercially available inhalation devices, or with other devices
for aerosol therapeutic product administration.
[0224] As a non-limiting example, in a preferred embodiment, a
phenylaminopyrimidine derivative compound as provided herein (e.g.,
imatinib) formulated to permit mist, gas-liquid suspension or
liquid nebulized, dry powder and/or metered-dose inhaled aerosol
administration to supply effective concentrations or amounts
conferring desired anti-inflammatory, anti-fibrotic or
tissue-remodeling benefits, for instance, to prevent, manage or
treat cardiac fibrosis in human and/or veterinary subjects. Such
embodiments provide for direct and high concentration delivery of
the imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof to
the pulmonary vasculature immediately upstream of the left atrium
and hence, to the coronary arterial system with interlumenal atrial
and ventricular exposure.
[0225] Because different drug products are known to vary in
efficacy depending on the dose, form, concentration and delivery
profile, the presently disclosed embodiments provide specific
formulation and delivery parameters that produce protection against
and treatment for cardiac fibrosis associated, by non-limiting
example with infection, surgery, radiation therapy, chemotherapy
and transplant rejection.
[0226] As a non-limiting example, in a preferred embodiment, a
phenylaminopyrimidine derivative compound as provided herein (e.g.,
imatinib) formulated to permit mist, gas-liquid suspension or
liquid nebulized, dry powder and/or metered-dose inhaled aerosol
administration to supply effective concentrations or amounts
conferring desired anti-inflammatory, anti-fibrotic or
tissue-remodeling benefits, for instance, to prevent, manage or
treat kidney fibrosis. Such embodiments provide for direct and high
concentration delivery of the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound to the pulmonary
vasculature immediately upstream of the left atrium, left ventical
and hence, to the kidney vasculature.
[0227] Because different drug products are known to vary in
efficacy depending on the dose, form, concentration and delivery
profile, the presently disclosed embodiments provide specific
formulation and delivery parameters that produce protection against
and treatment for kidney fibrosis associated, by non-limiting
example with infection, ureter calculi, malignant hypertension,
radiation therapy, diabetes, exposure to heavy metals, chemotherapy
and transplant rejection.
[0228] As a non-limiting example, in a preferred embodiment, a
phenylaminopyrimidine derivative compound as provided herein (e.g.,
imatinib) formulated to permit mist, gas-liquid suspension or
liquid nebulized, dry powder and/or metered-dose inhaled aerosol
administration to supply effective concentrations or amounts
conferring desired anti-inflammatory benefits, for instance, to
prevent, manage or treat heart or kidney toxicity. Such embodiments
provide for direct and high concentration delivery of the imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof
compound to the pulmonary vasculature immediately upstream of the
left atrium, left ventical, and hence, to the heart and kidney
vasculature.
[0229] Because different drug products are known to vary in
efficacy depending on the dose, form, concentration and delivery
profile, the presently disclosed embodiments provide specific
formulation and delivery parameters that produce protection against
and treatment for heart or kidney toxicity associated, by
non-limiting example with chemotherapy.
[0230] As a non-limiting example, in a preferred embodiment, a
phenylaminopyrimidine derivative compound as provided herein (e.g.,
imatinib) formulated to permit mist, gas-liquid suspension or
liquid nebulized, dry powder and/or metered-dose inhaled aerosol
administration to supply effective concentrations or amounts
conferring desired anti-inflammatory, anti-fibrotic or
tissue-remodeling benefits, for instance, to prevent, manage or
treat hepatic fibrosis. Such embodiments provide for direct and
high concentration delivery of the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound to the pulmonary
vasculature immediately upstream of the left atrium, left ventical
and hence, to the hepatic vasculature.
[0231] Because different drug products are known to vary in
efficacy depending on the dose, form, concentration and delivery
profile, the presently disclosed embodiments provide specific
formulation and delivery parameters that produce protection against
and treatment for hepatic fibrosis associated, by non-limiting
example with hepatic infection, hepatitis, alcohol overload,
autoimmune disease, radiation therapy, chemotherapy and transplant
rejection.
[0232] As a non-limiting example, a phenylaminopyrimidine
derivative compound as provided herein (e.g., imatinib) formulated
to permit mist, gas-liquid suspension or liquid nebulized, dry
powder and/or metered-dose nasal-injected or inhaled, or
orally-inhaled aerosol administration to supply effective
concentrations or amounts conferring desired anti-infective
benefits, for instance, to prevent, manage or treat disease
associated with active, previous or latent viral infection. If by
oral inhalation, such embodiments provide for direct and high
concentration delivery of the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof to the pulmonary vasculature
immediately upstream of the left atrium, left ventical and hence,
to the central nervous system. If by nasal injection or nasal
inhalation, such embodiments provide for direct and high
concentration delivery of the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof to the nasal and sinus vasculature
immediately upstream of the central nervous system.
[0233] Because different drug products are known to vary in
efficacy depending on the dose, form, concentration and delivery
profile, the presently disclosed embodiments provide specific
formulation and delivery parameters that produce protection against
and treatment of disease associated with active, previous or latent
viral infection.
[0234] As a non-limiting example, in a preferred embodiment, a
phenylaminopyrimidine derivative compound as provided herein (e.g.,
imatinib) formulated to permit mist, gas-liquid suspension or
liquid nebulized, dry powder and/or metered-dose inhaled aerosol
administration to supply effective concentrations or amounts
conferring desired anti-fibrotic, anti-inflammatory or
tissue-remodeling benefits, for instance, to prevent, manage or
treat patients with cystic fibrosis. Such embodiments may include
co-formulation or co-administration of a phenylaminopyrimidine
derivative compound with an antibiotic, steroid, hyperosmolar
solution, DNAse or other mucus thinning agent, or other agent.
[0235] Because different drug products are known to vary in
efficacy depending on the dose, form, concentration and delivery
profile, the presently disclosed embodiments provide specific
formulation and delivery parameters that produce protection against
and treatment for cystic fibrosis.
[0236] For the applications described herein, liquid nebulized, dry
powder or metered-dose aerosol imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound (or salt thereof) may be
co-administered, administered sequentially or prepared in a fixed
combination with an antimicrobial (e.g. tobramycin and/or other
aminoglycoside such as amikacin, aztreonam and/or other beta or
mono-bactam, ciprofloxacin, levofloxacin and/or other,
fluoroquinolones, azithromycin and/or other macrolides or
ketolides, tetracycline and/or other tetracyclines, quinupristin
and/or other streptogramins, linezolid and/or other oxazolidinones,
vancomycin and/or other glycopeptides, and chloramphenicol and/or
other phenicols, and colisitin and/or other polymyxins),
bronchodilator (e.g. beta-2 agonists and muscarinic antagonists),
corticosteroids (e.g. salmeterol, fluticasone and budesonide),
glucocorticoids (e.g. prednisone), Cromolyn, Nedocromil,
Leukotriene modifiers (e.g. montelukast, zafirlukast and zileuton)
hyperosmolar solution, DNAse or other mucus thinning agent,
interferon gamma, cyclophosphamide, colchicine, N-acetylcysteine,
azathioprine, bromhexine, endothelin receptor antagonist (e.g.
bosentan and ambrisentan), PDE5 inhibitor (e.g. sildenafil,
vardenafil and tadalafil), PDE4 inhibitor (e.g. roflumilast,
cilomilast, oglemilast, tetomilast and SB256066), prostinoid (e.g.
epoprostenol, iloprost and treprostinin), nitric oxide or nitric
oxide-donating compound, IL-13 blocker, IL-10 blocker,
CTGF-specific antibody, CCN2 inhibitors, angiotensin-converting
enzyme inhibitors, angiotensin receptor antagonists, PDGF
inhibitors, PPAR antagonist, oral imatinib, CCL2-specific antibody,
CXCR2 antogonist, triple growth factor kinase inhibitor,
anticoagulant, TNF blocker, tetracycline or tetracycline
derivative, 5-lipoxygenase inhibitor, pituitary hormone inhibitor,
TGF-beta-neutralizing antibody, copper chelator, angiotensin II
receptor antagonist, chemokine inhibitor, NF-kappaB inhibitor,
NF-kappaB antisense oligonucleotide, IKK-1 and -2 inhibitor (e.g.
imidazoquinoxaline or derivative, and quinazoline or derivative),
JNK2 and/or p38 MAPK inhibitor (e.g. pyridylimidazolbutyn-I-ol,
SB856553, SB681323, diaryl urea or derivative, and
indole-5-carboxamide), PI3K inhibitor, LTB4 inhibitor, antioxidant
(e.g. Mn-pentaazatetracyclohexacosatriene, M40419,
N-acetyl-L-cysteine, Mucomyst, Fluimucil, Nacystelyn, Erdosteine,
Ebeselen, thioredoxin, glutathione peroxidase memetrics, Curcumin
C3 complex, Resveratrol and analogs, Tempol, catalytic
antioxidants, and OxSODrol), TNF scavenger (e.g. infliximab,
ethercept, adalumimab, PEG-sTNFR 1, afelimomab, and antisense
TNF-alpha oligonucleotide), Interferon beta-1a (Avonex, Betaseron,
or Rebif), glatiramer acetate (Copaxone), mitoxantrone
(Novantrone), natalizumab (Tysabri), Methotrexate, azathioprine
(Imuran), intravenous immunoglobulin (IVIg), cyclophosphamide
(Cytoxan), lioresal (Baclofen), tizanidine (Zanaflex),
benzodiazepine, cholinergic medications, antidepressants and
amantadine.
[0237] As shown as a promising approach to treat cancer and
pulmonary arterial hypertension, to enable "cocktail therapy" or
"cocktail prophylaxis" in fibrotic disease, more specifically
idiopathic pulmonary fibrosis and other pulmonary fibrotic disease,
methods to administer inhaled imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof as either co-administered,
administered sequentially, or co-prescribed (such that medicines
are requested by a prescribing physician to be taken in some
sequence as combination therapy to treat the same disease) with
agents targeting cancer, fibrotic or inflammatory disease. By
non-limiting example, imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof is administered either in fixed
combination, co-administered, administered sequentially, or
co-prescribed with the monoclonal GS-6624 (formerly known as
AB0024), analog or another antibody targeting LOXL2 protein
associated with connective tissue biogenesis to reduce
inflammation, tumor stroma and/or fibrosis. By another non-limiting
example, imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof is administered either in fixed combination,
co-administered, administered sequentially, or co-prescribed with
IW001 (Type V collagen), analog or other collagen targeting
immunogenic tolerance to reduce inflammation, tumor stroma and/or
fibrosis. By another non-limiting example, imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof is administered
either in fixed combination, co-administered, administered
sequentially, or co-prescribed with PRM-151 (recombinant
pentraxin-2), analog or other molecule targeting regulation of the
injury response to reduce inflammation, tumor stroma and/or
fibrosis. By another non-limiting example, imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof is administered
either in fixed combination, co-administered, administered
sequentially, or co-prescribed with CC-930 (Jun kinase inhibitor),
analog or other Jun kinase inhibitor to reduce the inflammatory
response. By another non-limiting example, imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof is administered
either in fixed combination, co-administered, administered
sequentially, or co-prescribed with oral imatinib (a.k.a. Gleeve or
Glivec (tyrosin kinase inhibitor)), analog or other tyrosine
inhibitor to inhibit lung fibroblast-myofibroblast transformation
and proliferation as well as extracellular matrix production and
tumor stroma formation/maintenance through inhibition of PDFG and
transforming growth factor (TGF)-.beta. signaling. By another
non-limiting example, imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof is administered either in fixed
combination, co-administered, administered sequentially, or
co-prescribed with STX-100 (monoclonal antibody targeting integrin
alpha-v beta-6), analog or other antibody targeting integrin
alpha-v beta-6 or other integrin to reduce tumor stroma and/or
fibrosis. By another non-limiting example, imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof is administered
either in fixed combination, co-administered, administered
sequentially, or co-prescribed with QAX576 (monoclonal antibody
targeting interleukin 13 [IL-13]), analog or other antibody
targeting IL-13 to reduce tumor stroma and/or inflammation. By
another non-limiting example, imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof is administered either in fixed
combination, co-administered, administered sequentially, or
co-prescribed with FG-3019 (monoclonal antibody targeting
connective tissue growth factor [CTGF]), analog or other antibody
targeting CTGF to reduce tumor stroma and/or fibrosis. By another
non-limiting example, imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof is administered either in fixed
combination, co-administered, administered sequentially, or
co-prescribed with CNTO-888 (a monoclonal antibody targeting
chemokine [C--C motif] ligand 2 [CCL2]), analog or other antibody
targeting CCL2 to reduce tumor stroma and/or fibrosis. By another
non-limiting example, imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof is administered either in fixed
combination, co-administered, administered sequentially, or
co-prescribed with Esbriet, Pirespa or Pirfenex (trade names for
pirfenidone), or analog targeting inflammation, tumor stroma and/or
fibrosis. By another non-limiting example, imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof is administered
either in fixed combination, co-administered, administered
sequentially, or co-prescribed with BIBF-1120 (also known as
Vargatef; a triple kinase inhibitor targeting vascular endothelial
growth factor [VEGF], platelet-derived growth factor [PDGF] and
fibroblast growth factor [FGF]), analog or other triple kinase
inhibitor to reduce fibrosis, tumor stroma and/or inflammation.
[0238] As with administration of imatinib, oral and parenteral
routes of administration (by non-limiting example, intravenous and
subcutaneous) of other compounds, molecules and antibodies
targeting the reduction of inflammation, tumor stroma and/or
fibrosis is often associated with, by non-limiting example, adverse
reactions such as gastrointestinal side effects, liver, kidney,
skin, cardiovascular or other toxicities. As described herein for
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof,
the benefits of oral or intranasal inhalation directly to the lung
or tissues immediately downstream of the nasal and/or pulmonary
compartments will also benefit these compounds. Therefore, by
non-limiting example, the monoclonal GS-6624 (formerly known as
AB0024), analog or another antibody targeting LOXL2 protein
associated with connective tissue biogenesis to reduce
inflammation, tumor stroma and/or fibrosis may be administered by
oral or intranasal inhalation for direct delivery to the lung or
tissues immediately downstream of the nasal or pulmonary
compartments. By another non-limiting example, PRM-151 (recombinant
pentraxin-2), analog or other molecule targeting regulation of the
injury response to reduce inflammation and/or fibrosis may be
administered by oral or intranasal inhalation for direct delivery
to the lung or tissues immediately downstream of the nasal or
pulmonary compartments. By another non-limiting example, CC-930
(Jun kinase inhibitor), analog or other Jun kinase inhibitor to
reduce tumor stroma and/or the inflammatory response may be
administered by oral or intranasal inhalation for direct delivery
to the lung or tissues immediately downstream of the nasal or
pulmonary compartments. By another non-limiting example, oral
imatinib (a.k.a. Gleeve or Glivec (tyrosin kinase inhibitor)),
analog or other tyrosine inhibitor to inhibit lung
fibroblast-myofibroblast transformation and proliferation as well
as extracellular matrix production and tumor stroma
formation/maintenance through inhibition of PDFG and transforming
growth factor (TGF)-.beta. signaling may be administered by oral or
intranasal inhalation for direct delivery to the lung or tissues
immediately downstream of the nasal or pulmonary compartments. By
another non-limiting example, STX-100 (monoclonal antibody
targeting integrin alpha-v beta-6), analog or other antibody
targeting integrin alpha-v beta-6 or other integrin to reduce tumor
stroma and/or fibrosis may be administered by oral or intranasal
inhalation for direct delivery to the lung or tissues immediately
downstream of the nasal or pulmonary compartments. By another
non-limiting example, QAX576 (monoclonal antibody targeting
interleukin 13 [IL-13]), analog or other antibody targeting IL-13
to reduce tumor stroma and/or inflammation may be administered by
oral or intranasal inhalation for direct delivery to the lung or
tissues immediately downstream of the nasal or pulmonary
compartments. By another non-limiting example, FG-3019 (monoclonal
antibody targeting connective tissue growth factor [CTGF]), analog
or other antibody targeting CTGF to reduce tumor stroma and/or
fibrosis may be administered by oral or intranasal inhalation for
direct delivery to the lung or tissues immediately downstream of
the nasal or pulmonary compartments. By another non-limiting
example, CNTO-888 (a monoclonal antibody targeting chemokine [C--C
motif] ligand 2 [CCL2]), analog or other antibody targeting CCL2 to
reduce tumor stroma and/or fibrosis may be administered by oral or
intranasal inhalation for direct delivery to the lung or tissues
immediately downstream of the nasal or pulmonary compartments. By
another non-limiting example, BIBF-1120 (also known as Vargatef; a
triple kinase inhibitor targeting vascular endothelial growth
factor [VEGF], platelet-derived growth factor [PDGF] and fibroblast
growth factor [FGF]), analog or other triple kinase inhibitor to
reduce tumor stroma and/or fibrosis and/or inflammation may be
administered by oral or intranasal inhalation for direct delivery
to the lung or tissues immediately downstream of the nasal or
pulmonary compartments.
[0239] As shown as a promising approach to treat cancer and
pulmonary arterial hypertension, to enable "cocktail therapy" or
"cocktail prophylaxis" in cancer, more specifically lung cancer,
methods to administer inhaled imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof as either co-administered,
administered sequentially, or co-prescribed (such that medicines
are requested by a prescribing physician to be taken in some
sequence as combination therapy to treat the same disease) with
agents targeting cancer. Anti-cancer agents may include gefitinib
(Iressa, also known as ZD1839). Gefitinib is a selective inhibitor
of epidermal growth factor receptor's (EGFR) tyrosine kinase
domain. The target protein (EGFR) is a family of receptors which
includes Her1(erb-B1), Her2(erb-B2), and Her3(erb-B3). EGFR is
overexpressed in the cells of certain types of human
carcinomas--for example in lung and breast cancers. This leads to
inappropriate activation of the anti-apoptotic Ras signalling
cascade, eventually leading to uncontrolled cell proliferation.
Research on gefitinib-sensitive non-small cell lung cancers has
shown that a mutation in the EGFR tyrosine kinase domain is
responsible for activating anti-apoptotic pathways. These mutations
tend to confer increased sensitivity to tyrosine kinase inhibitors
such as gefitinib and erlotinib. Of the types of non-small cell
lung cancer histologies, adenocarcinoma is the type that most often
harbors these mutations. These mutations are more commonly seen in
Asians, women, and non-smokers (who also tend to more often have
adenocarcinoma). Gefitinib inhibits EGFR tyrosine kinase by binding
to the adenosine triphosphate (ATP)-binding site of the enzyme.
Thus the function of the EGFR tyrosine kinase in activating the
anti-apoptotic Ras signal transduction cascade is inhibited, and
malignant cells are inhibited. While gefitinib has yet to be proven
to be effective in other cancers, there is potential for its use in
the treatment of other cancers where EGFR overexpression is
involved. As gefitinib is a selective chemotherapeutic agent, its
tolerability profile is better than previous cytotoxic agents.
Adverse drug reactions (ADRs) are acceptable for a potentially
fatal disease. Acne-like rash is reported very commonly. Other
common adverse effects include: diarrhoea, nausea, vomiting,
anorexia, stomatitis, dehydration, skin reactions, paronychia,
asymptomatic elevations of liver enzymes, asthenia, conjunctivitis,
blepharitis. Infrequent adverse effects include: interstitial lung
disease, corneal erosion, aberrant eyelash and hair growth.
[0240] Another anti-cancer agent is Erlotinib (also known as
Tarceva). Erlotinib specifically targets the epidermal growth
factor receptor (EGFR) tyrosine kinase, which is highly expressed
and occasionally mutated in various forms of cancer. It binds in a
reversible fashion to the adenosine triphosphate (ATP) binding site
of the receptor. For the signal to be transmitted, two EGFR
molecules need to come together to form a homodimer. These then use
the molecule of ATP to trans-phosphorylate each other on tyrosine
residues, which generates phosphotyrosine residues, recruiting the
phosphotyrosine-binding proteins to EGFR to assemble protein
complexes that transduce signal cascades to the nucleus or activate
other cellular biochemical processes. By inhibiting the ATP,
formation of phosphotyrosine residues in EGFR is not possible and
the signal cascades are not initiated. Erlotinib has shown a
survival benefit in the treatment of lung cancer. Erlotinib is
approved for the treatment of locally advanced or metastatic
non-small cell lung cancer that has failed at least one prior
chemotherapy regimen. It is also approved in combination with
gemcitabine for treatment of locally advanced, unresectable, or
metastatic pancreatic cancer. In lung cancer, erlotinib has been
shown to be effective in patients with or without EGFR mutations,
but appears to be more effective in the group of patients with EGFR
mutations. The response rate among EGFR mutation positive patients
is approximately 60%. Patients who are non-smokers, and light
former smokers, with adenocarcinoma or subtypes like BAC are more
likely to have EGFR mutations, but mutations can occur in all types
of patients. EGFR positive patients are generally KRAS negative.
Erlotinib has recently been shown to be a potent inhibitor of
JAK2V617F activity. JAK2V617F is a mutant of tyrosine kinase JAK2,
is found in most patients with polycythemia vera (PV) and a
substantial proportion of patients with idiopathic myelofibrosis or
essential thrombocythemia. The study suggests that erlotinib may be
used for treatment of JAK2V617F-positive PV and other
myeloproliferative disorder. Rash occurs in the majority of
patients. This resembles acne and primarily involves the face and
neck. It is self-limited and resolves in the majority of cases,
even with continued use. Interestingly, some clinical studies have
indicated a correlation between the severity of the skin reactions
and increased survival though this has not been quantitatively
assessed. Cutaneous rash may be a surrogate marker of clinical
benefit. Other side effects include diarrhea, loss of appetite,
fatigue, rarely, interstitial pneumonitis, which is characterized
by cough and increased dyspnea. This may be severe and must be
considered among those patients whose breathing acutely worsens. It
has also been suggested that erlotinib can cause hearing loss. Rare
side effects include serious gastrointestinal tract, skin, and
ocular disorders. In addition, some people prescribed erlotinib
have developed serious or fatal gastrointestinal tract
perforations; "bullous, blistering, and exfoliative skin
conditions, some fatal; and serious eye problems such as corneal
lesions. Some of the cases, including ones which resulted in death,
were suggestive of Stevens-Johnson syndrome/toxic epidermal
necrolysis. Erlotinib is mainly metabolized by the liver enzyme
CYP3A4. Compounds which induce this enzyme (i.e. stimulate its
production), such as St John's wort, can lower erlotinib
concentrations, while inhibitors can increase concentrations. As
with other ATP competitive small molecule tyrosine kinase
inhibitors, such as imatinib in CML, patients rapidly develop
resistance. In the case of erlotinib this typically occurs 8-12
months from the start of treatment. Over 50% of resistance is
caused by a mutation in the ATP binding pocket of the EGFR kinase
domain involving substitution of a small polar threonine residue
with a large nonpolar methionine residue (T790M). While proponents
of the `gatekeeper` mutation hypothesis suggest this mutation
prevents the binding of erlotinib through steric hindrance,
research suggests that T790M confers an increase in ATP binding
affinity reducing the inhibitory effect of erlotinib. Approximately
20% of drug resistance is caused by amplification of the hepatocyte
growth factor receptor, which drives ERBB3 dependent activation of
PI3K. Other cases of resistance can involve numerous mutations,
including recruitment of a mutated IGF-1 receptor to homodimerize
with EGFR so forming a heterodimer. This allows activation of the
downstream effectors of EGFR even in the presence of an EGFR
inhibitor. Some IGR-1R inhibitors are in various stages of
development (based either around TKIs such as AG1024 or AG538 or
pyrrolo[2,3-d]-pyrimidine derivatives such as NVP-AEW541). The
monoclonal antibody figitumumab which targets the IGF-1R is
currently undergoing clinical trials. Another cause of resistance
can be inactivating mutations of the PTEN tumor suppressor which
allow increased activation of Akt independent of stimulation by
EGFR. The most promising approach to combating resistance is likely
to be combination therapy. Commencing treatment with a number of
different therapeutic agents with differing modes of action is
thought to provide the best defense against development of T790M
and other resistance conferring mutations.
[0241] Another anti-cancer agent is Bortezomib (originally
codenamed PS-341; marketed as Velcade and Bortecad). Bortezomib is
the first therapeutic proteasome inhibitor to be tested in humans.
It is approved in the U.S. for treating relapsed multiple myeloma
and mantle cell lymphoma. In multiple myeloma, complete clinical
responses have been obtained in patients with otherwise refractory
or rapidly advancing disease. Bortezomib was originally synthesized
as MG-341. After promising preclinical results, the drug (PS-341)
was tested in a small Phase I clinical trial on patients with
multiple myeloma cancer. Bortezomib (Velcade) is approved for use
in multiple myeloma. Another commercially available bortezomib
product--Bortenat, reportedly contains substantially more active
entity than declared, potentially and even more resulting in
increased toxicity. Moreover, Bortenat has some other chemical and
formulation deviations from the registered ethic product Velcade,
with unclear clinical impact. The boron atom in bortezomib binds
the catalytic site of the 26S proteasome with high affinity and
specificity. In normal cells, the proteasome regulates protein
expression and function by degradation of ubiquitylated proteins,
and also cleanses the cell of abnormal or misfolded proteins.
Clinical and preclinical data support a role in maintaining the
immortal phenotype of myeloma cells, and cell-culture and xenograft
data support a similar function in solid tumor cancers. While
multiple mechanisms are likely to be involved, proteasome
inhibition may prevent degradation of pro-apoptotic factors,
permitting activation of programmed cell death in neoplastic cells
dependent upon suppression of pro-apoptotic pathways. Recently, it
was found that bortezomib caused a rapid and dramatic change in the
levels of intracellular peptides that are produced by the
proteasome. Some intracellular peptides have been shown to be
biologically active, and so the effect of bortezomib on the levels
of intracellular peptides may contribute to the biological and/or
side effects of the drug. Bortezomib is rapidly cleared following
intravenous administration. Peak concentrations are reached at
about 30 minutes. Drug levels can no longer be measured after an
hour. Pharmacodynamics are measured by measuring proteasome
inhibition in peripheral blood mononuclear cells. The much greater
sensitivity of myeloma cell lines and mantle cell lines to
proteasome inhibition compared with normal peripheral blood
mononuclear cells and most other cancer cell lines is poorly
understood. Bortezomib is associated with peripheral neuropathy in
30% of patients; occasionally, it can be painful. This can be worse
in patients with pre-existing neuropathy. In addition,
myelosuppression causing neutropenia and thrombocytopenia can also
occur and be dose-limiting. However, these side effects are usually
mild relative to bone marrow transplantation and other treatment
options for patients with advanced disease. Bortezomib is
associated with a high rate of shingles, although prophylactic
acyclovir can reduce the risk of this. Gastro-intestinal effects
and asthenia are the most common adverse events. The established
the efficacy of bortezomib is 1.3 mg/m2 (with or without
dexamethasone) administered by intravenous bolus on days 1,4,8, and
11 of a 21-day cycle for a maximum of eight cycles in heavily
pretreated patients with relapsed/refractory multiple myeloma. The
demonstrated superiority of bortezomib is 1.3 mg/m2 over a
high-dose dexamethasone regimen (by example median TTP 6.2 vs 3.5
months, and 1-year survival 80% vs. 66%). Laboratory studies and
clinical trials are investigating whether it might be possible to
further increase the anticancer potency of bortezomib by combining
it with novel types of other pharmacologic agents. For example,
clinical trials have indicated that the addition of thalidomide,
lenalidomide, inhibitors of vascular endothelial growth factor
(VEGF), or arsenic trioxide might be beneficial. In laboratory
studies, it was found that bortezomib killed multiple myeloma cells
more efficiently when combined, for example, with histone
deacetylase inhibitors, thapsigargin, or celecoxib. There is
preclinical evidence that bortezomib is synergistic with Reolysin
in pancreatic cancer. However, the therapeutic efficacy and safety
of any of these latter combinations has not yet been evaluated in
cancer patients.
[0242] Another family of anti-cancer agent are Janus kinase
inhibitors. Also known as JAK inhibitors, these are a type of
medication that functions by inhibiting the activity of one or more
of the Janus kinase family of enzymes (JAK1, JAK2, JAK3, TYK2),
thereby interfering with the JAK-STAT signaling pathway. These
inhibitors have therapeutic application in the treatment of cancer
and inflammatory diseases. Cytokines play key roles in controlling
cell growth and the immune response. Many cytokines function by
binding to and activating type I and type II cytokine receptors.
These receptors in turn rely on the Janus kinase (JAK) family of
enzymes for signal transduction. Hence drugs that inhibit the
activity of these Janus kinases block cytokine signaling. More
specifically, Janus kinases phosphorylate activated cytokine
receptors. These phosphorylated receptor in turn recruit STAT
transcription factors which modulate gene transcription. The first
JAK inhibitor to reach clinical trials was tofacitinib. Tofacitinib
is a specific inhibitor of JAK3 (IC50=2 nM) thereby blocking the
activity of IL-2, IL-4, IL-15 and IL-21. Hence Th2 cell
differentiation is blocked and therefore tofacitinib is effective
in treating allergic diseases. Tofacitinib to a lesser extent also
inhibits JAK1 (IC50=100 nM) and JAK2 (IC50=20 nM) which in turn
blocks IFN-.gamma. and IL-6 signaling and consequently Th1 cell
differentiation. Examples of JAK inhibitors include: Ruxolitinib
against JAK1/JAK2 for psoriasis, myelofibrosis, and rheumatoid
arthritis; Tofacitinib (tasocitinib; CP-690550) against JAK3 for
psoriasis and rheumatoid arthritis; Baricitinib (LY3009104,
INCB28050) against JAK1/JAK2 for rheumatoid arthritis; CYT387
against JAK2 for myeloproliferative disorders; Lestaurtinib against
JAK2, for acute myelogenous leukemia (AML); Pacritinib (SB1518)
against JAK2 for relapsed lymphoma and advanced myeloid
malignancies, chronic idiopathic myelofibrosis (CIMF); and TG101348
against JAK2 for myelofibrosis.
[0243] Another family of anti-cancer agent is ALK inhibitors. ALK
inhibitors are potential anti-cancer drugs that act on tumors with
variations of anaplastic lymphoma kinase (ALK) such as an EML4-ALK
translocation. About 7% of Non-small cell lung carcinomas (NSCLC)
have EML4-ALK translocations. Examples of ALK inhibitors include:
Crizotinib (trade name Xalkori) is approved for NSCLC; AP26113 is
at the preclinical stage; and LDK378 is developed by Novartis as
the second-generation ALK inhibitor. NPM-ALK is a different
variation/fusion of ALK that drives anaplastic large-cell lymphomas
(ALCLs) and is the target of other ALK inhibitors. Crizotinib has
an aminopyridine structure, and functions as a protein kinase
inhibitor by competitive binding within the ATP-binding pocket of
target kinases. About 4% of patients with non-small cell lung
carcinoma have a chromosomal rearrangement that generates a fusion
gene between EML4 (`echinoderm microtubule-associated protein-like
4`) and ALK (`anaplastic lymphoma kinase`), which results in
constitutive kinase activity that contributes to carcinogenesis and
seems to drive the malignant phenotype. The kinase activity of the
fusion protein is inhibited by crizotinib. Patients with this gene
fusion are typically younger non-smokers who do not have mutations
in either the epidermal growth factor receptor gene (EGFR) or in
the K-Ras gene. The number of new cases of ALK-fusion NSLC is about
9,000 per year in the U.S. and about 45,000 worldwide. ALK
mutations are thought to be important in driving the malignant
phenotype in about 15% of cases of neuroblastoma, a rare form of
peripheral nervous system cancer that occurs almost exclusively in
very young children. Crizotinib inhibits the c-Met/Hepatocyte
growth factor receptor (HGFR) tyrosine kinase, which is involved in
the oncogenesis of a number of other histological forms of
malignant neoplasms. Crizotinib is currently thought to exert its
effects through modulation of the growth, migration, and invasion
of malignant cells. Other studies suggest that crizotinib might
also act via inhibition of angiogenesis in malignant tumors.
Crizotinib caused tumors to shrink or stabilize in 90% of 82
patients carrying the ALK fusion gene. Tumors shrank at least 30%
in 57% of people treated. Most had adenocarcinoma, and had never
smoked or were former smokers. They had undergone treatment with an
average of three other drugs prior to receiving crizotinib, and
only 10% were expected to respond to standard therapy. They were
given 250 mg crizotinib twice daily for a median duration of six
months. Approximately 50% of these patients suffered at least one
side effect, such as nausea, vomiting, or diarrhea. Some responses
to crizotinib have lasted up to 15 months. A phase 3 trial, PROFILE
1007, compares crizotinib to standard second line chemotherapy
(pemetrexed or taxotere) in the treatment of ALK-positive NSCLC.
Additionally, a phase 2 trial, PROFILE 1005, studies patients
meeting similar criteria who have received more than one line of
prior chemotherapy. Crizotinib (Xalkori) is approved to treat
certain late-stage (locally advanced or metastatic) non-small cell
lung cancers that express the abnormal anaplastic lymphoma kinase
(ALK) gene. Approval required a companion molecular test for the
EML4-ALK fusion.
[0244] Another anti-cancer agent is Crizotinib. Crizotinib is also
being tested in clinical trials of advanced disseminated anaplastic
large-cell lymphoma,[9] and neuroblastoma.
[0245] An anti-cancer target includes Bcl-2 (B-cell lymphoma 2).
Encoded by the BCL2 gene, is the founding member of the Bcl-2
family of regulator proteins that regulate cell death (apoptosis).
Bcl-2 derives its name from B-cell lymphoma 2, as it is the second
member of a range of proteins initially described in chromosomal
translocations involving chromosomes 14 and 18 in follicular
lymphomas. Bcl-2 orthologs have been identified in numerous mammals
for which complete genome data are available. The two isoforms of
Bcl-2, Isoform 1, also known as 1G5M, and Isoform 2, also known as
1G5O/1GJH, exhibit similar fold. However, results in the ability of
these isoforms to bind to the BAD and BAK proteins, as well as in
the structural topology and electrostatic potential of the binding
groove, suggest differences in antiapoptotic activity for the two
isoforms. Damage to the Bcl-2 gene has been identified as a cause
of a number of cancers, including melanoma, breast, prostate,
chronic lymphocytic leukemia, and lung cancer, and a possible cause
of schizophrenia and autoimmunity. It is also a cause of resistance
to cancer treatments. Cancer occurs as the result of a disturbance
in the homeostatic balance between cell growth and cell death.
Over-expression of anti-apoptotic genes, and under-expression of
pro-apoptotic genes, can result in the lack of cell death that is
characteristic of cancer. An example can be seen in lymphomas. The
over-expression of the anti-apoptotic Bcl-2 protein in lymphocytes
alone does not cause cancer. But simultaneous over-expression of
Bcl-2 and the proto-oncogene myc may produce aggressive B-cell
malignancies including lymphoma. In follicular lymphoma, a
chromosomal translocation commonly occurs between the fourteenth
and the eighteenth chromosomes--t(14;18)--which places the Bcl-2
gene next to the immunoglobulin heavy chain locus. This fusion gene
is deregulated, leading to the transcription of excessively high
levels of Bcl-2. This decreases the propensity of these cells for
undergoing apoptosis. Apoptosis also plays a very active role in
regulating the immune system. When it is functional, it can cause
immune unresponsiveness to self-antigens via both central and
peripheral tolerance. In the case of defective apoptosis, it may
contribute to etiological aspects of autoimmune diseases. The
autoimmune disease, type 1 diabetes can be caused by defective
apoptosis, which leads to aberrant T cell AICD and defective
peripheral tolerance. Due to the fact that dendritic cells are the
most important antigen presenting cells of the immune system, their
activity must be tightly regulated by such mechanisms as apoptosis.
Researchers have found that mice containing dendritic cells that
are Bim -/-, thus unable to induce effective apoptosis, obtain
autoimmune diseases more so than those that have normal dendritic
cells. Other studies have shown that the lifespan of dendritic
cells may be partly controlled by a timer dependent on
anti-apoptotic Bcl-2. Apoptosis plays a very important role in
regulating a variety of diseases that have enormous social impacts.
For example, schizophrenia is a neurodegenerative disease that may
result from an abnormal ratio of pro- and anti-apoptotic factors.
There is some evidence that this defective apoptosis may result
from abnormal expression of Bcl-2 and increased expression of
caspase-3. Further research into the family of Bcl-2 proteins will
provide a more complete picture on how these proteins interact with
each other to promote and inhibit apoptosis [citation needed]. An
understanding of the mechanisms involved may help develop new
therapies for treating cancer, autoimmune conditions, and
neurological diseases. Bcl-2 inhibitors include: An antisense
oligonucleotide drug Genasense (G3139) that targets Bcl-2. An
antisense DNA or RNA strand is non-coding and complementary to the
coding strand (which is the template for producing respectively RNA
or protein). An antisense drug is a short sequence of RNA that
hybridises with and inactivates mRNA, preventing the protein from
being formed. It was shown that the proliferation of human lymphoma
cells (with t(14;18) translocation) could be inhibited by antisense
RNA targeted at the start codon region of Bcl-2 mRNA. In vitro
studies led to the identification of Genasense, which is
complementary to the first 6 codons of Bcl-2 mRNA. Another BCL-2
inhibitor is ABT-73. ABT-73 is a novel inhibitor of Bcl-2, Bcl-xL
and Bcl-w, known as ABT-737. ABT-737 is one among many so-called
BH3 mimetic small molecule inhibitors (SMI) targeting Bcl-2 and
Bcl-2-related proteins such as Bcl-xL and Bcl-w but not A1 and
Mcl-1, which may prove valuable in the therapy of lymphoma and
other blood cancers. Another inhibitor is ABT-199. ABT-199 is a
so-called BH3-mimetic drug designed to block the function of the
Bcl-2 protein in patients with chronic lymphocytic leukemia.
Another Bcl-2 inhibitors is obatoclax (GX15-070) for small-cell
lung cancer. By inhibiting Bcl-2, Obatoclax induces apoptosis in
cancer cells, preventing tumor growth.
[0246] Another family of anti-cancer agents are PARP inhibitors.
PARP inhibitors are a group of pharmacological inhibitors of the
enzyme poly ADP ribose polymerase (PARP). They are developed for
multiple indications; the most important is the treatment of
cancer. Several forms of cancer are more dependent on PARP than
regular cells, making PARP an attractive target for cancer therapy.
In addition to their use in cancer therapy, PARP inhibitors are
considered a potential treatment for acute life-threatening
diseases, such as stroke and myocardial infarction, as well as for
long-term neurodegenerative diseases. DNA is damaged thousands of
times during each cell cycle, and that damage must be repaired.
BRCA1, BRCA2 and PALB2 are proteins that are important for the
repair of double-strand DNA breaks by the error-free homologous
recombination repair, or HRR, pathway. When the gene for either
protein is mutated, the change can lead to errors in DNA repair
that can eventually cause breast cancer. When subjected to enough
damage at one time, the altered gene can cause the death of the
cells. PARP1 is a protein that is important for repairing
single-strand breaks (`nicks` in the DNA). If such nicks persist
unrepaired until DNA is replicated (which must precede cell
division), then the replication itself can cause double strand
breaks to form. Drugs that inhibit PARP1 cause multiple double
strand breaks to form in this way, and in tumors with BRCA1, BRCA2
or PALB2 mutations these double strand breaks cannot be efficiently
repaired, leading to the death of the cells. Normal cells that
don't replicate their DNA as often as cancer cells, and that lacks
any mutated BRCA1 or BRCA2 still have homologous repair operating,
which allows them to survive the inhibition of PARP. Some cancer
cells that lack the tumor suppressor PTEN may be sensitive to PARP
inhibitors because of down-regulation of Rad51, a critical
homologous recombination component, although other data suggest
PTEN may not regulate Rad51. Hence PARP inhibitors may be effective
against many PTEN-defective tumors (e.g. some aggressive prostate
cancers). Cancer cells that are low in oxygen (e.g. in fast growing
tumors) are sensitive to PARP inhibitors. PARP inhibitors were
originally thought to work primarily by blocking PARP enzyme
activity, thus preventing the repair of DNA damage and ultimately
causing cell death. PARP inhibitors have an additional mode of
action: localizing PARP proteins at sites of DNA damage, which has
relevance to their anti-tumor activity. The trapped PARP
protein--DNA complexes are highly toxic to cells because they block
DNA replication. When the researchers tested three PARP inhibitors
for their differential ability to trap PARP proteins on damaged
DNA, they found that the trapping potency of the inhibitors varied
widely. The PARP family of proteins in humans includes PARP1 and
PARP2, which are DNA binding and repair proteins. When activated by
DNA damage, these proteins recruit other proteins that do the
actual work of repairing DNA. Under normal conditions, PARP1 and
PARP2 are released from DNA once the repair process is underway.
However, as this study shows, when they are bound to PARP
inhibitors, PARP1 and PARP2 become trapped on DNA. The researchers
showed that trapped PARP-DNA complexes are more toxic to cells than
the unrepaired single-strand DNA breaks that accumulate in the
absence of PARP activity, indicating that PARP inhibitors act as
PARP poisons. These findings suggest that there may be two classes
of PARP inhibitors, catalytic inhibitors that act mainly to inhibit
PARP enzyme activity and do not trap PARP proteins on DNA, and dual
inhibitors that both block PARP enzyme activity and act as PARP
poison. The main function of radiotherapy is to produce DNA strand
breaks, causing severe DNA damage and leading to cell death.
Radiotherapy has the potential to kill 100% of any targeted cells,
but the dose required to do so would cause unacceptable side
effects to healthy tissue. Radiotherapy therefore can only be given
up to a certain level of radiation exposure. Combining radiation
therapy with PARP inhibitors offers promise, since the inhibitors
would lead to formation of double strand breaks from the
single-strand breaks generated by the radiotherapy in tumor tissue
with BRCA1/BRCA2 mutations. This combination could therefore lead
to either more powerful therapy with the same radiation dose or
similarly powerful therapy with a lower radiation dose. Examples of
PARP inhibitors include: Iniparib (BSI 201) for breast cancer and
squamous cell lung cancer; Olaparib (AZD-2281) for breast, ovarian
and colorectal cancer; Rucaparib (AG014699, PF-01367338) for
metastatic breast and ovarian cancer; Veliparib (ABT-888) for
metastatic melanoma and breast cancer; CEP 9722 for non-small-cell
lung cancer (NSCLC); MK 4827 which inhibits both PARP1 and PARP2;
BMN-673 for advanced hematological malignancies and for advanced or
recurrent solid tumors; and 3-aminobenzamide.
[0247] Another family of anti-cancer target is the PI3K/AKT/mTOR
pathway. This pathway is an important signaling pathway for many
cellular functions such as growth control, metabolism and
translation initiation. Within this pathway there are many valuable
anti-cancer drug treatment targets and for this reason it has been
subject to a lot of research in recent years. A Phosphoinositide
3-kinase inhibitor (PI3K inhibitor) is a potential medical drug
that functions by inhibiting a Phosphoinositide 3-kinase enzyme
which is part of this pathway and therefore, through inhibition,
often results in tumor suppression. There are a number of different
classes and isoforms of PI3Ks. Class 1 PI3Ks have a catalytic
subunit known as p110, with four types (isoforms)--p110 alpha, p110
beta, p110 gamma and p110 delta. The inhibitors being studied
inhibit one or more isoforms of the class I PI3Ks. They are being
actively investigated for treatment of various cancers. Examples
include: Wortmannin an irreversible inhibitor of PI3K;
demethoxyviridin a derivative of wortmannin; and LY294002 a
reversible inhibitor of PI3K. Other PI3K inhibitors include:
Perifosine, for colorectal cancer and multiple myeloma; CAL101 an
oral PI3K delta for certain late-stage types of leukemia's; PX-866;
IPI-145, a novel inhibitor of PI3K delta and gamma, especially for
hematologic malignancies; BAY 80-6946, predominantly inhibiting
PI3K.alpha.,.delta. isoforms; BEZ235 a PI3K/mTOR dual inhibitor;
RP6503, a dual PI3K delta/gamma inhibitor for the treatment of
asthma and COPD; TGR 1202, oral PI3K delta inhibitor (also known as
RP5264); SF1126, the first PI3KI for B-cell chronic lymphocytic
leukemia (CLL); INK1117, a PI3K-alpha inhibitor; GDC-0941 IC50 of
3nM; BKM120; XL147 (also known as SAR245408); XL765 (also known as
SAR245409); Palomid 529; GSK1059615, where clinical trials were
terminated due to lack of sufficient exposure following single- and
repeat-dosing; ZSTK474, a potent inhibitor against p110a; PWT33597,
a dual PI3K-alpha/mTOR inhibitor--for advanced solid tumors;
IC87114 a selective inhibitor of p110.delta.. It has an IC50 of 100
nM for inhibition of p110-.delta.; TG100-115, inhibits all four
isoforms but has a 5-10 fold better potency against p110-.gamma.
and p110-.delta.; CAL263; RP6530, a dual PI3K delta/gamma inhibitor
for T-cell Lymphomas; PI-103 a dual PI3K-mTOR inhibitor; GNE-477, a
PI3K-alpha and mTOR inhibitor with IC50 values of 4 nM and 21 nM;
CUDC-907, also an HDAC inhibitor; and AEZS-136, which also inhibits
Erk1/2.
[0248] Another anti-cancer agent is Apatinib. Also known as
YN968D1, Apatinib is a tyrosine kinase inhibitor that selectively
inhibits the vascular endothelial growth factor receptor-2 (VEGFR2,
also known as KDR). It is an orally bioavailable, small molecule
agent which is thought to inhibit angiogenesis in cancer cells;
specifically apatinib inhibits VEGF-mediated endothelial cell
migration and proliferation thus blocking new blood vessel
formation in tumor tissue. This agent also mildly inhibits c-Kit
and c-SRC tyrosine kinases. Apatinib is an investigational cancer
drug currently undergoing clinical trials as a potential targeted
treatment for metastatic gastric carcinoma, metastatic breast
cancer and advanced hepatocellular carcinoma. Cancer patients were
administered varied doses of Apatinib daily for 28 days. Apatinib
was well tolerated at doses below 750 mg/day, 3 of 3 dose limiting
toxicities were reported at 1000 mg/day and the maximum tolerated
dose is determined to be 850 mg/day. The investigator also reported
of 65 cancer patients treated in Phase I/II, 1.54% had a complete
response, 12.31% had a partial response, 66.15% had stable disease
and 20% had progressive disease. A separate published report on the
safety and pharmacokinetics of apatinib in Human clinical studies
concludes that it has encouraging antitumor activity across a broad
range of cancer types. Some cancer cells have the ability to
develop resistance to the cytotoxic effects of certain cancer drugs
(called multidrug resistance). A study concluded that apatinib may
be useful in circumventing cancer cells' multidrug resistance to
certain conventional antineoplastic drugs. The study showed that
apatinib reverses the ABCB1- and ABCG2-mediated multidrug
resistance by inhibiting those functions and increasing the
intracellular concentrations of the antineoplastic drugs. This
study suggests that apatinib will be potentially effective in
combination therapies with conventional anticancer drugs especially
in cases where resistance to chemotherapy exists.
[0249] Another family of anti-cancer target is BRAF. BRAF is a
human gene that encodes B-Raf. The gene is also referred to as
proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene
homolog B1, while the protein is more formally known as
serine/threonine-protein kinase B-Raf. The B-Raf protein is
involved in sending signals inside cells, which are involved in
directing cell growth. In 2002, it was shown to be faulty (mutated)
in human cancers. Certain other inherited BRAF mutations cause
birth defects. Drugs that treat cancers driven by BRAF have been
developed. Vemurafenib and dabrafenib are approved for late-stage
melanoma. B-Raf is a member of the Raf kinase family of growth
signal transduction protein kinases. This protein plays a role in
regulating the MAP kinase/ERKs signaling pathway, which affects
cell division, differentiation, and secretion. B-Raf is a 766-amino
acid, regulated signal transduction serine/threonine-specific
protein kinase. Broadly speaking, it is composed of three conserved
domains characteristic of the Raf kinase family: conserved region 1
(CR1), a Ras-GTP-binding self-regulatory domain, conserved region 2
(CR2), a serine-rich hinge region, and conserved region 3 (CR3), a
catalytic protein kinase domain that phosphorylates a consensus
sequence on protein substrates. In its active conformation, B-Raf
forms dimers via hydrogen-bonding and electrostatic interactions of
its kinase domains. B-Raf is a serine/threonine-specific protein
kinase. As such, it catalyzes the phosphorylation of serine and
threonine residues in a consensus sequence on target proteins by
ATP, yielding ADP and a phosphorylated protein as products. Since
it is a highly regulated signal transduction kinase, B-Raf must
first bind Ras-GTP before becoming active as an enzyme. Once B-Raf
is activated, a conserved protein kinase catalytic core
phosphorylates protein substrates by promoting the nucleophilic
attack of the activated substrate serine or threonine hydroxyl
oxygen atom on the .gamma.-phosphate group of ATP through
bimolecular nucleophilic substitution. To effectively catalyze
protein phosphorylation via the bimolecular substitution of serine
and threonine residues with ADP as a leaving group, B-Raf must
first bind ATP and then stabilize the transition state as the
.gamma.-phosphate of ATP is transferred. Since constitutively
active B-Raf mutants commonly cause cancer (see Clinical
Significance) by excessively signaling cells to grow, inhibitors of
B-Raf have been developed for both the inactive and active
conformations of the kinase domain as cancer therapeutic
candidates. BAY43-9006 (Sorafenib, Nexavar)is a V600E mutant B-Raf
and C-Raf inhibitor approved by the FDA for the treatment of
primary liver and kidney cancer. Bay43-9006 disables the B-Raf
kinase domain by locking the enzyme in its inactive form. The
inhibitor accomplishes this by blocking the ATP binding pocket
through high-affinity for the kinase domain. It then binds key
activation loop and DFG motif residues to stop the movement of the
activation loop and DFG motif to the active conformation. Finally,
a trifluoromethyl phenyl moiety sterically blocks the DFG motif and
activation loop active conformation site, making it impossible for
the kinase domain to shift conformation to become active. The
distal pyridyl ring of BAY43-9006 anchors in the hydrophobic
nucleotide-binding pocket of the kinase N-lobe, interacting with
W531, F583, and F595. The hydrophobic interactions with catalytic
loop F583 and DFG motif F595 stabilize the inactive conformation of
these structures, decreasing the likelihood of enzyme activation.
Further hydrophobic interaction of K483, L514, and T529 with the
center phenyl ring increase the affinity of the kinase domain for
the inhibitor. Hydrophobic interaction of F595 with the center ring
as well decreases the energetic favorability of a DFG conformation
switch further. Finally, polar interactions of BAY43-9006 with the
kinase domain continue this trend of increasing enzyme affinity for
the inhibitor and stabilizing DFG residues in the inactive
conformation. E501 and C532 hydrogen bond the urea and pyridyl
groups of the inhibitor respectively while the urea carbonyl
accepts a hydrogen bond from D594's backbone amide nitrogen to lock
the DFG motif in place. The trifluoromethyl phenyl moiety cements
the thermodynamic favorability of the inactive conformation when
the kinase domain is bound to BAY43-9006 by sterically blocking the
hydrophobic pocket between the .alpha.C and .alpha.E helices that
the DFG motif and activation loop would inhabit upon shifting to
their locations in the active conformation of the protein. PLX4032
(Vemurafenib) is a V600 mutant B-Raf inhibitor approved by the FDA
for the treatment of late-stage melanoma. Unlike BAY43-9006, which
inhibits the inactive form of the kinase domain, Vemurafenib
inhibits the active "DFG-in" form of the kinase, firmly anchoring
itself in the ATP-binding site. By inhibiting only the active form
of the kinase, Vemurafenib selectively inhibits the proliferation
of cells with unregulated B-Raf, normally those that cause cancer.
Since Vemurafenib only differs from its precursor, PLX4720, in a
phenyl ring added for pharmacokinetic reasons, PLX4720's mode of
action is equivalent to Vemurafenib's. PLX4720 has good affinity
for the ATP binding site partially because its anchor region, a
7-azaindole bicyclic, only differs from the natural adenine that
occupies the site in two places where nitrogen atoms have been
replaced by carbon. This enables strong intermolecular interactions
like N7 hydrogen bonding to C532 and N1 hydrogen bonding to Q530 to
be preserved. Excellent fit within the ATP-binding hydrophobic
pocket (C532, W531, T529, L514, A481) increases binding affinity as
well. Ketone linker hydrogen bonding to water and difluoro-phenyl
fit in a second hydrophobic pocket (A481, V482, K483, V471, I527,
T529, L514, and F583) contribute to the exceptionally high binding
affinity overall. Selective binding to active Raf is accomplished
by the terminal propyl group that binds to a Raf-selective pocket
created by a shift of the .alpha.C helix. Selectivity for the
active conformation of the kinase is further increased by a
pH-sensitive deprotonated sulfonamide group that is stabilized by
hydrogen bonding with the backbone peptide NH of D594 in the active
state. In the inactive state, the inhibitor's sulfonamide group
interacts with the backbone carbonyl of that residue instead,
creating repulsion. Thus, Vemurafenib binds preferentially to the
active state of B-Raf's kinase domain. Mutations in the BRAF gene
can cause disease in two ways. First, mutations can be inherited
and cause birth defects. Second, mutations can appear later in life
and cause cancer, as an oncogene. Inherited mutations in this gene
cause cardiofaciocutaneous syndrome, a disease characterized by
heart defects, mental retardation and a distinctive facial
appearance. Acquired mutations in this gene have been found in
cancers, including non-Hodgkin lymphoma, colorectal cancer,
malignant melanoma, papillary thyroid carcinoma, non-small-cell
lung carcinoma, and adenocarcinoma of the lung. The V600E mutation
of the BRAF gene has been associated with hairy cell leukemia in
numerous studies and has been suggested for use in screening for
Lynch syndrome to reduce the number of patients undergoing
unnecessary MLH1 sequencing. As mentioned above, some
pharmaceutical firms are developing specific inhibitors of mutated
B-raf protein for anticancer use because B-Raf is a
well-understood, high yield target. Vemurafenib (RG7204 or
PLX4032), licensed as Zelboraf for the treatment of metastatic
melanoma, is the current state-of-the-art example for why active
B-Raf inhibitors are being pursued as drug candidates. Vemurafenib
is biochemically interesting as a mechanism to target cancer due to
its high efficacy and selectivity. B-Raf not only increased
metastatic melanoma patient chance of survival but raised the
response rate to treatment from 7-12% to 53% in the same amount of
time compared to the former best chemotherapeutic treatment:
dacarbazine. In spite of the drug's high efficacy, 20% of tumors
still develop resistance to the treatment. In mice, 20% of tumors
become resistant after 56 days. While the mechanisms of this
resistance are still disputed, some hypotheses include the
overexpression of B-Raf to compensate for high concentrations of
Vemurafenib and upstream upregulation of growth signaling. More
general B-raf inhibitors include GDC-0879, PLX-4720, Sorafenib
Tosylate, Dabrafenib and LGX818.
[0250] Another family of anti-cancer agent is the MEK inhibitor.
These are a chemical or drug that inhibits the mitogen-activated
protein kinase kinase enzymes MEK1 and/or MEK2. They can be used to
affect the MAPK/ERK pathway which is often overactive in some
cancers. Hence MEK inhibitors have potential for treatment of some
cancers, especially BRAF-mutated melanoma, and KRAS/BRAF mutated
colorectal cancer. Examples of MEK inhibitors include: Trametinib
(GSK1120212), for treatment of BRAF-mutated melanoma and possible
combination with BRAF inhibitor dabrafenib to treat BRAF-mutated
melanoma; Selumetinib, for non-small cell lung cancer (NSCLC);
MEK162, had phase 1 trial for biliary tract cancer and melanoma;
PD-325901, for breast cancer, colon cancer, and melanoma; XL518;
CI-1040 and PD035901.
[0251] Another family of anti-cancer agent is the CDK
(Cyclin-dependent kinase) inhibitor. CDK inhibitors are chemicals
that inhibits the function of CDKs. It is used to treat cancers by
preventing overproliferation of cancer cells. In many human
cancers, CDKs are overactive or CDK-inhibiting proteins are not
functional. Therefore, it is rational to target CDK function to
prevent unregulated proliferation of cancer cells. However, the
validity of CDK as a cancer target should be carefully assessed
because genetic studies have revealed that knockout of one specific
type of CDK often does not affect proliferation of cells or has an
effect only in specific tissue types. For example, most adult cells
in mice proliferate normally even without both CDK4 and CDK2.
Furthermore, specific CDKs are only active in certain periods of
the cell cycle. Therefore, the pharmacokinetics and dosing schedule
of the candidate compound must be carefully evaluated to maintain
active concentration of the drug throughout the entire cell cycle.
Types of CDK inhibitors include: Broad CDK inhibitors that target a
broad spectrum of CDKs; specific CDK inhibitors that target a
specific type of CDK; and multiple target inhibitors that target
CDKs as well as additional kinases such as VEGFR or PDGFR. Specific
examples include: P1446A-05 targeting CDK4 and PD-0332991 that
targets CDK4 and CDK6 for leukemia, melanoma and solid tumors.
[0252] Another anti-cancer agent is Salinomycin. Salinomycin is an
antibacterial and coccidiostat ionophore therapeutic drug.
Salinomycin has been shown to kill breast cancer stem cells in mice
at least 100 times more effectively than the anti-cancer drug
paclitaxel. The study screened 16,000 different chemical compounds
and found that only a small subset, including salinomycin and
etoposide, targeted cancer stem cells responsible for metastasis
and relapse. The mechanism of action by which salinomycin kills
cancer stem cells specifically remains unknown, but is thought to
be due to its action as a potassium ionophore due to the detection
of nigericin in the same compound screen. Studies performed in 2011
showed that salinomycin could induce apoptosis of human cancer
cells. Promising results from a few clinical pilote studies reveal
that salinomycin is able to effectively eliminate CSCs and to
induce partial clinical regression of heavily pretreated and
therapy-resistant cancers. The ability of salinomycin to kill both
CSCs and therapy-resistant cancer cells may define the compound as
a novel and an effective anticancer drug. It has been also shown
that Salinomycin and its derivatives exhibit potent
antiproliferative activity against the drug-resistant cancer cell
lines. Salinomycin is the key compound in the pharmaceutical
company Verastem's efforts to produce an anti-cancer-stem-cell
drug.
[0253] Drugs for non-small cell lung cancer may include: Abitrexate
(methotrexate), Abraxane (Paclitaxel Albumin-stabilized
Nanoparticle Formulation), Afatinib Dimaleate, Alimta (pemetrexed
disodium), Avastin (Bevacizumab), Carboplatin, Cisplatin,
Crizotinib, Erlotinib Hydrochloride, Folex (methotrexate), Folex
PFS (methotrexate), Gefitinib Gilotrif (afatinib dimaleate),
Gemcitabine Hydrochloride, Gemzar (gemcitabine hydrochloride),
Iressa (Gefitinib), Methotrexate, Methotrexate LPF (methotrexate),
Mexate (methotrexate), Mexate-AQ (methotrexate), Paclitaxel,
Paclitaxel Albumin-stabilized Nanoparticle Formulation, Paraplat
(carboplatin), Paraplatin (carboplatin), Pemetrexed Disodium,
Platinol (cisplatin), Platinol-AQ (Cisplatin), Tarceva (Erlotinib
Hydrochloride), Taxol (Paclitaxel), and Xalkori (Crizotinib).
[0254] Combinations approved for non-small cell lung cancer may
include: Carboplatin-Taxol and Gemcitabline-Cisplatin.
[0255] Drugs approved for small cell lung cancer may include:
Abitrexate (methotrexate), Etopophos (etoposide phosphate),
Etoposide, Etoposide Phosphate, Folex (methotrexate), Folex PFS
(methotrexate), Hycamtin (topotecan hydrochloride), Methotrexate,
Methotrexate LPF (methotrexate), Mexate (methotrexate), Mexate-AQ
(methotrexate), Toposar (etoposide), Topotecan Hydrochloride, and
VePesid (etoposide).
[0256] Agents that may serve as inhaled anti-cancer and/or inhaled
anti-fibrotic therapeutic agents may include: Gefitinib (Iressa,
also known as ZD1839); Erlotinib (also known as Tarceva);
Bortezomib (originally codenamed PS-341 and MG-341; marketed as
Velcade and Bortecad); Janus kinase inhibitors (also known as JAK
inhibitors), including: Tofacitinib (tasocitinib; CP-690550),
Ruxolitinib, Baricitinib (LY3009104, INCB28050), CYT387,
Lestaurtinib, Pacritinib (SB1518), and TG101348; ALK inhibitors,
including Crizotinib (trade name Xalkori), AP26113, LDK378, and
NPM-ALK; Bcl-2 inhibitors, including Genasense (G3139) ABT-73,
ABT-737, ABT-199, and Obatoclax (GX15-070); PARP inhibitors include
Iniparib (BSI 201), Olaparib (AZD-2281), Rucaparib (AG014699,
PF-01367338), Veliparib (ABT-888), CEP 9722, MK 4827, BMN-673, and
3-aminobenzamide; PI3K/AKT/mTOR pathway inhibitors including
Wortmannin, demethoxyviridin, LY294002, Perifosine, CAL101, PX-866,
IPI-145, BAY 80-6946, BEZ235, RP6503, TGR 1202, SF1126, INK1117,
GDC-0941, BKM120, XL147 (also known as SAR245408), XL765 (also
known as SAR245409), Palomid 529, GSK1059615, ZSTK474, PWT33597,
IC87114, TG100-115, CAL263, RP6530, PI-103, GNE-477, CUDC-907, and
AEZS-136. Other agents that may serve as inhaled anti-cancer and/or
inhaled anti-fibrotic therapeutic agents may include: Apatinib
(also known as YN968D1); BRAF inhibitors including Vemurafenib
(PLX4032 or RG7204 or Zelboraf), Dabrafenib, BAY43-9006 (Sorafenib,
Nexavar), GDC-0879, PLX-4720, Sorafenib Tosylate, and LGX818; MEK
inhibitors including Trametinib (GSK1120212), Selumetinib, MEK162,
PD-325901, XL518, CI-1040, and PD035901; CDK (Cyclin-dependent
kinase) inhibitors including P1446A-05, and PD-0332991;
Salinomycin, Abitrexate (methotrexate), Abraxane (Paclitaxel
Albumin-stabilized Nanoparticle Formulation), Afatinib Dimaleate,
Alimta (pemetrexed disodium), Avastin (Bevacizumab), Carboplatin,
Cisplatin, Crizotinib, Erlotinib Hydrochloride, Folex
(methotrexate), Folex PFS (methotrexate), Gilotrif (afatinib
dimaleate), Gemcitabine Hydrochloride, Gemzar (gemcitabine
hydrochloride), Iressa (Gefitinib), Methotrexate, Methotrexate LPF
(methotrexate), Mexate (methotrexate), Mexate-AQ (methotrexate),
Paclitaxel, Paclitaxel Albumin-stabilized Nanoparticle Formulation,
Paraplat (carboplatin), Paraplatin (carboplatin), Pemetrexed
Disodium, Platinol (cisplatin), Platinol-AQ (Cisplatin), Tarceva
(Erlotinib Hydrochloride), Taxol (Paclitaxel), Abitrexate
(methotrexate), Etopophos (etoposide phosphate), Etoposide,
Etoposide Phosphate, Folex (methotrexate), Folex PFS
(methotrexate), Hycamtin (topotecan hydrochloride), Methotrexate,
Methotrexate LPF (methotrexate), Mexate (methotrexate), Mexate-AQ
(methotrexate), Toposar (etoposide), Topotecan Hydrochloride, and
VePesid (etoposide). In addition to possible combinations of all
drugs listed above, other combinations for inhaled administration
may include: Carboplatin-Taxol and Gemcitabline-Cisplatin.
[0257] Aerosol administration directly to one or more desired
regions of the respiratory tract, which includes the upper
respiratory tract (e.g., nasal, sinus, and pharyngeal
compartments), the respiratory airways (e.g., laryngeal, tracheal,
and bronchial compartments) and the lungs or pulmonary compartments
(e.g., respiratory bronchioles, alveolar ducts, alveoli), may be
effected (e.g., "pulmonary delivery") in certain preferred
embodiments through intra-nasal or oral inhalation to obtain high
and titrated concentration of drug, pro-drug active or
sustained-release delivery to a site of respiratory pathology.
Aerosol administration such as by intra-nasal or oral inhalation
may also be used to provide drug, pro-drug active or
sustained-release delivery through the pulmonary vasculature (e.g.,
further to pulmonary delivery) to reach other tissues or organs, by
non-limiting example, the heart, brain, liver central nervous
system and/or kidney, with decreased risk of extra-respiratory
toxicity associated with non-respiratory routes of drug delivery.
Accordingly, because the efficacy of a particular
phenylaminopyrimidine derivative compound (e.g., imatinib)
therapeutic composition may vary depending on the formulation and
delivery parameters, certain embodiments described herein reflect
re-formulations of compositions and novel delivery methods for
recognized active drug compounds. Other embodiments contemplate
topical pathologies and/or infections that may also benefit from
the discoveries described herein, for example, through direct
exposure of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound formulation as provided herein to diseased
skin, rectum, vagina, urethra, urinary bladder, eye, and/or ear,
including aerosol delivery to a burn wound to prevent scarring.
[0258] In addition to the clinical and pharmacological criteria
according to which any composition intended for therapeutic
administration (such as the herein described imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound
formulations) may be characterized, those familiar with the art
will be aware of a number of physicochemical factors unique to a
given drug composition. These include, but are not limited to
aqueous solubility, viscosity, partitioning coefficient (Log P),
predicted stability in various formulations, osmolality, surface
tension, pH, pKa, pKb, dissolution rate, sputum permeability,
sputum binding/inactivation, taste, throat irritability and acute
tolerability.
[0259] Other factors to consider when selecting the particular
product form include physical chemistry of the formulation (e.g.,
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound formulation), the intended disease indication(s) for which
the formulation is to be used, clinical acceptance, and patient
compliance. As non-limiting examples, a desired imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound
formulation for aerosol delivery (e.g., by oral and/or intra-nasal
inhalation of a mist such as a nebulized suspension of liquid
particles, a dispersion of a dry powder formulation or aerosol
generated by meter-dose propellant), may be provided in the form of
a simple liquid such as an aqueous liquid (e.g., soluble imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof
compound with non-encapsulating soluble excipients/salts), a
complex liquid such as an aqueous liquid (e.g., imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof encapsulated or
complexed with soluble excipients such as lipids, liposomes,
cyclodextrins, microencapsulations, and emulsions), a complex
suspension (e.g., imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof as a low-solubility, stable nanosuspension alone, as
co-crystal/co-precipitate complexes, and/or as mixtures with low
solubility lipids such as solid-lipid nanoparticles), a dry powder
(e.g., dry powder imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound alone or in
co-crystal/co-precipitate/spray-dried complex or mixture with low
solubility excipients/salts or readily soluble blends such as
lactose), or an organic soluble or organic suspension solution, for
packaging and administration using an inhalation device such as a
metered-dose inhalation device.
[0260] Selection of a particular imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound formulation as provided
herein according to certain preferred embodiments may be influenced
by the desired product packaging. Factors to be considered in
selecting packaging may include, for example, intrinsic product
stability, whether the formulation may be subject to
lyophilization, device selection (e.g., liquid nebulizer,
dry-powder inhaler, meter-dose inhaler), and/or packaging form
(e.g., simple liquid or complex liquid formulation, whether
provided in a vial as a liquid or as a lyophilisate to be dissolved
prior to or upon insertion into the device; complex suspension
formulation whether provided in a vial as a liquid or as a
lyophilisate, and with or without a soluble salt/excipient
component to be dissolved prior to or upon insertion into the
device, or separate packaging of liquid and solid components; dry
powder formulations in a vial, capsule or blister pack; and other
formulations packaged as readily soluble or low-solubility solid
agents in separate containers alone or together with readily
soluble or low-solubility solid agents.
[0261] Packaged agents may be manufactured in such a way as to
provide imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound formulation composition for pulmonary
delivery that comprises a solution which is provided as imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof compound aqueous
solution having a pH from about 3.0 to about 11.0, more preferably
from about pH 4 to about pH 8, at a concentration of at least 0.001
mg/mL to about 200 mg/mL or at a concentration of at least 0.1
mg/mL to about 50 mg/mL, and having a total osmolality at least 50
mOsmol/kg to about 1000 mOsmol/kg, more preferably 200 to about 500
mOsmol/kg.
[0262] In some embodiments, the present invention relates to the
aerosol and/or topical delivery of a phenylaminopyrimidine
derivative compound (e.g., imatinib). Imatinib has favorable
solubility characteristics enabling dosing of clinically-desirable
levels by aerosol (e.g., through liquid nebulization, dry powder
dispersion or meter-dose administration) or topically (e.g.,
aqueous suspension, oily preparation or the like or as a drip,
spray, suppository, salve, or an ointment or the like), and can be
used in methods for acute or prophylactic treatment of a subject
having pulmonary fibrosis, or of a subject at risk for having
pulmonary fibrosis. Clinical criteria for determining when
pulmonary fibrosis is present, or when a subject is at risk for
having pulmonary fibrosis, are known to the art. Pulmonary delivery
via inhalation permits direct and titrated dosing directly to the
clinically-desired site with reduced systemic exposure.
[0263] In a preferred embodiment, the method treats or serves as
prophylaxis against interstitial lung disease (ILD) by
administering imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound formulation as an aerosol (e.g., a suspension
of liquid particles in air or another gas) to a subject having or
suspected to have interstitial lung disease. Interstitial lung
disease includes those conditions of idiopathic interstitial
pneumonias as defined by American Thoracic Society/European
Respiratory Society international multidisciplinary concensus
classification of the idiopathic interstitial pneumonias, AM. J.
Respir. Crit. Care Med. 165, 277-304 (2002). These include ILD of
known cause or association with connective tissue diseases,
occupational causes or drug side effect, idiopathic interstitial
pneumonias (e.g. idiopathic pulmonary fibrosis, non-specific
interstitial pneumonia, desquamative interstitial pneumonia,
respiratory bronchiolitis-ILD, cryptogenic organizing pneumonia,
acute interstitial pneumonia and lyphocytic interstitial
pneumonia), granulomatous lung disease (e.g., sarcodosis,
hypersensitivity pneumonitis and infection), and other forms of ILD
(e.g., lymphangioleiomyomatosis, pulmonary Langerhans' cell
histocytosis, eosinophilic pneumonia and pulmonary alveolar
proteinosis).
[0264] The therapeutic method may also include a diagnostic step,
such as identifying a subject with or suspected of having ILD. In
some embodiments, the method further sub-classifies into idiopathic
pulmonary fibrosis. In some embodiments, the delivered amount of
aerosol imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound (or salt thereof) formulation is sufficient
to provide acute, sub-acute, or chronic symptomatic relief, slowing
of fibrosis progression, halting fibrosis progression, reversing
fibrotic damage, and/or subsequent increase in survival and/or
improved quality of life.
[0265] The therapeutic method may also include a diagnostic step,
such as identifying a subject with or suspected of having fibrosis
in other tissues, by non-limiting example in the heart, liver,
kidney or skin. In some embodiments, the delivered amount of liquid
nebulized, dry powder or metered-dose aerosol imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound (or salt
thereof) formulation is sufficient to provide acute, sub-acute, or
chronic symptomatic relief, slowing of fibrosis progression,
halting fibrosis progression, reversing fibrotic damage, and/or
subsequent increase in survival and/or improved quality of
life.
[0266] The therapeutic method may also include a diagnostic step,
such as identifying a subject with or suspected of having multiple
sclerosis. In some embodiments, the delivered amount of liquid
nebulized, dry powder or metered-dose aerosol imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound (or salt
thereof) formulation is sufficient to provide acute, sub-acute, or
chronic symptomatic relief, slowing of demylination progression,
halting demylination progression, reversing demylinated damage,
and/or subsequent increase in survival and/or improved quality of
life.
[0267] In another embodiment, liquid nebulized, dry powder or
metered-dose aerosol imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound (or salt thereof) may be
co-administered, administered sequentially or prepared in a
fixed-combination with antimicrobial agents to also provide therapy
for a co-existing bacterial infection. By non-limiting example the
bacteria may be a gram-negative bacteria such as Pseudomonas
aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans,
Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas
maltophilia, Burkholderia cepacia, Aeromonas hydrophilia,
Escherichia coli, Citrobacter freundii, Salmonella typhimurium,
Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis,
Shigella dysenteriae, Shigella flexneri, Shigella sonnei,
Enterobacter cloacae, Enterobacter aerogenes, Klebsiella
pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella
tularensis, Morganella morganii, Proteus mirabilis, Proteus
vulgaris, Providencia alcalifaciens, Providencia rettgeri,
Providencia stuartii, Acinetobacter calcoaceticus, Acinetobacter
haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia
pseudotuberculosis, Yersinia intermedia, Bordetella pertussis,
Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus
influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus,
Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella
multocida, Pasteurella haemolytica, Branhamella catarrhalis,
Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni,
Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio
parahaemolyticus, Legionella pneumophila, Listeria monocytogenes,
Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella,
Gardnerella vaginalis, Bacteroides fragilis, Bacteroides
distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus,
Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides
uniformis, Bacteroides eggerthii, and Bacteroides splanchnicus. In
some embodiments of the methods described above, the bacteria are
gram-negative anaerobic bacteria, by non-limiting example these
include Bacteroides fragilis, Bacteroides distasonis, Bacteroides
3452A homology group, Bacteroides vulgatus, Bacteroides ovalus,
Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides
eggerthii, and Bacteroides splanchnicus. In some embodiments of the
methods described above, the bacteria are gram-positive bacteria,
by non-limiting example these include: Corynebacterium diphtheriae,
Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus
agalactiae, Streptococcus pyogenes, Streptococcus milleri;
Streptococcus (Group G); Streptococcus (Group C/F); Enterococcus
faecalis, Enterococcus faecium, Staphylococcus aureus,
Staphylococcus epidermidis, Staphylococcus saprophyticus,
Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus,
Staphylococcus haemolyticus, Staphylococcus hominis, and
Staphylococcus saccharolyticus. In some embodiments of the methods
described above, the bacteria are gram-positive anaerobic bacteria,
by non-limiting example these include Clostridium difficile,
Clostridium perfringens, Clostridium tetini, and Clostridium
botulinum. In some embodiments of the methods described above, the
bacteria are acid-fast bacteria, by non-limiting example these
include Mycobacterium tuberculosis, Mycobacterium avium,
Mycobacterium intracellulare, and Mycobacterium leprae. In some
embodiments of the methods described above, the bacteria are
atypical bacteria, by non-limiting example these include Chlamydia
pneumoniae and Mycoplasma pneumoniae.
[0268] As a non-limiting example, in a preferred embodiment, a
phenylaminopyrimidine derivative compound as provided herein (e.g.,
imatinib) formulated to permit mist, gas-liquid suspension or
liquid nebulized, dry powder and/or metered-dose inhaled aerosol
administration to supply effective concentrations or amounts to
produce and maintain threshold drug concentrations in the lung
and/or targeted downstream tissue, which may be measured as drug
levels in epithelial lining fluid (ELF), sputum, lung tissue,
bronchial lavage fluid (BAL), or by deconvolution of blood
concentrations through pharmacokinetic analysis. One embodiment
includes the use of aerosol administration, delivering high or
titrated concentration drug exposure directly to the affected
tissue for treatment of pulmonary fibrosis and inflammation
associated with ILD (including idiopathic pulmonary fibrosis)in
animals and humans. In one such embodiment, the peak lung ELF
levels achieved following aerosol administration to the lung will
be between 0.1 mg/mL and about 50 mg/mL imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. In another embodiment, the peak
lung wet tissue levels achieved following aerosol administration to
the lung will be between 0.004 mcg/gram lung tissue and about 500
mcg/gram lung tissue imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof.
[0269] As a non-limiting example, in a preferred embodiment, a
phenylaminopyrimidine derivative compound as provided herein (e.g.,
imatinib) formulated to permit mist, gas-liquid suspension or
liquid nebulized, dry powder and/or metered-dose inhaled aerosol
administration to supply effective concentrations or amounts to
produce and maintain threshold drug concentrations in the blood
and/or lung, which may be measured as drug levels in epithelial
lining fluid (ELF), sputum, lung tissue, bronchial lavage fluid
(BAL), or by deconvolution of blood concentrations through
pharmacokinetic analysis that absorb to the pulmonary vasculature
producing drug levels sufficient for extra-pulmonary therapeutics,
maintenance or prophylaxis. One embodiment includes the use of
aerosol administration, delivering high concentration drug exposure
in the pulmonary vasculature and subsequent tissues and associated
vasculature for treatment, maintenance and/or prophylaxis of, but
not limited to cardiac fibrosis, kidney fibrosis, hepatic fibrosis,
heart or kidney toxicity, or multiple sclerosis. In one such
embodiment, the peak tissue-specific plasma levels (e.g., heart,
kidney and liver) or cerebral spinal fluid levels (e.g. central
nervous system) achieved following aerosol administration to the
lung following oral inhalation or to the lung or nasal cavity
following intra-nasal administration will be between 0.1 mcg/mL and
about 50 mcg/mL imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof. In another embodiment, the peak lung wet tissue
levels achieved following aerosol administration to the lung will
be between 0.004 mcg/gram lung tissue and about 500 mcg/gram lung
tissue imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt
thereof.
[0270] In another embodiment, a method is provided for acute or
prophylactic treatment of a patient through non-oral or non-nasal
topical administration of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof (or a salt thereof) compound
formulation to produce and maintain threshold drug concentrations
at a burn site. One embodiment includes the use of aerosol
administration, delivering high concentration drug exposure
directly to the affected tissue for treatment or prevention of
scarring in skin. For example according to these and related
embodiments, the term aerosol may include a spray, mist, or other
nucleated liquid or dry powder form.
[0271] In another embodiment, a method is provided for acute or
prophylactic treatment of a patient through non-oral or non-nasal
topical administration of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound formulation to produce
and maintain threshold drug concentrations in the eye. One
embodiment includes the use of aerosol administration or
formulation drops to deliver high concentration drug exposure
directly to the affected tissue for treatment or prevention of
scarring following surgical glaucoma surgery (e.g., bleb fibrosis).
For example according to these and related embodiments, the term
aerosol may include a spray, mist, or other nucleated liquid or dry
powder form. A drop may be simple liquid or suspension
formulation.
[0272] In another embodiment, a phenylaminopyrimidine derivative
compound as provided herein (e.g., imatinib) formulation by
inhalation, wherein the inhaled liquid aerosol (e.g., following
liquid nebulization or metered-dose administration) or dry powder
aerosol has a mean particle size from about 1 micron to 10 microns
mass median aerodynamic diameter and a particle size geometric
standard deviation of less than or equal to about 3 microns. In
another embodiment, the particle size is 2 microns to about 5
microns mass median aerodynamic diameter and a particle size
geometric standard deviation of less than or equal to about 3
microns. In one embodiment, the particle size geometric standard
deviation is less than or equal to about 2 microns.
[0273] As a non-limiting example, in a preferred embodiment, a
phenylaminopyrimidine derivative compound as provided herein (e.g.,
imatinib) remains at the therapeutically effective concentration at
the site of pulmonary pathology, suspected pulmonary pathology,
and/or site of pulmonary absorption into the pulmonary vasculature
for at least about 1 minute, at least about a 5 minute period, at
least about a 10 min period, at least about a 20 min period, at
least about a 30 min period, at least about a 1 hour period, at
least a 2 hour period, at least about a 4 hour period, at least an
8 hour period, at least a 12 hour period, at least a 24 hour
period, at least a 48 hour period, at least a 72 hour period, or at
least one week. The effective imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof concentration is sufficient to
cause a therapeutic effect and the effect may be localized or
broad-acting to or from the site of pulmonary pathology.
[0274] As a non-limiting example, in a preferred embodiment, a
phenylaminopyrimidine derivative compound as provided herein (e.g.,
imatinib or salt thereof) following inhalation administration
remains at the therapeutically effective concentration at the site
of cardiac fibrosis, kidney fibrosis, hepatic fibrosis, heart or
kidney toxicity, or multiple sclerosis demylination for at least
about 1 minute, at least about a 5 minute period, at least about a
10 min period, at least about a 20 min period, at least about a 30
min period, at least about a 1 hour period, at least a 2 hour
period, at least about a 4 hour period, at least an 8 hour period,
at least a 12 hour period, at least a 24 hour period, at least a 48
hour period, at least a 72 hour period, or at least one week. The
effective imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof concentration is sufficient to cause a therapeutic
effect and the effect may be localized or broad-acting to or from
the site of extrapulmonary pathology.
[0275] In some embodiments, delivery sites such as a pulmonary
site, the an imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound formulation as provided herein is
administered in one or more administrations so as to achieve a
respirable delivered dose daily of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof of at least about 0.001 mg to
about 200 mg, including all integral values therein such as 0.005,
0.01, 0.05, 0.1, 0.2, 0.4, 0.8, 1, 2, 4, 6, 10, 15, 20, 25, 30, 35,
40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170,
180, 190 and 200 milligrams. In some embodiments, delivery sites
such as a pulmonary site, the an imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound formulation as provided
herein is administered in one or more administrations so as to
achieve a respirable delivered dose daily of imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof of at least about
0.1 mg to about 50 mg, including all integral values therein such
as 0.1, 0.2, 0.4, 0.8, 1, 2, 4, 6, 10, 15, 20, 25, 30, 35, 40, 45,
50 milligrams. In some embodiments, an imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound formulation as provided
herein is administered in one or more administrations so as to
achieve a respirable delivered dose daily of imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof of at least about
0.001 mg to about 200 mg, including all integral values therein
such as 0.005, 0.01, 0.05, 0.1, 0.2, 0.4, 0.8, 1, 2, 4, 6, 10, 15,
20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 95,
100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160,
165, 170, 175, 180, 185, 190, 195, and 200 milligrams. In some
embodiments, an imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound formulation as provided herein is
administered in one or more administrations so as to achieve a
respirable delivered dose daily of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof of at least about 0.1 mg to about
300 mg, including all integral values therein such as 0.1, 0.2,
0.4, 0.8, 1, 2, 4, 6, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60,
65, 70, 75, 80, 85, 90, 95, 95, 100, 105, 110, 115, 120, 125, 130,
135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195,
200 milligrams. The imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof formulation is administered in the
described respirable delivered dose in less than 60 minutes, less
than 50 minutes, less than 40 minutes, less than 30 minutes, less
than 20 minutes, less than 15 minutes, less than 10 minutes, less
than 7 minutes, less than 5 minutes, in less than 3 minutes, in
less than 2 minutes, in less than 1 minute, 10 inhalation breaths,
8 inhalation breaths, 6 inhalation breaths, 4 inhalation breaths, 3
inhalation breaths, 2 inhalation breaths or 1 inhalation breath. In
some embodiments, imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof formulation is administered in the described
respirable delivered dose using a breathing pattern of 1 second
inhalation and 2 seconds exhalation, 2 seconds inhalation and 2
seconds exhalation, 3 seconds inhalation and 2 seconds exhalation,
4 seconds inhalation and 2 seconds exhalation, 5 seconds inhalation
and 2 seconds exhalation, 6 seconds inhalation and 2 seconds
exhalation, 7 seconds inhalation and 2 seconds exhalation, and 8
seconds inhalation and 2 seconds exhalation, 9 seconds inhalation,
2 seconds exhalation, 10 seconds inhalation, 2 seconds exhalation,
1 second inhalation and 3 seconds exhalation, 2 seconds inhalation
and 3 seconds exhalation, 3 seconds inhalation and 3 seconds
exhalation, 4 seconds inhalation and 3 seconds exhalation, 5
seconds inhalation and 3 seconds exhalation, 6 seconds inhalation
and 3 seconds exhalation, 7 seconds inhalation and 3 seconds
exhalation, and 8 seconds inhalation and 3 seconds exhalation, 9
seconds inhalation, 3 seconds exhalation, 10 seconds inhalation, 3
seconds exhalation, 1 second inhalation and 4 seconds exhalation, 2
seconds inhalation and 4 seconds exhalation, 3 seconds inhalation
and 4 seconds exhalation, 4 seconds inhalation and 4 seconds
exhalation, 5 seconds inhalation and 4 seconds exhalation, 6
seconds inhalation and 4 seconds exhalation, 7 seconds inhalation
and 4 seconds exhalation, and 8 seconds inhalation and 4 seconds
exhalation, 9 seconds inhalation, 4 seconds exhalation, 10 seconds
inhalation, 4 seconds exhalation, 1 second inhalation and 5 seconds
exhalation, 2 seconds inhalation and 5 seconds exhalation, 3
seconds inhalation and 5 seconds exhalation, 4 seconds inhalation
and 5 seconds exhalation, 5 seconds inhalation and 5 seconds
exhalation, 6 seconds inhalation and 5 seconds exhalation, 7
seconds inhalation and 5 seconds exhalation, and 8 seconds
inhalation and seconds exhalation, 9 seconds inhalation, 5 seconds
exhalation, 10 seconds inhalation, 5 seconds exhalation, 1 second
inhalation and 6 seconds exhalation, 2 seconds inhalation and 4
seconds exhalation, 3 seconds inhalation and 6 seconds exhalation,
4 seconds inhalation and 4 seconds exhalation, 5 seconds inhalation
and 6 seconds exhalation, 6 seconds inhalation and 4 seconds
exhalation, 7 seconds inhalation and 6 seconds exhalation, and 8
seconds inhalation and 3 seconds exhalation, 9 seconds inhalation,
6 seconds exhalation, 10 seconds inhalation, 6 seconds exhalation,
1 second inhalation and 7 seconds exhalation, 2 seconds inhalation
and 7 seconds exhalation, 3 seconds inhalation and 7 seconds
exhalation, 4 seconds inhalation and 7 seconds exhalation, 5
seconds inhalation and 7 seconds exhalation, 6 seconds inhalation
and 7 seconds exhalation, 7 seconds inhalation and 7 seconds
exhalation, and 8 seconds inhalation and 7 seconds exhalation, 9
seconds inhalation, 7 seconds exhalation, 10 seconds inhalation, 7
seconds exhalation, 1 second inhalation and 8 seconds exhalation, 2
seconds inhalation and 8 seconds exhalation, 3 seconds inhalation
and 8 seconds exhalation, 4 seconds inhalation and 8 seconds
exhalation, 5 seconds inhalation and 8 seconds exhalation, 6
seconds inhalation and 8 seconds exhalation, 7 seconds inhalation
and 8 seconds exhalation, and 8 seconds inhalation and 8 seconds
exhalation, 9 seconds inhalation, 8 seconds exhalation, 10 seconds
inhalation, 8 seconds exhalation.
[0276] In some embodiments, delivery sites such as the nasal cavity
or sinus, imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound formulation is administered in one or more
administrations so as to achieve a nasal cavity or sinus deposited
dose daily of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof of at least about 0.001 mg to about 200 mg, including
all integral values therein such as 0.005, 0.01, 0.05, 0.1, 0.2,
0.4, 0.8, 1, 2, 4, 6, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70,
80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 and 200
milligrams. In some embodiments, delivery sites such as the nasal
cavity or sinus, imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound formulation is administered in one or more
administrations so as to achieve a nasal cavity or sinus deposited
dose daily of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof of at least about 0.1 mg to about 50 mg, including all
integral values therein such as 0.1, 0.2, 0.4, 0.8, 1, 2, 4, 6, 10,
15, 20, 25, 30, 35, 40, 45, 50 milligrams. In some embodiments,
delivery sites such as the nasal cavity or sinus, imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound
formulation is administered in one or more administrations so as to
achieve a nasal cavity or sinus deposited dose daily of imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof of at least
about 0.001 mg to about 200 mg, including all integral values
therein such as 0.005, 0.01, 0.05, 0.1, 0.2, 0.4, 0.8, 1, 2, 4, 6,
10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90,
95, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155,
160, 165, 170, 175, 180, 185, 190, 195, and 200 milligrams. In some
embodiments, delivery sites such as the nasal cavity or sinus,
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound formulation is administered in one or more administrations
so as to achieve a nasal cavity or sinus deposited dose daily of
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof of
at least about 0.1 mg to about 300 mg, including all integral
values therein such as 0.1, 0.2, 0.4, 0.8, 1, 2, 4, 6, 10, 15, 20,
25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 95,
100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160,
165, 170, 175, 180, 185, 190, 195, and 200 milligrams. The imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof
formulation is administered in the described nasal or sinus
deposited dose in less than 20 minutes, less than 15 minutes, less
than 10 minutes, less than 7 minutes, less than 5 minutes, in less
than 3 minutes, in less than 2 minutes, in less than 1 minute, 10
intranasal inhalation breaths, 8 intranasal inhalation breaths, 6
intranasal inhalation breaths, 4 intranasal inhalation breaths, 3
intranasal inhalation breaths, 2 intranasal inhalation breaths or 1
intranasal inhalation breath. In some embodiments, imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof formulation is
administered in the described respirable delivered dose using a
breathing pattern of 1 second inhalation and 2 seconds exhalation,
2 seconds inhalation and 2 seconds exhalation, 3 seconds inhalation
and 2 seconds exhalation, 4 seconds inhalation and 2 seconds
exhalation, 5 seconds inhalation and 2 seconds exhalation, 6
seconds inhalation and 2 seconds exhalation, 7 seconds inhalation
and 2 seconds exhalation, and 8 seconds inhalation and 2 seconds
exhalation, 9 seconds inhalation, 2 seconds exhalation, 10 seconds
inhalation, 2 seconds exhalation, 1 second inhalation and 3 seconds
exhalation, 2 seconds inhalation and 3 seconds exhalation, 3
seconds inhalation and 3 seconds exhalation, 4 seconds inhalation
and 3 seconds exhalation, 5 seconds inhalation and 3 seconds
exhalation, 6 seconds inhalation and 3 seconds exhalation, 7
seconds inhalation and 3 seconds exhalation, and 8 seconds
inhalation and 3 seconds exhalation, 9 seconds inhalation, 3
seconds exhalation, 10 seconds inhalation, 3 seconds exhalation, 1
second inhalation and 4 seconds exhalation, 2 seconds inhalation
and 4 seconds exhalation, 3 seconds inhalation and 4 seconds
exhalation, 4 seconds inhalation and 4 seconds exhalation, 5
seconds inhalation and 4 seconds exhalation, 6 seconds inhalation
and 4 seconds exhalation, 7 seconds inhalation and 4 seconds
exhalation, and 8 seconds inhalation and 4 seconds exhalation, 9
seconds inhalation, 4 seconds exhalation, 10 seconds inhalation, 4
seconds exhalation, 1 second inhalation and 5 seconds exhalation, 2
seconds inhalation and 5 seconds exhalation, 3 seconds inhalation
and 5 seconds exhalation, 4 seconds inhalation and 5 seconds
exhalation, 5 seconds inhalation and 5 seconds exhalation, 6
seconds inhalation and 5 seconds exhalation, 7 seconds inhalation
and 5 seconds exhalation, and 8 seconds inhalation and seconds
exhalation, 9 seconds inhalation, 5 seconds exhalation, 10 seconds
inhalation, 5 seconds exhalation, 1 second inhalation and 6 seconds
exhalation, 2 seconds inhalation and 4 seconds exhalation, 3
seconds inhalation and 6 seconds exhalation, 4 seconds inhalation
and 4 seconds exhalation, 5 seconds inhalation and 6 seconds
exhalation, 6 seconds inhalation and 4 seconds exhalation, 7
seconds inhalation and 6 seconds exhalation, and 8 seconds
inhalation and 3 seconds exhalation, 9 seconds inhalation, 6
seconds exhalation, 10 seconds inhalation, 6 seconds exhalation, 1
second inhalation and 7 seconds exhalation, 2 seconds inhalation
and 7 seconds exhalation, 3 seconds inhalation and 7 seconds
exhalation, 4 seconds inhalation and 7 seconds exhalation, 5
seconds inhalation and 7 seconds exhalation, 6 seconds inhalation
and 7 seconds exhalation, 7 seconds inhalation and 7 seconds
exhalation, and 8 seconds inhalation and 7 seconds exhalation, 9
seconds inhalation, 7 seconds exhalation, 10 seconds inhalation, 7
seconds exhalation, 1 second inhalation and 8 seconds exhalation, 2
seconds inhalation and 8 seconds exhalation, 3 seconds inhalation
and 8 seconds exhalation, 4 seconds inhalation and 8 seconds
exhalation, 5 seconds inhalation and 8 seconds exhalation, 6
seconds inhalation and 8 seconds exhalation, 7 seconds inhalation
and 8 seconds exhalation, and 8 seconds inhalation and 8 seconds
exhalation, 9 seconds inhalation, 8 seconds exhalation, 10 seconds
inhalation, 8 seconds exhalation.
[0277] In some embodiments of the methods described above, the
subject is a human. In some embodiments of the methods described
above, the subject is a human with ILD. In some embodiments, the
method further sub-classifies into idiopathic pulmonary fibrosis.
In some embodiments of the methods describe above, the human
subject may be mechanically ventilated.
[0278] In embodiments where a human is mechanically ventilated,
aerosol administration would be performed using an in-line device
(by non-limiting example, the Nektar Aeroneb Pro) or similar
adaptor with device for liquid nebulization. Aerosol administration
could also be performed using an in-line adaptor for dry powder or
metered-dose aerosol generation and delivery.
[0279] In some embodiments of the methods described above, the
subject is a human. In some embodiments of the methods described
above, the subject is a human requiring cardiac fibrosis therapy.
In some embodiments of the methods describe above, the human
subject may be mechanically ventilated.
[0280] In some embodiments of the methods described above, the
subject is a human. In some embodiments of the methods described
above, the subject is a human requiring kidney fibrosis therapy. In
some embodiments of the methods describe above, the human subject
may be mechanically ventilated.
[0281] In some embodiments of the methods described above, the
subject is a human. In some embodiments of the methods described
above, the subject is a human requiring hepatic fibrosis therapy.
In some embodiments of the methods describe above, the human
subject may be mechanically ventilated.
[0282] In some embodiments of the methods described above, the
subject is a human. In some embodiments of the methods described
above, the subject is a human requiring cardiac or kidney toxicity
therapy. In some embodiments of the methods describe above, the
human subject may be mechanically ventilated.
[0283] In some embodiments of the methods described above, the
subject is a human. In some embodiments of the methods described
above, the subject is a human requiring therapy for disease
resulting from active, previous or latent viral infection. In some
embodiments of the methods describe above, the human subject may be
mechanically ventilated.
[0284] In another embodiment, a pharmaceutical composition is
provided that includes a simple liquid imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound formulation with
non-encapsulating water soluble excipients as described above
having an osmolality from about 50 mOsmol/kg to about 6000
mOsmol/kg. In one embodiment, the osmolality is from about 50
mOsmol/kg to about 1000 mOsmol/kg. In one embodiment, the
osmolality is from about 400 mOsmol/kg to about 5000 mOsmol/kg. In
other embodiments the osmolality is from about 50, 100, 150, 200,
250, 300, 350, 400, 450, 500 mOsmol/kg to about 1000, 1100, 1200,
1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2400, 2600,
2800, 3000, 3200, 3400, 3600, 3800, 4000, 4200, 4400, 4600, 4800m
5000, 5200, 5400, 5600, 5800 and 6000 mOsmol/kg. With respect to
osmolality, and also elsewhere in the present application, "about"
when used to refer to a quantitative value means that a specified
quantity may be greater than or less than the indicated amount by
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19
or 20 percent of the stated numerical value.
[0285] In another embodiment, a pharmaceutical composition is
provided that includes a simple liquid imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound formulation having a
permeant ion concentration between from about 30 mM to about 300 mM
and preferably between from about 50 mM to 200 mM. In one such
embodiment, one or more permeant ions in the composition are
selected from the group consisting of chloride and bromide.
[0286] In another embodiment, a pharmaceutical composition is
provided that includes a complex liquid imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound formulation encapsulated
or complexed with water soluble excipients such as lipids,
liposomes, cyclodextrins, microencapsulations, and emulsions) as
described above having a solution osmolality from about 50
mOsmol/kg to about 6000 mOsmol/kg. In one embodiment, the
osmolality is from about 50 mOsmol/kg to about 1000 mOsmol/kg. In
one embodiment, the osmolality is from about100 mOsmol/kg to about
500 mOsmol/kg. In one embodiment, the osmolality is from about 400
mOsmol/kg to about 5000 mOsmol/kg.
[0287] In another embodiment, a pharmaceutical composition is
provided that includes a complex liquid imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound formulation having a
permeant ion concentration from about 30 mM to about 300 mM. In one
such embodiment, one or more permeant ions in the composition are
selected from the group consisting of chloride and bromide.
[0288] In another embodiment, a pharmaceutical composition is
provided that includes a complex liquid imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound formulation having a
permeant ion concentration from about 50 mM to about 200 mM. In one
such embodiment, one or more permeant ions in the composition are
selected from the group consisting of chloride and bromide.
[0289] In another embodiment, a pharmaceutical composition is
provided that includes a simple liquid formulation of imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof compound
formulation having an imatinib or phenylaminopyrimidine derivative
to multivalent cation positive charge molar ratio between about two
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compounds to about 0.1 to about 4 multivalent cation positive
charges. By non-limiting example, two imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compounds to one magnesium ion
(two cation positive charges), three imatinib or
phenylaminopyrimidine derivative compounds to one magnesium ions,
four imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt thereof
compounds to one magnesium ions, and two imatinib or salt thereof,
a phenylaminopyrimidine derivative or salt thereof, or other
tyrosine kinase inhibitor or salt thereof compounds to two
magnesium ions.
[0290] An unexpected finding was that divalent cations, by
non-limiting example magnesium, reduced imatinib dissolution time
and increased imatinib aqueous solubility in a molar
ratio-dependent manner. This increased saturation solubility is
enabling to deliver predicted-sufficient quantities of inhaled
liquid-nebulized imatinib to the lung. By example, one imatinib
molecules to three magnesium molecules exhibited a slower
dissolution time and reduced saturation solubility than one
imatinib molecule to one magnesium molecule. Moreover, one imatinib
molecules to one magnesium molecule exhibited a faster dissolution
time and greater aqueous solubility than an equal-molar ratio of
imatinib to sodium.
[0291] In another embodiment, a pharmaceutical conmposition is
provided that includes a complex liquid formulation of imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof compound
formulation having an imatinib or phenylaminopyrimidine derivative
to to about 0.1 to about 4 multivalent cation positive charges. By
non-limiting example, two imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compounds to one magnesium ion
(two cation positive charges), three imatinib or
phenylaminopyrimidine derivative compounds to one magnesium ions,
four imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt thereof
compounds to one magnesium ions, and two imatinib or salt thereof,
a phenylaminopyrimidine derivative or salt thereof, or other
tyrosine kinase inhibitor or salt thereof compounds to two
magnesium ions.
[0292] In another embodiment, a pharmaceutical composition is
provided that includes a complex liquid imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound formulation as a low
water-soluble stable nanosuspension alone or in
co-crystal/co-precipitate complexes, or mixtures with low
solubility lipids, such as lipid nanosuspensions) as described
above having a solution osmolality from about 50 mOsmol/kg to about
6000 mOsmol/kg. In one embodiment, the osmolality is from about 100
mOsmol/kg to about 500 mOsmol/kg. In one embodiment, the osmolality
is from about 400 mOsmol/kg to about 5000 mOsmol/kg.
[0293] In another embodiment, a pharmaceutical composition is
provided that includes a complex suspension of an imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound
formulation having a permeant ion concentration from about 30 mM to
about 300 mM. In one such embodiment, one or more permeant ions in
the composition are selected from the group consisting of chloride
and bromide.
[0294] In another embodiment, a pharmaceutical composition is
provided that includes a complex suspension of an imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound
formulation having a permeant ion concentration from about 50 mM to
about 200 mM. In one such embodiment, one or more permeant ions in
the composition are selected from the group consisting of chloride
and bromide.
[0295] In another embodiment, a pharmaceutical composition is
provided that includes a complex suspension of imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound
formulation having an imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof to multivalent cation positive
charge molar ratio between about one imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compounds to about 0.1 to about 4
multivalent cation positive charges. By non-limiting example, two
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compounds to one magnesium ion (two cation positive charges), three
imatinib or phenylaminopyrimidine derivative compounds to one
magnesium ions, four imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compounds to one magnesium ions,
and two imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compounds to two magnesium ions.
[0296] In other embodiments, an imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound formulation as provided
herein, or a pharmaceutical composition, is provided that includes
a taste-masking agent. As non-limiting examples, a taste-masking
agent may include a sugar, saccharin (e.g., sodium saccharin),
sweetener or other compound or agent that beneficially affects
taste, after-taste, perceived unpleasant saltiness, sourness or
bitterness, or that reduces the tendency of an oral or inhaled
formulation to irritate a recipient (e.g., by causing coughing or
sore throat or other undesired side effect, such as may reduce the
delivered dose or adversely influence patient compliance with a
prescribed therapeutic regimen). Certain taste-masking agents may
form complexes with imatinib or salt thereof, the
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof.
[0297] In certain embodiments that relate to the imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound
formulations disclosed herein, the formulation comprises an
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound and a taste-masking agent and may be optimized with
respect to a desired osmolality, and/or an optimized permeant ion
concentration. In certain such embodiments, the taste-masking agent
comprises saccharin (e.g., sodium saccharin), which according to
non-limiting theory affords certain advantages associated with the
ability of this taste-masking agent to provide desirable taste
effects even when present in extremely low concentrations, such as
may have little or no effect on the detectable osmolality of a
solution, thereby permitting the herein described formulations to
deliver aqueous solutions, organic or dry powder formulations in a
well-tolerated manner. In certain such embodiments, the
taste-masking agent comprises a chelating agent (e.g., EDTA or
divalent cation such as magnesium), which according to non-limiting
theory affords certain advantages associated with the ability of
this taste-masking agent to provide desirable taste effects by
masking taste-stimulating chemical moieties on imatinib of
phenylaminopyrimidine derivative. With divalent cations, inclusion
as a taste-masking agent may also substitute as an osmolality
adjusting agent, and pending the salt form may also provide the
permeant ion (e.g. magnesium chloride), thereby permitting the
herein described formulations to deliver aqueous solutions, organic
or dry powder formulations in a well-tolerated manner. Non-limiting
examples of these and related embodiments include an imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof compound
formulation for pulmonary delivery as described herein that
comprises an aqueous solution having a pH of from about 4 to about
8 and an osmolality of from about 50 to about 1000 mOsmol/kg (e.g.,
adjusted with sodium chloride), the solution comprising imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof compound and
sodium saccharin where the aqueous solution contains from about 0.1
mM to about 2.0 mM saccharin. A related non-limiting example
further comprises citrate (e.g., citric acid) in an aqueous
solution containing from about 1 mM to about 100 mM citrate. A
related non-limiting example further comprises or replace citrate
with phosphate (e.g., sodium phosphate) in an aqueous solution
containing from about 0.0 mM to about 100 mM phosphate. Another
related non-limiting example further comprises or replace citrate
with phosphate (e.g., sodium phosphate) in an aqueous solution
containing from about 0.5 mM to about 100 mM phosphate. By another
non-limiting examples, these and related embodiments include an
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound formulation for pulmonary delivery as described herein
that comprises an aqueous solution having a pH of from about 4 to
about 8 and an osmolality of from about 50 to about 5000 mOsmol/kg
(e.g., adjusted with magnesium chloride), the solution comprising
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound, wherein a divalent cation (e.g., berilium, magnesium, or
calcium) serves both to adjust osmolality and as a taste-masking
agent. Where included as a taste-masking agent, divalent cation
(e.g., magnesium) is added stoichiometrically with imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. By example, 1 mol
divalent ion to 2 mols imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, 1.5 mols divalent ion to 2 mols
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof, 2
mols divalent ion to 2 mols imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof, 3 mols divalent ion to 2 mols
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof; or other tyrosine kinase inhibitor or salt thereof,
or 4 mols divalent ion to 2 mols imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof. Where osmolality required further
increase sodium chloride or additional divalent salt may be used. A
related non-limiting example further comprises citrate (e.g.,
citric acid) in an aqueous solution containing from about 1 mM to
about 100 mM citrate. A related non-limiting example citrate is
replaced with phosphate (e.g., sodium phosphate) in an aqueous
solution containing from about 0.0 mM to about 100 mM phosphate. In
another related non-limiting example citrate is replaced with
phosphate (e.g., sodium phosphate) in an aqueous solution
containing from about 0.0 mM to about 100 mM phosphate.
[0298] In another embodiment, while the inclusion of the correct
molar ratio of magnesium to imatinib reduces dissolution time and
increases saturation solubility to a level required for sufficient
liquid nebulization delivery to the lung, an unexpected finding was
that this formulation additionally requires a taste masking agent
for acute tolerability upon inhalation of a nebulized solution. To
this end, between 0.1 and 1.0 micromolar saccharin enables the use
of this solubility-enabling formulation.
[0299] In another embodiment, a pharmaceutical composition may be
protected from light to avoid photodegradation. By non-limiting
example, this may occur by light-protected vials, ampoules,
blisters, capsules, or other colored or light-protected primary
packaging. By another non-limiting example, this may occur by use
of secondary packaging such as an aluminum or other light-protected
over-pouch, box or other secondary packaging.
[0300] In another embodiment, a pharmaceutical composition may be
protected from oxygen to protect from oxidation. By non-limiting
example, in solution this may occur by removing oxygen from
solution prior to or during compounding (e.g., sparging), and or
controlled the primary packaging head-space gas (e.g. using of
inert gas such as argon or nitrogen in the head space). Similarly,
by another non-limiting example, controlling the included secondary
packaging gas (e.g. with inert gas) may also be required. For
powder formulations this may be controlled by use of insert gas in
primary and/or secondary packaging. Meter-dose inhaled products may
benefit by the same means as described above for solution
products.
[0301] In another embodiment, imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof present in a pharmaceutical
composition may be protected from hydrolysis by inclusion of a
cationic metal ion. By non-limiting example, acid hydrolysis of
amide bonds decreases with an increased salt concentration.
Specifically, hydration number is important for this rate decrease,
as electrolyte hydration decreases the availability of free water
for the reaction. Thus, the rate decreases with increased salt and
increased hydration number. The order of increasing hydration
number: potassium<sodium<lithium<magnesium. The rate
decrease also nearly parallels ionic strength. By non-limiting
example, the addition of magnesium will stabilize the structure of
imatinib. It is known that imatinib chelates Fe(III) at a ratio of
3 imatinib molecules to 1 Fe(III). From this it follows that
imatinib will chelate magnesium at 2 imatinib molecules to 1
magnesium +2 charge. Therefore, for this purpose the addition of
magnesium or other cationic metal ion may be stoichiometric to the
amount of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof. By non-limiting example, 2 imatinib molecules to 0.1
magnesium molecules, 2 imatinib molecules to 0.25 magnesium
molecules, 2 imatinib molecules to 0.5 magnesium molecules, 2
imatinib molecules to 0.75 magnesium molecules, 2 imatinib
molecules to 1 magnesium molecules, 2 imatinib molecules to 1.5
magnesium molecules, 2 imatinib molecules to 2 magnesium molecules,
2 imatinib molecules to 3 magnesium molecules, 2 imatinib molecules
to 4 magnesium molecules, 2 imatinib molecules to 5 magnesium
molecules, 2 imatinib molecules to 6 magnesium molecules, 2
imatinib molecules to 7 magnesium molecules, 2 imatinib molecules
to 8 magnesium molecules, 2 imatinib molecules to 9 magnesium
molecules, 2 imatinib molecules to 10 magnesium molecules, 2
imatinib molecules to 12 magnesium molecules, 2 imatinib molecules
to 14 magnesium molecules, 2 imatinib molecules to 16 magnesium
molecules, 2 imatinib molecules to 18 magnesium molecules, or 2
imatinib molecules to 20 magnesium molecules. Potassium, sodium,
lithium or iron may substitute for magnesium in these ratios and
pharmaceutical composition. Included in the above pharmaceutical
composition is the maintenance of the buffers described herein, at
a pH from about 4.0 to about 8.0, and include MgCl2 or cationic
salt thereof at a level that provides an osmolality of 300 mOsmo/kg
and 600 mOsmo/kg. While 300 mOsmo/kg is discussed in the literature
as important for acute tolerability upon inhalation of this in a
nebulized solution, 600 mOsmo/kg has been shown in unpublished
studies to be well tolerated with other drug solutions. However, a
final solution osmolality up to 6000 mOsmo/kg is contemplated.
Unexpectantly, formulations described herein demonstrate good
tolerability at high osmolalities.
[0302] In another embodiment, a pharmaceutical composition of
liquid imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt thereof
may contain a solubility enhancing agent or co-solvent. By
non-limiting example, these may include ethanol, cetylpridinium
chloride, glycerin, lecithin, propylene glycol, polysorbate
(including polysorbate 20, 40, 60, 80 and 85), sorbitan triolate,
and the like. By further example, cetylpridinium chloride may be
used from about 0.01 mg/mL to about 4 mg/mL pharmaceutical
composition. Similarly, by another non-limiting example, ethanol
may be used from about 0.01% to about 30% pharmaceutical
composition. Similarly, by another non-limiting example, glycerin
may be used from about 0.01% to about 25% pharmaceutical
composition. Similarly, by another non-limiting example, lecithin
may be used from about 0.01% to about 4% pharmaceutical
composition. Similarly, by another non-limiting example, propylene
glycol may be used from about 0.01% to about 30% pharmaceutical
composition. Similarly, by another non-limiting example,
polysorbates may also be used from about 0.01% to about 10%
pharmaceutical composition. Similarly, by another non-limiting
example, sorbitan triolate may be used from about 0.01% to about
20% pharmaceutical composition.
[0303] In another embodiment, a pharmaceutical composition of
liquid or dry powder imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof may contain a chelated metal ion
to assist in solubility and/or dissolution of imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof. By non-limiting
example, these may include iron, magnesium, or calcium.
[0304] In another embodiment, a pharmaceutical composition of
liquid or dry powder imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof may contain a chelated metal ion
to assist in scavenging reactive oxygen species. By non-limiting
example, these may include iron, magnesium, or calcium. By
non-limiting example, for this purpose the addition of magnesium or
other cationic metal ion may be stoichiometric to the amount of
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof.
By non-limiting example, 2 imatinib molecules to 0.1 magnesium
molecules, 2 imatinib molecules to 0.25 magnesium molecules, 2
imatinib molecules to 0.5 magnesium molecules, 2 imatinib molecules
to 0.75 magnesium molecules, 2 imatinib molecules to 1 magnesium
molecules, 2 imatinib molecules to 1.5 magnesium molecules, 2
imatinib molecules to 2 magnesium molecules, 2 imatinib molecules
to 3 magnesium molecules, 2 imatinib molecules to 4 magnesium
molecules, 2 imatinib molecules to 5 magnesium molecules, 2
imatinib molecules to 6 magnesium molecules, 2 imatinib molecules
to 7 magnesium molecules, 2 imatinib molecules to 8 magnesium
molecules, 2 imatinib molecules to 9 magnesium molecules, 2
imatinib molecules to 10 magnesium molecules, 2 imatinib molecules
to 12 magnesium molecules, 2 imatinib molecules to 14 magnesium
molecules, 2 imatinib molecules to 16 magnesium molecules, 2
imatinib molecules to 18 magnesium molecules, or 2 imatinib
molecules to 20 magnesium molecules. Potassium, sodium, lithium or
iron may substitute for magnesium in these ratios and
pharmaceutical composition. Included in the above pharmaceutical
composition is the maintenance of the buffers described herein, at
a pH from about 4.0 to about 8.0, and include MgCl.sub.2 or
cationic salt thereof at a level that provides an osmolality of 300
mOsmo/kg and 600 mOsmo/kg. While 300 mOsmo/kg is discussed in the
literature as important for acute tolerability upon inhalation of
this in a nebulized solution, 600 mOsmo/kg has been shown in
unpublished studies to be well tolerated with other drug solutions.
However, a final solution osmolality up to 5000 mOsmo/kg is
contemplated.
[0305] In another embodiment, a salt form of imatinib, a
phenylaminopyrimidine derivative or tyrosine kinase inhibitor is
described. By non-limiting example, the counterion of the salt form
of imatinib, a phenylaminopyrimidine derivative or tyrosine kinase
inhibitor is acetate, acetonide, alanine, aluminum, arginine,
ascorbate, asparagine, aspartic acid, benzathine, benzoate,
besylate, bisulfate, bisulfite, bitartrate, bromide, calcium,
carbonate, camphorsulfonate, cetylpridinium, chloride,
chlortheophyllinate, cholinate, citrate, cysteine, deoxycholate,
diethanolamine, diethylamine, diphosphate, diproprionate,
disalicylate, edetate, edisylate, estolate, ethylamine,
ethylenediamine, ethandisulfonate, fumarate, gluceptate, gluconate,
glucuronate, glutamic acid, glutamine, glycine, hippurate,
histidine, hydrobromide, hydrochloride, hydroxide, iodide,
isethionate, isoleucine, lactate, lactobionate, laurylsulfate,
leucine, lysine, magnesium, malate, maleate, mandelate, meglumine,
mesylate, metabisulfate, metabisulfite, methionine, methylbromide,
methylsulfate, methyl p-hydroxybenzoate, mucate, naphthoate,
napsylate, nitrate, nitrite, octadecanoate, oleate, ornithine,
oxalate, pamoate, pentetate, phenylalanine, phosphate, piperazine,
polygalacturonate, potassium, procaine, proline, propionate, propyl
p-hydroxybenzoate, saccharin, salicylate, selenocysteine, serine,
silver, sodium, sorbitan, stearate, succinate, sulfate, sulfite,
sulfosalicylate, tartrate, threonine, tosylate, triethylamine,
triethiodide, trifluoroacetate, trioleate, tromethamine,
tryptophan, tyrosine, valerate, valine, xinafoate, or zinc. By
non-limiting example, these or other counterions may be
stoichiometric to the amount of imatinib or phenylaminopyrimidine
derivative. By non-limiting example, 1 imatinib or
phenylaminopyrimidine derivative molecule to 1 counterion molecule,
1 imatinib or phenylaminopyrimidine derivative molecule to 2
counterion molecules, 1 imatinib or phenylaminopyrimidine
derivative molecule to 3 counterion molecules, 1 imatinib or
phenylaminopyrimidine derivative molecule to 4 counterion molecule,
2 imatinib or phenylaminopyrimidine derivative molecules to 1
counterion molecule, 3 imatinib or phenylaminopyrimidine derivative
molecules to 1 counterion molecule, 4 imatinib or
phenylaminopyrimidine derivative molecules to 1 counterion
molecule. Included in the above pharmaceutical composition is the
maintenance of the buffers described herein, at a pH from about 4.0
to about 8.0, and may include an additional salt form at a level
that provides an osmolality of 50 mOsmo/kg and 600 mOsmo/kg. While
300 mOsmo/kg is discussed in the literature as important for acute
tolerability upon inhalation of this in a nebulized solution, 600
mOsmo/kg has been shown in unpublished studies to be well tolerated
with other drug solutions. However, a final solution osmolality up
to 5000 mOsmo/kg is contemplated.
[0306] In some embodiments, the imatinib salt form,
phenylaminopyrimidine derivative salt form or other tyrosine kinase
inhibitor salt form is prepared as a glutamate salt form. In
another embodiment, the imatinib salt form, phenylaminopyrimidine
derivative salt form or other tyrosine kinase inhibitor salt form
is an aspartate salt form. In another embodiment, the imatinib salt
form, phenylaminopyrimidine derivative salt form or other tyrosine
kinase inhibitor salt form is a citrate salt form. In another
embodiment, the imatinib salt form, phenylaminopyrimidine
derivative salt form or other tyrosine kinase inhibitor salt form
is a succinate salt form. In another embodiment, the imatinib salt
form, phenylaminopyrimidine derivative salt form or other tyrosine
kinase inhibitor salt form is a sulfate salt form. In another
embodiment, the imatinib salt form, phenylaminopyrimidine
derivative salt form or other tyrosine kinase inhibitor salt form
is a fumarate salt form. In another embodiment, the imatinib salt
form, phenylaminopyrimidine derivative salt form or other tyrosine
kinase inhibitor salt form is an acetate salt form. In another
embodiment, the imatinib salt form, phenylaminopyrimidine
derivative salt form or other tyrosine kinase inhibitor salt form
is a chloride salt form. In another embodiment, the imatinib salt
form, phenylaminopyrimidine derivative salt form or other tyrosine
kinase inhibitor salt form is a bromide salt form. In another
embodiment, the imatinib salt form, phenylaminopyrimidine
derivative salt form or other tyrosine kinase inhibitor salt form
is a phosphate salt form. In another embodiment, the imatinib salt
form, phenylaminopyrimidine derivative salt form or other tyrosine
kinase inhibitor salt form is an edetate salt form. In another
embodiment, the imatinib salt form, phenylaminopyrimidine
derivative salt form or other tyrosine kinase inhibitor salt form
is a lactate salt form. These exemplary imatinib salt forms or
phenylaminopyrimidine derivative salt forms or other tyrosine
kinase inhibitor salt forms may be included in pharmaceutical
compositions and or used in the methods described herein.
[0307] In some embodiments, described herein is a pharmaceutical
composition that includes: imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof; water; phosphate buffer or
citrate buffer; and optionally sodium chloride or magnesium
chloride. In some embodiments, described herein is a pharmaceutical
composition that includes: imatinib phosphate salt; water, and
optionally phosphate buffer or citrate buffer, or sodium chloride
or magnesium chloride. In some embodiments, described herein is a
pharmaceutical composition that includes: imatinib aspartate salt;
water, and optionally phosphate buffer or citrate buffer, or sodium
chloride or magnesium chloride. In some embodiments, described
herein is a pharmaceutical composition that includes: imatinib
fumarate salt; water, and optionally phosphate buffer or citrate
buffer, or sodium chloride or magnesium chloride. In some
embodiments, described herein is a pharmaceutical composition that
includes: imatinib chloride salt; water, and optionally phosphate
buffer or citrate buffer, or sodium chloride or magnesium chloride.
In some embodiments, described herein is a pharmaceutical
composition that includes: imatinib bromide salt; water, and
optionally phosphate buffer or citrate buffer, or sodium chloride
or magnesium chloride. In some embodiments, described herein is a
pharmaceutical composition that includes: imatinib or salt thereof,
a phenylaminopyrimidine derivative or salt thereof, or other
tyrosine kinase inhibitor or salt thereof; water; phosphate buffer
or citrate buffer; and optionally sodium chloride or magnesium
chloride. In other embodiments, described herein is a
pharmaceutical composition that includes: imatinib or salt thereof,
a phenylaminopyrimidine derivative or salt thereof, or other
tyrosine kinase inhibitor or salt thereof; water; a buffer; and at
least one additional ingredient selected from sodium chloride,
magnesium chloride, ethanol, propylene glycol, glycerol,
polysorbate 80, and cetylpyridinium bromide (or chloride). In some
embodiments, the buffer is phosphate buffer. In other embodiments,
the buffer is citrate buffer. In some embodiments, the
pharmaceutical composition includes 0.001 mg to 200 mg of imatinib
or salt thereof, for example, 0.005 mg, 0.01 mg, 0.05 mg, 0.1 mg,
0.5 mg, 1.0 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 25 mg, 50 mg,
75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg. In some
embodiments, the pharmaceutical composition includes 1 mg to 500 mg
of imatinib or salt thereof, for example, 5 mg, 10 mg, 15 mg, 25
mg, 37.5 mg, 75 mg, 100 mg, 115 mg, 150 mg, 190 mg, 220 mg or 500
mg. In some embodiments, the osmolality of the pharmaceutical
composition described herein is between about 50 mOsmo/kg to 6000
mOsmo/kg. In some embodiments, the pharmaceutical composition
optionally includes saccharin (e.g. sodium salt). Non-limiting
examples of pharmaceutical compositions described herein include
any one of the pharmaceutical compositions described in Tables 11 a
to 11 f of Example 5.
[0308] In some embodiments, pharmaceutical compositions described
herein include any one of the following liquid formulations:
TABLE-US-00001 Tyrosine Kinase Inhibitor Aqueous Formulations
Tyrosine Kinase Sodium Sodium Sodium Citrate Phosphate Fumarate
Inhibitor or salt Chloride Bromide Saccharin Buffer Buffer Buffer
pH Formulation thereof (mg/mL).sup.a (mM) (mM) (mM) (mM) (mM (mM)
Water (+/-2.0) 1 0.01 25 0.0 0.0 0.0 0.0 0.0 q.s. 6.0 2 0.01 200
0.0 0.0 0.0 0.0 0.0 q.s. 6.0 3 200 25 0.0 0.0 0.0 0.0 0.0 q.s. 6.0
4 200 200 0.0 0.0 0.0 0.0 0.0 q.s. 6.0 5 0.01 25 0.0 5.0 0.0 0.0
0.0 q.s. 6.0 6 0.01 25 0.0 0.1 0.0 0.0 0.0 q.s. 6.0 7 200 200 0.0
5.0 0.0 0.0 0.0 q.s. 6.0 8 200 200 0.0 0.1 0.0 0.0 0.0 q.s. 6.0 9
0.01 0.0 25 0.0 0.0 0.0 0.0 q.s. 6.0 10 0.01 0.0 200 0.0 0.0 0.0
0.0 q.s. 6.0 11 200 0.0 25 0.0 0.0 0.0 0.0 q.s. 6.0 12 200 0.0 200
0.0 0.0 0.0 0.0 q.s. 6.0 13 0.01 0.0 25 5.0 0.0 0.0 0.0 q.s. 6.0 14
0.01 0.0 25 0.1 0.0 0.0 0.0 q.s. 6.0 15 200 0.0 200 5.0 0.0 0.0 0.0
q.s. 6.0 16 200 0.0 200 0.1 0.0 0.0 0.0 q.s. 6.0 17 0.01 25 0.0 0.0
0.1 0.0 0.0 q.s. 5.0 18 0.01 200 0.0 0.0 0.1 0.0 0.0 q.s. 5.0 19
200 25 0.0 0.0 0.1 0.0 0.0 q.s. 5.0 20 200 200 0.0 0.0 0.1 0.0 0.0
q.s. 5.0 21 0.01 25 0.0 5.0 0.1 0.0 0.0 q.s. 5.0 22 0.01 25 0.0 0.1
0.1 0.0 0.0 q.s. 5.0 23 200 200 0.0 5.0 0.1 0.0 0.0 q.s. 5.0 24 200
200 0.0 0.1 0.1 0.0 0.0 q.s. 5.0 25 0.01 0.0 25 0.0 0.1 0.0 0.0
q.s. 5.0 26 0.01 0.0 200 0.0 0.1 0.0 0.0 q.s. 5.0 27 200 0.0 25 0.0
0.1 0.0 0.0 q.s. 5.0 28 200 0.0 200 0.0 0.1 0.0 0.0 q.s. 5.0 29
0.01 0.0 25 5.0 0.1 0.0 0.0 q.s. 5.0 30 0.01 0.0 25 0.1 0.1 0.0 0.0
q.s. 5.0 31 200 0.0 200 5.0 0.1 0.0 0.0 q.s. 5.0 32 200 0.0 200 0.1
0.1 0.0 0.0 q.s. 5.0 33 0.01 25 0.0 0.0 200 0.0 0.0 q.s. 5.0 34
0.01 200 0.0 0.0 200 0.0 0.0 q.s. 5.0 35 200 25 0.0 0.0 200 0.0 0.0
q.s. 5.0 36 200 200 0.0 0.0 200 0.0 0.0 q.s. 5.0 37 0.01 25 0.0 5.0
200 0.0 0.0 q.s. 5.0 38 0.01 25 0.0 0.1 200 0.0 0.0 q.s. 5.0 39 200
200 0.0 5.0 200 0.0 0.0 q.s. 5.0 40 200 200 0.0 0.1 200 0.0 0.0
q.s. 5.0 41 0.01 0.0 25 0.0 200 0.0 0.0 q.s. 5.0 42 0.01 0.0 200
0.0 200 0.0 0.0 q.s. 5.0 43 200 0.0 25 0.0 200 0.0 0.0 q.s. 5.0 44
200 0.0 200 0.0 200 0.0 0.0 q.s. 5.0 45 0.01 0.0 25 5.0 200 0.0 0.0
q.s. 5.0 46 0.01 0.0 25 0.1 200 0.0 0.0 q.s. 5.0 47 200 0.0 200 5.0
200 0.0 0.0 q.s. 5.0 48 200 0.0 200 0.1 200 0.0 0.0 q.s. 5.0 49
0.01 25 0.0 0.0 0.0 0.1 0.0 q.s. 6.5 50 0.01 200 0.0 0.0 0.0 0.1
0.0 q.s. 6.5 51 200 25 0.0 0.0 0.0 0.1 0.0 q.s. 6.5 52 200 200 0.0
0.0 0.0 0.1 0.0 q.s. 6.5 53 0.01 25 0.0 5.0 0.0 0.1 0.0 q.s. 6.5 54
0.01 25 0.0 0.1 0.0 0.1 0.0 q.s. 6.5 55 200 200 0.0 5.0 0.0 0.1 0.0
q.s. 6.5 56 200 200 0.0 0.1 0.0 0.1 0.0 q.s. 6.5 57 0.01 0.0 25 0.0
0.0 0.1 0.0 q.s. 6.5 58 0.01 0.0 200 0.0 0.0 0.1 0.0 q.s. 6.5 59
200 0.0 25 0.0 0.0 0.1 0.0 q.s. 6.5 60 200 0.0 200 0.0 0.0 0.1 0.0
q.s. 6.5 61 0.01 0.0 25 5.0 0.0 0.1 0.0 q.s. 6.5 62 0.01 0.0 25 0.1
0.0 0.1 0.0 q.s. 6.5 63 200 0.0 200 5.0 0.0 0.1 0.0 q.s. 6.5 64 200
0.0 200 0.1 0.0 0.1 0.0 q.s. 6.5 65 0.01 25 0.0 0.0 0.0 200 0.0
q.s. 6.5 66 0.01 200 0.0 0.0 0.0 200 0.0 q.s. 6.5 67 200 25 0.0 0.0
0.0 200 0.0 q.s. 6.5 68 200 200 0.0 0.0 0.0 200 0.0 q.s. 6.5 69
0.01 25 0.0 5.0 0.0 200 0.0 q.s. 6.5 70 0.01 25 0.0 0.1 0.0 200 0.0
q.s. 6.5 71 200 200 0.0 5.0 0.0 200 0.0 q.s. 6.5 72 200 200 0.0 0.1
0.0 200 0.0 q.s. 6.5 73 0.01 0.0 25 0.0 0.0 200 0.0 q.s. 6.5 74
0.01 0.0 200 0.0 0.0 200 0.0 q.s. 6.5 75 200 0.0 25 0.0 0.0 200 0.0
q.s. 6.5 76 200 0.0 200 0.0 0.0 200 0.0 q.s. 6.5 77 0.01 0.0 25 5.0
0.0 200 0.0 q.s. 6.5 78 0.01 0.0 25 0.1 0.0 200 0.0 q.s. 6.5 79 200
0.0 200 5.0 0.0 200 0.0 q.s. 6.5 80 200 0.0 200 0.1 0.0 200 0.0
q.s. 6.5 81 0.01 25 0.0 0.0 0.0 0.0 0.1 q.s. 5.0 82 0.01 200 0.0
0.0 0.0 0.0 0.1 q.s. 5.0 83 200 25 0.0 0.0 0.0 0.0 0.1 q.s. 5.0 84
200 200 0.0 0.0 0.0 0.0 0.1 q.s. 5.0 85 0.01 25 0.0 5.0 0.0 0.0 0.1
q.s. 5.0 86 0.01 25 0.0 0.1 0.0 0.0 0.1 q.s. 5.0 87 200 200 0.0 5.0
0.0 0.0 0.1 q.s. 5.0 88 200 200 0.0 0.1 0.0 0.0 0.1 q.s. 5.0 89
0.01 0.0 25 0.0 0.0 0.0 0.1 q.s. 5.0 90 0.01 0.0 200 0.0 0.0 0.0
0.1 q.s. 5.0 91 200 0.0 25 0.0 0.0 0.0 0.1 q.s. 5.0 92 200 0.0 200
0.0 0.0 0.0 0.1 q.s. 5.0 93 0.01 0.0 25 5.0 0.0 0.0 0.1 q.s. 5.0 94
0.01 0.0 25 0.1 0.0 0.0 0.1 q.s. 5.0 95 200 0.0 200 5.0 0.0 0.0 0.1
q.s. 5.0 96 200 0.0 200 0.1 0.0 0.0 0.1 q.s. 5.0 97 0.01 25 0.0 0.0
0.0 0.0 200 q.s. 5.0 98 0.01 200 0.0 0.0 0.0 0.0 200 q.s. 5.0 99
200 25 0.0 0.0 0.0 0.0 200 q.s. 5.0 100 200 200 0.0 0.0 0.0 0.0 200
q.s. 5.0 101 0.01 25 0.0 5.0 0.0 0.0 200 q.s. 5.0 102 0.01 25 0.0
0.1 0.0 0.0 200 q.s. 5.0 103 200 200 0.0 5.0 0.0 0.0 200 q.s. 5.0
104 200 200 0.0 0.1 0.0 0.0 200 q.s. 5.0 105 0.01 0.0 25 0.0 0.0
0.0 200 q.s. 5.0 106 0.01 0.0 200 0.0 0.0 0.0 200 q.s. 5.0 107 200
0.0 25 0.0 0.0 0.0 200 q.s. 5.0 108 200 0.0 200 0.0 0.0 0.0 200
q.s. 5.0 109 0.01 0.0 25 5.0 0.0 0.0 200 q.s. 5.0 110 0.01 0.0 25
0.1 0.0 0.0 200 q.s. 5.0 111 200 0.0 200 5.0 0.0 0.0 200 q.s. 5.0
112 200 0.0 200 0.1 0.0 0.0 200 q.s. 5.0 .sup.aMilligram/milliliter
tyrosine kinase inhibitor
[0309] In some embodiments, the tyrosine kinase inhibitor is a
phenylaminopyrimidine derivative. In some embodiments, the tyrosine
kinase inhibitor is imatinib. In some embodiments, a salt form of
the tyrosine kinase inhibitor is used.
[0310] In another embodiment, a pharmaceutical composition is
provided that includes a simple dry powder imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound alone in
dry powder form with or without a carrier agent such as
lactose.
[0311] In some embodiments, pharmaceutical compositions described
herein include any one of the following dry powder
formulations:
TABLE-US-00002 Tyrosine Kinase Inhibitor Dry Powder Formulations
Tyrosine Kinase Inhibitor or salt Lactose Mannitol Sodium For-
thereof (% (% of (% of Saccharin (% mulation of powder) powder)
powder) of powder) 1 0.001 99.999 0.0 0.0 2 0.010 99.990 0.0 0.0 3
0.100 99.900 0.0 0.0 4 1.000 99.000 0.0 0.0 5 10.000 90.000 0.0 0.0
6 100.000 0.000 0.0 0.0 7 0.001 0.0 99.999 0.0 8 0.010 0.0 99.990
0.0 9 0.100 0.0 99.900 0.0 10 1.000 0.0 99.000 0.0 11 10.000 0.0
90.000 0.0 12 100.000 0.0 0.000 0.0 13 0.001 99.998 0.0 0.001 14
0.001 99.989 0.0 0.010 15 0.001 99.899 0.0 0.100 16 0.010 99.989
0.0 0.001 17 0.010 99.980 0.0 0.010 18 0.010 99.890 0.0 0.100 19
0.100 99.899 0.0 0.001 20 0.100 99.890 0.0 0.010 21 0.100 99.800
0.0 0.100 22 1.000 98.999 0.0 0.001 23 1.000 98.990 0.0 0.010 24
1.000 98.900 0.0 0.100 25 10.000 89.999 0.0 0.001 26 10.000 89.990
0.0 0.010 27 10.000 89.900 0.0 0.100 28 99.999 0.000 0.0 0.001 29
99.990 0.000 0.0 0.010 30 99.900 0.000 0.0 0.100 31 0.001 0.0
99.998 0.001 32 0.001 0.0 99.989 0.010 33 0.001 0.0 99.899 0.100 34
0.010 0.0 99.989 0.001 35 0.010 0.0 99.980 0.010 36 0.010 0.0
99.890 0.100 37 0.100 0.0 99.899 0.001 38 0.100 0.0 99.890 0.010 39
0.100 0.0 99.800 0.100 40 1.000 0.0 98.999 0.001 41 1.000 0.0
98.990 0.010 42 1.000 0.0 98.900 0.100 43 10.000 0.0 89.999 0.001
44 10.000 0.0 89.990 0.010 45 10.000 0.0 89.900 0.100 46 99.999 0.0
0.000 0.001 47 99.990 0.0 0.000 0.010 48 99.900 0.0 0.000 0.100
[0312] There are two types of meter dose inhaler (MDI)
formulations: suspension formulations, in which microparticulate
drug is dispersed in a combination of propellants; and solution
formulations, in which the drug freely dissolves in either the
propellant or a combination of propellant and an acceptable
cosolvent. In some embodiments, pharmaceutical compositions
described herein include any one of the following meter dose
formulations:
TABLE-US-00003 Tyrosine Kinase Inhibitor Meter Dose Formulations or
Mixture of Propellants Thereof Tyrosine Kinase CFC-11 CFC-12
HFA-134a HFA-227 Ethanol Inhibitor or salt Propellant Propellant
Propellant Propellant Cosolvent thereof (% (% of (% of (% of (% of
(% of Metering Formulation of formulation) formulation)
formulation) formulation) formulation) formulation) Canister Valve
Actuator 1 0.001 99.999 0.0 0.0 0.0 0.0 + + + 2 0.010 99.990 0.0
0.0 0.0 0.0 + + + 3 0.100 99.900 0.0 0.0 0.0 0.0 + + + 4 1.000
99.000 0.0 0.0 0.0 0.0 + + + 5 10.000 90.000 0.0 0.0 0.0 0.0 + + +
6 0.001 99.989 0.0 0.0 0.0 0.01 + + + 7 0.001 99.899 0.0 0.0 0.0
0.10 + + + 8 0.001 98.999 0.0 0.0 0.0 1.00 + + + 9 0.001 89.999 0.0
0.0 0.0 10.0 + + + 10 0.010 99.980 0.0 0.0 0.0 0.01 + + + 11 0.010
99.890 0.0 0.0 0.0 0.10 + + + 12 0.010 98.990 0.0 0.0 0.0 1.00 + +
+ 13 0.010 89.990 0.0 0.0 0.0 10.0 + + + 14 0.100 99.890 0.0 0.0
0.0 0.01 + + + 15 0.100 99.800 0.0 0.0 0.0 0.10 + + + 16 0.100
98.900 0.0 0.0 0.0 1.00 + + + 17 0.100 89.900 0.0 0.0 0.0 10.0 + +
+ 18 1.000 98.990 0.0 0.0 0.0 0.01 + + + 19 1.000 98.900 0.0 0.0
0.0 0.10 + + + 20 1.000 98.000 0.0 0.0 0.0 1.00 + + + 21 1.000
89.000 0.0 0.0 0.0 10.0 + + + 22 10.000 89.990 0.0 0.0 0.0 0.01 + +
+ 23 10.000 89.900 0.0 0.0 0.0 0.10 + + + 24 10.000 89.000 0.0 0.0
0.0 1.00 + + + 25 10.000 80.000 0.0 0.0 0.0 10.0 + + + 26 0.001 0.0
99.999 0.0 0.0 0.0 + + + 27 0.010 0.0 99.990 0.0 0.0 0.0 + + + 28
0.100 0.0 99.900 0.0 0.0 0.0 + + + 29 1.000 0.0 99.000 0.0 0.0 0.0
+ + + 30 10.000 0.0 90.000 0.0 0.0 0.0 + + + 31 0.001 0.0 99.989
0.0 0.0 0.01 + + + 32 0.001 0.0 99.899 0.0 0.0 0.10 + + + 33 0.001
0.0 98.999 0.0 0.0 1.00 + + + 34 0.001 0.0 89.999 0.0 0.0 10.0 + +
+ 35 0.010 0.0 99.980 0.0 0.0 0.01 + + + 36 0.010 0.0 99.890 0.0
0.0 0.10 + + + 37 0.010 0.0 98.990 0.0 0.0 1.00 + + + 38 0.010 0.0
89.990 0.0 0.0 10.0 + + + 39 0.100 0.0 99.890 0.0 0.0 0.01 + + + 40
0.100 0.0 99.800 0.0 0.0 0.10 + + + 41 0.100 0.0 98.900 0.0 0.0
1.00 + + + 42 0.100 0.0 89.900 0.0 0.0 10.0 + + + 43 1.000 0.0
98.990 0.0 0.0 0.01 + + + 44 1.000 0.0 98.900 0.0 0.0 0.10 + + + 45
1.000 0.0 98.000 0.0 0.0 1.00 + + + 46 1.000 0.0 89.000 0.0 0.0
10.0 + + + 47 10.000 0.0 89.990 0.0 0.0 0.01 + + + 48 10.000 0.0
89.900 0.0 0.0 0.10 + + + 49 10.000 0.0 89.000 0.0 0.0 1.00 + + +
50 10.000 0.0 80.000 0.0 0.0 10.0 + + + 51 0.001 0.0 0.0 99.999 0.0
0.0 + + + 52 0.010 0.0 0.0 99.990 0.0 0.0 + + + 53 0.100 0.0 0.0
99.900 0.0 0.0 + + + 54 1.000 0.0 0.0 99.000 0.0 0.0 + + + 55
10.000 0.0 0.0 90.000 0.0 0.0 + + + 56 0.001 0.0 0.0 99.989 0.0
0.01 + + + 57 0.001 0.0 0.0 99.899 0.0 0.10 + + + 58 0.001 0.0 0.0
98.999 0.0 1.00 + + + 59 0.001 0.0 0.0 89.999 0.0 10.0 + + + 60
0.010 0.0 0.0 99.980 0.0 0.01 + + + 61 0.010 0.0 0.0 99.890 0.0
0.10 + + + 62 0.010 0.0 0.0 98.990 0.0 1.00 + + + 63 0.010 0.0 0.0
89.990 0.0 10.0 + + + 64 0.100 0.0 0.0 99.890 0.0 0.01 + + + 65
0.100 0.0 0.0 99.800 0.0 0.10 + + + 66 0.100 0.0 0.0 98.900 0.0
1.00 + + + 67 0.100 0.0 0.0 89.900 0.0 10.0 + + + 68 1.000 0.0 0.0
98.990 0.0 0.01 + + + 69 1.000 0.0 0.0 98.900 0.0 0.10 + + + 70
1.000 0.0 0.0 98.000 0.0 1.00 + + + 71 1.000 0.0 0.0 89.000 0.0
10.0 + + + 72 10.000 0.0 0.0 89.990 0.0 0.01 + + + 73 10.000 0.0
0.0 89.900 0.0 0.10 + + + 74 10.000 0.0 0.0 89.000 0.0 1.00 + + +
75 10.000 0.0 0.0 80.000 0.0 10.0 + + + 76 0.001 0.0 0.0 0.0 99.999
0.0 + + + 77 0.010 0.0 0.0 0.0 99.990 0.0 + + + 78 0.100 0.0 0.0
0.0 99.900 0.0 + + + 79 1.000 0.0 0.0 0.0 99.000 0.0 + + + 80
10.000 0.0 0.0 0.0 90.000 0.0 + + + 81 0.001 0.0 0.0 0.0 99.989
0.01 + + + 82 0.001 0.0 0.0 0.0 99.899 0.10 + + + 83 0.001 0.0 0.0
0.0 98.999 1.00 + + + 84 0.001 0.0 0.0 0.0 89.999 10.0 + + + 85
0.010 0.0 0.0 0.0 99.980 0.01 + + + 86 0.010 0.0 0.0 0.0 99.890
0.10 + + + 87 0.010 0.0 0.0 0.0 98.990 1.00 + + + 88 0.010 0.0 0.0
0.0 89.990 10.0 + + + 89 0.100 0.0 0.0 0.0 99.890 0.01 + + + 90
0.100 0.0 0.0 0.0 99.800 0.10 + + + 91 0.100 0.0 0.0 0.0 98.900
1.00 + + + 92 0.100 0.0 0.0 0.0 89.900 10.0 + + + 93 1.000 0.0 0.0
0.0 98.990 0.01 + + + 94 1.000 0.0 0.0 0.0 98.900 0.10 + + + 95
1.000 0.0 0.0 0.0 98.000 1.00 + + + 96 1.000 0.0 0.0 0.0 89.000
10.0 + + + 97 10.000 0.0 0.0 0.0 89.990 0.01 + + + 98 10.000 0.0
0.0 0.0 89.900 0.10 + + + 99 10.000 0.0 0.0 0.0 89.000 1.00 + + +
100 10.000 0.0 0.0 0.0 80.000 10.0 + + +
[0313] In another embodiment, the pharmaceutical composition used
in a liquid, dry powder or meter-dose inhalation device is provided
such that imatinib, phenylaminopyrimidine derivative, or other
tyrosine kinase inhibitor is not in a salt form.
[0314] In another embodiment, a pharmaceutical composition is
provided that includes a complex dry powder imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound
formulation in co-crystal/co-precipitate/spray dried complex or
mixture with low water soluble excipients/salts in dry powder form
with or without a carrier agent such as lactose.
[0315] In another embodiment, a system is provided for
administering an imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound that includes a container comprising a
solution of an imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound formulation and a nebulizer physically
coupled or co-packaged with the container and adapted to produce an
aerosol of the solution having a particle size from about 1 microns
to about 5 microns mean mass aerodynamic diameter, volumetric mean
diameter (VMD) or mass median diameter (MMD) and a particle size
geometric standard deviation of less than or equal to about 2.5
microns mean mass aerodynamic diameter. In one embodiment, the
particle size geometric standard deviation is less than or equal to
about 3.0 microns. In one embodiment, the particle size geometric
standard deviation is less than or equal to about 2.0 microns.
[0316] In another embodiment, a system is provided for
administering an imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound that includes a container comprising a dry
powder of an imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound and a dry powder inhaler coupled to the
container and adapted to produce a dispersed dry powder aerosol
having a particle size from about 1 microns to about 5 microns mean
mass aerodynamic and a particle size standard deviation of less
than or equal to about 3.0 microns. In one embodiment, the particle
size standard deviation is less than or equal to about 2.5 microns.
In one embodiment, the particle size standard deviation is less
than or equal to about 2.0 microns.
[0317] In another embodiment, a kit is provided that includes a
container comprising a pharmaceutical formulation comprising an
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound and an aerosolizer adapted to aerosolize the
pharmaceutical formulation (e.g., in certain preferred embodiments,
a liquid nebulizer) and deliver it to the lower respiratory tract,
for instance, to a pulmonary compartment such as alveoli, alveolar
ducts and/or bronchioles, following intraoral administration. The
formulation may also be delivered as a dry powder or through a
metered-dose inhaler.
[0318] In another embodiment, a kit is provided that includes a
container comprising a pharmaceutical formulation comprising an
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound and an aerosolizer adapted to aerosolize the
pharmaceutical formulation (e.g., in certain preferred embodiments,
a liquid nebulizer) and deliver it to a nasal cavity following
intranasal administration. The formulation may also be delivered as
a dry powder or through a metered-dose inhaler.
[0319] It should be understood that many carriers and excipients
may serve several functions, even within the same formulation.
[0320] Contemplated pharmaceutical compositions provide a
therapeutically effective amount of imatinib or
phenylaminopyrimidine derivative compound enabling, for example,
once-a-day, twice-a-day, three times a day, etc. administration. In
some embodiments, pharmaceutical compositions for inhaled delivery
provide an effective amount of imatinib or phenylaminopyrimidine
derivative compound enabling once-a-day dosing. In some
embodiments, pharmaceutical compositions for inhaled delivery
provide an effective amount of imatinib or phenylaminopyrimidine
derivative compound enabling twice-a-day dosing. In some
embodiments, pharmaceutical compositions for inhaled delivery
provide an effective amount of imatinib or phenylaminopyrimidine
derivative compound enabling three times-a-day dosing.
[0321] It is to be understood that both the foregoing general
description and the following detailed description are exemplary
and explanatory only and are not restrictive of the invention, as
claimed.
Certain Terminology
[0322] The term "mg" refers to milligram.
[0323] The term "mcg" refers to microgram.
[0324] The term "microM" refers to micromolar.
[0325] The term "QD" refers to once a day dosing.
[0326] The term "BID" refers to twice a day dosing.
[0327] The term "TID" refers to three times a day dosing.
[0328] The term "QID" refers to four times a day dosing.
[0329] As used herein, the term "about" is used synonymously with
the term "approximately." Illustratively, the use of the term
"about" with regard to a certain therapeutically effective
pharmaceutical dose indicates that values slightly outside the
cited values, .e.g., plus or minus 0.1% to 10%, which are also
effective and safe.
[0330] As used herein, the terms "comprising," "including," "such
as," and "for example" are used in their open, non-limiting
sense.
[0331] The terms "administration" or "administering" and "delivery"
or "delivery" refer to a method of giving to a mammal a dosage of a
therapeutic or prophylactic formulation, such as an imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof compound
formulation described herein, for example as an anti-inflammatory,
anti-fibrotic and/or anti-demylination pharmaceutical composition,
or for other purposes. The preferred delivery method or method of
administration can vary depending on various factors, e.g., the
components of the pharmaceutical composition, the desired site at
which the formulation is to be introduced, delivered or
administered, the site where therapeutic benefit is sought, or the
proximity of the initial delivery site to the downstream diseased
organ (e.g., aerosol delivery to the lung for absorption and
secondary delivery to the heart, kidney, liver, central nervous
system or other diseased destination). In some embodiments,
pharmaceutical compositions described herein are administered by
pulmonary administration.
[0332] The terms "pulmonary administration" or "inhalation" or
"pulmonary delivery" or "oral inhalation" or "intranasal
inhalation" and other related terms refer to a method of giving to
a mammal a dosage of a therapeutic or prophylactic formulation,
such as an imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound formulation described herein, by a route such
that the desired therapeutic or prophylactic agent is delivered to
the lungs of a mammal. Such delivery to the lung may occur by
intranasal administration, oral inhalation administration. Each of
these routes of administration may occur as inhalation of an
aerosol of formulations described herein. In some embodiments,
pulmonary administration occurs by passively delivering an aerosol
described herein by mechanical ventilation.
[0333] The terms "intranasal inhalation administration" and
"intranasal inhalation delivery" refer to a method of giving to a
mammal a dosage of an imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound formulation described
herein, by a route such that the formulation is targeting delivery
and absorption of the therapeutic formulation directly in the lungs
of the mammal through the nasal cavity. In some embodiments,
intranasal inhalation administration is performed with a
nebulizer.
[0334] The terms "intranasal administration" and "intranasal
delivery" refer to a method of giving to a mammal a dosage of a
therapeutic or prophylactic formulation, such as an imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof compound
formulation described herein, by a route such that the desired
therapeutic or prophylactic agent is delivered to the nasal cavity
or diseased organs downstream (e.g., aerosol delivery to the nasal
cavity for absorption and secondary delivery to the central nervous
system or other diseased destination). Such delivery to the nasal
cavity may occur by intranasal administration, wherein this route
of administration may occur as inhalation of an aerosol of
formulations described herein, injection of an aerosol of
formulations described herein, gavage of a formulation described
herein, or passively delivered by mechanical ventilation.
[0335] The terms "intraoccular administration" and "intraoccular
delivery" refer to a method of giving to a mammal a dosage of a
therapeutic or prophylactic formulation, such as an imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof compound
formulation described herein, by a route such that the desired
therapeutic or prophylactic agent is delivered to the eye. Such
delivery to the eye may occur by direct administration to the eye.
This route of administration may occur as spray of an aerosol of
formulations described herein, injection of an aerosol of
formulations described herein, or drops of a formulation described
herein.
[0336] "Oral administration" or "orally" or "oral" is a route of
administration where a substance (e.g. a pharmaceutical
composition) is taken through the mouth. In some embodiments, when
it is used without any further descriptors, it refers to
administration of a substance through the mouth and directly into
the gastrointestinal tract. Oral administration generally includes
a number of forms, such as tablets, pills, capsules, and
solutions.
[0337] The terms "oral inhalation administration" or "oral
inhalation delivery" or "oral inhalation" refer to a method of
giving to a mammal a dosage of an imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound formulation described
herein, through the mouth for delivery and absorption of the
formulation directly to the lungs of the mammal. In some
embodiments, oral inhalation administration is carried out by the
use of a nebulizer.
[0338] The term "abnormal liver function" may manifest as
abnormalities in levels of biomarkers of liver function, including
alanine transaminase, aspartate transaminase, bilirubin, and/or
alkaline phosphatase, and may be an indicator of drug-induced liver
injury. See FDA Draft Guidance for Industry. Drug-Induced Liver
Injury: Premarketing Clinical Evaluation, October 2007.
[0339] "Grade 2 liver function abnormalities" include elevations in
alanine transaminase (ALT), aspartate transaminase (AST), alkaline
phosphatase (ALP), or gamma-glutamyl transferase (GGT) greater than
2.5-times and less than or equal to 5-times the upper limit of
normal (ULN). Grade 2 liver function abnormalities also include
elevations of bilirubin levels greater than 1.5-times and less than
or equal to 3-times the ULN.
[0340] "Gastrointestinal adverse events" include but are not
limited to any one or more of the following: dyspepsia, nausea,
diarrhea, gastroesophageal reflux disease (GERD) and vomiting.
[0341] A "carrier" or "excipient" is a compound or material used to
facilitate administration of the compound, for example, to increase
the solubility of the compound. Solid carriers include, e.g.,
starch, lactose, dicalcium phosphate, sucrose, and kaolin. Liquid
carriers include, e.g., sterile water, saline, buffers, non-ionic
surfactants, and edible oils such as oil, peanut and sesame oils.
In addition, various adjuvants such as are commonly used in the art
may be included. These and other such compounds are described in
the literature, e.g., in the Merck Index, Merck & Company,
Rahway, N.J. Considerations for the inclusion of various components
in pharmaceutical compositions are described, e.g., in Gilman et
al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis
of Therapeutics, 8th Ed., Pergamon Press.
[0342] A "diagnostic" as used herein is a compound, method, system,
or device that assists in the identification and characterization
of a health or disease state. The diagnostic can be used in
standard assays as is known in the art.
[0343] "Patient" or "subject" are used interchangeably and refer to
a mammal.
[0344] The term "mammal" is used in its usual biological sense. In
some embodiments, a mammal is a human.
[0345] The term "ex vivo" refers to experimentation or manipulation
done in or on living tissue in an artificial environment outside
the organism.
[0346] The term "pharmaceutically acceptable carrier" or
"pharmaceutically acceptable excipient" includes any and all
solvents, dispersion media, coatings, antibacterial and antifungal
agents, isotonic and absorption delaying agents and the like. The
use of such media and agents for pharmaceutically active substances
is well known in the art. Except insofar as any conventional media
or agent is incompatible with the active ingredient, its use in the
therapeutic compositions is contemplated. Supplementary active
ingredients can also be incorporated into the compositions.
[0347] The term "pharmaceutically acceptable salt" refers to salts
that retain the biological effectiveness and properties of the
compounds of this invention and, which are not biologically or
otherwise undesirable. In many cases, the compounds of this
invention are capable of forming acid and/or base salts by virtue
of the presence of amino and/or carboxyl groups or groups similar
thereto. Pharmaceutically acceptable acid addition salts can be
formed with inorganic acids and organic acids. Inorganic acids from
which salts can be derived include, for example, hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and
the like. Organic acids from which salts can be derived include,
for example, acetic acid, propionic acid, naphtoic acid, oleic
acid, palmitic acid, pamoic (emboic) acid, stearic acid, glycolic
acid, pyruvic acid, oxalic acid, maleic acid, malonic acid,
succinic acid, fumaric acid, tartaric acid, citric acid, ascorbic
acid, glucoheptonic acid, glucuronic acid, lactic acid, lactobioic
acid, tartaric acid, benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,
salicylic acid, and the like. Pharmaceutically acceptable base
addition salts can be formed with inorganic and organic bases.
Inorganic bases from which salts can be derived include, for
example, sodium, potassium, lithium, ammonium, calcium, magnesium,
iron, zinc, copper, manganese, aluminum, and the like; particularly
preferred are the ammonium, potassium, sodium, calcium and
magnesium salts. Organic bases from which salts can be derived
include, for example, primary, secondary, and tertiary amines,
substituted amines including naturally occurring substituted
amines, cyclic amines, basic ion exchange resins, and the like,
specifically such as isopropylamine, trimethylamine, diethylamine,
triethylamine, tripropylamine, histidine, arginine, lysine,
benethamine, N-methyl-glucamine, and ethanolamine. Other acids
include dodecylsufuric acid, naphthalene-1,5-disulfonic acid,
naphthalene-2-sulfonic acid, and saccharin.
[0348] The term "pH-reducing acid" refers to acids that retain the
biological effectiveness and properties of the compounds of this
invention and, which are not biologically or otherwise undesirable.
Pharmaceutically acceptable pH-reducing acids include, for example,
inorganic acids such as, e.g., hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like. Also by
nonlimiting example, pH-reducing acids may also include organic
acids such as citric acid, acetic acid, propionic acid, naphtoic
acid, oleic acid, palmitic acid, pamoic (emboic) acid, stearic
acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid,
malonic acid, succinic acid, fumaric acid, tartaric acid, citric
acid, ascorbic acid, glucoheptonic acid, glucuronic acid, lactic
acid, lactobioic acid, tartaric acid, benzoic acid, cinnamic acid,
mandelic acid, methanesulfonic acid, ethanesulfonic acid,
p-toluenesulfonic acid, salicylic acid, and the like.
[0349] According to certain herein disclosed embodiments an
imatinib or a phenylaminopyrimidine derivative compound formulation
may comprise an "acidic excipient" that is typically present as an
acidic excipient aqueous solution. Examples of may include acid
salts such as phosphate, sulphate, nitrate, acetate, formate,
citrate, tartrate, propionate and sorbate, organic acids such as
carboxylic acids, sulfonic acids, phosphonic acids, phosphinic
acids, phosphoric monoesters, and phosphoric diesters, and/or other
organic acids that contain from 1 to 12 carbon atoms, citric acid,
acetic acid, formic acid, propionic acid, butyric acid, benzoic
acid, mono-, di-, and trichloroacetic acid, salicylic acid,
trifluoroacetic acid, benzenesulfonic acid, toluenesulfonic acid,
methylphosphonic acid, methylphosphinic acid, dimethylphosphinic
acid, and phosphonic acid monobutyl ester.
[0350] A "buffer" refers to a compound that functions to regulate
pH. In certain related embodiments the pH buffer is present under
conditions and in sufficient quantity to maintain a pH that is
"about" a recited pH value. "About" such a pH refers to the
functional presence of that buffer, which, as is known in the art,
may be a consequence of a variety of factors including pKa value(s)
of the buffer, buffer concentration, working temperature, effects
of other components of the composition on pKa (i.e., the pH at
which the buffer is at equilibrium between protonated and
deprotonated forms, typically the center of the effective buffering
range of pH values), and other factors.
[0351] Hence, "about" in the context of pH may be understood to
represent a quantitative variation in pH that may be more or less
than the recited value by no more than 0.5 pH units, more
preferably no more than 0.4 pH units, more preferably no more than
0.3 pH units, still more preferably no more than 0.2 pH units, and
most preferably no more than 0.1-0.15 pH units. As also noted
above, in certain embodiments a substantially constant pH (e.g., a
pH that is maintained within the recited range for an extended time
period) may be from about pH 4.0 to about pH 8.0, from about pH 4.0
to about pH 7.0, or from about pH 4.0 to about pH 6.8, or any other
pH or pH range as described herein, which in preferred embodiments
may be from about pH 4.0 to about pH 8.0 for an imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound
formulation, and greater than about pH 8.0 for an imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound aqueous
solution.
[0352] Therefore the pH buffer typically may comprise a composition
that, when present under appropriate conditions and in sufficient
quantity, is capable of maintaining a desired pH level as may be
selected by those familiar with the art, for example, buffers
comprising citrate, formate, malate, formate, pyridine, piperazine,
succinate, histidine, maleate, bis-Tris, pyrophosphate, PIPES,
ACES, histidine, MES, cacodylic acid, H2CO3/NaHCO3 and
N-(2-Acetamido)-2-iminodiacetic acid (ADA) or other buffers for
maintaining, preserving, enhancing, protecting or otherwise
promoting desired biological or pharmacological activity of an
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound, based on the disclosure herein. Suitable buffers may
include those in Table 1 or known to the art (see, e.g.,
Calbiochem.RTM. Biochemicals & Immunochemicals Catalog
2004/2005, pp. 68-69 and catalog pages cited therein, EMD
Biosciences, La Jolla, Calif.).
[0353] Non-limiting examples of buffers that may be used according
to certain embodiments disclosed herein, include but are not
limited to formate (pKa 3.77), Citric acid (pKa2 4.76), Malate
(pKa2 5.13), Pyridine (pKa 5.23), Piperazine ((pKa1) 5.33),
Succinate ((pKa2) 5.64), Histidine (pKa 6.04), Maleate ((pKa2)
6.24), Citric acid ((pKa3) 6.40), Bis-Tris (pKa 6.46),
Pyrophosphate ((pKa3) 6.70), PIPES (pKa 6.76), ACES (pKa 6.78),
Histidine (pKa 6.80), MES (pKa 6.15), Cacodylic acid (pKa 6.27),
H2CO3/NaHCO3 (pKa1) (6.37), ADA (N-(2-Acetamido)-2-iminodiacetic
acid) (pKa 6.60). In some embodiments, pharmaceutical compositions
disclosed herein include a citrate buffer or a phosphate buffer. In
some embodiments, pharmaceutical compositions disclosed herein
include a citrate buffer. In some embodiments, pharmaceutical
compositions disclosed herein include a phosphate buffer.
[0354] "Solvate" refers to the compound formed by the interaction
of a solvent and imatinib or a phenylaminopyrimidine derivative
compound, a metabolite, or salt thereof. Suitable solvates are
pharmaceutically acceptable solvates including hydrates.
[0355] By "therapeutically effective amount" or "pharmaceutically
effective amount" is meant imatinib or a phenylaminopyrimidine
derivative compound, as disclosed for this invention, which has a
therapeutic effect. The doses of imatinib or a
phenylaminopyrimidine derivative compound which are useful in
treatment are therapeutically effective amounts. Thus, as used
herein, a therapeutically effective amount means those amounts of
imatinib or a phenylaminopyrimidine derivative compound which
produce the desired therapeutic effect as judged by clinical trial
results and/or model animal pulmonary fibrosis, cardiac fibrosis,
kidney fibrosis, hepatic fibrosis, heart or kidney toxicity, or
disease resulting from active, previous or latent viral infection.
In particular embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compounds are administered in a
pre-determined dose, and thus a therapeutically effective amount
would be an amount of the dose administered. This amount and the
amount of the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound can be routinely determined by one of skill
in the art, and will vary, depending on several factors, such as
the therapeutic or prophylactic effect for fibrotic, inflammatory
or demylination injury occurs, and how distant that disease site is
from the initial respiratory location receiving the initial inhaled
aerosol dose. This amount can further depend upon the patient's
height, weight, sex, age and medical history. For prophylactic
treatments, a therapeutically effective amount is that amount which
would be effective to prevent a fibrotic, inflammatory or
demylination injury.
[0356] A "therapeutic effect" relieves, to some extent, one or more
of the symptoms associated with inflammation, fibrosis and/or
demylination. This includes slowing the progression of, or
preventing or reducing additional inflammation, fibrosis and/or
demylination. For IPF, a "therapeutic effect" is defined as a
patient-reported improvement in quality of life and/or a
statistically significant increase in or stabilization of exercise
tolerance and associated blood-oxygen saturation, reduced decline
in baseline forced vital capacity, decreased incidence in acute
exacerbations, increase in progression-free survival, increased
time-to-death or disease progression, and/or reduced lung fibrosis.
For cardiac fibrosis, a "therapeutic effect" is defined as a
patient-reported improvement in quality of life and/or a
statistically significant improvement in cardiac function, reduced
fibrosis, reduced cardiac stiffness, reduced or reversed valvular
stenosis, reduced incidence of arrhythmias and/or reduced atrial or
ventricular remodeling. For kidney fibrosis, a "therapeutic effect"
is defined as a patient-reported improvement in quality of life
and/or a statistically significant improvement in glomular
filtration rate and associated markers. For hepatic fibrosis, a
"therapeutic effect" is defined as a patient-reported improvement
in quality of life and/or a statistically significant lowering of
elevated aminotransferases (e.g., AST and ALT), alkaline
phosphatases, gamma-glutamyl transferase, bilirubin, prothrombin
time, globulins, as well as reversal of thromobocytopenia,
leukopenai and neutropenia and coagulation defects. Further a
potential reversal of imaging, endoscopic or other pathological
findings. For disease resulting from active, previous or latent
viral infection, a "therapeutic effect" is defined as a
patient-reported improvement in quality of life and/or a
statistically significant reduction in viral load, improved
exercise capacity and associated blood-oxygen saturation, FEV1
and/or FVC, a slowed or halted progression in the same,
progression-free survival, increased time-to-death or disease
progression, and/or reduced incidence or acute exacerbation or
reduction in neurologic symptoms. "Treat," "treatment," or
"treating," as used herein refers to administering a pharmaceutical
composition for therapeutic purposes. In some embodiments, treating
refers to alleviating, abating or ameliorating at least one symptom
of a disease or condition, preventing any additional symptoms from
arising, arresting the progression of at least one current symptom
of the disease or condition, relieving at least one of the symptoms
of a disease or condition, causing regression of the disease or
condition, relieving a condition caused by the disease or
condition, or stopping the symptoms of the disease or condition. In
some embodiments, the compositions described herein are used for
prophylactic treatment. The term "prophylactic treatment" refers to
treating a patient who is not yet diseased but who is susceptible
to, or otherwise at risk of, a particular disease, or who is
diseased but whose condition does not worsen while being treated
with the pharmaceutical compositions described herein. The term
"therapeutic treatment" refers to administering treatment to a
patient already suffering from a disease. Thus, in preferred
embodiments, treating is the administration to a mammal (either for
therapeutic or prophylactic purposes) of therapeutically effective
amounts of imatinib or a phenylaminopyrimidine derivative
compound.
[0357] "Treat," "treatment," or "treating," as used herein refers
to administering a pharmaceutical composition for prophylactic
and/or therapeutic purposes. The term "prophylactic treatment"
refers to treating a patient who is not yet diseased, but who is
susceptible to, or otherwise at risk of, a particular disease. The
term "therapeutic treatment" refers to administering treatment to a
patient already suffering from a disease. Thus, in preferred
embodiments, treating is the administration to a mammal (either for
therapeutic or prophylactic purposes) of therapeutically effective
amounts of imatinib or a phenylaminopyrimidine derivative
compound.
[0358] The term "dosing interval" refers to the time between
administrations of the two sequential doses of a pharmaceutical's
during multiple dosing regimens.
[0359] The "respirable delivered dose" is the amount of aerosolized
imatinib or a phenylaminopyrimidine derivative compound particles
inhaled during the inspiratory phase of the breath simulator that
is equal to or less than 5 microns.
[0360] "Lung Deposition" as used herein, refers to the fraction of
the nominal dose of an active pharmaceutical ingredient (API) that
is deposited on the inner surface of the lungs.
[0361] "Nominal dose," or "loaded dose" refers to the amount of
drug that is placed in the nebulizer prior to administration to a
mammal. The volume of solution containing the nominal dose is
referred to as the "fill volume."
[0362] "Enhanced pharmacokinetic profile" means an improvement in
some pharmacokinetic parameter. Pharmacokinetic parameters that may
be improved include, AUClast, AUC(0-.infin.) Tmax, and optionally a
Cmax. In some embodiments, the enhanced pharmacokinetic profile may
be measured quantitatively by comparing a pharmacokinetic parameter
obtained for a nominal dose of an active pharmaceutical ingredient
(API) administered with one type of inhalation device with the same
pharmacokinetic parameter obtained with oral administration of a
composition of the same active pharmaceutical ingredient (API).
[0363] "Blood plasma concentration" refers to the concentration of
an active pharmaceutical ingredient (API) in the plasma component
of blood of a subject or patient population.
[0364] "Respiratory condition," as used herein, refers to a disease
or condition that is physically manifested in the respiratory
tract, including, but not limited to, pulmonary fibrosis, cancer,
disease resulting from active, previous or latent viral infection,
bronchitis, chronic bronchitis, or emphysema.
[0365] "Nebulizer," as used herein, refers to a device that turns
medications, compositions, formulations, suspensions, and mixtures,
etc. into a fine mist or aerosol for delivery to the lungs.
Nebulizers may also be referred to as atomizers.
[0366] "Drug absorption" or simply "absorption" typically refers to
the process of movement of drug from site of delivery of a drug
across a barrier into a blood vessel or the site of action, e.g., a
drug being absorbed in the pulmonary capillary beds of the
alveoli.
Imatinib and Phenylaminopyrimidine Derivative Compounds
[0367] As also noted elsewhere herein, in preferred embodiments the
phenylaminopyrimidine derivative for use in a phenylaminopyrimidine
derivative formulation as described herein comprises imatinib
(4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrim-
idin-2-yl]amino}phenyl)benzamide) or a salt thereof. Imatinib has
the following structure:
##STR00001##
[0368] In some embodiments, a salt form of imatinib is used in any
of the embodiments contemplated herein. In some embodiments, the
counterion of the salt form of imatinib, is acetate, acetonide,
alanine, aluminum, arginine, ascorbate, asparagine, aspartic acid,
benzathine, benzoate, besylate, bisulfate, bisulfite, bitartrate,
bromide, calcium, carbonate, camphorsulfonate, cetylpridinium,
chloride, chlortheophyllinate, cholinate, citrate, cysteine,
deoxycholate, diethanolamine, diethylamine, diphosphate,
diproprionate, disalicylate, edetate, edisylate, estolate,
ethylamine, ethylenediamine, ethandisulfonate, fumarate,
gluceptate, gluconate, glucuronate, glutamic acid, glutamine,
glycine, hippurate, histidine, hydrobromide, hydrochloride,
hydroxide, iodide, isethionate, isoleucine, lactate, lactobionate,
laurylsulfate, leucine, lysine, magnesium, malate, maleate,
mandelate, meglumine, mesylate, metabisulfate, metabisulfite,
methionine, methylbromide, methylsulfate, methyl p-hydroxybenzoate,
mucate, naphthoate, napsylate, nitrate, nitrite, octadecanoate,
oleate, ornithine, oxalate, pamoate, pentetate, phenylalanine,
phosphate, piperazine, polygalacturonate, potassium, procaine,
proline, propionate, propyl p-hydroxybenzoate, saccharin,
salicylate, selenocysteine, serine, silver, sodium, sorbitan,
stearate, succinate, sulfate, sulfite, sulfosalicylate, tartrate,
threonine, tosylate, triethylamine, triethiodide, trifluoroacetate,
trioleate, tromethamine, tryptophan, tyrosine, valerate, valine,
xinafoate, or zinc. In some embodiments, an imatinib fumarate salt
form is used in any of the embodiments contemplated herein. In some
embodiments, an imatinib hydrochloride salt form is used in any of
the embodiments contemplated herein. In some embodiments, an
imatinib phosphate salt form is used in any of the embodiments
contemplated herein.
[0369] In some embodiments, a crystalline form an imatinib salt is
used in any of the embodiments described herein. In some
embodiments, the crystalline form an imatinib salt is used in the
manufacture of medicament that is in a form suitable for
administration to a mammal by inhalation with a nebulizer, a
metered dose inhaler, or a dry powder inhaler. In some embodiments,
a crystalline form an imatinib fumate salt is used in any of the
embodiments described herein. In some embodiments, a crystalline
form an imatinib hydrochloride salt is used in any of the
embodiments described herein. In some embodiments, a crystalline
form an imatinib phosphate salt is used in any of the embodiments
described herein.
[0370] In one aspect, described herein is a crystalline form an
imatinib fumate salt. In some embodiments, the crystalline form the
imatinib fumate salt is characterized as having an X-Ray powder
diffraction (XRPD) pattern substantially the same as the XRPD
pattern that is shown in FIG. 2. In some embodiments, the
crystalline form the imatinib fumate salt is characterized as
having an X-Ray powder diffraction (XRPD) pattern with the
following characteristic peaks:
TABLE-US-00004 Angle 2-Theta .degree. Intensity % 8.05 64 11.91
25.1 16.04 32.7 16.27 24 17.38 26.7 19.98 34.1 20.88 26.3 23.78
81.7 24.51 100 25.84 28.9 26.73 51.9 28.92 41.3
[0371] In one aspect, described herein is a crystalline form an
imatinib hydrochloride salt. In some embodiments, the crystalline
form the imatinib hydrochloride salt is characterized as having an
X-Ray powder diffraction (XRPD) pattern substantially the same as
the XRPD pattern that is shown in FIG. 3. In some embodiments, the
crystalline form the imatinib hydrochloride salt is characterized
as having an X-Ray powder diffraction (XRPD) pattern with the
following characteristic peaks:
TABLE-US-00005 Angle 2-Theta .degree. Intensity % 6.68 100 9.78 17
13.28 17 16.46 22.6 16.94 22.3 19.93 86.7 22.35 62.1 22.58 19.3
23.24 29.8 23.50 80.6 26.42 34.9 29.66 18.6
[0372] In one aspect, described herein is a crystalline form an
imatinib phosphate salt. In some embodiments, the crystalline form
the imatinib phosphate salt is characterized as having an X-Ray
powder diffraction (XRPD) pattern substantially the same as the
XRPD pattern that is shown in FIG. 4. In some embodiments, the
crystalline form the imatinib phosphate salt is characterized as
having an X-Ray powder diffraction (XRPD) pattern with the
following characteristic peaks:
TABLE-US-00006 Angle 2-Theta .degree. Intensity % 6.71 73.9 7.343
100 10.04 40.3 10.98 44 16.75 15.4 22.03 11 23.53 13.7 33.30 8.5
33.88 5.2
[0373] In some embodiments, the crystalline form the imatinib
phosphate salt is characterized as having an X-Ray powder
diffraction (XRPD) pattern substantially the same as the XRPD
pattern that is shown in FIG. 5. In some embodiments, the
crystalline form the imatinib phosphate salt is characterized as
having an X-Ray powder diffraction (XRPD) pattern with the
following characteristic peaks:
TABLE-US-00007 Angle 2-Theta .degree. Intensity % 3.68 8.2 7.34 100
10.99 35.9 14.65 6.2 14.81 4.3 18.35 4.7 22.05 6.5 24.85 2.6 33.35
3.4
[0374] In some embodiments, the crystalline form the imatinib
phosphate salt is characterized as having an X-Ray powder
diffraction (XRPD) pattern substantially the same as the XRPD
pattern that is shown in FIG. 6. In some embodiments, the
crystalline form the imatinib phosphate salt is characterized as
having an X-Ray powder diffraction (XRPD) pattern with the
following characteristic peaks:
TABLE-US-00008 Angle 2-Theta .degree. Intensity % 6.13 58.3 7.55 72
8.93 100 14.08 47.7 17.28 67.1 17.82 91.9 18.86 46.3 19.89 38.6
21.06 55.7 21.67 37.2 23.93 46.6 24.35 54.4 24.66 62.7 25.32
38.6
[0375] Although various embodiments are described with the use of
imatinib, it is noted that other phenylaminopyrimidine derivative
compounds, or salts thereof, may be used in place of imatinib. In
some embodiments, phenylaminopyrimidine derivative compounds
include, but are not limited to, those compounds that are
structurally similar to imatinib. In some embodiments,
phenylaminopyrimidine derivative compounds include, but are not
limited to, those compounds that are structurally similar to and
have the same type of biological activity as imatinib. In some
embodiments, phenylaminopyrimidine derivative compounds include,
but are not limited to, those compounds described in U.S. Pat. Nos.
5,521,184; 6,894,051; 6,958,335; and 7,544,799. In some
embodiments, phenylaminopyrimidine derivative compounds include,
but are not limited to, those compounds that are structurally
similar to and have the same type of biological activity as
compounds described in U.S. Pat. Nos. 5,521,184; 6,894,051;
6,958,335; and 7,544,799.
[0376] A kinase inhibitor is a type of enzyme inhibitor that blocks
the action of one or more kinases. A kinase is a kinase enzyme that
modifies other proteins by chemically adding phosphate groups to
them (phosphorylation). Examples of kinases include but are not
limited to serine/threonine-specific protein kinases and
tyrosine-specific kinases. Some examples of tyrosine-specific
kinases include, but are not limited to, platelet-derived growth
factor receptor (PDGFR),epidermal growth factor receptor (EGFR),
insulin receptor and insulin-like growth factor 1 receptor (IGF1R),
stem cell factor (SCF) receptor (also called c-kit). In some
embodiments, kinase inhibitors contemplated herein include tyrosine
kinase inhibitors. In some embodiments, the tyrosine kinase
inhibitors contemplated herein are platelet-derived growth factor
receptor inhibitors.
[0377] Kinase inhibitors contemplated herein include, but are not
limited to, imatinib or salt thereof, sorafenib or salt thereof,
nintedanib (vargatef) or salt thereof, sunitinib or salt thereof,
ponatinib or salt thereof, axitinib or salt thereof, tyrphostin AG
1296 or salt thereof, linifanib (ABT-869) or salt thereof,
dovitinib (TKI-258) or salt thereof, motesanib (AMG-706) or salt
thereof, pazopanib (GW786034) or salt thereof, masitinib (AB1010)
or salt thereof, tivozanib (AV-951) or salt thereof, amuvatinib
(MP-470) or salt thereof, Ki8751 or salt thereof, TSU-68 (SU6668,
orantinib) or salt thereof, CP-673451 or salt thereof, KRN 633 or
salt thereof, telatinib or salt thereof, PP121 or salt thereof,
crenolanib (CP-868596) or salt thereof, MK-2461 or salt
thereof.
Advantages of Inhaled Aerosol and Topical (Non-Oral) Drug
Delivery
[0378] Inhalation therapy of aerosolized imatinib or a
phenylaminopyrimidine derivative compound enables direct deposition
of the sustained-release or active substance in the respiratory
tract (be that intra-nasal or pulmonary) for therapeutic action at
that site of deposition or systemic absorption to regions
immediately down stream of the vascular absorption site. In the
case of central nervous system (CNS) deposition, intra-nasal
inhalation aerosol delivery deposits imatinib or a
phenylaminopyrimidine derivative compound directly upstream of the
CNS compartment.
[0379] Similar to the intra-nasal and pulmonary applications
described above, treatment or prevention of organs outside the
respiratory tract requires absorption to the systemic vascular
department for transport to these extra-respiratory sites. In the
case of treating or preventing fibrotic or inflammatory diseases
associated with the heart, liver and kidney, deposition of drug in
the respiratory tract, more specifically the deep lung will enable
direct access to these organs through the left atrium to either the
carotid arteries or coronary arteries. Similarly, in the case of
treating CNS disorder (e.g., multiple sclerosis), deposition of
drug in the respiratory tract (as defined above) or nasal cavity,
more specifically the absorption from the nasal cavity to the nasal
capillary beds for immediate access to the brain and CNS. This
direct delivery will permit direct dosing of high concentration
imatinib or a phenylaminopyrimidine derivative compound in the
absence of unnecessary systemic exposure. Similarly, this route
permits titration of the dose to a level that may be critical for
these indications.
[0380] Pharmaceutical Compositions
[0381] For purposes of the method described herein, a
phenylaminopyrimidine derivative compound, most preferably imatinib
may be administered using a liquid nebulization, dry powder or
metered-dose inhaler. In some embodiments, imatinib or a
phenylaminopyrimidine derivative compound disclosed herein is
produced as a pharmaceutical composition suitable for aerosol
formation, dose for indication, deposition location, pulmonary or
intra-nasal delivery for pulmonary, intranasal/sinus, or
extra-respiratory therapeutic action, good taste, manufacturing and
storage stability, and patient safety and tolerability.
[0382] In some embodiments, the isoform content of the manufactured
phenylaminopyrimidine derivative compound, most preferably imatinib
may be optimized for drug substance and drug product stability,
dissolution (in the case of dry powder or suspension formulations)
in the nose and/or lung, tolerability, and site of action (be that
lung, nasal/sinus, or regional tissue).
[0383] Manufacture
[0384] In some embodiments, imatinib drug product (DP) includes
imatinib at a concentration of about 1 mg/mL to about 100 mg/mL in
aqueous buffer (citrate or phosphate pH=4 to 8), plus optional
added inorganic salts (NaCl and/or MgCl.sub.2 and/or MgSO.sub.4).
In some embodiments, the imatinib drug product also includes
co-solvent(s) (by non-limiting example ethanol, propylene glycol,
and glycerin) and/or surfactant(s) (by non-limiting example Tween
80, Tween 60, lecithin, Cetylpyridinium, and Tween 20). In some
embodiments, the formulation also includes a taste-masking agent
(by non-limiting example sodium saccharin).
[0385] To achieve imatinib concentrations above 3 mg/mL,
manufacturing process are described. In one embodiment, the
manufacturing process includes high temperature imatinib aqueous
dissolution, followed by co-solvent and/or surfactant and/or salt
addition, and subsequent cooling to ambient temperature. In this
process, added co-solvent and/or surfactant and/or salt stabilize
the high-temperature-dissolved imatinib during the cooling process
and provide a stable, high-concentration, ambient-temperature
formulation of imatinib. In some embodiments, the processing
temperature is 30.degree. C., 35.degree. C., 40.degree. C.,
45.degree. C., 50.degree. C., 55.degree. C., 60.degree. C.,
65.degree. C., 70.degree. C., 75.degree. C., 80.degree. C.,
85.degree. C., 90.degree. C., 95.degree. C., 100.degree. C. or
other pressure-enabled increased temperature. In some embodiments,
the process includes addition of surfactant and/or co-solvent
and/or salt at the highest temperature or incrementally-lower
temperature as the solution is cooled. In some embodiments,
addition of surfactant and/or co-solvent and/or salt occurs all at
once or incrementally during a maintained temperature or as the
solution is cooled. The time by which the solution is maintained at
the highest temperature is from 0 minutes to 24 hours. The time by
which the solution is cooled from the highest temperature is from 0
minutes to 24 hours. In some embodiments, the solution is protected
from light. In some embodiments, the solution is sparged to remove
or lower the oxygen concentration. In some embodiments, the head
space of the reaction container includes an inert gas or mixture of
inert gases. Inert gases include, but are not limited to, nitrogen
and argon. In some embodiments, the imatinib drug product includes
co-solvent(s) in the concentration range of 0% to 100% in otherwise
buffered aqueous solution. In some embodiments, the imatinib drug
product includes co-solvent(s) at a concentration of about 1% to
about 25%. Co-solvents include, but are not limited to, ethanol,
glycerin or propylene glycol. In some embodiments, the imatinib
drug product includes surfactant(s) in the concentration range of
0% to 100% in otherwise buffered aqueous solution. In some
embodiments, the imatinib drug product includes surfactant(s) at a
concentration of about 0.1% to about 10%. Surfactants include, but
are not limited to Tween 20, Tween 60, Tween 80, Cetylpyridinium
Bromide, or Lecithin. In some embodiments, the imatinib drug
product includes a buffer. In some embodiments, the buffer includes
salt and/or acid forms of agents such as citrate, phosphate or
formate at a concentration between 0 mM to 1000 mM. In some
embodiments, the buffer includes salt and/or acid forms of agents
such as citrate, phosphate or formate at a concentration between
about 1 mM and about 50 mM. In some embodiments, the imatinib drug
product includes a salt. In some embodiments, the salt is present
at a concentration between 0% to 100%. In some embodiments, the
salt is present at a concentration between about 0.1% and about 5%.
In some embodiments, the salt is sodium chloride, magnesium
chloride, magnesium sulfate or barium chloride. In some
embodiments, a sweetening agent is added to the imatinib drug
product. In some embodiments, the sweetening agent is saccharin or
a salt thereof. In some embodiments, the sweetening agent is
present at a concentration between about 0.01 mM and about 10 mM.
In some embodiments, the pH of the buffered solution will be
between about 2.0 and about 10.0.
[0386] In another embodiment, the manufacturing process includes
excess co-solvent and/or surfactant and/or cation addition to a
super-saturated imatinib aqueous solution. Upon dissolution in the
excess co-solvent and/or surfactant and/or cation aqueous solution,
the formulation is diluted to reduce co-solvent and/or surfactant
and/or cation concentrations to within the concentration range
generally-recognized as safe and/or non-toxic and/or
non-irritable.
[0387] In some embodiments, the manufacturing process is as
described in the Examples.
Administration
[0388] The phenylaminopyrimidine derivative compound, most
preferably imatinib as disclosed herein can be administered at a
therapeutically effective dosage, e.g., a dosage sufficient to
provide treatment for the disease states previously described. In
some embodiments, for example, a daily aerosol dose of imatinib in
an imatinib compound formulation may be from about 0.001 mg to
about 6.6 mg imatinib/kg of body weigh per dose. In some
embodiments, for example, a daily aerosol dose of imatinib,
phenylaminopyrimidine derivative or other tyrosine kinase inhibitor
compound in an imatinib, phenylaminopyrimidine derivative or other
tyrosine kinase inhibitor compound formulation may be from about
0.00001 mg to about 3.3 mg imatinib, phenylaminopyrimidine
derivative or other tyrosine kinase inhibitor compound/kg of body
weigh per dose. In some embodiments, for administration to a 70 kg
person, the dosage range would be about 0.07 mg to about 463 mg
imatinib per dose or up to about 0.280 mg to about 1852 mg imatinib
day. In some embodiments, for administration to a 60 kg person, the
dosage range would be about 0.001 mg to about 200 mg imatinib per
dose or up to about 0.006 mg to about 1200 mg imatinib day. The
amount of active compound administered will, of course, be
dependent on the subject and disease state being treated, the
severity of the affliction, the manner and schedule of
administration, the location of the disease (e.g., whether it is
desired to effect intra-nasal or upper airway delivery, pharyngeal
or laryngeal delivery, bronchial delivery, pulmonary delivery
and/or pulmonary delivery with subsequent systemic or central
nervous system absorption), and the judgment of the prescribing
physician; for example, a likely dose range for aerosol
administration of imatinib in preferred embodiments, or in other
embodiments of phenylaminopyrimidine derivative compound or
tyrosine kinase inhibitor would be about 0.28 to 1852 mg per day or
about 0.0.001 to 1200 mg per day.
[0389] Inhibitors of CYP enzymes reduce imatinib metabolism
resulting in elevated blood levels and associated toxicity. As many
products effecting CYP enzymes are useful to different patient
populations, permitting their use would be beneficial. While the
oral route is already at the maximum permissible dose, any
inhibition of the enzymes described above elevates imatinib blood
levels and increases the rate and severity of the toxic events
described herein. Because oral inhalation and intranasal inhalation
delivery of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof can achieve effective lung tissue levels with much
less drug than that required by the oral product, resulting blood
levels are significantly lower and consequences associated with CYP
enzyme inhibitory properties described herein are removed. Thus,
permitting use of these CYP inhibitory enzyme products currently
contraindicated with the oral medicine.
[0390] Administration of the phenylaminopyrimidine derivative
compound, most preferably imatinib as disclosed herein, such as a
pharmaceutically acceptable salt thereof, can be via any of the
accepted modes of administration for agents that serve similar
utilities including, but not limited to, aerosol inhalation such as
nasal and/or oral inhalation of a mist or spray containing liquid
particles, for example, as delivered by a nebulizer.
[0391] Pharmaceutically acceptable compositions thus may include
solid, semi-solid, liquid and aerosol dosage forms, such as, e.g.,
powders, liquids, suspensions, complexations, liposomes,
particulates, or the like. Preferably, the compositions are
provided in unit dosage forms suitable for single administration of
a precise dose. The unit dosage form can also be assembled and
packaged together to provide a patient with a weekly or monthly
supply and can also incorporate other compounds such as saline,
taste masking agents, pharmaceutical excipients, and other active
ingredients or carriers.
[0392] The phenylaminopyrimidine derivative compound, most
preferably imatinib as disclosed herein, such as a pharmaceutically
acceptable salt thereof, can be administered either alone or more
typically in combination with a conventional pharmaceutical
carrier, excipient or the like (e.g., mannitol, lactose, starch,
magnesium stearate, sodium saccharin, talcum, cellulose, sodium
crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate,
magnesium chloride, magnesium sulfate, calcium chloride, lactose,
sucrose, glucose and the like). if desired, the pharmaceutical
composition can also contain minor amounts of nontoxic auxiliary
substances such as wetting agents, emulsifying agents, solubilizing
agents, pH buffering agents and the like (e.g., citric acid,
ascorbic acid, sodium phosphate, potassium phosphate, sodium
acetate, sodium citrate, cyclodextrin derivatives, sorbitan
monolaurate, triethanolamine acetate, triethanolamine oleate, and
the like). Generally, depending on the intended mode of
administration, the pharmaceutical formulation will contain about
0.005% to 95%, preferably about 0.1% to 50% by weight of a compound
of the invention. Actual methods of preparing such dosage forms are
known, or will be apparent, to those skilled in this art; for
example, see Remington's Pharmaceutical Sciences, Mack Publishing
Company, Easton, Pa.
[0393] In one preferred embodiment, the compositions will take the
form of a unit dosage form such as vial containing a liquid, solid
to be suspended, dry powder, lyophilisate, or other composition and
thus the composition may contain, along with the active ingredient,
a diluent such as lactose, sucrose, dicalcium phosphate, or the
like; a lubricant such as magnesium stearate or the like; and a
binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin,
cellulose, cellulose derivatives or the like.
[0394] Liquid pharmaceutically administrable compositions can, for
example, be prepared by dissolving, dispersing, etc. an active
compound as defined above and optional pharmaceutical adjuvants in
a carrier (e.g., water, saline, aqueous dextrose, glycerol,
glycols, ethanol or the like) to form a solution or suspension.
Solutions to be aerosolized can be prepared in conventional forms,
either as liquid solutions or suspensions, as emulsions, or in
solid forms suitable for dissolution or suspension in liquid prior
to aerosol production and inhalation. The percentage of active
compound contained in such aerosol compositions is highly dependent
on the specific nature thereof, as well as the activity of the
compound and the needs of the subject. However, percentages of
active ingredient of 0.01% to 90% in solution are employable, and
will be higher if the composition is a solid, which will be
subsequently diluted to the above percentages. In some embodiments,
the composition will comprise 0.25%-50.0% of the active agent in
solution.
[0395] Imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound formulations can be separated into two groups; those of
simple formulation and complex formulations providing taste-masking
for improved tolerability, pH-optimized for stability and
tolerability, immediate or sustained-release, and/or
area-under-the-curve (AUC) shape-enhancing properties. Simple
formulations can be further separated into three groups. 1. Simple
formulations may include water-based liquid formulations for
nebulization. By non-limiting example water-based liquid
formulations may consist of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound alone or with
non-encapsulating water soluble excipients. 2. Simple formulations
may also include organic-based liquid formulations for nebulization
or meter-dose inhaler. By non-limiting example organic-based liquid
formulations may consist of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound or with non-encapsulating
organic soluble excipients. 3. Simple formulations may also include
dry powder formulations for administration with a dry powder
inhaler. By non-limiting example dry powder formulations may
consist of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound alone or with either water soluble or organic
soluble non-encapsulating excipients with or without a carrier
agent such as lactose. Complex formulations can be further
separated into five groups. 1. Complex formulations may include
water-based liquid formulations for nebulization. By non-limiting
example water-based liquid complex formulations may consist of
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound encapsulated or complexed with water-soluble excipients
such as lipids, liposomes, cyclodextrins, microencapsulations, and
emulsions. 2. Complex formulations may also include organic-based
liquid formulations for nebulization or meter-dose inhaler. By
non-limiting example organic-based liquid complex formulations may
consist of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound encapsulated or complexed with
organic-soluble excipients such as lipids, microencapsulations, and
reverse-phase water-based emulsions. 3. Complex formulations may
also include low-solubility, water-based liquid formulations for
nebulization. By non-limiting example low-solubility, water-based
liquid complex formulations may consist of imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound as a
low-water soluble, stable nanosuspension alone or in
co-crystal/co-precipitate excipient complexes, or mixtures with low
solubility lipids, such as lipid nanosuspensions. 4. Complex
formulations may also include low-solubility, organic-based liquid
formulations for nebulization or meter-dose inhaler. By
non-limiting example low-solubility, organic-based liquid complex
formulations may consist of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound as a low-organic soluble,
stable nanosuspension alone or in co-crystal/co-precipitate
excipient complexes, or mixtures with low solubility lipids, such
as lipid nanosuspensions. 5. Complex formulations may also include
dry powder formulations for administration using a dry powder
inhaler. By non-limiting example, complex dry powder formulations
may consist of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound in co-crystal/co-precipitate/spray dried
complex or mixture with low-water soluble excipients/salts in dry
powder form with or without a carrier agent such as lactose.
Specific methods for simple and complex formulation preparation are
described herein.
Aerosol Delivery
[0396] Imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt thereof
compounds as described herein are preferably directly administered
as an aerosol to a site of pulmonary pathology including pulmonary
fibrosis, cancer or disease site resulting from active, previous or
latent viral infection. The aerosol may also be delivered to the
pulmonary compartment for absorption into the pulmonary vasculature
for therapy or prophylaxis of extra-pulmonary pathologies such as
fibrotic diseases of the heart, kidney, liver, eye or surgical
site, viral infection, cancer, or pulmonary or intra-nasal delivery
for extra-pulmonary or extra-nasal cavity disease resulting from
active, previous or latent viral infection associated with the
central nervous system.
[0397] Several device technologies exist to deliver either dry
powder or liquid aerosolized products. Dry powder formulations
generally require less time for drug administration, yet longer and
more expensive development efforts. Conversely, liquid formulations
have historically suffered from longer administration times, yet
have the advantage of shorter and less expensive development
efforts. Imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compounds disclosed herein range in solubility, are
generally stable and have a range of tastes. In one such
embodiment, imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compounds are water soluble at pH 4 to pH 8, are
stable in aqueous solution and have limited to no taste. Such a
phenylaminopyrimidine derivative includes imatinib.
[0398] Accordingly, in one embodiment, a particular formulation of
the imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound disclosed herein is combined with a particular
aerosolizing device to provide an aerosol for inhalation that is
optimized for maximum drug deposition at a site of infection, lung
cancer, pulmonary fibrosis, pulmonary arterial hypertension,
pulmonary or intra-nasal site for systemic absorption for
extra-nasal and/or extra-pulmonary indications, and maximal
tolerability. Factors that can be optimized include solution or
solid particle formulation, rate of delivery, and particle size and
distribution produced by the aerosolizing device.
Particle Size and Distribution
[0399] The distribution of aerosol particle/droplet size can be
expressed in terms of either: [0400] the mass median aerodynamic
diameter (MMAD)--the droplet size at which half of the mass of the
aerosol is contained in smaller droplets and half in larger
droplets; [0401] volumetric mean diameter (VMD); [0402] mass median
diameter (MMD); [0403] the fine particle fraction (FPF)--the
percentage of particles that are <5 .mu.m in diameter.
[0404] These measures have been used for comparisons of the in
vitro performance of different inhaler device and drug
combinations. In general, the higher the fine particle fraction,
the higher the proportion of the emitted dose that is likely to
deposit the lung.
[0405] Generally, inhaled particles are subject to deposition by
one of two mechanisms: impaction, which usually predominates for
larger particles, and sedimentation, which is prevalent for smaller
particles. Impaction occurs when the momentum of an inhaled
particle is large enough that the particle does not follow the air
stream and encounters a physiological surface. In contrast,
sedimentation occurs primarily in the deep lung when very small
particles which have traveled with the inhaled air stream encounter
physiological surfaces as a result of random diffusion within the
air stream.
[0406] For pulmonary administration, the upper airways are avoided
in favor of the middle and lower airways. Pulmonary drug delivery
may be accomplished by inhalation of an aerosol through the mouth
and throat. Particles having a mass median aerodynamic diameter
(MMAD) of greater than about 5 microns generally do not reach the
lung; instead, they tend to impact the back of the throat and are
swallowed and possibly orally absorbed. Particles having diameters
of about 1 to about 5 microns are small enough to reach the upper-
to mid-pulmonary region (conducting airways), but are too large to
reach the alveoli. Smaller particles, i.e., about 0.5 to about 2
microns, are capable of reaching the alveolar region. Particles
having diameters smaller than about 0.5 microns can also be
deposited in the alveolar region by sedimentation, although very
small particles may be exhaled. Measures of particle size can be
referred to as volumetric mean diameter (VMD), mass median diameter
(MMD), or MMAD. These measurements may be made by impaction (MMD
and MMAD) or by laser (VMD). For liquid particles, VMD, MMD and
MMAD may be the same if environmental conditions are maintained,
e.g., standard humidity. However, if humidity is not maintained,
MMD and MMAD determinations will be smaller than VMD due to
dehydration during impactor measurements. For the purposes of this
description, VMD, MMD and MMAD measurements are considered to be
under standard conditions such that descriptions of VMD, MMD and
MMAD will be comparable. Similarly, dry powder particle size
determinations in MMD and MMAD are also considered comparable.
[0407] In some embodiments, the particle size of the aerosol is
optimized to maximize the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound deposition at the site of
pulmonary pathology and/or extra-pulmonary, systemic or central
nervous system distribution, and to maximize tolerability (or in
the later case, systemic absorption). Aerosol particle size may be
expressed in terms of the mass median aerodynamic diameter (MMAD).
Large particles (e.g., MMAD>5 .mu.m) may deposit in the upper
airway because they are too large to navigate the curvature of the
upper airway. Small particles (e.g., MMAD<2 .mu.m) may be poorly
deposited in the lower airways and thus become exhaled, providing
additional opportunity for upper airway deposition. Hence,
intolerability (e.g., cough and bronchospasm) may occur from upper
airway deposition from both inhalation impaction of large particles
and settling of small particles during repeated inhalation and
expiration. Thus, in one embodiment, an optimum particle size is
used (e.g., MMAD=2-5 .mu.m) in order to maximize deposition at a
mid-lung and to minimize intolerability associated with upper
airway deposition. Moreover, generation of a defined particle size
with limited geometric standard deviation (GSD) may optimize
deposition and tolerability. Narrow GSD limits the number of
particles outside the desired MMAD size range. In one embodiment,
an aerosol containing one or more compounds disclosed herein is
provided having a MMAD from about 2 microns to about 5 microns with
a GSD of less than or equal to about 2.5 microns. In another
embodiment, an aerosol having an MMAD from about 2.8 microns to
about 4.3 microns with a GSD less than or equal to 2 microns is
provided. In another embodiment, an aerosol having an MMAD from
about 2.5 microns to about 4.5 microns with a GSD less than or
equal to 1.8 microns is provided.
[0408] In some embodiments, the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound that is intended for
respiratory delivery (for either systemic or local distribution)
can be administered as aqueous formulations, as suspensions or
solutions in halogenated hydrocarbon propellants, or as dry
powders. Aqueous formulations may be aerosolized by liquid
nebulizers employing either hydraulic or ultrasonic atomization.
Propellant-based systems may use suitable pressurized metered-dose
inhalers (pMDIs). Dry powders may use dry powder inhaler devices
(DPIs), which are capable of dispersing the drug substance
effectively. A desired particle size and distribution may be
obtained by choosing an appropriate device.
[0409] Lung Deposition as used herein, refers to the fraction of
the nominal dose of an active pharmaceutical ingredient (API) that
is bioavailable at a specific site of pharmacologic activity upon
administration of the agent to a patient via a specific delivery
route. For example, a lung deposition of 30% means 30% of the
active ingredient in the inhalation device just prior to
administration is deposited in the lung. Likewise, a lung
deposition of 60% means 60% of the active ingredient in the
inhalation device just prior to administration is deposited in the
lung, and so forth. Lung deposition can be determined using methods
of scintigraphy or deconvolution. In some embodiments, the present
invention provides for methods and inhalation systems for the
treatment or prophylaxis of a respiratory condition in a patient,
comprising administering to the patient a nominal dose of imatinib
or a phenylaminopyrimidine derivative compound with a liquid
nebulizer. In some embodiments, the liquid nebulizer is a high
efficiency liquid nebulizer. In some embodiments a lung deposition
of imatinib or a phenylaminopyrimidine derivative compound of at
least about 7%, at least about 10%, at least about 15%, at least
about 20%, at least about 25%, at least about 30%, at least about
35%, at least about 40%, at least about 45%, at least about 50%, at
least about 55%, at least about 60%, at least about 65%, at least
about 70%, at least about 75%, at least about 80%, or at least
about 85%, based on the nominal dose of imatinib or a
phenylaminopyrimidine derivative compound is achieved.
[0410] There are two main methods used to measure aerosol
deposition in the lungs. First, .gamma.-scintigraphy is performed
by radiolabeling the drug with a substance like 99m-technetium, and
scanning the subject after inhalation of the drug. This technique
has the advantage of being able to quantify the proportion of
aerosol inhaled by the patient, as well as regional distribution in
the upper airway and lungs. Second, since most of the drug
deposited in the lower airways will be absorbed into the
bloodstream, pharmacokinetic techniques are used to measure lung
deposition. This technique can assess the total amount of ICSs that
interacts with the airway epithelium and is absorbed systemically,
but will miss the small portion that may be expectorated or
swallowed after mucociliary clearance, and cannot tell us about
regional distribution. Therefore, .gamma.-scintigraphy and
pharmacokinetic studies are in many cases considered
complementary.
[0411] In some embodiments, administration of the imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound with a
liquid nebulizer provides a GSD of emitted droplet size
distribution of about 1.0 .mu.m to about 2.5 .mu.m, about 1.2 .mu.m
to about 2.0 .mu.m, or about 1.0 .mu.m to about 2.0 .mu.m. In some
embodiments, the MMAD is about 0.5 .mu.m to about 5 .mu.m, or about
1 to about 4 .mu.m or less than about 5 .mu.m. In some embodiments,
the VMD is about 0.5 .mu.m to about 5 .mu.m, or about 1 to about 4
.mu.m or less than about 5 .mu.m.
[0412] Fine Particle Fraction (FPF) describes the efficiency of a
nebulizer inhalation device. FPF represents the percentage of the
delivered aerosol dose, or inhaled mass, with droplets of diameter
less than 5.0 .mu.m. Droplets of less than 5.0 .mu.m in diameter
are considered to penetrate to the lung. In some embodiments,
administration of an aqueous inhalation imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof solution with a liquid nebulizer
provides a RDD of at least about 30%, at least about 35%, at least
about 40%, at least about 45%, at least about 50%, at least about
55%, at least about 60%, at least about 65%, at least about 70%, at
least about 75%, or at least about 80%.
[0413] The Delivered Dose (DD) of drug to a patient is the certain
portion of volume of liquid filled into the nebulizer, i.e. the
fill volume, which is emitted from the mouthpiece of the device.
The difference between the nominal dose and the DD is the amount of
volume lost primarily to residues, i.e. the amount of fill volume
remaining in the nebulizer after administration, or is lost in
aerosol form during expiration of air from the patient and
therefore not deposited in the patient's body. In some embodiments,
the DD of the nebulized formulations described herein is at least
about 30%, at least about 35%, at least about 40%, at least about
45%, at least about 50%, at least about 55%, at least about 60%, at
least about 65%, at least about 70%, or at least about 80%.
[0414] The Respirable Delivered Dose (RDD) is an expression of the
delivered mass of drug contained within emitted droplets from a
nebulizer that are small enough to reach and deposit on the surface
epithelium of the patients lung. The RDD is determined by
multiplying the DD by the FPF.
[0415] In one embodiment, described herein an aqueous droplet
containing imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound, wherein the aqueous droplet has a diameter
less than about 5.0 .mu.m. In some embodiments, the aqueous droplet
has a diameter less than about 5.0 .mu.m, less than about 4.5
.mu.m, less than about 4.0 .mu.m, less than about 3.5 .mu.m, less
than about 3.0 .mu.m, less than about 2.5 .mu.m, less than about
2.0 .mu.m, less than about 1.5 .mu.m, or less than about 1.0 .mu.m.
In some embodiments, the aqueous droplet further comprises one or
more cosolvents. In some embodiments, the one or more cosolvents
are selected from ethanol and propylene glycol. In some
embodiments, the aqueous droplet further comprises a buffer. In
some embodiments, the buffer is a citrate buffer or a phosphate
buffer. In some embodiments, the droplet was produced from a liquid
nebulizer and an aqueous solution of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound as described herein. In
some embodiments, the aqueous droplet was produced from an aqueous
solution that has concentration of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof between about 0.1 mg/mL and about
60 mg/mL and an osmolality from about 50 mOsmol/kg to about 6000
mOsmol/kg. In some embodiments, the aqueous droplet was produced
from an aqueous solution that has concentration of imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound between
about 0.001 mg/mL and about 200 mg/mL and an osmolality from about
50 mOsmol/kg to about 6000 mOsmol/kg. In some embodiments, the
osmolality is greater than about 100 mOsmol/kg. In some
embodiments, the osmolality is greater than about 400 mOsmol/kg. In
some embodiments, the osmolality is greater than about 1000
mOsmol/kg. In some embodiments, the osmolality is greater than
about 2000 mOsmol/kg. In some embodiments, the osmolality is
greater than about 3000 mOsmol/kg. In some embodiments, the
osmolality is greater than about 4000 mOsmol/kg. In some
embodiments, the osmolality is greater than about 5000
mOsmol/kg.
[0416] Also described are aqueous aerosols comprising a plurality
of aqueous droplets of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound as described herein. In
some embodiments, the at least about 30% of the aqueous droplets in
the aerosol have a diameter less than about 5 .mu.m. In some
embodiments, at least about 35%, at least about 40%, at least about
45%, at least about 50%, at least about 55%, at least about 60%, at
least about 65%, at least about 70%, at least about 75%, at least
about 80%, at least about 85%, or at least about 90% of the aqueous
droplets in the aerosol have a diameter less than about 5 .mu.m. In
some embodiments, the aqueous aerosols are produced with a liquid
nebulizer. In some embodiments, the aqueous aerosols are produced
with a high efficiency liquid nebulizer.
Liquid Nebulizer
[0417] In one embodiment, a nebulizer is selected on the basis of
allowing the formation of an aerosol of an imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound disclosed
herein having an MMAD predominantly between about 1 to about 5
microns. In one embodiment, the delivered amount of imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof compound
provides a therapeutic effect for pulmonary pathology and/or
extra-pulmonary, systemic, tissue or central nervous system
distribution.
[0418] Previously, two types of nebulizers, jet and ultrasonic,
have been shown to be able to produce and deliver aerosol particles
having sizes between 2 and 4 micron. These particle sizes have been
shown as being optimal for middle airway deposition. However,
unless a specially formulated solution is used, these nebulizers
typically need larger volumes to administer sufficient amount of
drug to obtain a therapeutic effect. A jet nebulizer utilizes air
pressure breakage of an aqueous solution into aerosol droplets. An
ultrasonic nebulizer utilizes shearing of the aqueous solution by a
piezoelectric crystal. Typically, however, the jet nebulizers are
only about 10% efficient under clinical conditions, while the
ultrasonic nebulizer is only about 5% efficient. The amount of
pharmaceutical deposited and absorbed in the lungs is thus a
fraction of the 10% in spite of the large amounts of the drug
placed in the nebulizer. The amount of drug that is placed in the
nebulizer prior to administration to the mammal is generally
referred to the "nominal dose," or "loaded dose." The volume of
solution containing the nominal dose is referred to as the "fill
volume." Smaller particle sizes or slow inhalation rates permit
deep lung deposition. Both middle-lung and alveolar deposition may
be desired for this invention depending on the indication, e.g.,
middle and/or alveolar deposition for pulmonary fibrosis and
systemic delivery. Exemplary disclosure of compositions and methods
for formulation delivery using nebulizers can be found in, e.g., US
2006/0276483, including descriptions of techniques, protocols and
characterization of aerosolized mist delivery using a vibrating
mesh nebulizer.
[0419] Accordingly, in one embodiment, a vibrating mesh nebulizer
is used to deliver in preferred embodiments an aerosol of the
imatinib compound as disclosed herein, or in other embodiments, a
phenylaminopyrimidine derivative compound as disclosed herein. A
vibrating mesh nebulizer comprises a liquid storage container in
fluid contact with a diaphragm and inhalation and exhalation
valves. In one embodiment, about 0.01 to about 6 ml of the imatinib
compound formulation (or in another related embodiment, of a
phenylaminopyrimidine derivative or other tyrosine kinase inhibitor
compound formulation) is placed in the storage container and the
aerosol generator is engaged producing atomized aerosol of particle
sizes selectively between about 1 and about 5 micron. In one
embodiment, about 1 to about 6 ml of the imatinib compound
formulation (or in another related embodiment, of a
phenylaminopyrimidine derivative compound formulation) is placed in
the storage container and the aerosol generator is engaged
producing atomized aerosol of particle sizes selectively between
about 1 and about 5 micron. In one embodiment, about 0.01 to about
10 mL of the imatinib compound formulation (or in another related
embodiment, of a phenylaminopyrimidine derivative compound
formulation) is placed in the storage container and the aerosol
generator is engaged producing atomized aerosol of particle sizes
selectively between about 1 and about 5 micron. In one embodiment,
about 1 to about 10 mL of the imatinib compound formulation (or in
another related embodiment, of a phenylaminopyrimidine derivative
compound formulation) is placed in the storage container and the
aerosol generator is engaged producing atomized aerosol of particle
sizes selectively between about 1 and about 5 micron. In one
embodiment, about the volume of the imatinib compound formulation
(or in another related embodiment, of a phenylaminopyrimidine
derivative compound formulation) that is originally placed in the
storage container and the aerosol generator is replaced to increase
the administered dose size.
[0420] In some embodiments an imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound formulation as disclosed
herein, is placed in a liquid nebulization inhaler and prepared in
dosages to deliver from about 0.01 mg to about 200 mg from a dosing
solution of about 0.01 mL to about 6 mL with MMAD particles sizes
between about 1 to about 5 micron being produced.
[0421] In some embodiments an imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound formulation as disclosed
herein, is placed in a liquid nebulization inhaler and prepared in
dosages to deliver from about 0.01 mg to about 200 mg from a dosing
solution of about 0.01 to about 7 ml with MMAD particles sizes
between about 1 to about 5 micron being produced.
[0422] By non-limiting example, a nebulized imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound may be
administered in the described respirable delivered dose in less
than about 20 min, less than about 15 min, less than about 10 min,
less than about 7 min, less than about 5 min, less than about 3
min, less than about 2 min, less than about 1 min, less than about
0.5 minutes, in less than five breaths, in less than four breaths,
in less than three breaths, in less than two breaths, or in one
breath.
[0423] By non-limiting example, a nebulized imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound may be
administered in the described respirable delivered dose using a
breath-actuated nebulizer in less than about 20 min, less than
about 10 min, less than about 7 min, less than about 5 min, less
than about 3 min, or less than about 2 min, less than about 1 min,
less than about 0.5 minutes, in less than five breaths, in less
than four breaths, in less than three breaths, in less than two
breaths, or in one breath.
[0424] By non-limiting example, in other circumstances, a nebulized
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound may achieve improved tolerability and/or exhibit an
area-under-the-curve (AUC) shape-enhancing characteristic when
administered over longer periods of time. Under these conditions,
the described respirable delivered dose in more than about 1 min,
preferably more than about 2 min, preferably more than about 3 min,
more preferably more than about 5 min, more preferably more than
about 7 min, more preferably more than about 10 min, and in some
cases most preferable from about 10 to about 20 min.
[0425] As disclosed herein, there is provided a
phenylaminopyrimidine derivative compound formulation composition
comprising an imatinib compound aqueous solution having a pH from
about 4.0 to about pH 8.0 where the imatinib compound is present at
a concentration from about 0.001 mg/mL to about 200 mg/mL imatinib
or salt thereof. In certain other embodiments the imatinib compound
formulation is provided as an aqueous solution having a pH of from
about 4.0 to about 8.0, the solution comprising an imatinib
compound at a concentration of from about 0.001 mg/mL to about 200
mg/mL imatinib or salt thereof; and citrate buffer or phosphate
buffer at a concentration of from about 0 mM to about 50 mM. In
certain other embodiments the imatinib compound formulation is
provided as an aqueous solution having a pH of from about 4.0 to
about 8.0, the solution comprising an imatinib compound at a
concentration of from about 0.001 mg/mL to about 200 mg/mL imatinib
phosphate salt; and optionally a citrate buffer or phosphate buffer
at a concentration of from about 0 mM to about 50 mM. In certain
other embodiments the imatinib compound formulation is provided as
an aqueous solution having a pH of from about 4.0 to about 8.0, the
solution comprising an imatinib compound at a concentration of from
about 0.001 mg/mL to about 200 mg/mL imatinib; and a buffer that
has a pKa between 4.7 and 6.8 and that is present at a
concentration sufficient to maintain or maintain after titration
with acid or base a pH from about 4.0 to about 8.0 for a time
period sufficient to enable marketable product shelf-life storage.
In certain other embodiments the imatinib compound formulation is
provided as an aqueous solution having a pH of from about 4.0 to
about 8.0, the solution comprising an imatinib compound at a
concentration of from about 0.001 mg/mL to about 200 mg/mL imatinib
phosphate salt; and optionally a buffer that has a pKa between 4.7
and 6.8 and that is present at a concentration sufficient to
maintain or maintain after titration with acid or base a pH from
about 4.0 to about 8.0 for a time period sufficient to enable
marketable product shelf-life storage.
[0426] In some embodiments, described herein is a pharmaceutical
composition that includes: imatinib; water; phosphate buffer or
citrate buffer; and optionally sodium chloride or magnesium
chloride. In other embodiments, described herein is a
pharmaceutical composition that includes: imatinib phosphate salt;
water and optionally sodium chloride or magnesium chloride. In
other embodiments, described herein is a pharmaceutical composition
that includes: imatinib; water; a buffer; and at least one
additional ingredient selected from sodium chloride, magnesium
chloride, ethanol, propylene glycol, glycerol, polysorbate 80, and
cetylpyridinium bromide (or chloride). In some embodiments, the
buffer is phosphate buffer. In other embodiments, the buffer is
citrate buffer. In some embodiments, the pharmaceutical composition
includes 1 mg to 500 mg of imatinib, for example, 5 mg, 10 mg, 15
mg, 25 mg, 37.5 mg, 75 mg, 100 mg, 115 mg, 150 mg, 190 mg, 220 mg,
or 500 mg. In some embodiments, the pharmaceutical composition
includes 0.001 mg to 200 mg of imatinib or salt thereof, for
example 0.001 mg, 0.005 mg, 0.01 mg, 0.05 mg, 0.1 mg, 0.5 mg, 1 mg,
2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 25 mg, 50 mg, 75 mg, 100 mg,
125 mg, 150 mg, 175 mg, or 200 mg. In some embodiments, the
osmolality of the pharmaceutical composition described herein is
between about 50 mOsmo/kg to 6000 mOsmo/kg. In some embodiments,
the osmolality of the pharmaceutical composition described herein
is between about 50 mOsmo/kg to 5000 mOsmo/kg. In some embodiments,
the pharmaceutical composition optionally includes saccharin (e.g.
sodium salt). In some embodiments, such a pharmaceutical
composition is placed in a liquid nebulization inhaler to deliver
from about 1 mg to about 500 mg from a dosing solution of about 0.5
to about 6 mL with MMAD particles sizes between about 1 to about 5
micron being produced. In some embodiments, such a pharmaceutical
composition is placed in a liquid nebulization inhaler to deliver
from about 0.001 mg to about 200 mg from a dosing solution of about
0.01 to about 6 mL with MMAD particles sizes between about 1 to
about 5 micron being produced. In some embodiments, such a
pharmaceutical composition is placed in a liquid nebulization
inhaler to deliver from about 1 mg to about 500 mg from a dosing
solution of about 0.5 to about 7 mL with MMAD particles sizes
between about 1 to about 5 micron being produced. In some
embodiments, such a pharmaceutical composition is placed in a
liquid nebulization inhaler to deliver from about 1 mg to about 500
mg from a dosing solution of about 0.01 to about 7 mL with MMAD
particles sizes between about 1 to about 5 micron being produced.
In some embodiments such a nebulized pharmaceutical composition may
deliver between about 0.0001 mg and about 25 mg imatinib or
phenylaminopyrimidine derivative in aerosol particles with a MMAD
between 1 and 5 microns in each inhaled breath. In some embodiments
such a nebulized pharmaceutical composition may deliver between
about 0.0001 mg and about 200 mg imatinib or phenylaminopyrimidine
derivative in aerosol particles with a MMAD between 1 and 5 microns
in each inhaled breath. In some embodiments, 1 mg imatinib, a
phenylaminopyrimidine derivative, or other tyrosine kinase
inhibitor delivered in 10 breaths, whereby at least 50% of the
inhaled particles are between 1 and 5 microns, 0.05 mg imatinib
phenylaminopyrimidine derivative, or other tyrosine kinase
inhibitor will be delivered in each breath. In some embodiments, 1
mg imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
delivered in 15 breaths per minute over 10 minutes, whereby 50% of
the inhaled particles are between 1 and 5 microns, 0.0033 mg
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
will be delivered in each breath. In some embodiments, 1 mg
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
delivered in 20 breaths per minute over 20 minutes, whereby 50% of
the inhaled particles are between 1 and 5 microns, 0.00125 mg
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
will be delivered in each breath. In some embodiments, 200 mg
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
delivered in 10 breaths over 1 minute, whereby 50% of the inhaled
particles are between 1 and 5 microns, 10 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof will be delivered
in each breath. In some embodiments, 200 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof delivered in 15
breaths per minute over 10 minutes, whereby 50% of the inhaled
particles are between 1 and 5 microns, 0.67 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof will be delivered
in each breath. By another non-limiting example, in some
embodiments, 200 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof delivered in 20 breaths per minute
over 20 minutes, whereby 50% of the inhaled particles are between 1
and 5 microns, 0.25 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof will be delivered in each breath.
In some embodiments, 20 mg imatinib or phenylaminopyrimidine
derivative, or other tyrosine kinase inhibitor compound delivered
in 10 breaths over 1 minute, whereby 50% of the inhaled particles
are between 1 and 5 microns, 1 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof will be delivered in each breath.
In some embodiments, 20 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof delivered in 15 breaths per minute
over 10 minutes, whereby 50% of the inhaled particles are between 1
and 5 microns, about 0.067 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof will be delivered in each
breath.
[0427] In some embodiments, a nebulized imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound may be administered in
the described respirable delivered dose in less than about 20 min,
less than about 10 min, less than about 7 min, less than about 5
min, less than about 3 min, less than about 2 min, less than 1 min,
less than 0.5 min, in five breaths, in four breaths, in three
breaths, in two breaths, or in one breath.
[0428] For aqueous and other non-pressurized liquid systems, a
variety of nebulizers (including small volume nebulizers) are
available to aerosolize the formulations. Compressor-driven
nebulizers incorporate jet technology and use compressed air to
generate the liquid aerosol. Such devices are commercially
available from, for example, Healthdyne Technologies, Inc.;
Invacare, Inc.; Mountain Medical Equipment, Inc.; Pari Respiratory,
Inc.; Mada Medical, Inc.; Puritan-Bennet; Schuco, Inc., DeVilbiss
Health Care, Inc.; and Hospitak, Inc. Ultrasonic nebulizers rely on
mechanical energy in the form of vibration of a piezoelectric
crystal to generate respirable liquid droplets and are commercially
available from, for example, Omron Heathcare, Inc., Boehringer
Ingelheim, and DeVilbiss Health Care, Inc. Vibrating mesh
nebulizers rely upon either piezoelectric or mechanical pulses to
respirable liquid droplets generate. Other examples of nebulizers
for use with imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof described herein are described in U.S. Pat. Nos.
4,268,460; 4,253,468; 4,046,146; 3,826,255; 4,649,911; 4,510,929;
4,624,251; 5,164,740; 5,586,550; 5,758,637; 6,644,304; 6,338,443;
5,906,202; 5,934,272; 5,960,792; 5,971,951; 6,070,575; 6,192,876;
6,230,706; 6,349,719; 6,367,470; 6,543,442; 6,584,971; 6,601,581;
4,263,907; 5,709,202; 5,823,179; 6,192,876; 6,644,304; 5,549,102;
6,083,922; 6,161,536; 6,264,922; 6,557,549; and 6,612,303 all of
which are hereby incorporated by reference in their entirety.
[0429] Any known inhalation nebulizer suitable to provide delivery
of a medicament as described herein may be used in the various
embodiments and methods described herein. Such nebulizers include,
e.g., jet nebulizers, ultrasonic nebulizers, pulsating membrane
nebulizers, nebulizers with a vibrating mesh or plate with multiple
apertures, and nebulizers comprising a vibration generator and an
aqueous chamber (e.g., Pari eFlow.RTM.). Commercially available
nebulizers suitable for use in the present invention can include
the Aeroneb.RTM., MicroAir.RTM., Aeroneb.RTM. Pro, and Aeroneb.RTM.
Go, Aeroneb.RTM. Solo, Aeroneb.RTM. Solo/Idehaler combination,
Aeroneb.RTM. Solo or Go Idehaler-Pocket.RTM. combination, PARI
LC-Plus.RTM., PARI LC-Star.RTM., PARI Sprint.RTM., eFlow and eFlow
Rapid.RTM., Pari Boy.RTM. N and Pari Duraneb.RTM. (PARI, GmbH),
MicroAir.RTM. (Omron Healthcare, Inc.), Halolite.RTM. (Profile
Therapeutics Inc.), Respimat.RTM. (Boehringer Ingelheim),
Aerodose.RTM. (Aerogen, Inc, Mountain View, Calif.), Omron
Elite.RTM. (Omron Healthcare, Inc.), Omron Microair.RTM. (Omron
Healthcare, Inc.), Mabismist II.RTM. (Mabis Healthcare, Inc.),
Lumiscope.RTM. 6610, (The Lumiscope Company, Inc.), Airsep
Mystique.RTM., (AirSep Corporation), Acorn-1 and Acorn-II (Vital
Signs, Inc.), Aquatower.RTM. (Medical Industries America),
Ava-Neb.RTM. (Hudson Respiratory Care Incorporated), Cirrus.RTM.
(Intersurgical Incorporated), Dart.RTM. (Professional Medical
Products), Devilbiss.RTM. Pulmo Aide (DeVilbiss Corp.),
Downdraft.RTM. (Marquest), Fan Jet.RTM. (Marquest), MB-5 (Mefar),
Misty Neb.RTM. (Baxter), Salter 8900 (Salter Labs), Sidestream.RTM.
(Medic-Aid), Updraft-II.RTM. (Hudson Respiratory Care), Whisper
Jet.RTM. (Marquest Medical Products), Aiolos.RTM. (Aiolos Medicnnsk
Teknik), Inspiron.RTM. (Intertech Resources, Inc.), Optimist.RTM.
(Unomedical Inc.), Prodomo.RTM., Spira.RTM. (Respiratory Care
Center), AERx.RTM. and AERx Essence.TM. (Aradigm), Respirgard
II.RTM., Sonik.RTM. LDI Nebulizer (Evit Labs), Swirler W
Radioaerosol System (AMICI, Inc.), Maquet SUN 145 ultrasonic,
Schill untrasonic, compare and compare Elite from Omron, Monoghan
AeroEclipse BAN, Transneb, DeVilbiss 800, AerovectRx,
Porta-Neb.RTM., Freeway Freedom.TM., Sidestream, Ventstream and
I-neb produced by Philips, Inc. By further non-limiting example,
U.S. Pat. No. 6,196,219, is hereby incorporated by reference in its
entirety.
[0430] Any of these and other known nebulizers suitable to provide
delivery of a aqueous inhalation medicament as described herein may
be used in the various embodiments and methods described herein. In
some embodiments, the nebulizers are available from, e.g., Pari
GmbH (Starnberg, Germany), DeVilbiss Healthcare (Heston, Middlesex,
UK), Healthdyne, Vital Signs, Baxter, Allied Health Care, Invacare,
Hudson, Omron, Bremed, AirSep, Luminscope, Medisana, Siemens,
Aerogen, Mountain Medical, Aerosol Medical Ltd. (Colchester, Essex,
UK), AFP Medical (Rugby, Warwickshire, UK), Bard Ltd. (Sunderland,
UK), Carri-Med Ltd. (Dorking, UK), Plaem Nuiva (Brescia, Italy),
Henleys Medical Supplies (London, UK), Intersurgical (Berkshire,
UK), Lifecare Hospital Supplies (Leies, UK), Medic-Aid Ltd. (West
Sussex, UK), Medix Ltd. (Essex, UK), Sinclair Medical Ltd. (Surrey,
UK), and many others.
[0431] Other nebulizers suitable for use in the methods and systems
describe herein can include, but are not limited to, jet nebulizers
(optionally sold with compressors), ultrasonic nebulizers, and
others. Exemplary jet nebulizers for use herein can include Pari LC
plus/ProNeb, Pari LC plus/ProNeb Turbo, Pari LCPlus/Dura Neb 1000
& 2000 Pari LC plus/Walkhaler, Pari LC plus/Pari Master, Pari
LC star, Omron CompAir XL Portable Nebulizer System (NE-C18 and
JetAir Disposable nebulizer), Omron compare Elite Compressor
Nebulizer System (NE-C21 and Elite Air Reusable Nebulizer, Pari LC
Plus or Pari LC Star nebulizer with Proneb Ultra compressor,
Pulomo-aide, Pulmo-aide LT, Pulmo-aide traveler, Invacare Passport,
Inspiration Healthdyne 626, Pulmo-Neb Traveler, DeVilbiss 646,
Whisper Jet, AcornII, Misty-Neb, Allied aerosol, Schuco Home Care,
Lexan Plasic Pocet Neb, SideStream Hand Held Neb, Mobil Mist,
Up-Draft, Up-DraftII, T Up-Draft, ISO-NEB, Ava-Neb, Micro Mist, and
PuImoMate.
[0432] Exemplary ultrasonic nebulizers suitable to provide delivery
of a medicament as described herein can include MicroAir, UltraAir,
Siemens Ultra Nebulizer 145, CompAir, Pulmosonic, Scout, 5003
Ultrasonic Neb, 5110 Ultrasonic Neb, 5004 Desk Ultrasonic
Nebulizer, Mystique Ultrasonic, Lumiscope's Ultrasonic Nebulizer,
Medisana Ultrasonic Nebulizer, Microstat Ultrasonic Nebulizer, and
Mabismist Hand Held Ultrasonic Nebulizer. Other nebulizers for use
herein include 5000 Electromagnetic Neb, 5001 Electromagnetic Neb
5002 Rotary Piston Neb, Lumineb I Piston Nebulizer 5500, Aeroneb
Portable Nebulizer System, Aerodose Inhaler, and AeroEclipse Breath
Actuated Nebulizer. Exemplary nebulizers comprising a vibrating
mesh or plate with multiple apertures are described by R. Dhand in
New Nebuliser Technology--Aerosol Generation by Using a Vibrating
Mesh or Plate with Multiple Apertures, Long-Term Healthcare
Strategies 2003, (July 2003), p. 1-4 and Respiratory Care, 47:
1406-1416 (2002), the entire disclosure of each of which is hereby
incorporated by reference.
[0433] Additional nebulizers suitable for use in the presently
described invention include nebulizers comprising a vibration
generator and an aqueous chamber. Such nebulizers are sold
commercially as, e.g., Pari eFlow, and are described in U.S. Pat.
Nos. 6,962,151, 5,518,179, 5,261,601, and 5,152,456, each of which
is specifically incorporated by reference herein.
[0434] The parameters used in nebulization, such as flow rate, mesh
membrane size, aerosol inhalation chamber size, mask size and
materials, valves, and power source may be varied as applicable to
provide delivery of a medicament as described herein to maximize
their use with different types and aqueous inhalation mixtures.
[0435] In some embodiments, the drug solution is formed prior to
use of the nebulizer by a patient. In other embodiments, the drug
is stored in the nebulizer in liquid form, which may include a
suspension, solution, or the like. In other embodiments, the drug
is store in the nebulizer in solid form. In this case, the solution
is mixed upon activation of the nebulizer, such as described in
U.S. Pat. No. 6,427,682 and PCT Publication No. WO 03/035030, both
of which are hereby incorporated by reference in their entirety. In
these nebulizers, the solid drug, optionally combined with
excipients to form a solid composition, is stored in a separate
compartment from a liquid solvent.
[0436] The liquid solvent is capable of dissolving the solid
composition to form a liquid composition, which can be aerosolized
and inhaled. Such capability is, among other factors, a function of
the selected amount and, potentially, the composition of the
liquid. To allow easy handling and reproducible dosing, the sterile
aqueous liquid may be able to dissolve the solid composition within
a short period of time, possibly under gentle shaking. In some
embodiments, the final liquid is ready to use after no longer than
about 30 seconds. In some cases, the solid composition is dissolved
within about 20 seconds, and advantageously, within about 10
seconds. As used herein, the terms "dissolve(d)", "dissolving", and
"dissolution" refer to the disintegration of the solid composition
and the release, i.e., the dissolution, of the active compound. As
a result of dissolving the solid composition with the liquid
solvent a liquid composition is formed in which the active compound
is contained in the dissolved state. As used herein, the active
compound is in the dissolved state when at least about 90 wt.-% are
dissolved, and more preferably when at least about 95 wt.-% are
dissolved.
[0437] With regard to basic separated-compartment nebulizer design,
it primarily depends on the specific application whether it is more
useful to accommodate the aqueous liquid and the solid composition
within separate chambers of the same container or primary package,
or whether they should be provided in separate containers. If
separate containers are used, these are provided as a set within
the same secondary package. The use of separate containers is
especially preferred for nebulizers containing two or more doses of
the active compound. There is no limit to the total number of
containers provided in a multi-dose kit. In one embodiment, the
solid composition is provided as unit doses within multiple
containers or within multiple chambers of a container, whereas the
liquid solvent is provided within one chamber or container. In this
case, a favorable design provides the liquid in a metered-dose
dispenser, which may consist of a glass or plastic bottle closed
with a dispensing device, such as a mechanical pump for metering
the liquid. For instance, one actuation of the pumping mechanism
may dispense the exact amount of liquid for dissolving one dose
unit of the solid composition.
[0438] In another embodiment for multiple-dose
separated-compartment nebulizers, both the solid composition and
the liquid solvent are provided as matched unit doses within
multiple containers or within multiple chambers of a container. For
instance, two-chambered containers can be used to hold one unit of
the solid composition in one of the chambers and one unit of liquid
in the other. As used herein, one unit is defined by the amount of
drug present in the solid composition, which is one unit dose. Such
two-chambered containers may, however, also be used advantageously
for nebulizers containing only one single drug dose.
[0439] In one embodiment of a separated-compartment nebulizer, a
blister pack having two blisters is used, the blisters representing
the chambers for containing the solid composition and the liquid
solvent in matched quantities for preparing a dose unit of the
final liquid composition. As used herein, a blister pack represents
a thermoformed or pressure-formed primary packaging unit, most
likely comprising a polymeric packaging material that optionally
includes a metal foil, such as aluminum. The blister pack may be
shaped to allow easy dispensing of the contents. For instance, one
side of the pack may be tapered or have a tapered portion or region
through which the content is dispensable into another vessel upon
opening the blister pack at the tapered end. The tapered end may
represent a tip.
[0440] In some embodiments, the two chambers of the blister pack
are connected by a channel, the channel being adapted to direct
fluid from the blister containing the liquid solvent to the blister
containing the solid composition. During storage, the channel is
closed with a seal. In this sense, a seal is any structure that
prevents the liquid solvent from contacting the solid composition.
The seal is preferably breakable or removable; breaking or removing
the seal when the nebulizer is to be used will allow the liquid
solvent to enter the other chamber and dissolve the solid
composition. The dissolution process may be improved by shaking the
blister pack. Thus, the final liquid composition for inhalation is
obtained, the liquid being present in one or both of the chambers
of the pack connected by the channel, depending on how the pack is
held.
[0441] According to another embodiment, one of the chambers,
preferably the one that is closer to the tapered portion of the
blister pack communicates with a second channel, the channel
extending from the chamber to a distal position of the tapered
portion. During storage, this second channel does not communicate
with the outside of the pack but is closed in an air-tight fashion.
Optionally, the distal end of the second channel is closed by a
breakable or removable cap or closure, which may e.g., be a
twist-off cap, a break-off cap, or a cut-off cap.
[0442] In one embodiment, a vial or container having two
compartments is used, the compartment representing the chambers for
containing the solid composition and the liquid solvent in matched
quantities for preparing a dose unit of the final liquid
composition. The liquid composition and a second liquid solvent may
be contained in matched quantities for preparing a dose unit of the
final liquid composition (by non-limiting example in cases where
two soluble excipients or the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound and excipient are
unstable for storage, yet desired in the same mixture for
administration.
[0443] In some embodiments, the two compartments are physically
separated but in fluid communication such as when so the vial or
container are connected by a channel or breakable barrier, the
channel or breakable barrier being adapted to direct fluid between
the two compartments to enable mixing prior to administration.
During storage, the channel is closed with a seal or the breakable
barrier intact. In this sense, a seal is any structure that
prevents mixing of contents in the two compartments. The seal is
preferably breakable or removable; breaking or removing the seal
when the nebulizer is to be used will allow the liquid solvent to
enter the other chamber and dissolve the solid composition or in
the case of two liquids permit mixing. The dissolution or mixing
process may be improved by shaking the container. Thus, the final
liquid composition for inhalation is obtained, the liquid being
present in one or both of the chambers of the pack connected by the
channel or breakable barrier, depending on how the pack is
held.
[0444] The solid composition itself can be provided in various
different types of dosage forms, depending on the physicochemical
properties of the drug, the desired dissolution rate, cost
considerations, and other criteria. In one of the embodiments, the
solid composition is a single unit. This implies that one unit dose
of the drug is comprised in a single, physically shaped solid form
or article. In other words, the solid composition is coherent,
which is in contrast to a multiple unit dosage form, in which the
units are incoherent.
[0445] Examples of single units which may be used as dosage forms
for the solid composition include tablets, such as compressed
tablets, film-like units, foil-like units, wafers, lyophilized
matrix units, and the like. In a preferred embodiment, the solid
composition is a highly porous lyophilized form. Such
lyophilizates, sometimes also called wafers or lyophilized tablets,
are particularly useful for their rapid disintegration, which also
enables the rapid dissolution of the active compound.
[0446] On the other hand, for some applications the solid
composition may also be formed as a multiple unit dosage form as
defined above. Examples of multiple units are powders, granules,
microparticles, pellets, beads, lyophilized powders, and the like.
In one embodiment, the solid composition is a lyophilized powder.
Such a dispersed lyophilized system comprises a multitude of powder
particles, and due to the lyophilization process used in the
formation of the powder, each particle has an irregular, porous
microstructure through which the powder is capable of absorbing
water very rapidly, resulting in quick dissolution.
[0447] Another type of multiparticulate system which is also
capable of achieving rapid drug dissolution is that of powders,
granules, or pellets from water-soluble excipients which are coated
with the drug, so that the drug is located at the outer surface of
the individual particles. In this type of system, the water-soluble
low molecular weight excipient is useful for preparing the cores of
such coated particles, which can be subsequently coated with a
coating composition comprising the drug and, preferably, one or
more additional excipients, such as a binder, a pore former, a
saccharide, a sugar alcohol, a film-forming polymer, a plasticizer,
or other excipients used in pharmaceutical coating
compositions.
[0448] In another embodiment, the solid composition resembles a
coating layer that is coated on multiple units made of insoluble
material. Examples of insoluble units include beads made of glass,
polymers, metals, and mineral salts. Again, the desired effect is
primarily rapid disintegration of the coating layer and quick drug
dissolution, which is achieved by providing the solid composition
in a physical form that has a particularly high surface-to-volume
ratio. Typically, the coating composition will, in addition to the
drug and the water-soluble low molecular weight excipient, comprise
one or more excipients, such as those mentioned above for coating
soluble particles, or any other excipient known to be useful in
pharmaceutical coating compositions.
[0449] To achieve the desired effects, it may be useful to
incorporate more than one water-soluble low molecular weight
excipient into the solid composition. For instance, one excipient
may be selected for its drug carrier and diluent capability, while
another excipient may be selected to adjust the pH. If the final
liquid composition needs to be buffered, two excipients that
together form a buffer system may be selected.
[0450] In one embodiment, the liquid to be used in a
separated-compartment nebulizer is an aqueous liquid, which is
herein defined as a liquid whose major component is water. The
liquid does not necessarily consist of water only; however, in one
embodiment it is purified water. In another embodiment, the liquid
contains other components or substances, preferably other liquid
components, but possibly also dissolved solids. Liquid components
other than water which may be useful include propylene glycol,
glycerol, and polyethylene glycol. One of the reasons to
incorporate a solid compound as a solute is that such a compound is
desirable in the final liquid composition, but is incompatible with
the solid composition or with a component thereof, such as the
active ingredient.
[0451] Another desirable characteristic for the liquid solvent is
that it is sterile. An aqueous liquid would be subject to the risk
of considerable microbiological contamination and growth if no
measures were taken to ensure sterility. In order to provide a
substantially sterile liquid, an effective amount of an acceptable
antimicrobial agent or preservative can be incorporated or the
liquid can be sterilized prior to providing it and to seal it with
an air-tight seal. In one embodiment, the liquid is a sterilized
liquid free of preservatives and provided in an appropriate
air-tight container. However, according to another embodiment in
which the nebulizer contains multiple doses of the active compound,
the liquid may be supplied in a multiple-dose container, such as a
metered-dose dispenser, and may require a preservative to prevent
microbial contamination after the first use.
High Efficiency Liquid Nebulizers
[0452] High efficiency liquid nebulizers are inhalation devices
that are adapted to deliver a large fraction of a loaded dose to a
patient. Some high efficiency liquid nebulizers utilize
microperforated membranes. In some embodiments, the high efficiency
liquid nebulizer also utilizes one or more actively or passively
vibrating microperforated membranes. In some embodiments, the high
efficiency liquid nebulizer contains one or more oscillating
membranes. In some embodiments, the high efficiency liquid
nebulizer contains a vibrating mesh or plate with multiple
apertures and optionally a vibration generator with an aerosol
mixing chamber. In some such embodiments, the mixing chamber
functions to collect (or stage) the aerosol from the aerosol
generator. In some embodiments, an inhalation valve is also used to
allow an inflow of ambient air into the mixing chamber during an
inhalation phase and is closed to prevent escape of the aerosol
from the mixing chamber during an exhalation phase. In some such
embodiments, the exhalation valve is arranged at a mouthpiece which
is removably mounted at the mixing chamber and through which the
patient inhales the aerosol from the mixing chamber. In yet some
other embodiments, the high efficiency liquid nebulizer contains a
pulsating membrane. In some embodiments, the high efficiency liquid
nebulizer is continuously operating.
[0453] In some embodiments, the high efficiency liquid nebulizer
contains a vibrating microperforated membrane of tapered nozzles
against a bulk liquid will generate a plume of droplets without the
need for compressed gas. In these embodiments, a solution in the
microperforated membrane nebulizer is in contact with a membrane,
the opposite side of which is open to the air. The membrane is
perforated by a large number of nozzle orifices of an atomizing
head. An aerosol is created when alternating acoustic pressure in
the solution is built up in the vicinity of the membrane causing
the fluid on the liquid side of the membrane to be emitted through
the nozzles as uniformly sized droplets.
[0454] Some embodiments the high efficiency liquid nebulizers use
passive nozzle membranes and a separate piezoelectric transducer
that are in contact with the solution. In contrast, some high
efficiency liquid nebulizers employ an active nozzle membrane,
which use the acoustic pressure in the nebulizer to generate very
fine droplets of solution via the high frequency vibration of the
nozzle membrane.
[0455] Some high efficiency liquid nebulizers contain a resonant
system. In some such high efficiency liquid nebulizers, the
membrane is driven by a frequency for which the amplitude of the
vibrational movement at the center of the membrane is particularly
large, resulting in a focused acoustic pressure in the vicinity of
the nozzle; the resonant frequency may be about 100 kHz. A flexible
mounting is used to keep unwanted loss of vibrational energy to the
mechanical surroundings of the atomizing head to a minimum. In some
embodiments, the vibrating membrane of the high efficiency liquid
nebulizer may be made of a nickel-palladium alloy by
electroforming.
[0456] In some embodiments, the high efficiency liquid nebulizer
(i) achieves lung deposition of at least about 5%, at least about
6%, at least about 7%, at least about 8%, at least about 9%, at
least about 10%, at least about 15%, at least about 20%, at least
about 25%, at least about 30%, at least about 35%, at least about
40%, at least about 45%, at least about 50%, at least about 55%, at
least about 60%, at least about 65%, at least about 70%, at least
about 75%, at least about 80%, or at least about 85%, based on the
nominal dose of the imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound administered to the
mammal.
[0457] In some embodiments, the high efficiency liquid nebulizer
(ii) provides a Geometric Standard Deviation (GSD) of emitted
droplet size distribution of the solution administered with the
high efficiency liquid nebulizer of about 1.0 .mu.m to about 2.5
.mu.m, about 1.2 .mu.m to about 2.5 .mu.m, about 1.3 .mu.m to about
2.0 .mu.m, at least about 1.4 .mu.m to about 1.9 .mu.m, at least
about 1.5 .mu.m to about 1.9 .mu.m, about 1.5 .mu.m, about 1.7
.mu.m, or about 1.9 .mu.m.
[0458] In some embodiments, the high efficiency liquid nebulizer
(iii) provides a mass median aerodynamic diameter (MMAD) of droplet
size of the solution emitted with the high efficiency liquid
nebulizer of about 1 .mu.m to about 5 .mu.m, about 2 to about 4
.mu.m, or about 2.5 to about 4.0 .mu.m. In some embodiments, the
high efficiency liquid nebulizer (iii) provides a volumetric mean
diameter (VMD) 1 .mu.m to about 5 .mu.m, about 2 to about 4 .mu.m,
or about 2.5 to about 4.0 .mu.m. In some embodiments, the high
efficiency liquid nebulizer (iii) provides a mass median diameter
(MMD) 1 .mu.m to about 5 .mu.m, about 2 to about 4 .mu.m, or about
2.5 to about 4.0 .mu.m.
[0459] In some embodiments, the high efficiency liquid nebulizer
(iv) provides a fine particle fraction (FPF=%.ltoreq.5 microns) of
droplets emitted from the high efficiency nebulizer of at least
about 60%, at least about 65%, at least about 70%, at least about
75%, at least about 80%, at least about 85%, or at least about
90%.
[0460] In some embodiments, the high efficiency liquid nebulizer
(v) provides an output rate of at least 0.1 mL/min, at least 0.2
mL/min, at least 0.3 mL/min, at least 0.4 mL/min, at least 0.5
mL/min, at least 0.6 mL/min, at least 0.8 mL/min, or at least 1.0
mL/min.
[0461] In some embodiments, the high efficiency liquid nebulizer
(vi) delivers at least about 20%, at least about 25%, at least
about 30%, at least about 35%, at least about 40%, at least about
45%, at least about 50%,at least about 55%, at least about 60%, at
least about 65%, at least about 70%, at least about 75%, or at
least about 80% of the fill volume to the mammal.
[0462] In some embodiments, the high efficiency liquid nebulizer
provides an RDD of at least about 5%, at least about 6%, at least
about 7%, at least about 8%, at least about 9%, at least about 10%,
at least about 15%, at least about 20%, at least about 25%, at
least about 30%, at least about 35%, at least about 40%, at least
about 45%, at least about 50%, at least about 55%, at least about
60%, at least about 65%, at least about 70%, at least about 75%, at
least about 80%, or at least about 85%.
[0463] In some embodiments, the high efficiency liquid nebulizer is
characterized as providing one or more of (i), (ii), (iii) (iv),
(v), or (vi). In some embodiments, the high efficiency liquid
nebulizer is characterized as providing at least one, at least two,
at least three, at least four, at least five, or all six of (i),
(ii), (iii) (iv), (v), or (vi).
[0464] Additional features of a high efficiency liquid nebulizer
with perforated membranes are disclosed in U.S. Pat. Nos.
6,962,151, 5,152,456, 5,261,601, and 5,518,179, US 6,983,747, each
of which is hereby incorporated by reference in its entirety. Other
embodiments of the high efficiency liquid nebulizers contain
oscillatable membranes. Features of these high efficiency liquid
nebulizers are disclosed in U.S. Pat. Nos. 7,252,085; 7,059,320;
6,983,747, each of which is hereby incorporated by reference in its
entirety.
[0465] Commercial high efficiency liquid nebulizers are available
from: PARI (Germany) under the trade name eFlow.RTM.; Nektar
Therapeutics (San Carlos, Calif.) under the trade names
AeroNeb.RTM. Go and AeroNeb.RTM. Pro, and AeroNeb.RTM. Solo,
Respironics (Murrysville, Calif.) under the trade names I-Neb.RTM.,
Omron (Bannockburn, Ill.) under the trade name Micro-Air.RTM., and
Activaero (Germany) under the trade name Akita.RTM.. Commercial
High Efficiency Nebulizers are also available from Aerogen (Galway,
Ireland) utilizing the OnQ.RTM. nebulizer technology.
Meter Dose Inhaler (MDI)
[0466] A propellant driven inhaler (pMDI) releases a metered dose
of medicine upon each actuation. The medicine is formulated as a
suspension or solution of a drug substance in a suitable propellant
such as a halogenated hydrocarbon. pMDIs are described in, for
example, Newman, S. P., Aerosols and the Lung, Clarke et al., eds.,
pp. 197-224 (Butterworths, London, England, 1984).
[0467] In some embodiments, the particle size of the drug substance
in an MDI may be optimally chosen. In some embodiments, the
particles of active ingredient have diameters of less than about 50
microns. In some embodiments, the particles have diameters of less
than about 10 microns. In some embodiments, the particles have
diameters of from about 1 micron to about 5 microns. In some
embodiments, the particles have diameters of less than about 1
micron. In one advantageous embodiment, the particles have
diameters of from about 2 microns to about 5 microns.
[0468] By non-limiting example, metered-dose inhalers (MDI), the
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound disclosed herein are prepared in dosages to deliver from
about 34 mcg to about 463 mg from a formulation meeting the
requirements of the MDI. The imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound disclosed herein may be
soluble in the propellant, soluble in the propellant plus a
co-solvent (by non-limiting example ethanol), soluble in the
propellant plus an additional moiety promoting increased solubility
(by non-limiting example glycerol or phospholipid), or as a stable
suspension or micronized, spray-dried or nanosuspension.
[0469] By non-limiting example, a metered-dose imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound may be
administered in the described respirable delivered dose in 10 or
fewer inhalation breaths, or in 8 or fewer inhalation breaths, or
in 6 or fewer inhalation breaths, or in 4 or fewer inhalation
breaths, or in 2 or fewer inhalation breaths.
[0470] The propellants for use with the MDIs may be any propellants
known in the art. Examples of propellants include
chlorofluorocarbons (CFCs) such as dichlorodifluoromethane,
trichlorofluoromethane, and dichlorotetrafluoroethane;
hydrofluoroalkanes (HFAs); and carbon dioxide. It may be
advantageous to use HFAs instead of CFCs due to the environmental
concerns associated with the use of CFCs. Examples of medicinal
aerosol preparations containing HFAs are presented in U.S. Pat.
Nos. 6,585,958; 2,868,691 and 3,014,844, all of which are hereby
incorporated by reference in their entirety. In some embodiments, a
co-solvent is mixed with the propellant to facilitate dissolution
or suspension of the drug substance.
[0471] In some embodiments, the propellant and active ingredient
are contained in separate containers, such as described in U.S.
Pat. No. 4,534,345, which is hereby incorporated by reference in
its entirety.
[0472] In some embodiments, the MDI used herein is activated by a
patient pushing a lever, button, or other actuator. In other
embodiments, the release of the aerosol is breath activated such
that, after initially arming the unit, the active compound aerosol
is released once the patient begins to inhale, such as described in
U.S. Pat. Nos. 6,672,304; 5,404,871; 5,347,998; 5,284,133;
5,217,004; 5,119,806; 5,060,643; 4,664,107; 4,648,393; 3,789,843;
3,732,864; 3,636,949; 3,598,294; 3,565,070; 3,456,646; 3,456,645;
and 3,456,644, each of which is hereby incorporated by reference in
its entirety. Such a system enables more of the active compound to
get into the lungs of the patient. Another mechanism to help a
patient get adequate dosage with the active ingredient may include
a valve mechanism that allows a patient to use more than one breath
to inhale the drug, such as described in U.S. Pat. Nos. 4,470,412
and 5,385,140, both of which are hereby incorporated by reference
in their entirety.
[0473] Additional examples of MDIs known in the art and suitable
for use herein include U.S. Pat. Nos. 6,435,177; 6,585,958;
5,642,730; 6,223,746; 4,955,371; 5,404,871; 5,364,838; and
6,523,536, all of which are hereby incorporated by reference in
their entirety.
Dry Powder Inhaler (DPI)
[0474] There are two major designs of dry powder inhalers. One
design is the metering device in which a reservoir for the drug is
placed within the device and the patient adds a dose of the drug
into the inhalation chamber. The second is a factory-metered device
in which each individual dose has been manufactured in a separate
container. Both systems depend upon the formulation of drug into
small particles of mass median diameters from about 1 to about 5
micron, and usually involve co-formulation with larger excipient
particles (typically 100 micron diameter lactose particles). Drug
powder is placed into the inhalation chamber (either by device
metering or by breakage of a factory-metered dosage) and the
inspiratory flow of the patient accelerates the powder out of the
device and into the oral cavity. Non-laminar flow characteristics
of the powder path cause the excipient-drug aggregates to
decompose, and the mass of the large excipient particles causes
their impaction at the back of the throat, while the smaller drug
particles are deposited deep in the lungs.
[0475] As with liquid nebulization and MDIs, particle size of the
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound aerosol formulation may be optimized. If the particle size
is larger than about 5 micron MMAD then the particles are deposited
in upper airways. If the particle size of the aerosol is smaller
than about 1 micron then it is delivered into the alveoli and may
get transferred into the systemic blood circulation.
[0476] By non-limiting example, in dry powder inhalers, the
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound disclosed herein are prepared in dosages to disperse and
deliver from about 34 mcg to about 463 mg from a dry powder
formulation.
[0477] By non-limiting example, a dry powder imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound may be
administered in the described respirable delivered dose in 10 or
fewer inhalation breaths, or in 8 or fewer inhalation breaths, or
in 6 or fewer inhalation breaths, or in 4 or fewer inhalation
breaths, or in 2 or fewer inhalation breaths.
[0478] In some embodiments, a dry powder inhaler (DPI) is used to
dispense the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound described herein. DPIs contain the drug
substance in fine dry particle form. Typically, inhalation by a
patient causes the dry particles to form an aerosol cloud that is
drawn into the patient's lungs. The fine dry drug particles may be
produced by any technique known in the art. Some well-known
techniques include use of a jet mill or other comminution
equipment, precipitation from saturated or super saturated
solutions, spray drying, in situ micronization (Hovione), or
supercritical fluid methods. Typical powder formulations include
production of spherical pellets or adhesive mixtures. In adhesive
mixtures, the drug particles are attached to larger carrier
particles, such as lactose monohydrate of size about 50 to about
100 microns in diameter. The larger carrier particles increase the
aerodynamic forces on the carrier/drug agglomerates to improve
aerosol formation. Turbulence and/or mechanical devices break the
agglomerates into their constituent parts. The smaller drug
particles are then drawn into the lungs while the larger carrier
particles deposit in the mouth or throat. Some examples of adhesive
mixtures are described in U.S. Pat. No. 5,478,578 and PCT
Publication Nos. WO 95/11666, WO 87/05213, WO 96/23485, and WO
97/03649, all of which are incorporated by reference in their
entirety. Additional excipients may also be included with the drug
substance.
[0479] There are three common types of DPIs, all of which may be
used with the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compounds described herein. In a single-dose DPI, a
capsule containing one dose of dry drug substance/excipients is
loaded into the inhaler. Upon activation, the capsule is breached,
allowing the dry powder to be dispersed and inhaled using a dry
powder inhaler. To dispense additional doses, the old capsule must
be removed and an additional capsule loaded. Examples of
single-dose DPIs are described in U.S. Pat. Nos. 3,807,400;
3,906,950; 3,991,761; and 4,013,075, all of which are hereby
incorporated by reference in their entirety. In a multiple unit
dose DPI, a package containing multiple single dose compartments is
provided. For example, the package may comprise a blister pack,
where each blister compartment contains one dose. Each dose can be
dispensed upon breach of a blister compartment. Any of several
arrangements of compartments in the package can be used. For
example, rotary or strip arrangements are common. Examples of
multiple unit does DPIs are described in EPO Patent Application
Publication Nos. 0211595A2, 0455463A1, and 0467172A1, all of which
are hereby incorporated by reference in their entirety. In a
multi-dose DPI, a single reservoir of dry powder is used.
Mechanisms are provided that measure out single dose amounts from
the reservoir to be aerosolized and inhaled, such as described in
U.S. Pat. Nos. 5,829,434; 5,437,270; 2,587,215; 5,113,855;
5,840,279; 4,688,218; 4,667,668; 5,033,463; and 4,805,811 and PCT
Publication No. WO 92/09322, all of which are hereby incorporated
by reference in their entirety.
[0480] In some embodiments, auxiliary energy in addition to or
other than a patient's inhalation may be provided to facilitate
operation of a DPI. For example, pressurized air may be provided to
aid in powder de-agglomeration, such as described in U.S. Pat. Nos.
3,906,950; 5,113,855; 5,388,572; 6,029,662 and PCT Publication Nos.
WO 93/12831, WO 90/07351, and WO 99/62495, all of which are hereby
incorporated by reference in their entirety. Electrically driven
impellers may also be provided, such as described in U.S. Pat. Nos.
3,948,264; 3,971,377; 4,147,166; 6,006,747 and PCT Publication No.
WO 98/03217, all of which are hereby incorporated by reference in
their entirety. Another mechanism is an electrically powered
tapping piston, such as described in PCT Publication No. WO
90/13327, which is hereby incorporated by reference in its
entirety. Other DPIs use a vibrator, such as described in U.S. Pat.
Nos. 5,694,920 and 6,026,809, both of which are hereby incorporated
by reference in their entirety. Finally, a scraper system may be
employed, such as described in PCT Publication No. WO 93/24165,
which is hereby incorporated by reference in its entirety.
[0481] Additional examples of DPIs for use herein are described in
U.S. Pat. Nos. 4,811,731; 5,113,855; 5,840,279; 3,507,277;
3,669,113; 3,635,219; 3,991,761; 4,353,365; 4,889,144, 4,907,538;
5,829,434; 6,681,768; 6,561,186; 5,918,594; 6,003,512; 5,775,320;
5,740,794; and 6,626,173, all of which are hereby incorporated by
reference in their entirety.
[0482] In some embodiments, a spacer or chamber may be used with
any of the inhalers described herein to increase the amount of drug
substance that gets absorbed by the patient, such as is described
in U.S. Pat. Nos. 4,470,412; 4,790,305; 4,926,852; 5,012,803;
5,040,527; 5,024,467; 5,816,240; 5,027,806; and 6,026,807, all of
which are hereby incorporated by reference in their entirety. For
example, a spacer may delay the time from aerosol production to the
time when the aerosol enters a patient's mouth. Such a delay may
improve synchronization between the patient's inhalation and the
aerosol production. A mask may also be incorporated for infants or
other patients that have difficulty using the traditional
mouthpiece, such as is described in U.S. Pat. Nos. 4,809,692;
4,832,015; 5,012,804; 5,427,089; 5,645,049; and 5,988,160, all of
which are hereby incorporated by reference in their entirety.
[0483] Dry powder inhalers (DPIs), which involve deaggregation and
aerosolization of dry powder particles, normally rely upon a burst
of inspired air that is drawn through the unit to deliver a drug
dosage. Such devices are described in, for example, U.S. Pat. No.
4,807,814, which is directed to a pneumatic powder ejector having a
suction stage and an injection stage; SU 628930 (Abstract),
describing a hand-held powder disperser having an axial air flow
tube; Fox et al., Powder and Bulk Engineering, pages 33-36 (March
1988), describing a venturi eductor having an axial air inlet tube
upstream of a venturi restriction; EP 347 779, describing a
hand-held powder disperser having a collapsible expansion chamber,
and U.S. Pat. No. 5,785,049, directed to dry powder delivery
devices for drugs.
[0484] Commercial examples of dry powder inhalers that can be used
with the imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound formulations described herein include the
Aerolizer, Turohaler, Handihaler and Discus.
Solution/Dispersion Formulations
[0485] In one embodiment, aqueous formulations containing soluble
or nanoparticulate drug particles are provided. For aqueous aerosol
formulations, the drug may be present at a concentration from about
34 mcg/mL to about 463 mg/mL. In some embodiments the drug is
present at a concentration from about 1 mg/mL to about 463 mg/mL,
or about 1 mg/mL to about 400 mg/mL, or about 0.1 mg/mL to about
360 mg/mL, or about 1 mg/mL to about 300 mg/mL, or about 1 mg/mL to
about 200 mg/mL, about 1 mg/mL to about 100 mg/mL, or about 1 mg/mL
to about 50 mg/mL, or about 5 mg/mL to about 50 mg/mL, or about 10
mg/mL to about 50 mg/mL. For aqueous solution dispersion aerosol
formulations, the drug may be present at a concentration from about
0.001/mL to about 200 mg/mL. In some embodiments the drug is
present at a concentration from about 0.001 mg/mL to about 200
mg/mL, or about 0.001 mg/mL to about 100 mg/mL, or about 0.001
mg/mL to about 50 mg/mL, or about 0.001 mg/mL to about 40 mg/mL, or
about 0.001 mg/mL to about 30 mg/mL, about 0.001 mg/mL to about 20
mg/mL, or about 0.001 mg/mL to about 16 mg/mL, or about 0.001 mg/mL
to about 12 mg/mL, or about 0.001 mg/mL to about 8 mg/mL, or about
0.001 mg/mL to about 4 mg/mL, or about 0.001 mg/mL to about 2
mg/mL, or about 0.001 mg/mL to about 1 mg/mL, or about 0.01 mg/mL
to about 1 mg/mL, or about 0.01 mg/mL to about 2 mg/mL, about 0.01
mg/mL to about 4 mg/mL, or about 0.01 mg/mL to about 8 mg/mL, or
about 0.01 mg/mL to about 12 mg/mL, or about 0.01 mg/mL to about 16
mg/mL, or about 0.01 mg/mL to about 20 mg/mL, or about 0.01 mg/mL
to about 30 mg/mL, or about 0.01 mg/mL to about 40 mg/mL, or about
0.01 mg/mL to about 50 mg/mL, or about 0.01 mg/mL to about 100
mg/mL, about 0.01 mg/mL to about 150 mg/mL, or about 0.01 mg/mL to
about 200 mg/mL. Such formulations provide effective delivery to
appropriate areas of the lung, with the more concentrated aerosol
formulations having the additional advantage of enabling large
quantities of drug substance to be delivered to the lung in a very
short period of time. In one embodiment, a formulation is optimized
to provide a well tolerated formulation. Accordingly, in one
embodiment, imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound disclosed herein are formulated to have good
taste, pH from about 4.0 to about 8.0, osmolarity from about 100 to
about 5000 mOsmol/kg. In some embodiments, the osmolarity is from
about 100 to about 1000 mOsmol/kg. In some embodiments, the
osmolarity is from about 200 to about 500 mOsmol/kg. In some
embodiments, the permeant ion concentration is from about 30 to
about 300 mM.
[0486] In some embodiments, described herein is an aqueous
pharmaceutical composition comprising imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound, water and one or more
additional ingredients selected from co-solvents, tonicity agents,
sweeteners, surfactants, wetting agents, chelating agents,
anti-oxidants, inorganic salts, and buffers. It should be
understood that many excipients may serve several functions, even
within the same formulation.
[0487] In some embodiments, pharmaceutical compositions described
herein do not include any thickening agents.
[0488] In some embodiments, the concentration of imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound in the
aqueous pharmaceutical composition is between about 0.1 mg/mL and
about 100 mg/mL. In some embodiments, the concentration of imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof
compound in the pharmaceutical composition is between about
0.001/mL to about 200 mg/mL. In some embodiments the drug is
present at a concentration from about 0.001 mg/mL to about 200
mg/mL, or about 0.001 mg/mL to about 100 mg/mL, or about 0.001
mg/mL to about 50 mg/mL, or about 0.001 mg/mL to about 40 mg/mL, or
about 0.001 mg/mL to about 30 mg/mL, about 0.001 mg/mL to about 20
mg/mL, or about 0.001 mg/mL to about 16 mg/mL, or about 0.001 mg/mL
to about 12 mg/mL, or about 0.001 mg/mL to about 8 mg/mL, or about
0.001 mg/mL to about 4 mg/mL, or about 0.001 mg/mL to about 2
mg/mL, or about 0.001 mg/mL to about 1 mg/mL, or about 0.01 mg/mL
to about 1 mg/mL, or about 0.01 mg/mL to about 2 mg/mL, about 0.01
mg/mL to about 4 mg/mL, or about 0.01 mg/mL to about 8 mg/mL, or
about 0.01 mg/mL to about 12 mg/mL, or about 0.01 mg/mL to about 16
mg/mL, or about 0.01 mg/mL to about 20 mg/mL, or about 0.01 mg/mL
to about 30 mg/mL, or about 0.01 mg/mL to about 40 mg/mL, or about
0.01 mg/mL to about 50 mg/mL, or about 0.01 mg/mL to about 100
mg/mL, about 0.01 mg/mL to about 150 mg/mL, or about 0.01 mg/mL to
about 200 mg/mL.
[0489] In some embodiments, the pH is between about pH 4.0 and
about pH 8.0. In some embodiments, the pH is between about pH 5.0
and about pH 8.0. In some embodiments, the pH is between about pH
6.0 and about pH 8.0. In some embodiments, the pH is between about
pH 6.5 and about pH 8.0. In some embodiments, the pH is between
about pH 4.0 and about pH 7.5. In some embodiments, the pH is
between about pH 4.0 and about pH 7.0. In some embodiments, the pH
is between about pH 4.0 and about pH 6.5. In some embodiments, the
pH is between about pH 4.0 and about pH 6.0.
[0490] In some embodiments, the aqueous pharmaceutical composition
includes one or more co-solvents. In some embodiments, the aqueous
pharmaceutical composition includes one or more co-solvents, where
the total amount of co-solvents is from about 1% to about 50% v/v
of the total volume of the composition. In some embodiments, the
aqueous pharmaceutical composition includes one or more
co-solvents, where the total amount of co-solvents is from about 1%
to about 50% v/v, from about 1% to about 40% v/v, from about 1% to
about 30% v/v, or from about 1% to about 25% v/v, of the total
volume of the composition. Co-solvents include, but are not limited
to, ethanol, propylene glycol and glycerol. In some embodiments,
the aqueous pharmaceutical composition includes ethanol at about 1%
v/v to about 25%. In some embodiments, the aqueous pharmaceutical
composition includes ethanol at about 1% v/v to about 15%. In some
embodiments, the aqueous pharmaceutical composition includes
ethanol at about 1% v/v, 2% v/v, 3% v/v, 4% v/v, 5% v/v, 6% v/v, 7%
v/v, 8% v/v, 9% v/v, 10% v/v, 11% v/v, 12% v/v, 13% v/v, 14% v/v,
15% v/v, 16% v/v, 17% v/v, 18% v/v, 19% v/v, 20% v/v, 21% v/v, 22%
v/v, 23% v/v, 24% v/v, or 25% v/v. In some embodiments, the aqueous
pharmaceutical composition includes glycerol at about 1% v/v to
about 25%. In some embodiments, the aqueous pharmaceutical
composition includes glycerol at about 1% v/v to about 15%. In some
embodiments, the aqueous pharmaceutical composition includes
glycerol at about 1% v/v, 2% v/v, 3% v/v, 4% v/v, 5% v/v, 6% v/v,
7% v/v, 8% v/v, 9% v/v, 10% v/v, 11% v/v, 12% v/v, 13% v/v, 14%
v/v, 15% v/v, 16% v/v, 17% v/v, 18% v/v, 19% v/v, 20% v/v, 21% v/v,
22% v/v, 23% v/v, 24% v/v, or 25% v/v. In some embodiments, the
aqueous pharmaceutical composition includes propylene glycol at
about 1% v/v to about 50%. In some embodiments, the aqueous
pharmaceutical composition includes propylene glycol at about 1%
v/v to about 25%. In some embodiments, the aqueous pharmaceutical
composition includes propylene glycol at about 1% v/v, 2% v/v, 3%
v/v, 4% v/v, 5% v/v, 6% v/v, 7% v/v, 8% v/v, 9% v/v, 10% v/v, 11%
v/v, 12% v/v, 13% v/v, 14% v/v, 15% v/v, 16% v/v, 17% v/v, 18% v/v,
19% v/v, 20% v/v, 21% v/v, 22% v/v, 23% v/v, 24% v/v, or 25%
v/v.
[0491] In some embodiments, the aqueous pharmaceutical composition
includes ethanol at about 1% v/v to about 25% and propylene glycol
at about 1% v/v to about 50%. In some embodiments, the aqueous
pharmaceutical composition includes ethanol at about 1% v/v to
about 15% and propylene glycol at about 1% v/v to about 30%. In
some embodiments, the aqueous pharmaceutical composition includes
ethanol at about 1% v/v to about 8% and propylene glycol at about
1% v/v to about 16%. In some embodiments, the aqueous
pharmaceutical composition includes ethanol and twice as much
propylene glycol, based on volume.
[0492] In some embodiments, the aqueous pharmaceutical composition
includes a buffer. In some embodiments, the buffer is a citrate
buffer or a phosphate buffer. In some embodiments, the buffer is a
citrate buffer. In some embodiments, the buffer is a phosphate
buffer.
[0493] In some embodiments, the aqueous pharmaceutical composition
consists essentially of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound, water, ethanol and/or
propylene glycol, a buffer to maintain the pH at about 4 to 8 and
optionally one or more ingredients selected from salts,
surfactants, and sweeteners (taste-masking agents). In some
embodiments, the one or more inorganic salts are selected from
tonicity agents. In some embodiments, the one or more inorganic
salts are selected from sodium chloride and magnesium chloride.
[0494] In some embodiments, the aqueous pharmaceutical composition
consists essentially of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound at a concentration of
about 10 mg/mL to about 50 mg/mL, water, one or two cosolvents
(ethanol at a concentration of about 1% v/v to about 25% v/v and/or
propylene glycol at a concentration of about 1% v/v to about 50%
v/v), a buffer to maintain the pH at about 4 to 8 and optionally
one or more ingredients selected from inorganic salts, surfactants,
and sweeteners (taste-masking agents).
[0495] In one embodiment, the solution or diluent used for
preparation of aerosol formulations has a pH range from about 4.0
to about 8.0. This pH range improves tolerability. When the aerosol
is either acidic or basic, it can cause bronchospasm and cough.
Although the safe range of pH is relative and some patients may
tolerate a mildly acidic aerosol, while others will experience
bronchospasm. Any aerosol with a pH of less than about 4.0
typically induces bronchospasm. Aerosols having pH greater than
about 8.0 may have low tolerability because body tissues are
generally unable to buffer alkaline aerosols. Aerosols with
controlled pH below about 4.0 and over about 8.0 typically result
in lung irritation accompanied by severe bronchospasm cough and
inflammatory reactions. For these reasons as well as for the
avoidance of bronchospasm, cough or inflammation in patients, the
optimum pH for the aerosol formulation was determined to be between
about pH 4.0 to about pH 8.0.
[0496] By non-limiting example, compositions may also include a
buffer or a pH adjusting agent, typically a salt prepared from an
organic acid or base. Representative buffers include organic acid
salts of citric acid, ascorbic acid, gluconic acid, carbonic acid,
tartaric acid, succinic acid, acetic acid, or phthalic acid, Tris,
tromethamine, hydrochloride, or phosphate buffers.
[0497] Many patients have increased sensitivity to various chemical
tastes, including bitter, salt, sweet, metallic sensations. To
create well-tolerated drug products, by non-limiting example taste
masking may be accomplished through the addition of taste-masking
excipients, adjusted osmolality, and sweeteners.
[0498] Many patients have increased sensitivity to various chemical
agents and have high incidence of bronchospastic, asthmatic or
other coughing incidents. Their airways are particularly sensitive
to hypotonic or hypertonic and acidic or alkaline conditions and to
the presence of any permanent ion, such as chloride. Any imbalance
in these conditions or a presence of chloride above certain value
leads to bronchospastic or inflammatory events and/or cough which
greatly impair treatment with inhalable formulations. Both these
conditions prevent efficient delivery of aerosolized drugs into the
endobronchial space.
[0499] In some embodiments, the osmolality of aqueous solutions of
the imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound disclosed herein are adjusted by providing excipients. In
some cases, a certain amount of chloride or another anion is needed
for successful and efficacious delivery of aerosolized imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof compound.
[0500] In some embodiments, the osmolality of aqueous solutions of
the imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound disclosed herein is greater than 100 mOsmol/kg. In some
embodiments, the osmolality of aqueous solutions of the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof compound
disclosed herein is greater than 300 mOsmol/kg. In some
embodiments, the osmolality of aqueous solutions of the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof compound
disclosed herein is greater than 1000 mOsmol/kg. In some
embodiments, aerosol delivery of aqueous solutions with high
osmolality (i.e. greater than about 300 mOsmol/kg) have high
incidence of bronchospastic, asthmatic or other coughing incidents.
In some embodiments, aerosol delivery of the aqueous solutions
having high osmolality (i.e. greater than about 300 mOsmol/kg) as
described do not increase the incidence of bronchospastic,
asthmatic or other coughing incidents.
[0501] In some embodiments, the osmolality of aqueous solutions of
the imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound disclosed herein are are greater than 100 mOsmol/kg above
by providing excipients. In some cases, a certain amount of
chloride or another anion is needed for successful and efficacious
delivery of aerosolized imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound
[0502] In some embodiments, the formulation for an aerosol imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof
compound may comprise from about 34 mcg to about 463 mg imatinib or
salt thereof, or a phenylaminopyrimidine derivative or salt thereof
compound per about 1 to about 5 ml of dilute saline (between 1/10
to 2/1 normal saline). Accordingly, the concentration of an
imatinib or salt thereof, or a phenylaminopyrimidine derivative or
salt thereof compound solution may be greater than about 34 mcg/ml,
greater than about 463 mcg/ml, greater than about 1 mg/ml, greater
than about 2 mg/mL, greater than about 3.0 mg/mL, greater than
about 3.7 mg/mL, greater than about 10 mg/mL, greater than about 37
mg/mL, greater than about 50 mg/ml, greater than about 100 mg/mL,
or greater than 463 mg/mL.
[0503] In some embodiments, the formulation for an aerosol imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof
compound may comprise from about 0.001 mg to about 200 mg imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof
compound per about 1 to about 5 ml of dilute saline (between 1/10
to 2/1 normal saline). Accordingly, the concentration of an
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound solution may be greater than about 0.001 mg/ml, greater
than about 200 mg/ml, greater than about 0.01 mg/ml, greater than
about 0.1 mg/mL, greater than about 1.0 mg/mL, greater than about 2
mg/mL, greater than about 4 mg/mL, greater than about 8 mg/mL,
greater than about 12 mg/ml, greater than about 16 mg/mL, greater
than about 20 mg/mL, greater than about 50 mg/mL, greater than
about 100 mg/mL, greater than about 150 mg/mL or greater than about
200 mg/mL.
[0504] In some embodiments, solution osmolality is from about 100
mOsmol/kg to about 6000 mOsmol/kg. In some embodiments, solution
osmolality is from about 100 mOsmol/kg to about 5000 mOsmol/kg. In
some other embodiments, the solution osmolality is from about 400
mOsmol/kg to about 5000 mOsmol/kg.
[0505] In one embodiments, permeant ion concentration is from about
25 mM to about 400 mM. In various other embodiments, permeant ion
concentration is from about 30 mM to about 300 mM; from about 40 mM
to about 200 mM; and from about 50 mM to about 150 mM.
Solid Particle Formulations
[0506] In some embodiments, solid drug nanoparticles are provided
for use in generating dry aerosols or for generating nanoparticles
in liquid suspension. Powders comprising nanoparticulate drug can
be made by spray-drying aqueous dispersions of a nanoparticulate
drug and a surface modifier to form a dry powder which consists of
aggregated drug nanoparticles. In one embodiment, the aggregates
can have a size of about 1 to about 2 microns which is suitable for
deep lung delivery. The aggregate particle size can be increased to
target alternative delivery sites, such as the upper bronchial
region or nasal mucosa by increasing the concentration of drug in
the spray-dried dispersion or by increasing the droplet size
generated by the spray dryer.
[0507] Alternatively, an aqueous dispersion of drug and surface
modifier can contain a dissolved diluent such as lactose or
mannitol which, when spray dried, forms respirable diluent
particles, each of which contains at least one embedded drug
nanoparticle and surface modifier. The diluent particles with
embedded drug can have a particle size of about 1 to about 2
microns, suitable for deep lung delivery. In addition, the diluent
particle size can be increased to target alternate delivery sites,
such as the upper bronchial region or nasal mucosa by increasing
the concentration of dissolved diluent in the aqueous dispersion
prior to spray drying, or by increasing the droplet size generated
by the spray dryer.
[0508] Spray-dried powders can be used in DPIs or pMDIs, either
alone or combined with freeze-dried nanoparticulate powder. In
addition, spray-dried powders containing drug nanoparticles can be
reconstituted and used in either jet or ultrasonic nebulizers to
generate aqueous dispersions having respirable droplet sizes, where
each droplet contains at least one drug nanoparticle. Concentrated
nanoparticulate dispersions may also be used in these embodiments
of the invention.
[0509] Nanoparticulate drug dispersions can also be freeze-dried to
obtain powders suitable for nasal or pulmonary delivery. Such
powders may contain aggregated nanoparticulate drug particles
having a surface modifier. Such aggregates may have sizes within a
respirable range, e.g., about 1 to about 5 microns MMAD.
[0510] Freeze dried powders of the appropriate particle size can
also be obtained by freeze drying aqueous dispersions of drug and
surface modifier, which additionally contain a dissolved diluent
such as lactose or mannitol. In these instances the freeze dried
powders consist of respirable particles of diluent, each of which
contains at least one embedded drug nanoparticle.
[0511] Freeze-dried powders can be used in DPIs or pMDIs, either
alone or combined with spray-dried nanoparticulate powder. In
addition, freeze-dried powders containing drug nanoparticles can be
reconstituted and used in either jet or ultrasonic nebulizers to
generate aqueous dispersions that have respirable droplet sizes,
where each droplet contains at least one drug nanoparticle.
[0512] One embodiment of the invention is directed to a process and
composition for propellant-based systems comprising nanoparticulate
drug particles and a surface modifier. Such formulations may be
prepared by wet milling the coarse drug substance and surface
modifier in liquid propellant, either at ambient pressure or under
high pressure conditions. Alternatively, dry powders containing
drug nanoparticles may be prepared by spray-drying or freeze-drying
aqueous dispersions of drug nanoparticles and the resultant powders
dispersed into suitable propellants for use in conventional pMDIs.
Such nanoparticulate pMDI formulations can be used for either nasal
or pulmonary delivery. For pulmonary administration, such
formulations afford increased delivery to the deep lung regions
because of the small (e.g., about 1 to about 2 microns MMAD)
particle sizes available from these methods. Concentrated aerosol
formulations can also be employed in pMDIs.
[0513] Another embodiment is directed to dry powders which contain
nanoparticulate compositions for pulmonary or nasal delivery. The
powders may consist of respirable aggregates of nanoparticulate
drug particles, or of respirable particles of a diluent which
contains at least one embedded drug nanoparticle. Powders
containing nanoparticulate drug particles can be prepared from
aqueous dispersions of nanoparticles by removing the water via
spray-drying or lyophilization (freeze drying). Spray-drying is
less time consuming and less expensive than freeze-drying, and
therefore more cost-effective. However, certain drugs, such as
biologicals benefit from lyophilization rather than spray-drying in
making dry powder formulations.
[0514] Conventional micronized drug particles used in dry powder
aerosol delivery having particle diameters of from about 1 to about
5 microns MMAD are often difficult to meter and disperse in small
quantities because of the electrostatic cohesive forces inherent in
such powders. These difficulties can lead to loss of drug substance
to the delivery device as well as incomplete powder dispersion and
sub-optimal delivery to the lung. Many drug compounds, particularly
proteins and peptides, are intended for deep lung delivery and
systemic absorption. Since the average particle sizes of
conventionally prepared dry powders are usually in the range of
from about 1 to about 5 microns MMAD, the fraction of material
which actually reaches the alveolar region may be quite small.
Thus, delivery of micronized dry powders to the lung, especially
the alveolar region, is generally very inefficient because of the
properties of the powders themselves.
[0515] The dry powder aerosols which contain nanoparticulate drugs
can be made smaller than comparable micronized drug substance and,
therefore, are appropriate for efficient delivery to the deep lung.
Moreover, aggregates of nanoparticulate drugs are spherical in
geometry and have good flow properties, thereby aiding in dose
metering and deposition of the administered composition in the lung
or nasal cavities.
[0516] Dry nanoparticulate compositions can be used in both DPIs
and pMDIs. As used herein, "dry" refers to a composition having
less than about 5% water.
[0517] In one embodiment, compositions are provided containing
nanoparticles which have an effective average particle size of less
than about 1000 nm, more preferably less than about 400 nm, less
than about 300 nm, less than about 250 nm, or less than about 200
nm, as measured by light-scattering methods. By "an effective
average particle size of less than about 1000 nm" it is meant that
at least 50% of the drug particles have a weight average particle
size of less than about 1000 nm when measured by light scattering
techniques. Preferably, at least 70% of the drug particles have an
average particle size of less than about 1000 nm, more preferably
at least 90% of the drug particles have an average particle size of
less than about 1000 nm, and even more preferably at least about
95% of the particles have a weight average particle size of less
than about 1000 nm.
[0518] For aqueous aerosol formulations, the nanoparticulate
imatinib or salt thereof, or a phenylaminopyrimidine derivative or
salt thereof compound agent may be present at a concentration of
about 34 mcg/mL up to about 463 mg/mL. For dry powder aerosol
formulations, the nanoparticulate agent may be present at a
concentration of about 34 mg/g up to about 463 mg/g, depending on
the desired drug dosage. Concentrated nanoparticulate aerosols,
defined as containing a nanoparticulate drug at a concentration of
about 34 mcg/mL up to about 463 mg/mL for aqueous aerosol
formulations, and about 34 mg/g up to about 463 mg/g for dry powder
aerosol formulations, are specifically provided. Such formulations
provide effective delivery to appropriate areas of the lung or
nasal cavities in short administration times, i.e., less than about
3-15 seconds per dose as compared to administration times of up to
4 to 20 minutes as found in conventional pulmonary nebulizer
therapies.
[0519] For aqueous aerosol formulations, the nanoparticulate
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound agent may be present at a concentration of about 0.001
mg/mL up to about 200 mg/mL. For dry powder aerosol formulations,
the nanoparticulate agent may be present at a concentration of
about 0.001 mg/g up to about 200 mg/g, depending on the desired
drug dosage. Concentrated nanoparticulate aerosols, defined as
containing a nanoparticulate drug at a concentration of about 0.001
mg/mL up to about 200 mg/mL for aqueous aerosol formulations, and
about 0.001 mg/g up to about 200 mg/g for dry powder aerosol
formulations, are specifically provided. Such formulations provide
effective delivery to appropriate areas of the lung or nasal
cavities in short administration times, i.e., less than about 3-15
seconds per dose as compared to administration times of up to 4 to
20 minutes as found in conventional pulmonary nebulizer
therapies.
[0520] Nanoparticulate drug compositions for aerosol administration
can be made by, for example, (1) nebulizing a dispersion of a
nanoparticulate drug, obtained by either grinding or precipitation;
(2) aerosolizing a dry powder of aggregates of nanoparticulate drug
and surface modifier (the aerosolized composition may additionally
contain a diluent); or (3) aerosolizing a suspension of
nanoparticulate drug or drug aggregates in a non-aqueous
propellant. The aggregates of nanoparticulate drug and surface
modifier, which may additionally contain a diluent, can be made in
a non-pressurized or a pressurized non-aqueous system. Concentrated
aerosol formulations may also be made via such methods.
[0521] Milling of aqueous drug to obtain nanoparticulate drug may
be performed by dispersing drug particles in a liquid dispersion
medium and applying mechanical means in the presence of grinding
media to reduce the particle size of the drug to the desired
effective average particle size. The particles can be reduced in
size in the presence of one or more surface modifiers.
Alternatively, the particles can be contacted with one or more
surface modifiers after attrition. Other compounds, such as a
diluent, can be added to the drug/surface modifier composition
during the size reduction process. Dispersions can be manufactured
continuously or in a batch mode.
[0522] Another method of forming nanoparticle dispersion is by
microprecipitation. This is a method of preparing stable e presence
of one or more surface modifiers and one or more colloid stability
enhancing surface active agents free of any trace toxic solvents or
solubilized heavy metal impurities. Such a method comprises, for
example, (1) dissolving the drug in a suitable solvent with mixing;
(2) adding the formulation from step (1) with mixing to a solution
comprising at least one surface modifier to form a clear solution;
and (3) precipitating the formulation from step (2) with mixing
using an appropriate nonsolvent. The method can be followed by
removal of any formed salt, if present, by dialysis or
diafiltration and concentration of the dispersion by conventional
means. The resultant nanoparticulate drug dispersion can be
utilized in liquid nebulizers or processed to form a dry powder for
use in a DPI or pMDI.
[0523] In a non-aqueous, non-pressurized milling system, a
non-aqueous liquid having a vapor pressure of about 1 atm or less
at room temperature and in which the drug substance is essentially
insoluble may be used as a wet milling medium to make a
nanoparticulate drug composition. In such a process, a slurry of
drug and surface modifier may be milled in the non-aqueous medium
to generate nanoparticulate drug particles. Examples of suitable
non-aqueous media include ethanol, trichloromonofluoromethane,
(CFC-11), and dichlorotetrafluoroethane (CFC-114). An advantage of
using CFC-11 is that it can be handled at only marginally cool room
temperatures, whereas CFC-114 requires more controlled conditions
to avoid evaporation. Upon completion of milling the liquid medium
may be removed and recovered under vacuum or heating, resulting in
a dry nanoparticulate composition. The dry composition may then be
filled into a suitable container and charged with a final
propellant. Exemplary final product propellants, which ideally do
not contain chlorinated hydrocarbons, include HFA-134a
(tetrafluoroethane) and HFA-227 (heptafluoropropane). While
non-chlorinated propellants may be preferred for environmental
reasons, chlorinated propellants may also be used in this
embodiment of the invention.
[0524] In a non-aqueous, pressurized milling system, a non-aqueous
liquid medium having a vapor pressure significantly greater than 1
atm at room temperature may be used in the milling process to make
nanoparticulate drug compositions. If the milling medium is a
suitable halogenated hydrocarbon propellant, the resultant
dispersion may be filled directly into a suitable pMDI container.
Alternately, the milling medium can be removed and recovered under
vacuum or heating to yield a dry nanoparticulate composition. This
composition can then be filled into an appropriate container and
charged with a suitable propellant for use in a pMDI.
[0525] Spray drying is a process used to obtain a powder containing
nanoparticulate drug particles following particle size reduction of
the drug in a liquid medium. In general, spray-drying may be used
when the liquid medium has a vapor pressure of less than about 1
atm at room temperature. A spray-dryer is a device which allows for
liquid evaporation and drug powder collection. A liquid sample,
either a solution or suspension, is fed into a spray nozzle. The
nozzle generates droplets of the sample within a range of about 20
to about 100 micron in diameter which are then transported by a
carrier gas into a drying chamber. The carrier gas temperature is
typically from about 80 to about 200.degree. C. The droplets are
subjected to rapid liquid evaporation, leaving behind dry particles
which are collected in a special reservoir beneath a cyclone
apparatus. Smaller particles in the range down about 1 micron to
about 5 microns are also possible.
[0526] If the liquid sample consists of an aqueous dispersion of
nanoparticles and surface modifier, the collected product will
consist of spherical aggregates of the nanoparticulate drug
particles. If the liquid sample consists of an aqueous dispersion
of nanoparticles in which an inert diluent material was dissolved
(such as lactose or mannitol), the collected product will consist
of diluent (e.g., lactose or mannitol) particles which contain
embedded nanoparticulate drug particles. The final size of the
collected product can be controlled and depends on the
concentration of nanoparticulate drug and/or diluent in the liquid
sample, as well as the droplet size produced by the spray-dryer
nozzle. Collected products may be used in conventional DPIs for
pulmonary or nasal delivery, dispersed in propellants for use in
pMDIs, or the particles may be reconstituted in water for use in
nebulizers.
[0527] In some instances it may be desirable to add an inert
carrier to the spray-dried material to improve the metering
properties of the final product. This may especially be the case
when the spray dried powder is very small (less than about 5
micron) or when the intended dose is extremely small, whereby dose
metering becomes difficult. In general, such carrier particles
(also known as bulking agents) are too large to be delivered to the
lung and simply impact the mouth and throat and are swallowed. Such
carriers typically consist of sugars such as lactose, mannitol, or
trehalose. Other inert materials, including polysaccharides and
cellulosics, may also be useful as carriers.
[0528] Spray-dried powders containing nanoparticulate drug
particles may used in conventional DPIs, dispersed in propellants
for use in pMDIs, or reconstituted in a liquid medium for use with
nebulizers.
[0529] For compounds that are denatured or destabilized by heat,
such as compounds having a low melting point (i.e., about 70 to
about 150.degree. C.), or for example, biologics, sublimation is
preferred over evaporation to obtain a dry powder nanoparticulate
drug composition. This is because sublimation avoids the high
process temperatures associated with spray-drying. In addition,
sublimation, also known as freeze-drying or lyophilization, can
increase the shelf stability of drug compounds, particularly for
biological products. Freeze-dried particles can also be
reconstituted and used in nebulizers. Aggregates of freeze-dried
nanoparticulate drug particles can be blended with either dry
powder intermediates or used alone in DPIs and pMDIs for either
nasal or pulmonary delivery.
[0530] Sublimation involves freezing the product and subjecting the
sample to strong vacuum conditions. This allows for the formed ice
to be transformed directly from a solid state to a vapor state.
Such a process is highly efficient and, therefore, provides greater
yields than spray-drying. The resultant freeze-dried product
contains drug and modifier(s). The drug is typically present in an
aggregated state and can be used for inhalation alone (either
pulmonary or nasal), in conjunction with diluent materials
(lactose, mannitol, etc.), in DPIs or pMDIs, or reconstituted for
use in a nebulizer.
Liposomal Compositions
[0531] In some embodiments, imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compounds disclosed herein may be
formulated into liposome particles, which can then be aerosolized
for inhaled delivery. Lipids which are useful in the present
invention can be any of a variety of lipids including both neutral
lipids and charged lipids. Carrier systems having desirable
properties can be prepared using appropriate combinations of
lipids, targeting groups and circulation enhancers. Additionally,
the compositions provided herein can be in the form of liposomes or
lipid particles, preferably lipid particles. As used herein, the
term "lipid particle" refers to a lipid bilayer carrier which
"coats" a nucleic acid and has little or no aqueous interior. More
particularly, the term is used to describe a self-assembling lipid
bilayer carrier in which a portion of the interior layer comprises
cationic lipids which form ionic bonds or ion-pairs with negative
charges on the nucleic acid (e.g., a plasmid phosphodiester
backbone). The interior layer can also comprise neutral or
fusogenic lipids and, in some embodiments, negatively charged
lipids. The outer layer of the particle will typically comprise
mixtures of lipids oriented in a tail-to-tail fashion (as in
liposomes) with the hydrophobic tails of the interior layer. The
polar head groups present on the lipids of the outer layer will
form the external surface of the particle.
[0532] Liposomal bioactive agents can be designed to have a
sustained therapeutic effect or lower toxicity allowing less
frequent administration and an enhanced therapeutic index.
Liposomes are composed of bilayers that entrap the desired
pharmaceutical. These can be configured as multilamellar vesicles
of concentric bilayers with the pharmaceutical trapped within
either the lipid of the different layers or the aqueous space
between the layers.
[0533] By non-limiting example, lipids used in the compositions may
be synthetic, semi-synthetic or naturally-occurring lipids,
including phospholipids, tocopherols, steroids, fatty acids,
glycoproteins such as albumin, negatively-charged lipids and
cationic lipids. Phosholipids include egg phosphatidylcholine
(EPC), egg phosphatidylglycerol (EPG), egg phosphatidylinositol
(EPI), egg phosphatidylserine (EPS), phosphatidylethanolamine
(EPE), and egg phosphatidic acid (EPA); the soya counterparts, soy
phosphatidylcholine (SPC); SPG, SPS, SPI, SPE, and SPA; the
hydrogenated egg and soya counterparts (e.g., HEPC, HSPC), other
phospholipids made up of ester linkages of fatty acids in the 2 and
3 of glycerol positions containing chains of 12 to 26 carbon atoms
and different head groups in the 1 position of glycerol that
include choline, glycerol, inositol, serine, ethanolamine, as well
as the corresponding phosphatidic acids. The chains on these fatty
acids can be saturated or unsaturated, and the phospholipid can be
made up of fatty acids of different chain lengths and different
degrees of unsaturation. In particular, the compositions of the
formulations can include dipalmitoylphosphatidylcholine (DPPC), a
major constituent of naturally-occurring lung surfactant as well as
dioleoylphosphatidylcholine (DOPC) and dioleoylphosphatidylglycerol
(DOPG). Other examples include dimyristoylphosphatidycholine (DMPC)
and dimyristoylphosphatidylglycerol (DMPG)
dipalmitoylphosphatidcholine (DPPC) and
dipalmitoylphosphatidylglycerol (DPPG)
distearoylphosphatidylcholine (DSPC) and
distearoylphosphatidylglycerol (DSPG),
dioleylphosphatidylethanolamine (DOPE) and mixed phospholipids like
palmitoylstearoylphosphatidylcholine (PSPC) and
palmitoylstearoylphosphatidylglycerol (PSPG), and single acylated
phospholipids like mono-oleoyl-phosphatidylethanolamine (MOPE).
[0534] In a preferred embodiment, PEG-modified lipids are
incorporated into the compositions of the present invention as the
aggregation-preventing agent. The use of a PEG-modified lipid
positions bulky PEG groups on the surface of the liposome or lipid
carrier and prevents binding of DNA to the outside of the carrier
(thereby inhibiting cross-linking and aggregation of the lipid
carrier). The use of a PEG-ceramide is often preferred and has the
additional advantages of stabilizing membrane bilayers and
lengthening circulation lifetimes. Additionally, PEG-ceramides can
be prepared with different lipid tail lengths to control the
lifetime of the PEG-ceramide in the lipid bilayer. In this manner,
"programmable" release can be accomplished which results in the
control of lipid carrier fusion. For example, PEG-ceramides having
C20-acyl groups attached to the ceramide moiety will diffuse out of
a lipid bilayer carrier with a half-life of 22 hours. PEG-ceramides
having C14- and C8-acyl groups will diffuse out of the same carrier
with half-lives of 10 minutes and less than 1 minute, respectively.
As a result, selection of lipid tail length provides a composition
in which the bilayer becomes destabilized (and thus fusogenic) at a
known rate. Though less preferred, other PEG-lipids or
lipid-polyoxyethylene conjugates are useful in the present
compositions. Examples of suitable PEG-modified lipids include
PEG-modified phosphatidylethanolamine and phosphatidic acid,
PEG-modified diacylglycerols and dialkylglycerols, PEG-modified
dialkylamines and PEG-modified 1,2-diacyloxypropan-3-amines.
Particularly preferred are PEG-ceramide conjugates (e.g.,
PEG-Cer-C8, PEG-Cer-C14 or PEG-Cer-C20) which are described in U.S.
Pat. No. 5,820,873, incorporated herein by reference.
[0535] The compositions of the present invention can be prepared to
provide liposome compositions which are about 50 nm to about 400 nm
in diameter. One with skill in the art will understand that the
size of the compositions can be larger or smaller depending upon
the volume which is encapsulated. Thus, for larger volumes, the
size distribution will typically be from about 80 nm to about 300
nm.
Surface Modifiers
[0536] Imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt thereof
compounds disclosed herein may be prepared in a pharmaceutical
composition with suitable surface modifiers which may be selected
from known organic and inorganic pharmaceutical excipients. Such
excipients include low molecular weight oligomers, polymers,
surfactants and natural products. Preferred surface modifiers
include nonionic and ionic surfactants. Two or more surface
modifiers can be used in combination.
[0537] Representative examples of surface modifiers include cetyl
pyridinium chloride, gelatin, casein, lecithin (phosphatides),
dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic
acid, benzalkonium chloride, calcium stearate, glycerol
monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax,
sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol
ethers such as cetomacrogol 1000), polyoxyethylene castor oil
derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., the
commercially available Tweens.TM., such as e.g., Tween 20.TM., and
Tween 80.TM., (ICI Specialty Chemicals)); polyethylene glycols
(e.g., Carbowaxs 3350.TM., and 1450.TM., and Carbopol 934.TM.,
(Union Carbide)), dodecyl trimethyl ammonium bromide,
polyoxyethylenestearates, colloidal silicon dioxide, phosphates,
sodium dodecylsulfate, carboxymethylcellulose calcium,
hydroxypropyl cellulose (HPC, HPC-SL, and HPC-L), hydroxypropyl
methylcellulose (HPMC), carboxymethylcellulose sodium,
methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose,
magnesium aluminum silicate, triethanolamine, polyvinyl alcohol
(PVA), polyvinylpyrrolidone (PVP),
4-(1,1,3,3-tetaamethylbutyl)-phenol polymer with ethylene oxide and
formaldehyde (also known as tyloxapol, superione, and triton),
poloxamers (e.g., Pluronics F68.TM., and F108.TM., which are block
copolymers of ethylene oxide and propylene oxide); poloxamines
(e.g., Tetronic 908.TM., also known as Poloxamine 908.TM., which is
a tetrafunctional block copolymer derived from sequential addition
of propylene oxide and ethylene oxide to ethylenediamine (BASF
Wyandotte Corporation, Parsippany, N.J.)); a charged phospholipid
such as dimyristoyl phophatidyl glycerol, dioctylsulfosuccinate
(DOSS); Tetronic 1508.TM.; (T-1508) (BASF Wyandotte Corporation),
dialkylesters of sodium sulfosuccinic acid (e.g., Aerosol OT.TM.,
which is a dioctyl ester of sodium sulfosuccinic acid (American
Cyanamid)); Duponol P.TM., which is a sodium lauryl sulfate
(DuPont); Tritons X-200.TM., which is an alkyl aryl polyether
sulfonate (Rohm and Haas); Crodestas F-110.TM., which is a mixture
of sucrose stearate and sucrose distearate (Croda Inc.);
p-isononylphenoxypoly-(glycidol), also known as Olin-log.TM., or
Surfactant 10-G.TM., (Olin Chemicals, Stamford, Conn.); Crodestas
SL-40.TM., (Croda, Inc.); and SA9OHCO, which is C.sub.18 H.sub.37
CH.sub.2 (CON(CH.sub.3)--CH.sub.2 (CHOH).sub.4 (CH.sub.2 OH).sub.2
(Eastman Kodak Co.); decanoyl-N-methylglucamide; n-decyl
.beta.-D-glucopyranoside; n-decyl .beta.-D-maltopyranoside;
n-dodecyl .beta.-D-glucopyranoside; n-dodecyl .beta.-D-maltoside;
heptanoyl-N-methylglucamide; n-heptyl-.beta.-D-glucopyranoside;
n-heptyl .beta.-D-thioglucoside; n-hexyl .beta.-D-glucopyranoside;
nonanoyl-N-methylglucamide; n-noyl .beta.-D-glucopyranoside;
octanoyl-N-methylglucarmide; n-octyl-.beta.-D-glucopyranoside;
octyl .beta.-D-thioglucopyranoside; and the like. Tyloxapol is a
particularly preferred surface modifier for the pulmonary or
intranasal delivery of steroids, even more so for nebulization
therapies.
[0538] Examples of surfactants for use in the solutions disclosed
herein include, but are not limited to, ammonium laureth sulfate,
cetamine oxide, cetrimonium chloride, cetyl alcohol, cetyl
myristate, cetyl palmitate, cocamide DEA, cocamidopropyl betaine,
cocamidopropylamine oxide, cocamide MEA, DEA lauryl sulfate,
di-stearyl phthalic acid amide, dicetyl dimethyl ammonium chloride,
dipalmitoylethyl hydroxethylmonium, disodium laureth
sulfosuccinate, di(hydrogenated) tallow phthalic acid, glyceryl
dilaurate, glyceryl distearate, glyceryl oleate, glyceryl stearate,
isopropyl myristate nf, isopropyl palmitate nf, lauramide DEA,
lauramide MEA, lauramide oxide, myristamine oxide, octyl
isononanoate, octyl palmitate, octyldodecyl neopentanoate,
olealkonium chloride, PEG-2 stearate, PEG-32 glyceryl
caprylate/caprate, PEG-32 glyceryl stearate, PEG-4 and PEG-150
stearate & distearate, PEG-4 to PEG-150 laurate &
dilaurate, PEG-4 to PEG-150 oleate & dioleate, PEG-7 glyceryl
cocoate, PEG-8 beeswax, propylene glycol stearate, sodium C14-16
olefin sulfonate, sodium lauryl sulfoacetate, sodium lauryl
sulphate, sodium trideceth sulfate, stearalkonium chloride,
stearamide oxide, TEA-dodecylbenzene sulfonate, TEA lauryl
sulfate
[0539] Most of these surface modifiers are known pharmaceutical
excipients and are described in detail in the Handbook of
Pharmaceutical Excipients, published jointly by the American
Pharmaceutical Association and The Pharmaceutical Society of Great
Britain (The Pharmaceutical Press, 1986), specifically incorporated
by reference. The surface modifiers are commercially available
and/or can be prepared by techniques known in the art. The relative
amount of drug and surface modifier can vary widely and the optimal
amount of the surface modifier can depend upon, for example, the
particular drug and surface modifier selected, the critical micelle
concentration of the surface modifier if it forms micelles, the
hydrophilic-lipophilic-balance (HLB) of the surface modifier, the
melting point of the surface modifier, the water solubility of the
surface modifier and/or drug, the surface tension of water
solutions of the surface modifier, etc.
[0540] In the present invention, the optimal ratio of drug to
surface modifier is .about.0.1% to .about.99.9% imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound, more
preferably about 10% to about 90%.
Microspheres
[0541] Microspheres can be used for pulmonary delivery of imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof
compounds by first adding an appropriate amount of drug compound to
be solubilzed in water. For example, an aqueous imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound solution
may be dispersed in methylene chloride containing a predetermined
amount (0.1-1% w/v) of poly(DL-lactide-co-glycolide) (PLGA) by
probe sonication for 1-3 min on an ice bath. Separately, an
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound may be solubilized in methylene chloride containing PLGA
(0.1-1% w/v). The resulting water-in-oil primary emulsion or the
polymer/drug solution will be dispersed in an aqueous continuous
phase consisting of 1-2% polyvinyl alcohol (previously cooled to
4.degree. C.) by probe sonication for 3-5 min on an ice bath. The
resulting emulsion will be stirred continuously for 2-4 hours at
room temperature to evaporate methylene chloride. Microparticles
thus formed will be separated from the continuous phase by
centrifuging at 8000-10000 rpm for 5-10 min. Sedimented particles
will be washed thrice with distilled water and freeze dried.
Freeze-dried imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound microparticles will be stored at -20.degree.
C.
[0542] By non-limiting example, a spray drying approach will be
employed to prepare imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound microspheres. An
appropriate amount of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound will be solubilized in
methylene chloride containing PLGA (0.1-1%). This solution will be
spray dried to obtain the microspheres.
[0543] By non-limiting example, imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound microparticles will be
characterized for size distribution (requirement: 90%<5 .mu.m,
95%<10 .mu.m), shape, drug loading efficiency and drug release
using appropriate techniques and methods.
[0544] By non-limiting example, this approach may also be used to
sequester and improve the water solubility of solid, AUC
shape-enhancing formulations, such as low-solubility imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof compounds or
salt forms for nanoparticle-based formulations.
[0545] A certain amount of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound can be first dissolved in
the minimal quantity of ethanol 96% necessary to maintain the
fluoroquinolnoe in solution when diluted with water from 96 to 75%.
This solution can then be diluted with water to obtain a 75%
ethanol solution and then a certain amount of paracetamol can be
added to obtain the following w/w drug/polymer ratios: 1:2, 1:1,
2:1, 3:1, 4:1, 6:1, 9:1, and 19:1. These final solutions are
spray-dried under the following conditions: feed rate, 15 mL/min;
inlet temperature, 110.degree. C.; outlet temperature, 85.degree.
C.; pressure 4 bar and throughput of drying air, 35 m3/hr. Powder
is then collected and stored under vacuum in a dessiccator.
Solid Lipid Particles
[0546] Preparation of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound solid lipid particles may
involve dissolving the drug in a lipid melt (phospholipids such as
phophatidyl choline and phosphatidyl serine) maintained at least at
the melting temperature of the lipid, followed by dispersion of the
drug-containing melt in a hot aqueous surfactant solution
(typically 1-5% w/v) maintained at least at the melting temperature
of the lipid. The coarse dispersion will be homogenized for 1-10
min using a Microfluidizer.RTM. to obtain a nanoemulsion. Cooling
the nanoemulsion to a temperature between 4-25.degree. C. will
re-solidify the lipid, leading to formation of solid lipid
nanoparticles. Optimization of formulation parameters (type of
lipid matrix, surfactant concentration and production parameters)
will be performed so as to achieve a prolonged drug delivery. By
non-limiting example, this approach may also be used to sequester
and improve the water solubility of solid, AUC shape-enhancing
formulations, such as low-solubility imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compounds or salt forms for
nanoparticle-based formulations.
Melt-Extrusion AUC Shape-Enhancing Formulation
[0547] Melt-Extrusion AUC shape-enhancing imatinib or salt thereof,
a phenylaminopyrimidine derivative or salt thereof, or other
tyrosine kinase inhibitor or salt thereof compound formulations may
be preparation by dissolving the drugs in micelles by adding
surfactants or preparing micro-emulsion, forming inclusion
complexes with other molecules such as cyclodextrins, forming
nanoparticles of the drugs, or embedding the amorphous drugs in a
polymer matrix. Embedding the drug homogeneously in a polymer
matrix produces a solid dispersion. Solid dispersions can be
prepared in two ways: the solvent method and the hot melt method.
The solvent method uses an organic solvent wherein the drug and
appropriate polymer are dissolved and then (spray) dried. The major
drawbacks of this method are the use of organic solvents and the
batch mode production process. The hot melt method uses heat in
order to disperse or dissolve the drug in an appropriate polymer.
The melt-extrusion process is an optimized version of the hot melt
method. The advantage of the melt-extrusion approach is lack of
organic solvent and continuous production process. As the
melt-extrusion is a novel pharmaceutical technique, the literature
dealing with it is limited. The technical set-up involves a mixture
and extrusion of imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound, hydroxypropyl-b-cyclodextrin (HP-b-CD), and
hydroxypropylmethylcellulose (HPMC), in order to, by non-limiting
example create a AUC shape-enhancing formulation of imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof compound.
Cyclodextrin is a toroidal-shaped molecule with hydroxyl groups on
the outer surface and a cavity in the center. Cyclodextrin
sequesters the drug by forming an inclusion complex. The complex
formation between cyclodextrins and drugs has been investigated
extensively. It is known that water-soluble polymer interacts with
cyclodextrin and drug in the course of complex formation to form a
stabilized complex of drug and cyclodextrin co-complexed with the
polymer. This complex is more stable than the classic
cyclodextrin-drug complex. As one example, HPMC is water soluble;
hence using this polymer with HP-b-CD in the melt is expected to
create an aqueous soluble AUC shape-enhancing formulation. By
non-limiting example, this approach may also be used to sequester
and improve the water solubility of solid, AUC shape-enhancing
formulations, such as low-solubility imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compounds or salt forms for
nanoparticle-based formulations.
Co-Precipitates
[0548] Co-precipitate imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound formulations may be
prepared by formation of co-precipitates with pharmacologically
inert, polymeric materials. It has been demonstrated that the
formation of molecular solid dispersions or co-precipitates to
create an AUC shape-enhancing formulations with various
water-soluble polymers can significantly slow their in vitro
dissolution rates and/or in vivo absorption. In preparing powdered
products, grinding is generally used for reducing particle size,
since the dissolution rate is strongly affected by particle size.
Moreover, a strong force (such as grinding) may increase the
surface energy and cause distortion of the crystal lattice as well
as reducing particle size. Co-grinding drug with
hydroxypropylmethylcellulose, b-cyclodextrin, chitin and chitosan,
crystalline cellulose, and gelatin, may enhance the dissolution
properties such that AUC shape-enhancement is obtained for
otherwise readily bioavailable imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compounds. By non-limiting
example, this approach may also be used to sequester and improve
the water solubility of solid, AUC shape-enhancing formulations,
such as low-solubility imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compounds or salt forms for
nanoparticle-based formulations.
Dispersion-Enhancing Peptides
[0549] Compositions may include one or more di- or tripeptides
containing two or more leucine residues. By further non-limiting
example, U.S. Pat. No. 6,835,372 disclosing dispersion-enhancing
peptides, is hereby incorporated by reference in its entirety. This
patent describes the discovery that di-leucyl-containing dipeptides
(e.g., dileucine) and tripeptides are superior in their ability to
increase the dispersibility of powdered composition.
[0550] In another embodiment, highly dispersible particles
including an amino acid are administered. Hydrophobic amino acids
are preferred. Suitable amino acids include naturally occurring and
non-naturally occurring hydrophobic amino acids. Some naturally
occurring hydrophobic amino acids, including but not limited to,
non-naturally occurring amino acids include, for example,
beta-amino acids. Both D, L and racemic configurations of
hydrophobic amino acids can be employed. Suitable hydrophobic amino
acids can also include amino acid analogs. As used herein, an amino
acid analog includes the D or L configuration of an amino acid
having the following formula: --NH--CHR--CO--, wherein R is an
aliphatic group, a substituted aliphatic group, a benzyl group, a
substituted benzyl group, an aromatic group or a substituted
aromatic group and wherein R does not correspond to the side chain
of a naturally-occurring amino acid. As used herein, aliphatic
groups include straight chained, branched or cyclic C1-C8
hydrocarbons which are completely saturated, which contain one or
two heteroatoms such as nitrogen, oxygen or sulfur and/or which
contain one or more units of desaturation. Aromatic groups include
carbocyclic aromatic groups such as phenyl and naphthyl and
heterocyclic aromatic groups such as imidazolyl, indolyl, thienyl,
furanyl, pyridyl, pyranyl, oxazolyl, benzothienyl, benzofuranyl,
quinolinyl, isoquinolinyl and acridintyl.
[0551] Suitable substituents on an aliphatic, aromatic or benzyl
group include --OH, halogen (--Br, --Cl, --I and --F)--O(aliphatic,
substituted aliphatic, benzyl, substituted benzyl, aryl or
substituted aryl group), --CN, --NO.sub.2, --COOH, --NH.sub.2, --NH
(aliphatic group, substituted aliphatic, benzyl, substituted
benzyl, aryl or substituted aryl group), --N(aliphatic group,
substituted aliphatic, benzyl, substituted benzyl, aryl or
substituted aryl group).sub.2, --COO (aliphatic group, substituted
aliphatic, benzyl, substituted benzyl, aryl or substituted aryl
group), --CONH.sub.2, --CONH (aliphatic, substituted aliphatic
group, benzyl, substituted benzyl, aryl or substituted aryl
group)), --SH, --S (aliphatic, substituted aliphatic, benzyl,
substituted benzyl, aromatic or substituted aromatic group) and
--NH--C(.dbd.NH)--NH.sub.2. A substituted benzylic or aromatic
group can also have an aliphatic or substituted aliphatic group as
a substituent. A substituted aliphatic group can also have a
benzyl, substituted benzyl, aryl or substituted aryl group as a
substituent. A substituted aliphatic, substituted aromatic or
substituted benzyl group can have one or more substituents.
Modifying an amino acid substituent can increase, for example, the
lypophilicity or hydrophobicity of natural amino acids which are
hydrophilic.
[0552] A number of the suitable amino acids, amino acids analogs
and salts thereof can be obtained commercially. Others can be
synthesized by methods known in the art.
[0553] Hydrophobicity is generally defined with respect to the
partition of an amino acid between a nonpolar solvent and water.
Hydrophobic amino acids are those acids which show a preference for
the nonpolar solvent. Relative hydrophobicity of amino acids can be
expressed on a hydrophobicity scale on which glycine has the value
0.5. On such a scale, amino acids which have a preference for water
have values below 0.5 and those that have a preference for nonpolar
solvents have a value above 0.5. As used herein, the term
hydrophobic amino acid refers to an amino acid that, on the
hydrophobicity scale, has a value greater or equal to 0.5, in other
words, has a tendency to partition in the nonpolar acid which is at
least equal to that of glycine.
[0554] Examples of amino acids which can be employed include, but
are not limited to: glycine, proline, alanine, cysteine,
methionine, valine, leucine, tyosine, isoleucine, phenylalanine,
tryptophan. Preferred hydrophobic amino acids include leucine,
isoleucine, alanine, valine, phenylalanine and glycine.
Combinations of hydrophobic amino acids can also be employed.
Furthermore, combinations of hydrophobic and hydrophilic
(preferentially partitioning in water) amino acids, where the
overall combination is hydrophobic, can also be employed.
[0555] The amino acid can be present in the particles of the
invention in an amount of at least 10 weight %. Preferably, the
amino acid can be present in the particles in an amount ranging
from about 20 to about 80 weight %. The salt of a hydrophobic amino
acid can be present in the particles of the invention in an amount
of at least 10 weight percent. Preferably, the amino acid salt is
present in the particles in an amount ranging from about 20 to
about 80 weight %. In preferred embodiments the particles have a
tap density of less than about 0.4 g/cm3.
[0556] Methods of forming and delivering particles which include an
amino acid are described in U.S. Pat. No. 6,586,008, entitled Use
of Simple Amino Acids to Form Porous Particles During Spray Drying,
the teachings of which are incorporated herein by reference in
their entirety.
Proteins/Amino Acids
[0557] Protein excipients may include albumins such as human serum
albumin (HSA), recombinant human albumin (rHA), gelatin, casein,
hemoglobin, and the like. Suitable amino acids (outside of the
dileucyl-peptides of the invention), which may also function in a
buffering capacity, include alanine, glycine, arginine, betaine,
histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine,
isoleucine, valine, methionine, phenylalanine, aspartame, tyrosine,
tryptophan, and the like. Preferred are amino acids and
polypeptides that function as dispersing agents. Amino acids
falling into this category include hydrophobic amino acids such as
leucine, valine, isoleucine, tryptophan, alanine, methionine,
phenylalanine, tyrosine, histidine, and proline.
Dispersibility-enhancing peptide excipients include dimers,
trimers, tetramers, and pentamers comprising one or more
hydrophobic amino acid components such as those described
above.
Carbohydrates
[0558] By non-limiting example, carbohydrate excipients may include
monosaccharides such as fructose, maltose, galactose, glucose,
D-mannose, sorbose, and the like; disaccharides, such as lactose,
sucrose, trehalose, cellobiose, and the like; polysaccharides, such
as raffinose, melezitose, maltodextrins, dextrans, starches, and
the like; and alditols, such as mannitol, xylitol, maltitol,
lactitol, xylitol sorbitol (glucitol), pyranosyl sorbitol,
myoinositol, isomalt, trehalose and the like.
Polymers
[0559] By non-limiting example, compositions may also include
polymeric excipients/additives, e.g., polyvinylpyrrolidones,
derivatized celluloses such as hydroxymethylcellulose,
hydroxyethylcellulose, and hydroxypropylmethylcellulose, Ficolls (a
polymeric sugar), hydroxyethylstarch, dextrates (by non-limiting
example cyclodextrins may include,
2-hydroxypropyl-beta-cyclodextrin,
2-hydroxypropyl-gamma-cyclodextrin, randomly methylated
beta-cyclodextrin, dimethyl-alpha-cyclodextrin,
dimethyl-beta-cyclodextrin, maltosyl-alpha-cyclodextrin,
glucosyl-1-alpha-cyclodextrin, glucosyl-2-alpha-cyclodextrin,
alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, and
sulfobutylether-beta-cyclodextrin), polyethylene glycols, and
pectin may also be used.
[0560] Highly dispersible particles administered comprise a
bioactive agent and a biocompatible, and preferably biodegradable
polymer, copolymer, or blend. The polymers may be tailored to
optimize different characteristics of the particle including: i)
interactions between the agent to be delivered and the polymer to
provide stabilization of the agent and retention of activity upon
delivery; ii) rate of polymer degradation and, thereby, rate of
drug release profiles; iii) surface characteristics and targeting
capabilities via chemical modification; and iv) particle
porosity.
[0561] Surface eroding polymers such as polyanhydrides may be used
to form the particles. For example, polyanhydrides such as
poly[(p-carboxyphenoxy)hexane anhydride] (PCPH) may be used.
Biodegradable polyanhydrides are described in U.S. Pat. No.
4,857,311. Bulk eroding polymers such as those based on polyesters
including poly(hydroxy acids) also can be used. For example,
polyglycolic acid (PGA), polylactic acid (PLA), or copolymers
thereof may be used to form the particles. The polyester may also
have a charged or functionalizable group, such as an amino acid. In
a preferred embodiment, particles with controlled release
properties can be formed of poly(D,L-lactic acid) and/or
poly(DL-lactic-co-glycolic acid) ("PLGA") which incorporate a
surfactant such as dipalmitoyl phosphatidylcholine (DPPC).
[0562] Other polymers include polyamides, polycarbonates,
polyalkylenes such as polyethylene, polypropylene, poly(ethylene
glycol), poly(ethylene oxide), poly(ethylene terephthalate), poly
vinyl compounds such as polyvinyl alcohols, polyvinyl ethers, and
polyvinyl esters, polymers of acrylic and methacrylic acids,
celluloses and other polysaccharides, and peptides or proteins, or
copolymers or blends thereof. Polymers may be selected with or
modified to have the appropriate stability and degradation rates in
vivo for different controlled drug delivery applications.
[0563] Highly dispersible particles can be formed from
functionalized polyester graft copolymers, as described in Hrkach
et al., Macromolecules, 28: 4736-4739 (1995); and Hrkach et al.,
"Poly(L-Lactic acid-co-amino acid) Graft Copolymers: A Class of
Functional Biodegradable Biomaterials" in Hydrogels and
Biodegradable Polymers for Bioapplications, ACS Symposium Series
No. 627, Raphael M, Ottenbrite et al., Eds., American Chemical
Society, Chapter 8, pp. 93-101, 1996.
[0564] In a preferred embodiment of the invention, highly
dispersible particles including a bioactive agent and a
phospholipid are administered. Examples of suitable phospholipids
include, among others, phosphatidylcholines,
phosphatidylethanolamines, phosphatidylglycerols,
phosphatidylserines, phosphatidylinositols and combinations
thereof. Specific examples of phospholipids include but are not
limited to phosphatidylcholines dipalmitoyl phosphatidylcholine
(DPPC), dipalmitoyl phosphatidylethanolamine (DPPE), distearoyl
phosphatidyicholine (DSPC), dipalmitoyl phosphatidyl glycerol
(DPPG) or any combination thereof. Other phospholipids are known to
those skilled in the art. In a preferred embodiment, the
phospholipids are endogenous to the lung.
[0565] The phospholipid, can be present in the particles in an
amount ranging from about 0 to about 90 weight %. More commonly it
can be present in the particles in an amount ranging from about 10
to about 60 weight %.
[0566] In another embodiment of the invention, the phospholipids or
combinations thereof are selected to impart controlled release
properties to the highly dispersible particles. The phase
transition temperature of a specific phospholipid can be below,
about or above the physiological body temperature of a patient.
Preferred phase transition temperatures range from 30 degrees C. to
50 degrees C. (e.g., within +/-10 degrees of the normal body
temperature of patient). By selecting phospholipids or combinations
of phospholipids according to their phase transition temperature,
the particles can be tailored to have controlled release
properties. For example, by administering particles which include a
phospholipid or combination of phospholipids which have a phase
transition temperature higher than the patient's body temperature,
the release of dopamine precursor, agonist or any combination of
precursors and/or agonists can be slowed down. On the other hand,
rapid release can be obtained by including in the particles
phospholipids having lower transition temperatures.
Taste Masking, Flavor, Other
[0567] As also described above, imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound formulations disclosed
herein and related compositions, may further include one or more
taste-masking agents such as flavoring agents, inorganic salts
(e.g., sodium chloride), sweeteners, antioxidants, antistatic
agents, surfactants (e.g., polysorbates such as "TWEEN 20" and
"TWEEN 80"), sorbitan esters, saccharin (e.g., sodium saccharin or
other saccharin forms, which as noted elsewhere herein may be
present in certain embodiments at specific concentrations or at
specific molar ratios relative to a phenylaminopyrimidine
derivative compound such as imatinib), bicarbonate, cyclodextrins,
lipids (e.g., phospholipids such as lecithin and other
phosphatidylcholines, phosphatidylethanolamines), fatty acids and
fatty esters, steroids (e.g., cholesterol), and chelating agents
(e.g., EDTA, zinc and other such suitable cations). Other
pharmaceutical excipients and/or additives suitable for use in the
compositions according to the invention are listed in "Remington:
The Science & Practice of Pharmacy", 19.sup.th ed., Williams
& Williams, (1995), and in the "Physician's Desk Reference",
52.sup.nd ed., Medical Economics, Montvale, N.J. (1998).
[0568] By way of non-limiting example, taste-masking agents in
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound formulations, may include the use of flavorings,
sweeteners, and other various coating strategies, for instance,
sugars such as sucrose, dextrose, and lactose, carboxylic acids,
menthol, amino acids or amino acid derivatives such as arginine,
lysine, and monosodium glutamate, and/or synthetic flavor oils and
flavoring aromatics and/or natural oils, extracts from plants,
leaves, flowers, fruits, etc. and combinations thereof. These may
include cinnamon oils, oil of wintergreen, peppermint oils, clover
oil, bay oil, anise oil, eucalyptus, vanilla, citrus oil such as
lemon oil, orange oil, grape and grapefruit oil, fruit essences
including apple, peach, pear, strawberry, raspberry, cherry, plum,
pineapple, apricot, etc. Additional sweeteners include sucrose,
dextrose, aspartame (Nutrasweet.RTM.), acesulfame-K, sucralose and
saccharin (e.g., sodium saccharin or other saccharin forms, which
as noted elsewhere herein may be present in certain embodiments at
specific concentrations or at specific molar ratios relative to a
phenylaminopyrimidine derivative compound such as imatinib),
organic acids (by non-limiting example citric acid and aspartic
acid). Such flavors may be present at from about 0.05 to about 4
percent by weight, and may be present at lower or higher amounts as
a factor of one or more of potency of the effect on flavor,
solubility of the flavorant, effects of the flavorant on solubility
or other physicochemical or pharmacokinetic properties of other
formulation components, or other factors.
[0569] Another approach to improve or mask the unpleasant taste of
an inhaled drug may be to decrease the drug's solubility, e.g.,
drugs must dissolve to interact with taste receptors. Hence, to
deliver solid forms of the drug may avoid the taste response and
result in the desired improved taste affect. Non-limiting methods
to decrease solubility of an imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound solubility are described
herein, for example, through the use in formulation of particular
salt forms of phenylaminopyrimidine derivative compound, such as
complexation with xinafoic acid, oleic acid, stearic acid and/or
pamoic acid. Additional co-precipitating agents include
dihydropyridines and a polymer such as polyvinyl pyrrolidone.
[0570] Moreover, taste-masking may be accomplished by creation of
lipopilic vesicles. Additional coating or capping agents include
dextrates (by non-limiting example cyclodextrins may include,
2-hydroxypropyl-beta-cyclodextrin,
2-hydroxypropyl-gamma-cyclodextrin, randomly methylated
beta-cyclodextrin, dimethyl-alpha-cyclodextrin,
dimethyl-beta-cyclodextrin, maltosyl-alpha-cyclodextrin,
glucosyl-1-alpha-cyclodextrin, glucosyl-2-alpha-cyclodextrin,
alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, and
sulfobutylether-beta-cyclodextrin), modified celluloses such as
ethyl cellulose, methyl cellulose, hydroxypropyl cellulose,
hydroxyl propyl methyl cellulose, polyalkylene glycols,
polyalkylene oxides, sugars and sugar alcohols, waxes, shellacs,
acrylics and mixtures thereof. By non-limiting example, other
methods to deliver non-dissolved forms of an imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound according
to certain embodiments or, in other embodiments, non-dissolved
forms of an imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compound, are to administer the drug alone or in a
simple, non-solubility affecting formulation, such as a crystalline
micronized, dry powder, spray-dried, and/or nanosuspension
formulation.
[0571] An alternative according to certain other preferred
embodiments is to include taste-modifying agents in the imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof compound
formulation. These embodiments contemplate including in the
formulation a taste-masking substance that is mixed with, coated
onto or otherwise combined with the active medicament imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor or salt thereof compound or salt
thereof. Inclusion of one or more such agents in these formulations
may also serve to improve the taste of additional pharmacologically
active compounds that are included in the formulations in addition
to the imatinib or salt thereof, a phenylaminopyrimidine derivative
or salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound, e.g., a mucolytic agent. Non-limiting examples of such
taste-modifying substances include acid phospholipids,
lysophospholipid, tocopherol polyethyleneglycol succinate, and
embonic acid (pamoate). Many of these agents can be used alone or
in combination with imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound (or a salt thereof) or,
in separate embodiments, imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound for aerosol
administration.
Mucolytic Agents
[0572] Methods to produce formulations that combine agents to
reduce sputum viscosity during aerosol treatment with an imatinib
or salt thereof, a phenylaminopyrimidine derivative or salt
thereof, or other tyrosine kinase inhibitor or salt thereof
compound include the following. These agents can be prepared in
fixed combination or be administered in succession with aerosol
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound therapy.
[0573] The most commonly prescribed agent is N-acetylcysteine
(NAC), which depolymerizes mucus in vitro by breaking disulphide
bridges between macromolecules. It is assumed that such reduction
of sputum tenacity facilitates its removal from the respiratory
tract. In addition, NAC may act as an oxygen radical scavenger. NAC
can be taken either orally or by inhalation. Differences between
these two methods of administration have not been formally studied.
After oral administration, NAC is reduced to cysteine, a precursor
of the antioxidant glutathione, in the liver and intestine. The
antioxidant properties could be useful in preventing decline of
lung function in cystic fibrosis (CF), or pulmonary fibrotic
diseases (e.g., idiopathic pulmonmary fibrosis). Nebulized NAC is
commonly prescribed to patients with CF, in particular in
continental Europe, in order to improve expectoration of sputum by
reducing its tenacity. The ultimate goal of this is to slow down
the decline of lung function in CF.
[0574] L-lysine-N-acetylcysteinate (ACC) or Nacystelyn (NAL) is a
novel mucoactive agent possessing mucolytic, antioxidant, and
anti-inflammatory properties. Chemically, it is a salt of ACC. This
drug appears to present an activity superior to its parent molecule
ACC because of a synergistic mucolytic activity of L-lysine and
ACC. Furthermore, its almost neutral pH (6.2) allows its
administration in the lungs with a very low incidence of
bronchospasm, which is not the case for the acidic ACC (pH 2.2).
NAL is difficult to formulate in an inhaled form because the
required lung dose is very high (approximately 2 mg) and the
micronized drug is sticky and cohesive and it is thus problematic
to produce a redispersable formulation. NAL was first developed as
a chlorofluorocarbon (CFC) containing metered-dose inhaler (MDI)
because this form was the easiest and the fastest to develop to
begin the preclinical and the first clinical studies. NAL MDI
delivered 2 mg per puff, from which approximately 10% was able to
reach the lungs in healthy volunteers. One major inconvenience of
this formulation was patient compliance because as many as 12 puffs
were necessary to obtain the required dose. Furthermore, the
progressive removal of CFC gases from medicinal products combined
with the problems of coordination met in a large proportion of the
patient population (12) have led to the development of a new
galenical form of NAL. A dry powder inhaler (DPI) formulation was
chosen to resolve the problems of compliance with MDIs and to
combine it with an optimal, reproducible, and comfortable way to
administer the drug to the widest possible patient population,
including young children.
[0575] The DPI formulation of NAL involved the use of a
nonconventional lactose (usually reserved for direct compression of
tablets), namely, a roller-dried (RD) anhydrous .beta.-lactose.
When tested in vitro with a monodose DPI device, this powder
formulation produces a fine particle fraction (FPF) of at least 30%
of the nominal dose, namely three times higher than that with MDIs.
This approach may be used in combination with an imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound for either
co-administration or fixed combination therapy.
[0576] In addition to mucolytic activity, excessive neutrophil
elastase activity within airways of cystic fibrosis (CF) patients
results in progressive lung damage. Disruption of disulfide bonds
on elastase by reducing agents may modify its enzymatic activity.
Three naturally occurring dithiol reducing systems were examined
for their effects on elastase activity: 1) Escherichia coli
thioredoxin (Trx) system, 2) recombinant human thioredoxin (rhTrx)
system, and 3) dihydrolipoic acid (DHLA). The Trx systems consisted
of Trx, Trx reductase, and NADPH. As shown by spectrophotometric
assay of elastase activity, the two Trx systems and DHLA inhibited
purified human neutrophil elastase as well as the elastolytic
activity present in the soluble phase (sol) of CF sputum. Removal
of any of the three Trx system constituents prevented inhibition.
Compared with the monothiols N-acetylcysteine and reduced
glutathione, the dithiols displayed greater elastase inhibition. To
streamline Trx as an investigational tool, a stable reduced form of
rhTrx was synthesized and used as a single component. Reduced rhTrx
inhibited purified elastase and CF sputum sol elastase without
NADPH or Trx reductase. Because Trx and DHLA have mucolytic
effects, we investigated changes in elastase activity after
mucolytic treatment. Unprocessed CF sputum was directly treated
with reduced rhTrx, the Trx system, DHLA, or DNase. The Trx system
and DHLA did not increase elastase activity, whereas reduced rhTrx
treatment increased sol elastase activity by 60%. By contrast, the
elastase activity after DNase treatment increased by 190%. The
ability of Trx and DHLA to limit elastase activity combined with
their mucolytic effects makes these compounds potential therapies
for CF.
[0577] In addition, bundles of F-actin and DNA present in the
sputum of cystic fibrosis (CF) patients but absent from normal
airway fluid contribute to the altered viscoelastic properties of
sputum that inhibit clearance of infected airway fluid and
exacerbate the pathology of CF. One approach to alter these adverse
properties is to remove these filamentous aggregates using DNase to
enzymatically depolymerize DNA to constituent monomers and gelsolin
to sever F-actin to small fragments. The high densities of negative
surface charge on DNA and F-actin suggest that the bundles of these
filaments, which alone exhibit a strong electrostatic repulsion,
may be stabilized by multivalent cations such as histones,
antimicrobial peptides, and other positively charged molecules
prevalent in airway fluid. Furthermore, as a matter-a-fact, it has
been observed that bundles of DNA or F-actin formed after addition
of histone H1 or lysozyme are efficiently dissolved by soluble
multivalent anions such as polymeric aspartate or glutamate.
Addition of poly-aspartate or poly-glutamate also disperses DNA and
actin-containing bundles in CF sputum and lowers the elastic moduli
of these samples to levels comparable to those obtained after
treatment with DNase I or gelsolin. Addition of poly-aspartic acid
also increased DNase activity when added to samples containing DNA
bundles formed with histone H1. When added to CF sputum,
poly-aspartic acid significantly reduced the growth of bacteria,
suggesting activation of endogenous antibacterial factors. These
findings suggest that soluble multivalent anions have potential
alone or in combination with other mucolytic agents to selectively
dissociate the large bundles of charged biopolymers that form in CF
sputum.
[0578] Hence, NAC, unfractionated heparin, reduced glutathione,
dithiols, Trx, DHLA, other monothiols, DNAse, dornase alfa,
hypertonic formulations (e.g., osmolalities greater than about 350
mOsmol/kg), multivalent anions such as polymeric aspartate or
glutamate, glycosidases and other examples listed above can be
combined with imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor or
salt thereof compounds and other mucolytic agents for aerosol
administration to improve antifibrotic and/or antiinflammatory
activity through better distribution from reduced sputum viscosity,
and improved clinical outcome through improved pulmonary function
(from improved sputum mobility and mucociliary clearance) and
decreased lung tissue damage from the immune inflammatory
response.
Characterization of Inhalation Devices
[0579] The efficiency of a particular inhalation device can be
measured by many different ways, including an analysis of
pharmacokinetic properties, measurement of lung deposition
percentage, measurement of respirable delivery dose (RDD), a
determination of output rates, geometric standard deviation values
(GSD), and mass median aerodynamic diameter values (MMAD) among
others.
[0580] Methods and systems for examining a particular inhalation
device are known. One such system consists of a computer means and
a hollow cylinder in a pump means with a connecting piece to which
an inhalation device is to be connected. In the pump means there is
a piston rod, which extends out of the hollow cylinder. A linear
drive unit can be activated in such a manner that one or more
breathing pattern will be simulated on the connecting piece of the
pump means. In order to be able to carry out the evaluation of the
inhalation device, the computer is connected in an advantageous
configuration with a data transmission means. With the aid of the
data transmission means, the computer can be connected with another
computer with specific data banks, in order to exchange the data of
breathing patterns. In this manner, a breathing pattern library
which is as representative as possible can be very rapidly formed.
U.S. Pat. No. 6,106,479 discloses this method for examining an
inhalation device in more detail, and is hereby incorporated by
reference in its entirety.
Pharmacokinetic Profile
[0581] Pharmacokinetics is concerned with the uptake, distribution,
metabolism and excretion of a drug substance. A pharmacokinetic
profile comprises one or more biological measurements designed to
measure the absorption, distribution, metabolism and excretion of a
drug substance. One way of visualizing a pharmacokinetic profile is
by means of a blood plasma concentration curve, which is a graph
depicting mean active ingredient blood plasma concentration on the
Y-axis and time (usually in hours) on the X-axis. Some
pharmacokinetic parameters that may be visualized by means of a
blood plasma concentration curve include: [0582] Cmax: The maximum
plasma concentration in a patient. [0583] AUC: area under the curve
[0584] TOE: time of exposure [0585] T1/2: period of time it takes
for the amount in a patient of drug to decrease by half [0586]
T.sub.max: The time to reach maximum plasma concentration in a
patient
[0587] Pharmacokinetics (PK) is concerned with the time course of a
therapeutic agent, such as imatinib, or a phenylaminopyrimidine
derivative compound concentration in the body. Pharmacodynamics
(PD) is concerned with the relationship between pharmacokinetics
and efficacy in vivo. PK/PD parameters correlate the therapeutic
agent, such as exposure with efficacious activity. Accordingly, to
predict the therapeutic efficacy of a therapeutic agent, such as
with diverse mechanisms of action different PK/PD parameters may be
used.
[0588] Any standard pharmacokinetic protocol can be used to
determine blood plasma concentration profile in humans following
administration of a formulation comprising imatinib or a
phenylaminopyrimidine derivative compound described herein, and
thereby establish whether that formulation meets the
pharmacokinetic criteria set out herein. For example, but in no way
limiting, a type of a randomized single-dose crossover study can be
utilized using a group of healthy adult human subjects. The number
of subjects can be sufficient to provide adequate control of
variation in a statistical analysis, and is typically about 8 or
greater, although in certain embodiments a smaller group can be
used. In one embodiment, a subject receives administration, at time
zero, a single dose of a test inhalation mixture comprising
imatinib or a phenylaminopyrimidine derivative compound. Blood
samples are collected from each subject prior to administration and
at several intervals after administration. Plasma can be separated
from the blood samples by centrifugation and the separated plasma
is analyzed, for example, by a validated high performance liquid
chromatography/tandem weight spectrometry (LC/APCI-MS/MS) procedure
such as, for example, those described in Ramu et al., Journal of
Chromatography B, 751:49-59 (2001). In other embodiments, data from
a single subject may be collected and may be used to construct a pK
profile and may be indicative of an enhanced pharmacokinetic
profile. In still other embodiments, appropriate in vitro models
may be used to construct a pK profile and may be demonstrate or
indicate an enhanced pharmacokinetic profile.
[0589] In some embodiments, a human pK profile can be may be
obtained by the use of allometric scaling. In one embodiment, rat
aerosol lung data and plasma delivery is scaled to provide an
indication of possible humans data. In one embodiment, allometric
scaling uses parameters established in the US FDA Guidance for
Industry--Estimating the Maximum Safe Starting Dose in Initial
Clinical Trials for Therapeutics in Adult Healthy Volunteers.
[0590] Any aqueous inhalable mixture giving the desired
pharmacokinetic profile may be suitable for administration
according to the present methods.
[0591] As used herein, the "peak period" of a pharmaceutical's in
vivo concentration is defined as that time of the pharmaceutical
dosing interval when the pharmaceutical concentration is not less
than 50% of its maximum plasma or site-of-disease concentration. In
some embodiments, "peak period" is used to describe an interval of
imatinib or a phenylaminopyrimidine derivative compound dosing.
[0592] In some embodiments, when considering treatment of lung
diseases, a method or system described herein provides at least a
two-fold enhancement in pharmacokinetic profile for treatment of
the lung disease. In some embodiments, the methods and systems
described herein provide at least a two-fold enhancement in the
lung tissue pharmacokinetic profile of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound as compared to oral
administration.
[0593] In some embodiments, the amount of imatinib or salt thereof,
a phenylaminopyrimidine derivative or salt thereof, or other
tyrosine kinase inhibitor or salt thereof compound that is
administered to a human by inhalation may be calculated by
measuring the amount of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound and associated
metabolites that are found in the urine. In some embodiments, about
80% of administered imatinib is excreted in the urine. In some
embodiments, the calculation based on compound and metabolites in
urine may be done through a 48 urine collection (following a single
administration), whereby the total amount of imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compound delivered
to the human is the sum of measured imatinib and its metabolites.
By non-limiting example, knowing that 80% of imatinib is excreted,
a 50 mg sum urinary measurement of imatinib and its metabolites
would translate to a delivered dose of about 63 mg (50 mg divided
by 80%). If by non-limiting example, the inhaled aerosol
fine-particle fraction (FPF) is 75%, one may assume that about 75%
of the drug deposited in the lung (and about 25% was swallowed, and
subsequently absorbed from the gut with 80% excreted in the urine).
Integrating these two calculations, of a 63 mg delivered dose (as
measured by urinary excretion), about 47 mg would be the amount of
inhaled aerosol imatinib delivered to the lung (the actual RDD;
calculated as the product of 63 mg and a 75% FPF). This RDD can
then be used in a variety of calculations, including lung tissue
concentration.
[0594] In some embodiments, method or systems described herein
provide pharmacokinetic profiles of imatinib or
phenylaminopyrimidine derivative compounds as described herein. In
some embodiments, method or systems described herein provide
pharmacokinetic profiles of imatinib or phenylaminopyrimidine
derivative compounds as in Examples 6 and 7.
[0595] In some embodiments, efficacy of imatinib or
phenylaminopyrimidine derivative compounds in the treatment of
pulmonary fibrosis is achieved through repeated administration to a
human by inhalation. In some embodiments, administration of
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compounds to a human by inhalation provides higher Cmax levels as
compared to oral delivery. In some embodiments, solutions of
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compounds that are administered by inhalation provide higher Cmax
levels as compared to oral delivery. In some embodiments, the peak
period is used to define the optimal dosing schedule of the
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor or salt thereof
compound. In some embodiments, solutions of imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor or salt thereof compounds are
administered more than once a week.
[0596] Small intratracheal aerosol doses deliver a
rapidly-eliminated high lung Cmax and low AUC. Human, animal and in
vitro studies all indicate that imatinib efficacy is dose
responsive (i.e. larger doses correlate with improved efficacy) and
suggest Cmax is a key driver in imatinib efficacy. While lung Cmax
appears important for efficacy, more regular imatinib exposure also
appears important to enhance this effect. In some embodiments, in
the context of treating lung diseases in a human, more frequent
direct-lung administration of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor or salt thereof compound may provide benefit
through both repeat high Cmax dosing and providing more regular
exposure of the active therapeutic agent.
[0597] In some embodiments, described herein is a method for the
treatment of lung disease in a mammal comprising administering
directly to the lungs of the mammal in need thereof imatinib or
salt thereof, or a phenylaminopyrimidine derivative compound or
salt thereof, on a continuous dosing schedule, wherein the observed
lung tissue Cmax of a dose of imatinib a phenylaminopyrimidine
derivative, or other tyrosine kinase inhibitor compound is greater
than 0.1 mcg/gram lung tissue. In some embodiments, the observed
lung tissue Cmax from a dose of imatinib or salt thereof, or a
phenylaminopyrimidine derivative compound or salt thereof, is
greater than 0.5 mcg/gram lung tissue. In some embodiments, the
observed lung tissue Cmax from a dose of imatinib or salt thereof,
or a phenylaminopyrimidine derivative compound or salt thereof, is
greater than 1.0 mcg/gram lung tissue. In some embodiments, the
observed lung tissue Cmax from a dose of imatinib or salt thereof,
or a phenylaminopyrimidine derivative compound or salt thereof, is
greater than 5 mcg/gram lung tissue. In some embodiments, the
observed lung tissue Cmax from a dose of imatinib or salt thereof,
or a phenylaminopyrimidine derivative compound or salt thereof, is
greater than 10 mcg/gram lung tissue. In some embodiments, the
observed lung tissue Cmax from a dose of imatinib or salt thereof,
or a phenylaminopyrimidine derivative compound or salt thereof, is
greater than 15 mcg/gram lung tissue. In some embodiments, the
observed lung tissue Cmax from a dose of imatinib or salt thereof,
or a phenylaminopyrimidine derivative compound or salt thereof, is
greater than 20 mcg/gram lung tissue. In some embodiments, the
observed lung tissue Cmax from a dose of imatinib or salt thereof,
or a phenylaminopyrimidine derivative compound or salt thereof, is
greater than 25 mcg/gram lung tissue. In some embodiments, the
observed lung tissue Cmax from a dose of imatinib or salt thereof,
or a phenylaminopyrimidine derivative compound or salt thereof, is
greater than 30 mcg/gram lung tissue. In some embodiments, the
observed lung tissue Cmax from a dose of imatinib or salt thereof,
or a phenylaminopyrimidine derivative compound or salt thereof, is
greater than 35 mcg/gram lung tissue. In some embodiments, the
observed lung tissue Cmax from a dose of imatinib or salt thereof,
or a phenylaminopyrimidine derivative compound or salt thereof, is
greater than 40 mcg/gram lung tissue. In some embodiments, the
observed lung tissue Cmax from a dose of imatinib or salt thereof,
or a phenylaminopyrimidine derivative compound or salt thereof, is
greater than 45 mcg/gram lung tissue. In some embodiments, the
observed lung tissue Cmax from a dose of imatinib or salt thereof,
or a phenylaminopyrimidine derivative compound or salt thereof, is
greater than 50 mcg/gram lung tissue. In some embodiments, the dose
comprises an aqueous solution of imatinib or salt thereof, or a
phenylaminopyrimidine derivative compound or salt thereof. In some
embodiments, the dose is administered with a liquid nebulizer.
[0598] In some embodiments, described herein is a method for the
treatment of lung disease in a mammal comprising administering
directly to the lungs of the mammal in need thereof imatinib or
salt thereof, or a phenylaminopyrimidine derivative compound or
salt thereof, on a continuous dosing schedule, wherein the observed
lung tissue Cmax of a dose of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor compound or salt thereof, is greater than 0.001
mcg/gram lung tissue. In some embodiments, the observed lung tissue
Cmax from a dose of imatinib or salt thereof, or a
phenylaminopyrimidine derivative compound or salt thereof, is
greater than 0.005 mcg/gram lung tissue. In some embodiments, the
observed lung tissue Cmax from a dose of imatinib or salt thereof,
a phenylaminopyrimidine derivative or salt thereof, or other
tyrosine kinase inhibitor compound or salt thereof, is greater than
0.01 mcg/gram lung tissue. In some embodiments, the observed lung
tissue Cmax from a dose of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor compound or salt thereof, is greater than 0.05
mcg/gram lung tissue. In some embodiments, the observed lung tissue
Cmax from a dose of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor compound or salt thereof, is greater than 0.1
mcg/gram lung tissue. In some embodiments, the observed lung tissue
Cmax from a dose of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor compound or salt thereof, is greater than 0.5
mcg/gram lung tissue. In some embodiments, the observed lung tissue
Cmax from a dose of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor compound or salt thereof, is greater than 1.0
mcg/gram lung tissue. In some embodiments, the observed lung tissue
Cmax from a dose of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor compound or salt thereof, is greater than 5
mcg/gram lung tissue. In some embodiments, the observed lung tissue
Cmax from a dose of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor compound or salt thereof, is greater than 10
mcg/gram lung tissue. In some embodiments, the observed lung tissue
Cmax from a dose of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor compound or salt thereof, is greater than 15
mcg/gram lung tissue. In some embodiments, the observed lung tissue
Cmax from a dose of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor compound or salt thereof, is greater than 20
mcg/gram lung tissue. In some embodiments, the observed lung tissue
Cmax from a dose of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor compound or salt thereof, is greater than 25
mcg/gram lung tissue. In some embodiments, the observed lung tissue
Cmax from a dose of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor compound or salt thereof, is greater than 30
mcg/gram lung tissue. In some embodiments, the dose comprises an
aqueous solution of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor compound or salt thereof. In some embodiments, the
observed lung tissue Cmax from a dose of imatinib or salt thereof,
a phenylaminopyrimidine derivative or salt thereof, or other
tyrosine kinase inhibitor compound or salt thereof, is greater than
40 mcg/gram lung tissue. In some embodiments, the dose comprises an
aqueous solution of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor compound or salt thereof. In some embodiments, the
observed lung tissue Cmax from a dose of imatinib or salt thereof,
a phenylaminopyrimidine derivative or salt thereof, or other
tyrosine kinase inhibitor compound or salt thereof, is greater than
50 mcg/gram lung tissue. In some embodiments, the dose comprises an
aqueous solution of imatinib or salt thereof, a
phenylaminopyrimidine derivative compound or salt thereof, or other
tyrosine kinase inhibitor or salt thereof. In some embodiments, the
dose is administered with a liquid nebulizer. In some embodiments,
the dose is administered as a dry powder dispersion. In some
embodiments, the dose is administered with a meter dosed
inhaler.
Methods of Dosing and Treatment Regimens
[0599] In one aspect, imatinib or salt thereof, or a
phenylaminopyrimidine derivative compound or salt thereof, is
administered daily to humans in need of therapy with imatinib or a
phenylaminopyrimidine derivative compound. In some embodiments,
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor compound or salt
thereof, is administered by inhalation to the human. In some
embodiments, the imatinib or salt thereof, or a
phenylaminopyrimidine derivative compound or salt thereof, is
administered more than once a week. In some embodiments, the
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor compound or salt
thereof, is administered on a continuous daily dosing schedule. In
some embodiments, the single doses of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor compound or salt thereof, is administered more
than once a week, more than twice a week, more than three times a
week, more than four times a week, more than five times a week more
than six times a week or daily. In some embodiments, imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor compound or salt thereof, is
administered once-a-day. In some embodiments, imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor compound or salt thereof, is
administered twice-a-day. In some embodiments, imatinib or salt
thereof, phenylaminopyrimidine derivative or salt thereof, or other
tyrosine kinase inhibitor compound or salt thereof, is administered
three times-a-day. In some embodiments, imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor compound or salt thereof, is administered four
times-a-day. In some embodiments, imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor compound or salt thereof, is administered five
times-a-day. In some embodiments, imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor compound or salt thereof, is administered six
times-a-day. In some embodiments, imatinib or salt thereof,
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor compound or salt thereof, is administered every
other day. In some embodiments, imatinib or salt thereof,
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor compound or salt thereof, is administered twice a
week.
[0600] In some embodiments, doses of imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor compound or salt thereof, employed for treatment
of the diseases or conditions described herein in humans are
typically in the range of from about 0.001 mg to about 10 mg
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor compound or salt
thereof/kg of body weigh per dose. In some embodiments, doses of
imatinib or salt thereof, a phenylaminopyrimidine derivative or
salt thereof, or other tyrosine kinase inhibitor compound or salt
thereof, employed for treatment of the diseases or conditions
described herein in humans are typically in the range of from about
0.00001 mg to about 3.3 mg imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor compound or salt thereof/kg of body weigh per
dose. In one embodiment, the desired dose is conveniently presented
in a single dose or in divided doses administered simultaneously
(or over a short period of time) or at appropriate intervals, for
example as two, three, four or more sub-doses per day. In some
embodiments, imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor
compound or salt thereof, is conveniently presented in divided
doses that are administered simultaneously (or over a short period
of time) once a day. In some embodiments, imatinib or salt thereof,
a phenylaminopyrimidine derivative or salt thereof, or other
tyrosine kinase inhibitor compound or salt thereof, is conveniently
presented in divided doses that are administered in equal portions
twice-a-day.
[0601] In some embodiments, imatinib or salt thereof, a
phenylaminopyrimidine derivative or salt thereof, or other tyrosine
kinase inhibitor compound or salt thereof, is administered by
inhalation daily to the human. In some embodiments, imatinib or
salt thereof, a phenylaminopyrimidine derivative or salt thereof,
or other tyrosine kinase inhibitor compound or salt thereof, is
administered orally to the human at a dose from about 0.001 mg to
about 10 mg imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor
compound or salt thereof per kg of body weigh per dose. In some
embodiments, imatinib or salt thereof, a phenylaminopyrimidine
derivative or salt thereof, or other tyrosine kinase inhibitor
compound or salt thereof, is administered orally to the human at a
dose from about 0.00001 mg to about 3.3 mg imatinib or salt
thereof, a phenylaminopyrimidine derivative or salt thereof, or
other tyrosine kinase inhibitor compound or salt thereof per kg of
body weigh per dose. In some embodiments, imatinib or salt thereof,
a phenylaminopyrimidine derivative or salt thereof, or other
tyrosine kinase inhibitor compound or salt thereof, is administered
by inhalation to the human on a continuous daily dosing
schedule.
[0602] The term "continuous dosing schedule" refers to the
administration of a particular therapeutic agent at regular
intervals. In some embodiments, continuous dosing schedule refers
to the administration of a particular therapeutic agent at regular
intervals without any drug holidays from the particular therapeutic
agent. In some other embodiments, continuous dosing schedule refers
to the administration of a particular therapeutic agent in
alternating cycles of drug administration followed by a drug
holiday (e.g. wash out period) from the particular therapeutic
agent. For example, in some embodiments the therapeutic agent is
administered once a day, twice a day, three times a day, once a
week, twice a week, three times a week, four times a week, five
times a week, six times a week, seven times a week, every other
day, every third day, every fourth day, daily for a week followed
by a week of no administration of the therapeutic agent, daily for
a two weeks followed by one or two weeks of no administration of
the therapeutic agent, daily for three weeks followed by one, two
or three weeks of no administration of the therapeutic agent, daily
for four weeks followed by one, two, three or four weeks of no
administration of the therapeutic agent, weekly administration of
the therapeutic agent followed by a week of no administration of
the therapeutic agent, or biweekly administration of the
therapeutic agent followed by two weeks of no administration of the
therapeutic agent.
[0603] The term "continuous daily dosing schedule" refers to the
administration of a particular therapeutic agent everyday at
roughly the same time each day.
[0604] In some embodiments, the amount of imatinib or a
phenylaminopyrimidine derivative compound is administered
once-a-day. In some other embodiments, the amount of imatinib or a
phenylaminopyrimidine derivative compound is administered
twice-a-day. In some other embodiments, the amount of imatinib or a
phenylaminopyrimidine derivative compound is administered three
times a day.
[0605] In certain embodiments wherein improvement in the status of
the disease or condition in the human is not observed, the daily
dose of imatinib or a phenylaminopyrimidine derivative compound is
increased. In some embodiments, a once-a-day dosing schedule is
changed to a twice-a-day dosing schedule. In some embodiments, a
three times a day dosing schedule is employed to increase the
amount of imatinib or a phenylaminopyrimidine derivative compound
that is administered. In some embodiments, the frequency of
administration by inhalation is increased in order to provide
repeat high Cmax levels on a more regular basis. In some
embodiments, the frequency of administration by inhalation is
increased in order to provide maintained or more regular exposure
to imatinib. In some embodiments, the frequency of administration
by inhalation is increased in order to provide repeat high Cmax
levels on a more regular basis and provide maintained or more
regular exposure to imatinib.
[0606] In some embodiments, the amount of repeat high Cmax dosing
providing more regular exposure of the active therapeutic agent
that is given to the human varies depending upon factors such as,
but not limited to, condition and severity of the disease or
condition, and the identity (e.g., weight) of the human, and the
particular additional therapeutic agents that are administered (if
applicable). The various embodiments described above can be
combined to provide further embodiments. All of the U.S. patents,
U.S. patent application publications, U.S. patent applications,
foreign patents, foreign patent applications and non-patent
publications referred to in this specification are incorporated
herein by reference, in their entirety. Aspects of the embodiments
can be modified, if necessary to employ concepts of the various
patents, applications and publications to provide yet further
embodiments. These and other changes can be made to the embodiments
in light of the above-detailed description. In general, in the
following claims, the terms used should not be construed to limit
the claims to the specific embodiments disclosed in the
specification and the claims, but should be construed to include
all possible embodiments along with the full scope of equivalents
to which such claims are entitled. Accordingly, the claims are not
limited by the disclosure.
EXAMPLES
Example 1. Compound Screening Platform
[0607] Rat and human derived pulmonary tissue are cut in pieces and
placed on a polystyrene petri dish containing
antibiotics/antimycotics and LG DMEM 10% FBS 1% P/S media. Cells
are expanded in LG DMEM 10% FBS 1% P/S media until an appropriate
number of cells are available. All experiments will be performed
before passage 10. Expanded rat and human pulmonary fibroblasts are
trypsinized and plated in 6-well plates containing a coverslip,
attachment factor and media followed by overnight incubation. After
incubation, media is changed to 1% FBS LG DMEM. Fibroblast to
myofibroblast differentiation and or proliferation is induced with
2.5 to 10 ng/mL active tumor growth factor beta 1 (TGF-beta1). The
kinetics of differentiated myofibroblast appearance is measured by
assessing incubated cells at 12, 24, 36, 48 and 72 hours
post-TGF-beta1 induction. Each cell condition is performed in
triplicate. At each time point, cells are fixed using
paraformaldehyde and stained for F-actin, DAPI, and alpha-SMA (for
myofibroblast formation). Proliferation is quantified
microscopically. This method may employ difference cell lines such
as pulmonary aerterial smooth muscle cells and/or may be induced by
other cytokines, such as platelet-derived growth factor (PDGF).
After processing cells for immunohistochemistry, cells will be
imaged using an Olympus 1X-81 fluorescent microscope and analyzed
using Metamorph Premier software.
[0608] To assess a drug's effect on fibroblast proliferation,
differentiation and/or collagen production, potential therapeutics
may be added at the same time, prior to or after addition of
TGF.beta., PDGF or other inducing cytokine. Non-limiting examples
of potential therapeutic agents include all those listed herein.
Moreover, addition of potential therapeutic may be done to mimic a
drugs in vivo pharmacokinetic profile. By example, an
orally-administered drug for a pulmonary indication would have a
characteristic vascular and pulmonary absorption phase, Cmax, Tmax,
AUC and elimination half-life. By comparison, an inhaled drug may
exhibit pharmacokinetic characteristics that differ from the oral
route. By example, inhalation may deliver a higher lung Cmax, more
rapid lung Tmax, higher lung AUC, be rapidly eliminated from the
lung and/or may result in less residual drug. By non-limiting
example, to employ the assay described herein, an oral drug under
consideration for inhaled aerosol delivery may be exposed to
fibroblasts or other cell type in the presence of TGF-beta (or
other cytokine) using that drug's real or estimated oral
pharmacokinetic profile. Seperately or in parallel, in a separate
set of wells expose the same cell type in the presence of TGF-beta
(or other cytokine) using that drugs real or estimated inhaled
pharmacokinetic profile. This may be accomplished by time-course
dilution or addition of the potential therapeutic. Moreover, this
assay may be used to mimic repetitive TGF-beta or other cytokine
exposure and/or therapeutic regimen (by example once a day, twice a
day or three times a day) to assess the effect this may have on the
drugs anti-proliferative, anti-differentiation, anti-collagen
production and/or other measurable endpoint. By non-limiting
example, markers of fibroblast activation, proliferation and/or
myofibroblast differentiation and collagen production may include
alpha-SMA, SMAD, GAPDH, HSP47, pro-collagen, markers of endoplasmic
reticulum un-folded protein response (UPR, e.g., GRP78) and many
others. Detection of these components may be by Western and
Northern blot analysis, microscopy, phosphorylation signaling, gene
and protein array technology, and metagenomic analysis.
[0609] In addition to identifying individual drugs that interfere
with fibroblast proliferation, differentiation and myofibroblast
collage production, this assay may also be employed to assess the
effect of drug combinations. Further, through these drugs having
different targets, this and variations of this assay may be used to
dissect the role of different targets in fibrosis formation and the
fibrotic disease, stroma formation and/or stroma-associated
metastatic processes.
Example 2. PDGF-Induced Fibroblast Proliferation
[0610] The impact of imatinib, sorafinib and vargatef on inhibiting
PDGF-induced fibroblast proliferation was determined in primary
human fibroblasts. Briefly, fibroblasts were seeded at 2,500
cells/well in 96-well flat clear bottom Falcon plates in 10% FBS
F12/DMEM Media with 1% Pen/Strep. These cells were left in a 37
degree incubator (5% CO.sub.2) for 24 hours to allow the cells to
adhere to the plate. The media was then removed, washed with PBS
and replaced the media with 0.5% FBS F12/DMEM Media with 1%
Pen/Strep for another 24 hours. To characterize the impact exposure
duration of each drug on inhibiting proliferation, cells were
pretreated with or without drug (0.5 to 50 nM) for 30 minutes,
washed and either replaced with 0.5% FBS F12/DMEM media with 1%
Pen/Strep +/-20 ng/mL PDGF-BB (short-duration drug exposure
mimicking pulmonary inhalation pharmacokinetics) or 0.5% FBS
F12/DMEM media with 1% Pen/Strep +/-20 ng/mL PDGF-BB and the
initial drug concentration (long duration drug exposure mimicking
oral pharmacokinetics). After 72 hours of viable cells was assessed
using the MTS assay. Drug concentrations tested were not cytotoxic
(data not shown).
TABLE-US-00009 TABLE 1 Impact of imatinib and exposure duration on
PDGF-induced fibroblast differentiation Imatinib Exposure Imatinib
Short Duration Long Duration nM Proliferation* SEM Proliferation*
SEM 0 0.457 0.103 0.457 0.102 0.5 0.422 0.119 0.486 0.119 5.0 0.330
0.167 0.406 0.143 50.0 0.197 0.277 0.322 0.185 *Relative
proliferation
[0611] Results from Table 1 show that imatinib is dose-responsive
in inhibiting PDGF-induced fibroblast proliferation. The data also
show that only short-term imatinib exposure is required for this
activity with a fifty-percent inhibitory concentration (IC50) of
greater than about 50 nM.
TABLE-US-00010 TABLE 2 Impact of sorafinib and exposure duration on
PDGF-induced fibroblast differentiation Sorafinib Exposure
Sorafinib Short Duration Long Duration nM Proliferation* SEM
Proliferation* SEM 0 0.292 0.112 0.292 0.115 0.5 0.117 0.223 0.313
0.096 5.0 -0.010 0.447 0.175 0.226 50.0 -0.147 0.315 0.130 0.222
*Relative proliferation
[0612] Results from Table 2 show that sorafinib is dose-responsive
in inhibiting PDGF-induced fibroblast proliferation. The data also
show that only short-term sorafinib exposure is required for this
activity with a fifty-percent inhibitory concentration (IC50) of
about 30 nM.
TABLE-US-00011 TABLE 3 Impact of vargatef and exposure duration on
PDGF-induced fibroblast differentiation Vargatef Exposure Vargatef
Short Duration Long Duration nM Proliferation* SEM Proliferation*
SEM 0 0.160 0.080 0.160 0.065 0.5 0.115 0.070 0.003 0.095 5.0 0.011
0.185 -0.359 0.120 50.0 -0.175 0.047 -0.642 0.068 *Relative
proliferation
[0613] Results from Table 3 show that vargatef is dose-responsive
in inhibiting PDGF-induced fibroblast proliferation. The data also
show that only short-term vargatef exposure is required for this
activity with a fifty-percent inhibitory concentration (IC50) of
about 3 nM.
Example 3. Salt Screen Study of Imatinib
[0614] Crystallization experiments were carried out in a 96-well
quartz microtiter plate to identify suitable salt forms of imatinib
for use in any of the embodiments described herein. In this
experiment stoichiometric volumes of stock solutions of imatinib
(free drug) in ethanol (EtOH), dioxane, methanol (MeOH), or
tetrahydrofuran (THF) and of the selected salt formers in various
solvents (including water) were mixed and subsequently evaporated
under N2 flow for 2.5 days using the flow-channel system described
in the PCT publication WO 03/026797 A2. Both Raman spectra (with
five accumulations per spectrum) and optical microscopy images were
recorded for two or more positions in each well when feasible.
Table 4 lists the salt formers, the solvents used for stock
solution formation, the behavior of the solutions upon mixing, the
appearance of the solid residues after evaporation, and the results
of Raman spectroscopy for the evaporation experiments on a
well-by-well basis. The Raman spectra were evaluated by comparing
them with the spectra of the corresponding salt formers, the
relevant solvents, and the crystalline starting material (imatinib
free base).
TABLE-US-00012 TABLE 4 Summary of the Salt-Screen results from
evaporation experiments Visual Solvent appearance (for Solvent
Observation of residue imatinib (for salt upon mixing (after Salt
free base) former) the reagents evaporation) L-aspartate EtOH
H.sub.2O C liquid (ASP) dioxane H.sub.2O C amorphous MeOH H.sub.2O
C thin film THF H.sub.2O C amorphous citrate EtOH EtOH C droplets
(CIT) dioxane dioxane C thin film MeOH MeOH C amorphous THF
H.sub.2O C amorphous edetate EtOH H.sub.2O S partially (EDTA)
crystalline. dioxane H.sub.2O S partially crystalline MeOH H.sub.2O
S amorphous THF H.sub.2O S amorphous fumarate EtOH EtOH C mixed
morph. (FUM) dioxane dioxane C mixed morph. MeOH MeOH C amorphous
THF H.sub.2O C amorphous hydro- EtOH H.sub.2O C thin film bromide
dioxane H.sub.2O C droplets (HBr) MeOH H.sub.2O C mixed morph. THF
H.sub.2O Y mixed morph hydro- EtOH H.sub.2O C amorphous chloride
dioxane H.sub.2O C droplets (HCl) MeOH H.sub.2O C mixed morph. THF
H.sub.2O Y mixed morph. D-lactate EtOH EtOH C amorphous (DLA)
dioxane dioxane C liquid MeOH MeOH C amorphous THF H.sub.2O C
amorphous phosphate EtOH H.sub.2O C amorphous (PO4) dioxane
H.sub.2O P droplets MeOH H.sub.2O C mixed morph. THF H.sub.2O C
mixed morph. propionate EtOH EtOH C amorphous (PRT) dioxane dioxane
C amorphous MeOH MeOH C amorphous THF H.sub.2O C amorphous
saccharinate EtOH EtOH C amorphous (SAC) dioxane dioxane C
amorphous MeOH MeOH C amorphous THF H.sub.2O C amorphous sulfate
EtOH H.sub.2O Y mixed morph. (SO4) dioxane H.sub.2O Y fine needles
MeOH H.sub.2O Y mixed morph. THF H.sub.2O Y mixed morph. L-tartrate
EtOH EtOH C droplets (LTA) dioxane dioxane C mixed morph. MeOH MeOH
C amorphous THF H.sub.2O C amorphous C = solution remained
colorless and macroscopically clear, Y = solution became yellow, P
=precipitation occurred (solution became cloudy), or S = one of the
reagents was a suspension and remained so upon mixing.
[0615] Suspension equilibration experiments were performed using
the solid residues obtained upon completion of the evaporation
experiments. One hundred microliters of water (H2O), isopropyl
alcohol (2PrOH), toluene, or ethyl acetate (EtOAc) was added to
appropriate wells. The plate was shaken at 300 rpm for 72 hours
with the temperature being cycled between 25.degree. C. and
35.degree. C. The solvents were subsequently evaporated under dry
N2 flow for .about.2.5 days, and the plate was examined by Raman
spectroscopy (with five accumulations per spectrum) and optical
microscopy. The results of the suspension equilibration experiments
are presented in Table 5, using the abbreviations defined
above.
TABLE-US-00013 TABLE 5 Summary of the results from suspension
equilibration experiments Salt Solvent Residue (after evaporation)
L-aspartate H.sub.2O liquid/amorphous (ASP) 2PrOH amorphous toluene
thin needles EtOAc mixed morphologies citrate H.sub.2O amorphous
(CIT) 2PrOH droplets toluene amorphous EtOAc mixed morphologies
edetate H.sub.2O amorphous (EDTA) 2PrOH mixed morphologies toluene
mixed morphologies EtOAc amorphous film fumarate H.sub.2O amorphous
(FUM) 2PrOH amorphous toluene mixed morphologies EtOAc crystalline
rods hydrobromide H.sub.2O mixed morphologies (HBr) 2PrOH amorphous
toluene mixed (incl. needles) EtOAc mixed morphologies
hydrochloride H.sub.2O amorphous (HCl) 2PrOH amorphous toluene
mixed (incl. needles) EtOAc mixed morphologies D-lactate H.sub.2O
amorphous (DLA) 2PrOH amorphous toluene mixed morphologies EtOAc
amorphous phosphate H.sub.2O amorphous (PO4) 2PrOH droplets toluene
mixed (incl. needles) EtOAc mixed morphologies propionate H.sub.2O
amorphous (PRT) 2PrOH mixed morphologies toluene crystalline EtOAc
crystalline saccharinate H.sub.2O amorphous (SAC) 2PrOH amorphous
droplets toluene amorphous droplets EtOAc amorphous droplets Salt
Solvent Residue (after evaporation) sulfate H.sub.2O amorphous film
(SO4) 2PrOH mixed morphologies toluene amorphous EtOAc mixed
morphologies L-tartrate H.sub.2O amorphous (LTA) 2PrOH amorphous
toluene crystalline EtOAc amorphous
[0616] A quick-screen search for possible salts of imatinib free
base was carried out with a total of eight solvent mixtures (four
for evaporation and four for suspension equilibration) and twelve
salt formers. A 1:1 ratio of the free drug to the salt former was
used in all cases, and the solvents were subsequently evaporated.
Upon completion of the Raman measurements of the products of the
evaporation experiments, the solid residues were suspended in four
solvents and temperature cycled between 25 and 35.degree. C. for
three days. The solvents were subsequently evaporated, and the
solid residues were re-examined.
[0617] The results of the evaporation experiments are in Table 4
for convenience. The results of the suspension equilibration
experiments are presented in Table 5.
[0618] Although many of the products of the suspension
equilibration experiments were crystalline, the Raman spectra
revealed that the crystals often corresponded to the free base
starting material. Only one new lead, a fumarate salt, was obtained
from the suspension equilibration experiments although the
hydrochloride, hydrobromide, and phosphoric acid leads found in the
evaporation experiments were again observed in the suspension
equilibration experiments. The L-aspartate lead was no longer
observed, but one well showed a Raman spectrum similar to that
obtained from hydrochloric acid and hydrobromic acid, suggesting
that this might be a polymorph as well.
Example 4. Salt Scale Up and Characterization
[0619] Based upon initial screen observations the following
imatinib salts were selected for scale up and characterization.
[0620] Powder X-ray Diffraction, Bruker D8 (G.16.SYS.S013):
[0621] Reflection geometry, Bragg-Brentano; Copper K.sub..alpha.
radiation, 40 kV/40 mA; variable divergence slit; LynxEye detector
with 3.degree. window; step size, 0.02.degree. 2.theta.; step time,
37 s. The samples were rotated (0.5 rps) during the
measurement.
[0622] Sample preparation: The samples were generally prepared
without any special treatment other than the application of slight
pressure to get a flat surface. Silicon single crystal sample
holder types: a) standard holder for polymorph screening, 0.1 mm
deep, less than 20 mg sample required; b) 0.5 mm deep, 12 mm cavity
diameter, ca. 40 mg required; c) 1.0 mm deep, 12 mm cavity
diameter, ca. 80 mg required. Normally samples were measured
uncovered. Kapton foil or PMMA "dom" covers are always indicated on
the diffractogram with the sample identification.
[0623] Short
[0624] Diffractometer Bruker D8, Instrument Nr. G.16.SYS.S013
[0625] Data evaluation software: EVA version 14.0.0.0 (Nur
zutreffend wenn im Rontgenlabor mit legacy Software
ausgedruckt/ausgewertet)
[0626] Stoe Diffractometer
[0627] Stoe STADI P with MYTHEN1K detector, Instrument Nr.:
G.52.SYS.S072, transmission geometry, curved Ge-monochromator, Cu
K.alpha..sub.1 radiation
[0628] Instrument Software: WinXPOW Version 3.0.1.13 GMP
[0629] Sample Preparation
[0630] Samples are generally prepared without any pretreatment
under a stereo microscope. To improve the random orientation of the
particles, the samples are sometimes gently ground before
preparation.
[0631] For identification tests the samples (2-20 mg) are
sandwiched between two cellulose acetate films and fixed into a
Stoe holder with an 8 mm mask. If quantitative information is
required then the samples are filled into a 12 mm (inner diameter)
distance washer with a glued on bottom acetate film. Silicon grease
can be used to fix the top film. Finally a slight pressure might be
applied with a glass slide to get a flat surface.
[0632] The pre-treatment if any, the thickness of the washers, the
possible use of other film covers or the safety containment cell
(SCell) are reported and become part of the electronic raw
data.
[0633] The use of washers 0.4 or 0.8 mm requiring c. 40/80 mg
material allows improving detection limits and reproducibility but
leads to some loss of peak resolution and .degree. (2.theta.)
accuracy.
[0634] Standard Testing Parameters
[0635] Standard preparation: without washer, between acetate films;
for HiPo samples: 0.4 mm washer in SCell
[0636] Radiation: Cu K.alpha..sub.1 with 40 kV, 40 mA
[0637] Collimator: 0.5.times.10 mm
[0638] Sample rotation: 1 rps
[0639] Scan range: at least 1.5-40.degree. (2.theta.)
[0640] Detector Distance: resulting to 0.01.degree. (2.theta.)
intrinsic resolution
[0641] Detector Step: 1.degree. (2.theta.)
[0642] Time per step: 12 seconds resulting in a total measuring
time of c. 15 min
[0643] Binning: 2 channels=1 data point every 0.02.degree.
(2.theta.)
[0644] Imatinib Fumarate
[0645] Suspended 1:1.1 (imatinib free base)/(salt former) in 1:1
dioxane/H.sub.2O and temperature cycled between 25-35.degree. C.
for 2 days with sonication after 1 day. A crystalline solid
formed.
[0646] The XRPD of imatinib fumarate is presented in FIG. 2.
Representative peaks include those in the following Table:
TABLE-US-00014 TABLE 6 Representative peaks for Imatinib Fumarate
Angle 2-Theta .degree. Intensity % 8.05 64 11.91 25.1 16.04 32.7
16.27 24 17.38 26.7 19.98 34.1 20.88 26.3 23.78 81.7 24.51 100
25.84 28.9 26.73 51.9 28.92 41.3
[0647] Imatinib Hydrochloride
[0648] Suspended 1:1.1 (imatinib free base)/(salt former) in 1:1
EtOH/2PrOH, sonicated, and then temperature cycled between
25-35.degree. C. for 2 days. Continued to temperature cycle between
25-35.degree. C. for 2 days; recovered solid by filter
centrifugation.
[0649] The XRPD of imatinib hydrochloride is presented in FIG. 3.
Representative peaks include those in the following Table:
TABLE-US-00015 TABLE 7 Representative peaks for Imatinib
Hydrochloride Angle 2-Theta .degree. Intensity % 6.68 100 9.78 17
13.28 17 16.46 22.6 16.94 22.3 19.93 86.7 22.35 62.1 22.58 19.3
23.24 29.8 23.50 80.6 26.42 34.9 29.66 18.6
[0650] Imatinib Phosphate--Pattern 1
[0651] Evaporated 1:1 (imatinib free base)/(salt former) from
.about.5:2 MeOH/H.sub.2O. A mostly crystalline solid was obtained
and examined. The XRPD of imatinib phosphate is presented in FIG.
4. Representative peaks include those in the following Table:
TABLE-US-00016 TABLE 8 Representative peaks for Imatinib Phosphate:
Angle 2-Theta .degree. Intensity % 6.71 73.9 7.343 100 10.04 40.3
10.98 44 16.75 15.4 22.03 11 23.53 13.7 33.30 8.5 33.88 5.2
[0652] Shows no evidence of degradation.
[0653] Imatinib Phosphate--Pattern 2
[0654] Suspended 1:1.1 (imatinib free base)/(salt former) in
.about.4:1 H2O/THF and temperature cycled between 25-35.degree. C.
for 1 day. Evaporated solvent. Suspended solid in H2O and
temperature cycled between 25-35.degree. C. for 1 day. Evaporated
solvent. Suspended solid in toluene and temperature cycled between
25-35.degree. C. for 5 days with periodic sonication; recovered
solid by filter centrifugation. Dried remaining sample under vacuum
for 5.5 hours. The solid obtained is quite soluble in water.
Elemental analysis confirms that it is a monophosphate.
[0655] The XRPD of imatinib phosphate is presented in FIG. 5.
Representative peaks include those in the following Table:
TABLE-US-00017 TABLE 9 Representative peaks for Imatinib Phosphate:
Angle 2-Theta .degree. Intensity % 3.68 8.2 7.34 100 10.99 35.9
14.65 6.2 14.81 4.3 18.35 4.7 22.05 6.5 24.85 2.6 33.35 3.4
[0656] TG-FTIR of the post-PXRD sample showed a 10.9 wt.-% H2O loss
between 25.degree. C. and 180.degree. C., followed by
decomposition. This H2O loss agrees with that theoretically
expected for a tetrahydrate of the monophosphate salt, but the H2O
molecules do not appear to be tightly bound.
[0657] Imatinib Phosphate--Pattern 3
[0658] Suspended 1:1 (imatinib free base, 300.9 mg)/(salt former,
H.sub.3PO.sub.4, 12.155 ml/0.05 mol/l) in .about.15 ml MeOH at room
temperature with periodic sonication for 2 min. Evaporated solvent
at r.t. under gentle N.sub.2 flow to obtain a solid. Suspended
solid in 1.5 ml toluene and temperature cycled between
25-35.degree. C. for 3 days; recovered solid by filter
centrifugation. Dried remaining sample under vacuum for 2 hours.
Elemental analysis confirms that it is a monophosphate.
[0659] The XRPD of imatinib phosphate is presented in FIG. 6.
Representative peaks include those in the following Table:
TABLE-US-00018 TABLE 10 Representative peaks for Imatinib
Phosphate: Angle 2-Theta .degree. Intensity % 6.13 58.3 7.55 72
8.93 100 14.08 47.7 17.28 67.1 17.82 91.9 18.86 46.3 19.89 38.6
21.06 55.7 21.67 37.2 23.93 46.6 24.35 54.4 24.66 62.7 25.32
38.6
Example 5: Formulations
[0660] Representative formulations are described in the following
Tables.
TABLE-US-00019 TABLE 11a Imatinib mesylate formulations Imatinib
Sodium Sodium Sodium Citrate Phosphate Fumarate Mesylate Chloride
Bromide Saccharin Buffer Buffer Buffer pH Formulation (mg/mL).sup.a
(mM) (mM) (mM) (mM) (mM (mM) Water (+/-2.0) 1 0.01 25 0.0 0.0 0.0
0.0 0.0 q.s. 5.8 2 0.01 200 0.0 0.0 0.0 0.0 0.0 q.s. 5.8 3 200 25
0.0 0.0 0.0 0.0 0.0 q.s. 5.8 4 200 200 0.0 0.0 0.0 0.0 0.0 q.s. 5.8
5 0.01 25 0.0 5.0 0.0 0.0 0.0 q.s. 5.8 6 0.01 25 0.0 0.1 0.0 0.0
0.0 q.s. 5.8 7 200 200 0.0 5.0 0.0 0.0 0.0 q.s. 5.8 8 200 200 0.0
0.1 0.0 0.0 0.0 q.s. 5.8 9 0.01 0.0 25 0.0 0.0 0.0 0.0 q.s. 5.8 10
0.01 0.0 200 0.0 0.0 0.0 0.0 q.s. 5.8 11 200 0.0 25 0.0 0.0 0.0 0.0
q.s. 5.8 12 200 0.0 200 0.0 0.0 0.0 0.0 q.s. 5.8 13 0.01 0.0 25 5.0
0.0 0.0 0.0 q.s. 5.8 14 0.01 0.0 25 0.1 0.0 0.0 0.0 q.s. 5.8 15 200
0.0 200 5.0 0.0 0.0 0.0 q.s. 5.8 16 200 0.0 200 0.1 0.0 0.0 0.0
q.s. 5.8 17 0.01 25 0.0 0.0 0.1 0.0 0.0 q.s. 5.0 18 0.01 200 0.0
0.0 0.1 0.0 0.0 q.s. 5.0 19 200 25 0.0 0.0 0.1 0.0 0.0 q.s. 5.0 20
200 200 0.0 0.0 0.1 0.0 0.0 q.s. 5.0 21 0.01 25 0.0 5.0 0.1 0.0 0.0
q.s. 5.0 22 0.01 25 0.0 0.1 0.1 0.0 0.0 q.s. 5.0 23 200 200 0.0 5.0
0.1 0.0 0.0 q.s. 5.0 24 200 200 0.0 0.1 0.1 0.0 0.0 q.s. 5.0 25
0.01 0.0 25 0.0 0.1 0.0 0.0 q.s. 5.0 26 0.01 0.0 200 0.0 0.1 0.0
0.0 q.s. 5.0 27 200 0.0 25 0.0 0.1 0.0 0.0 q.s. 5.0 28 200 0.0 200
0.0 0.1 0.0 0.0 q.s. 5.0 29 0.01 0.0 25 5.0 0.1 0.0 0.0 q.s. 5.0 30
0.01 0.0 25 0.1 0.1 0.0 0.0 q.s. 5.0 31 200 0.0 200 5.0 0.1 0.0 0.0
q.s. 5.0 32 200 0.0 200 0.1 0.1 0.0 0.0 q.s. 5.0 33 0.01 25 0.0 0.0
200 0.0 0.0 q.s. 5.0 34 0.01 200 0.0 0.0 200 0.0 0.0 q.s. 5.0 35
200 25 0.0 0.0 200 0.0 0.0 q.s. 5.0 36 200 200 0.0 0.0 200 0.0 0.0
q.s. 5.0 37 0.01 25 0.0 5.0 200 0.0 0.0 q.s. 5.0 38 0.01 25 0.0 0.1
200 0.0 0.0 q.s. 5.0 39 200 200 0.0 5.0 200 0.0 0.0 q.s. 5.0 40 200
200 0.0 0.1 200 0.0 0.0 q.s. 5.0 41 0.01 0.0 25 0.0 200 0.0 0.0
q.s. 5.0 42 0.01 0.0 200 0.0 200 0.0 0.0 q.s. 5.0 43 200 0.0 25 0.0
200 0.0 0.0 q.s. 5.0 44 200 0.0 200 0.0 200 0.0 0.0 q.s. 5.0 45
0.01 0.0 25 5.0 200 0.0 0.0 q.s. 5.0 46 0.01 0.0 25 0.1 200 0.0 0.0
q.s. 5.0 47 200 0.0 200 5.0 200 0.0 0.0 q.s. 5.0 48 200 0.0 200 0.1
200 0.0 0.0 q.s. 5.0 49 0.01 25 0.0 0.0 0.0 0.1 0.0 q.s. 6.5 50
0.01 200 0.0 0.0 0.0 0.1 0.0 q.s. 6.5 51 200 25 0.0 0.0 0.0 0.1 0.0
q.s. 6.5 52 200 200 0.0 0.0 0.0 0.1 0.0 q.s. 6.5 53 0.01 25 0.0 5.0
0.0 0.1 0.0 q.s. 6.5 54 0.01 25 0.0 0.1 0.0 0.1 0.0 q.s. 6.5 55 200
200 0.0 5.0 0.0 0.1 0.0 q.s. 6.5 56 200 200 0.0 0.1 0.0 0.1 0.0
q.s. 6.5 57 0.01 0.0 25 0.0 0.0 0.1 0.0 q.s. 6.5 58 0.01 0.0 200
0.0 0.0 0.1 0.0 q.s. 6.5 59 200 0.0 25 0.0 0.0 0.1 0.0 q.s. 6.5 60
200 0.0 200 0.0 0.0 0.1 0.0 q.s. 6.5 61 0.01 0.0 25 5.0 0.0 0.1 0.0
q.s. 6.5 62 0.01 0.0 25 0.1 0.0 0.1 0.0 q.s. 6.5 63 200 0.0 200 5.0
0.0 0.1 0.0 q.s. 6.5 64 200 0.0 200 0.1 0.0 0.1 0.0 q.s. 6.5 65
0.01 25 0.0 0.0 0.0 200 0.0 q.s. 6.5 66 0.01 200 0.0 0.0 0.0 200
0.0 q.s. 6.5 67 200 25 0.0 0.0 0.0 200 0.0 q.s. 6.5 68 200 200 0.0
0.0 0.0 200 0.0 q.s. 6.5 69 0.01 25 0.0 5.0 0.0 200 0.0 q.s. 6.5 70
0.01 25 0.0 0.1 0.0 200 0.0 q.s. 6.5 71 200 200 0.0 5.0 0.0 200 0.0
q.s. 6.5 72 200 200 0.0 0.1 0.0 200 0.0 q.s. 6.5 73 0.01 0.0 25 0.0
0.0 200 0.0 q.s. 6.5 74 0.01 0.0 200 0.0 0.0 200 0.0 q.s. 6.5 75
200 0.0 25 0.0 0.0 200 0.0 q.s. 6.5 76 200 0.0 200 0.0 0.0 200 0.0
q.s. 6.5 77 0.01 0.0 25 5.0 0.0 200 0.0 q.s. 6.5 78 0.01 0.0 25 0.1
0.0 200 0.0 q.s. 6.5 79 200 0.0 200 5.0 0.0 200 0.0 q.s. 6.5 80 200
0.0 200 0.1 0.0 200 0.0 q.s. 6.5 81 0.01 25 0.0 0.0 0.0 0.0 0.1
q.s. 5.0 82 0.01 200 0.0 0.0 0.0 0.0 0.1 q.s. 5.0 83 200 25 0.0 0.0
0.0 0.0 0.1 q.s. 5.0 84 200 200 0.0 0.0 0.0 0.0 0.1 q.s. 5.0 85
0.01 25 0.0 5.0 0.0 0.0 0.1 q.s. 5.0 86 0.01 25 0.0 0.1 0.0 0.0 0.1
q.s. 5.0 87 200 200 0.0 5.0 0.0 0.0 0.1 q.s. 5.0 88 200 200 0.0 0.1
0.0 0.0 0.1 q.s. 5.0 89 0.01 0.0 25 0.0 0.0 0.0 0.1 q.s. 5.0 90
0.01 0.0 200 0.0 0.0 0.0 0.1 q.s. 5.0 91 200 0.0 25 0.0 0.0 0.0 0.1
q.s. 5.0 92 200 0.0 200 0.0 0.0 0.0 0.1 q.s. 5.0 93 0.01 0.0 25 5.0
0.0 0.0 0.1 q.s. 5.0 94 0.01 0.0 25 0.1 0.0 0.0 0.1 q.s. 5.0 95 200
0.0 200 5.0 0.0 0.0 0.1 q.s. 5.0 96 200 0.0 200 0.1 0.0 0.0 0.1
q.s. 5.0 97 0.01 25 0.0 0.0 0.0 0.0 200 q.s. 5.0 98 0.01 200 0.0
0.0 0.0 0.0 200 q.s. 5.0 99 200 25 0.0 0.0 0.0 0.0 200 q.s. 5.0 100
200 200 0.0 0.0 0.0 0.0 200 q.s. 5.0 101 0.01 25 0.0 5.0 0.0 0.0
200 q.s. 5.0 102 0.01 25 0.0 0.1 0.0 0.0 200 q.s. 5.0 103 200 200
0.0 5.0 0.0 0.0 200 q.s. 5.0 104 200 200 0.0 0.1 0.0 0.0 200 q.s.
5.0 105 0.01 0.0 25 0.0 0.0 0.0 200 q.s. 5.0 106 0.01 0.0 200 0.0
0.0 0.0 200 q.s. 5.0 107 200 0.0 25 0.0 0.0 0.0 200 q.s. 5.0 108
200 0.0 200 0.0 0.0 0.0 200 q.s. 5.0 109 0.01 0.0 25 5.0 0.0 0.0
200 q.s. 5.0 110 0.01 0.0 25 0.1 0.0 0.0 200 q.s. 5.0 111 200 0.0
200 5.0 0.0 0.0 200 q.s. 5.0 112 200 0.0 200 0.1 0.0 0.0 200 q.s.
5.0 .sup.aMilligram/milliliter imatinib
[0661] 36.4 mg Imatinib in the mesylate salt form dissolved quickly
in 7.5 mL 0.9% sodium chloride (about 4.9 mg/mL). However,
dissolved imatinib mesylate formulations turned cloudy after 30
minutes at room temperature. Comparatively, 10.8 mg imatinib in the
phosphate salt form dissolved quickly in 1.0 mL 0.9% sodium
chloride (about 10.8 mg/mL), but no precipitation was observed
during the following 1 week observation period for imatinib
phosphate. Moreover, in the absence of additional buffers,
water-dissolved imatinib phosphate resulted in an
inhalation-acceptable pH of about 5.1. Use of saline instead of
water resulted in a similarly acceptable pH. Table 11 b imatinib
phosphate formulations 1 and 2 were similarly stable.
TABLE-US-00020 TABLE 11b Imatinib phosphate formulations Imatinib
Sodium Sodium Sodium Citrate Phosphate Fumarate pH Formu- Phosphate
Chloride Bromide Saccharin Buffer Buffer Buffer (+/- lation
(mg/mL).sup.a (mM) (mM) (mM) (mM) (mM (mM) Water 2.0) 1 4.0 150 0.0
0.0 0.0 0.0 0.0 q.s. 5.1 2 20.0 150 0.0 0.0 0.0 0.0 0.0 q.s. 5.1 3
0.01 25 0.0 0.0 0.0 0.0 0.0 q.s. 5.1 4 0.01 200 0.0 0.0 0.0 0.0 0.0
q.s. 5.1 5 200 25 0.0 0.0 0.0 0.0 0.0 q.s. 5.1 6 200 200 0.0 0.0
0.0 0.0 0.0 q.s. 5.1 7 0.01 25 0.0 5.0 0.0 0.0 0.0 q.s. 5.1 8 0.01
25 0.0 0.1 0.0 0.0 0.0 q.s. 5.1 9 200 200 0.0 5.0 0.0 0.0 0.0 q.s.
5.1 10 200 200 0.0 0.1 0.0 0.0 0.0 q.s. 5.1 11 0.01 0.0 25 0.0 0.0
0.0 0.0 q.s. 5.1 12 0.01 0.0 200 0.0 0.0 0.0 0.0 q.s. 5.1 13 200
0.0 25 0.0 0.0 0.0 0.0 q.s. 5.1 14 200 0.0 200 0.0 0.0 0.0 0.0 q.s.
5.1 15 0.01 0.0 25 5.0 0.0 0.0 0.0 q.s. 5.1 16 0.01 0.0 25 0.1 0.0
0.0 0.0 q.s. 5.1 17 200 0.0 200 5.0 0.0 0.0 0.0 q.s. 5.1 18 200 0.0
200 0.1 0.0 0.0 0.0 q.s. 5.1 19 0.01 25 0.0 0.0 0.1 0.0 0.0 q.s.
5.0 20 0.01 200 0.0 0.0 0.1 0.0 0.0 q.s. 5.0 21 200 25 0.0 0.0 0.1
0.0 0.0 q.s. 5.0 22 200 200 0.0 0.0 0.1 0.0 0.0 q.s. 5.0 23 0.01 25
0.0 5.0 0.1 0.0 0.0 q.s. 5.0 24 0.01 25 0.0 0.1 0.1 0.0 0.0 q.s.
5.0 25 200 200 0.0 5.0 0.1 0.0 0.0 q.s. 5.0 26 200 200 0.0 0.1 0.1
0.0 0.0 q.s. 5.0 27 0.01 0.0 25 0.0 0.1 0.0 0.0 q.s. 5.0 28 0.01
0.0 200 0.0 0.1 0.0 0.0 q.s. 5.0 29 200 0.0 25 0.0 0.1 0.0 0.0 q.s.
5.0 30 200 0.0 200 0.0 0.1 0.0 0.0 q.s. 5.0 31 0.01 0.0 25 5.0 0.1
0.0 0.0 q.s. 5.0 32 0.01 0.0 25 0.1 0.1 0.0 0.0 q.s. 5.0 33 200 0.0
200 5.0 0.1 0.0 0.0 q.s. 5.0 34 200 0.0 200 0.1 0.1 0.0 0.0 q.s.
5.0 35 0.01 25 0.0 0.0 200 0.0 0.0 q.s. 5.0 36 0.01 200 0.0 0.0 200
0.0 0.0 q.s. 5.0 37 200 25 0.0 0.0 200 0.0 0.0 q.s. 5.0 38 200 200
0.0 0.0 200 0.0 0.0 q.s. 5.0 39 0.01 25 0.0 5.0 200 0.0 0.0 q.s.
5.0 40 0.01 25 0.0 0.1 200 0.0 0.0 q.s. 5.0 41 200 200 0.0 5.0 200
0.0 0.0 q.s. 5.0 42 200 200 0.0 0.1 200 0.0 0.0 q.s. 5.0 43 0.01
0.0 25 0.0 200 0.0 0.0 q.s. 5.0 44 0.01 0.0 200 0.0 200 0.0 0.0
q.s. 5.0 45 200 0.0 25 0.0 200 0.0 0.0 q.s. 5.0 46 200 0.0 200 0.0
200 0.0 0.0 q.s. 5.0 47 0.01 0.0 25 5.0 200 0.0 0.0 q.s. 5.0 48
0.01 0.0 25 0.1 200 0.0 0.0 q.s. 5.0 49 200 0.0 200 5.0 200 0.0 0.0
q.s. 5.0 50 200 0.0 200 0.1 200 0.0 0.0 q.s. 5.0 51 0.01 25 0.0 0.0
0.0 0.1 0.0 q.s. 6.5 52 0.01 200 0.0 0.0 0.0 0.1 0.0 q.s. 6.5 53
200 25 0.0 0.0 0.0 0.1 0.0 q.s. 6.5 54 200 200 0.0 0.0 0.0 0.1 0.0
q.s. 6.5 55 0.01 25 0.0 5.0 0.0 0.1 0.0 q.s. 6.5 56 0.01 25 0.0 0.1
0.0 0.1 0.0 q.s. 6.5 57 200 200 0.0 5.0 0.0 0.1 0.0 q.s. 6.5 58 200
200 0.0 0.1 0.0 0.1 0.0 q.s. 6.5 59 0.01 0.0 25 0.0 0.0 0.1 0.0
q.s. 6.5 60 0.01 0.0 200 0.0 0.0 0.1 0.0 q.s. 6.5 61 200 0.0 25 0.0
0.0 0.1 0.0 q.s. 6.5 62 200 0.0 200 0.0 0.0 0.1 0.0 q.s. 6.5 63
0.01 0.0 25 5.0 0.0 0.1 0.0 q.s. 6.5 64 0.01 0.0 25 0.1 0.0 0.1 0.0
q.s. 6.5 65 200 0.0 200 5.0 0.0 0.1 0.0 q.s. 6.5 66 200 0.0 200 0.1
0.0 0.1 0.0 q.s. 6.5 67 0.01 25 0.0 0.0 0.0 200 0.0 q.s. 6.5 68
0.01 200 0.0 0.0 0.0 200 0.0 q.s. 6.5 69 200 25 0.0 0.0 0.0 200 0.0
q.s. 6.5 70 200 200 0.0 0.0 0.0 200 0.0 q.s. 6.5 71 0.01 25 0.0 5.0
0.0 200 0.0 q.s. 6.5 72 0.01 25 0.0 0.1 0.0 200 0.0 q.s. 6.5 73 200
200 0.0 5.0 0.0 200 0.0 q.s. 6.5 74 200 200 0.0 0.1 0.0 200 0.0
q.s. 6.5 75 0.01 0.0 25 0.0 0.0 200 0.0 q.s. 6.5 76 0.01 0.0 200
0.0 0.0 200 0.0 q.s. 6.5 77 200 0.0 25 0.0 0.0 200 0.0 q.s. 6.5 78
200 0.0 200 0.0 0.0 200 0.0 q.s. 6.5 79 0.01 0.0 25 5.0 0.0 200 0.0
q.s. 6.5 80 0.01 0.0 25 0.1 0.0 200 0.0 q.s. 6.5 81 200 0.0 200 5.0
0.0 200 0.0 q.s. 6.5 82 200 0.0 200 0.1 0.0 200 0.0 q.s. 6.5 83
0.01 25 0.0 0.0 0.0 0.0 0.1 q.s. 5.0 84 0.01 200 0.0 0.0 0.0 0.0
0.1 q.s. 5.0 85 200 25 0.0 0.0 0.0 0.0 0.1 q.s. 5.0 86 200 200 0.0
0.0 0.0 0.0 0.1 q.s. 5.0 87 0.01 25 0.0 5.0 0.0 0.0 0.1 q.s. 5.0 88
0.01 25 0.0 0.1 0.0 0.0 0.1 q.s. 5.0 89 200 200 0.0 5.0 0.0 0.0 0.1
q.s. 5.0 90 200 200 0.0 0.1 0.0 0.0 0.1 q.s. 5.0 91 0.01 0.0 25 0.0
0.0 0.0 0.1 q.s. 5.0 92 0.01 0.0 200 0.0 0.0 0.0 0.1 q.s. 5.0 93
200 0.0 25 0.0 0.0 0.0 0.1 q.s. 5.0 94 200 0.0 200 0.0 0.0 0.0 0.1
q.s. 5.0 95 0.01 0.0 25 5.0 0.0 0.0 0.1 q.s. 5.0 96 0.01 0.0 25 0.1
0.0 0.0 0.1 q.s. 5.0 97 200 0.0 200 5.0 0.0 0.0 0.1 q.s. 5.0 98 200
0.0 200 0.1 0.0 0.0 0.1 q.s. 5.0 99 0.01 25 0.0 0.0 0.0 0.0 200
q.s. 5.0 100 0.01 200 0.0 0.0 0.0 0.0 200 q.s. 5.0 101 200 25 0.0
0.0 0.0 0.0 200 q.s. 5.0 102 200 200 0.0 0.0 0.0 0.0 200 q.s. 5.0
103 0.01 25 0.0 5.0 0.0 0.0 200 q.s. 5.0 104 0.01 25 0.0 0.1 0.0
0.0 200 q.s. 5.0 105 200 200 0.0 5.0 0.0 0.0 200 q.s. 5.0 106 200
200 0.0 0.1 0.0 0.0 200 q.s. 5.0 107 0.01 0.0 25 0.0 0.0 0.0 200
q.s. 5.0 108 0.01 0.0 200 0.0 0.0 0.0 200 q.s. 5.0 109 200 0.0 25
0.0 0.0 0.0 200 q.s. 5.0 110 200 0.0 200 0.0 0.0 0.0 200 q.s. 5.0
111 0.01 0.0 25 5.0 0.0 0.0 200 q.s. 5.0 112 0.01 0.0 25 0.1 0.0
0.0 200 q.s. 5.0 113 200 0.0 200 5.0 0.0 0.0 200 q.s. 5.0 114 200
0.0 200 0.1 0.0 0.0 200 q.s. 5.0 .sup.aMilligram/milliliter
imatinib
TABLE-US-00021 TABLE 11c Imatinib chloride formulations Imatinib
Sodium Sodium Sodium Citrate Phosphate Fumarate pH Formu- Chloride
Chloride Bromide Saccharin Buffer Buffer Buffer (+/- lation
(mg/mL).sup.a (mM) (mM) (mM) (mM) (mM (mM) Water 2.0) 1 0.01 25 0.0
0.0 0.0 0.0 0.0 q.s. 7.0 2 0.01 200 0.0 0.0 0.0 0.0 0.0 q.s. 7.0 3
200 25 0.0 0.0 0.0 0.0 0.0 q.s. 7.0 4 200 200 0.0 0.0 0.0 0.0 0.0
q.s. 7.0 5 0.01 25 0.0 5.0 0.0 0.0 0.0 q.s. 7.0 6 0.01 25 0.0 0.1
0.0 0.0 0.0 q.s. 7.0 7 200 200 0.0 5.0 0.0 0.0 0.0 q.s. 7.0 8 200
200 0.0 0.1 0.0 0.0 0.0 q.s. 7.0 9 0.01 0.0 25 0.0 0.0 0.0 0.0 q.s.
7.0 10 0.01 0.0 200 0.0 0.0 0.0 0.0 q.s. 7.0 11 200 0.0 25 0.0 0.0
0.0 0.0 q.s. 7.0 12 200 0.0 200 0.0 0.0 0.0 0.0 q.s. 7.0 13 0.01
0.0 25 5.0 0.0 0.0 0.0 q.s. 7.0 14 0.01 0.0 25 0.1 0.0 0.0 0.0 q.s.
7.0 15 200 0.0 200 5.0 0.0 0.0 0.0 q.s. 7.0 16 200 0.0 200 0.1 0.0
0.0 0.0 q.s. 7.0 17 0.01 25 0.0 0.0 0.1 0.0 0.0 q.s. 5.0 18 0.01
200 0.0 0.0 0.1 0.0 0.0 q.s. 5.0 19 200 25 0.0 0.0 0.1 0.0 0.0 q.s.
5.0 20 200 200 0.0 0.0 0.1 0.0 0.0 q.s. 5.0 21 0.01 25 0.0 5.0 0.1
0.0 0.0 q.s. 5.0 22 0.01 25 0.0 0.1 0.1 0.0 0.0 q.s. 5.0 23 200 200
0.0 5.0 0.1 0.0 0.0 q.s. 5.0 24 200 200 0.0 0.1 0.1 0.0 0.0 q.s.
5.0 25 0.01 0.0 25 0.0 0.1 0.0 0.0 q.s. 5.0 26 0.01 0.0 200 0.0 0.1
0.0 0.0 q.s. 5.0 27 200 0.0 25 0.0 0.1 0.0 0.0 q.s. 5.0 28 200 0.0
200 0.0 0.1 0.0 0.0 q.s. 5.0 29 0.01 0.0 25 5.0 0.1 0.0 0.0 q.s.
5.0 30 0.01 0.0 25 0.1 0.1 0.0 0.0 q.s. 5.0 31 200 0.0 200 5.0 0.1
0.0 0.0 q.s. 5.0 32 200 0.0 200 0.1 0.1 0.0 0.0 q.s. 5.0 33 0.01 25
0.0 0.0 200 0.0 0.0 q.s. 5.0 34 0.01 200 0.0 0.0 200 0.0 0.0 q.s.
5.0 35 200 25 0.0 0.0 200 0.0 0.0 q.s. 5.0 36 200 200 0.0 0.0 200
0.0 0.0 q.s. 5.0 37 0.01 25 0.0 5.0 200 0.0 0.0 q.s. 5.0 38 0.01 25
0.0 0.1 200 0.0 0.0 q.s. 5.0 39 200 200 0.0 5.0 200 0.0 0.0 q.s.
5.0 40 200 200 0.0 0.1 200 0.0 0.0 q.s. 5.0 41 0.01 0.0 25 0.0 200
0.0 0.0 q.s. 5.0 42 0.01 0.0 200 0.0 200 0.0 0.0 q.s. 5.0 43 200
0.0 25 0.0 200 0.0 0.0 q.s. 5.0 44 200 0.0 200 0.0 200 0.0 0.0 q.s.
5.0 45 0.01 0.0 25 5.0 200 0.0 0.0 q.s. 5.0 46 0.01 0.0 25 0.1 200
0.0 0.0 q.s. 5.0 47 200 0.0 200 5.0 200 0.0 0.0 q.s. 5.0 48 200 0.0
200 0.1 200 0.0 0.0 q.s. 5.0 49 0.01 25 0.0 0.0 0.0 0.1 0.0 q.s.
6.5 50 0.01 200 0.0 0.0 0.0 0.1 0.0 q.s. 6.5 51 200 25 0.0 0.0 0.0
0.1 0.0 q.s. 6.5 52 200 200 0.0 0.0 0.0 0.1 0.0 q.s. 6.5 53 0.01 25
0.0 5.0 0.0 0.1 0.0 q.s. 6.5 54 0.01 25 0.0 0.1 0.0 0.1 0.0 q.s.
6.5 55 200 200 0.0 5.0 0.0 0.1 0.0 q.s. 6.5 56 200 200 0.0 0.1 0.0
0.1 0.0 q.s. 6.5 57 0.01 0.0 25 0.0 0.0 0.1 0.0 q.s. 6.5 58 0.01
0.0 200 0.0 0.0 0.1 0.0 q.s. 6.5 59 200 0.0 25 0.0 0.0 0.1 0.0 q.s.
6.5 60 200 0.0 200 0.0 0.0 0.1 0.0 q.s. 6.5 61 0.01 0.0 25 5.0 0.0
0.1 0.0 q.s. 6.5 62 0.01 0.0 25 0.1 0.0 0.1 0.0 q.s. 6.5 63 200 0.0
200 5.0 0.0 0.1 0.0 q.s. 6.5 64 200 0.0 200 0.1 0.0 0.1 0.0 q.s.
6.5 65 0.01 25 0.0 0.0 0.0 200 0.0 q.s. 6.5 66 0.01 200 0.0 0.0 0.0
200 0.0 q.s. 6.5 67 200 25 0.0 0.0 0.0 200 0.0 q.s. 6.5 68 200 200
0.0 0.0 0.0 200 0.0 q.s. 6.5 69 0.01 25 0.0 5.0 0.0 200 0.0 q.s.
6.5 70 0.01 25 0.0 0.1 0.0 200 0.0 q.s. 6.5 71 200 200 0.0 5.0 0.0
200 0.0 q.s. 6.5 72 200 200 0.0 0.1 0.0 200 0.0 q.s. 6.5 73 0.01
0.0 25 0.0 0.0 200 0.0 q.s. 6.5 74 0.01 0.0 200 0.0 0.0 200 0.0
q.s. 6.5 75 200 0.0 25 0.0 0.0 200 0.0 q.s. 6.5 76 200 0.0 200 0.0
0.0 200 0.0 q.s. 6.5 77 0.01 0.0 25 5.0 0.0 200 0.0 q.s. 6.5 78
0.01 0.0 25 0.1 0.0 200 0.0 q.s. 6.5 79 200 0.0 200 5.0 0.0 200 0.0
q.s. 6.5 80 200 0.0 200 0.1 0.0 200 0.0 q.s. 6.5 81 0.01 25 0.0 0.0
0.0 0.0 0.1 q.s. 5.0 82 0.01 200 0.0 0.0 0.0 0.0 0.1 q.s. 5.0 83
200 25 0.0 0.0 0.0 0.0 0.1 q.s. 5.0 84 200 200 0.0 0.0 0.0 0.0 0.1
q.s. 5.0 85 0.01 25 0.0 5.0 0.0 0.0 0.1 q.s. 5.0 86 0.01 25 0.0 0.1
0.0 0.0 0.1 q.s. 5.0 87 200 200 0.0 5.0 0.0 0.0 0.1 q.s. 5.0 88 200
200 0.0 0.1 0.0 0.0 0.1 q.s. 5.0 89 0.01 0.0 25 0.0 0.0 0.0 0.1
q.s. 5.0 90 0.01 0.0 200 0.0 0.0 0.0 0.1 q.s. 5.0 91 200 0.0 25 0.0
0.0 0.0 0.1 q.s. 5.0 92 200 0.0 200 0.0 0.0 0.0 0.1 q.s. 5.0 93
0.01 0.0 25 5.0 0.0 0.0 0.1 q.s. 5.0 94 0.01 0.0 25 0.1 0.0 0.0 0.1
q.s. 5.0 95 200 0.0 200 5.0 0.0 0.0 0.1 q.s. 5.0 96 200 0.0 200 0.1
0.0 0.0 0.1 q.s. 5.0 97 0.01 25 0.0 0.0 0.0 0.0 200 q.s. 5.0 98
0.01 200 0.0 0.0 0.0 0.0 200 q.s. 5.0 99 200 25 0.0 0.0 0.0 0.0 200
q.s. 5.0 100 200 200 0.0 0.0 0.0 0.0 200 q.s. 5.0 101 0.01 25 0.0
5.0 0.0 0.0 200 q.s. 5.0 102 0.01 25 0.0 0.1 0.0 0.0 200 q.s. 5.0
103 200 200 0.0 5.0 0.0 0.0 200 q.s. 5.0 104 200 200 0.0 0.1 0.0
0.0 200 q.s. 5.0 105 0.01 0.0 25 0.0 0.0 0.0 200 q.s. 5.0 106 0.01
0.0 200 0.0 0.0 0.0 200 q.s. 5.0 107 200 0.0 25 0.0 0.0 0.0 200
q.s. 5.0 108 200 0.0 200 0.0 0.0 0.0 200 q.s. 5.0 109 0.01 0.0 25
5.0 0.0 0.0 200 q.s. 5.0 110 0.01 0.0 25 0.1 0.0 0.0 200 q.s. 5.0
111 200 0.0 200 5.0 0.0 0.0 200 q.s. 5.0 112 200 0.0 200 0.1 0.0
0.0 200 q.s. 5.0 .sup.aMilligram/milliliter imatinib
TABLE-US-00022 TABLE 11d Imatinib fumarate formulations Imatinib
Sodium Sodium Sodium Citrate Phosphate Fumarate pH Formu- Fumarate
Chloride Bromide Saccharin Buffer Buffer Buffer (+/- lation
(mg/mL).sup.a (mM) (mM) (mM) (mM) (mM (mM) Water 2.0) 1 0.01 25 0.0
0.0 0.0 0.0 0.0 q.s. 5.0 2 0.01 200 0.0 0.0 0.0 0.0 0.0 q.s. 5.0 3
200 25 0.0 0.0 0.0 0.0 0.0 q.s. 5.0 4 200 200 0.0 0.0 0.0 0.0 0.0
q.s. 5.0 5 0.01 25 0.0 5.0 0.0 0.0 0.0 q.s. 5.0 6 0.01 25 0.0 0.1
0.0 0.0 0.0 q.s. 5.0 7 200 200 0.0 5.0 0.0 0.0 0.0 q.s. 5.0 8 200
200 0.0 0.1 0.0 0.0 0.0 q.s. 5.0 9 0.01 0.0 25 0.0 0.0 0.0 0.0 q.s.
5.0 10 0.01 0.0 200 0.0 0.0 0.0 0.0 q.s. 5.0 11 200 0.0 25 0.0 0.0
0.0 0.0 q.s. 5.0 12 200 0.0 200 0.0 0.0 0.0 0.0 q.s. 5.0 13 0.01
0.0 25 5.0 0.0 0.0 0.0 q.s. 5.0 14 0.01 0.0 25 0.1 0.0 0.0 0.0 q.s.
5.0 15 200 0.0 200 5.0 0.0 0.0 0.0 q.s. 5.0 16 200 0.0 200 0.1 0.0
0.0 0.0 q.s. 5.0 17 0.01 25 0.0 0.0 0.1 0.0 0.0 q.s. 5.0 18 0.01
200 0.0 0.0 0.1 0.0 0.0 q.s. 5.0 19 200 25 0.0 0.0 0.1 0.0 0.0 q.s.
5.0 20 200 200 0.0 0.0 0.1 0.0 0.0 q.s. 5.0 21 0.01 25 0.0 5.0 0.1
0.0 0.0 q.s. 5.0 22 0.01 25 0.0 0.1 0.1 0.0 0.0 q.s. 5.0 23 200 200
0.0 5.0 0.1 0.0 0.0 q.s. 5.0 24 200 200 0.0 0.1 0.1 0.0 0.0 q.s.
5.0 25 0.01 0.0 25 0.0 0.1 0.0 0.0 q.s. 5.0 26 0.01 0.0 200 0.0 0.1
0.0 0.0 q.s. 5.0 27 200 0.0 25 0.0 0.1 0.0 0.0 q.s. 5.0 28 200 0.0
200 0.0 0.1 0.0 0.0 q.s. 5.0 29 0.01 0.0 25 5.0 0.1 0.0 0.0 q.s.
5.0 30 0.01 0.0 25 0.1 0.1 0.0 0.0 q.s. 5.0 31 200 0.0 200 5.0 0.1
0.0 0.0 q.s. 5.0 32 200 0.0 200 0.1 0.1 0.0 0.0 q.s. 5.0 33 0.01 25
0.0 0.0 200 0.0 0.0 q.s. 5.0 34 0.01 200 0.0 0.0 200 0.0 0.0 q.s.
5.0 35 200 25 0.0 0.0 200 0.0 0.0 q.s. 5.0 36 200 200 0.0 0.0 200
0.0 0.0 q.s. 5.0 37 0.01 25 0.0 5.0 200 0.0 0.0 q.s. 5.0 38 0.01 25
0.0 0.1 200 0.0 0.0 q.s. 5.0 39 200 200 0.0 5.0 200 0.0 0.0 q.s.
5.0 40 200 200 0.0 0.1 200 0.0 0.0 q.s. 5.0 41 0.01 0.0 25 0.0 200
0.0 0.0 q.s. 5.0 42 0.01 0.0 200 0.0 200 0.0 0.0 q.s. 5.0 43 200
0.0 25 0.0 200 0.0 0.0 q.s. 5.0 44 200 0.0 200 0.0 200 0.0 0.0 q.s.
5.0 45 0.01 0.0 25 5.0 200 0.0 0.0 q.s. 5.0 46 0.01 0.0 25 0.1 200
0.0 0.0 q.s. 5.0 47 200 0.0 200 5.0 200 0.0 0.0 q.s. 5.0 48 200 0.0
200 0.1 200 0.0 0.0 q.s. 5.0 49 0.01 25 0.0 0.0 0.0 0.1 0.0 q.s.
6.5 50 0.01 200 0.0 0.0 0.0 0.1 0.0 q.s. 6.5 51 200 25 0.0 0.0 0.0
0.1 0.0 q.s. 6.5 52 200 200 0.0 0.0 0.0 0.1 0.0 q.s. 6.5 53 0.01 25
0.0 5.0 0.0 0.1 0.0 q.s. 6.5 54 0.01 25 0.0 0.1 0.0 0.1 0.0 q.s.
6.5 55 200 200 0.0 5.0 0.0 0.1 0.0 q.s. 6.5 56 200 200 0.0 0.1 0.0
0.1 0.0 q.s. 6.5 57 0.01 0.0 25 0.0 0.0 0.1 0.0 q.s. 6.5 58 0.01
0.0 200 0.0 0.0 0.1 0.0 q.s. 6.5 59 200 0.0 25 0.0 0.0 0.1 0.0 q.s.
6.5 60 200 0.0 200 0.0 0.0 0.1 0.0 q.s. 6.5 61 0.01 0.0 25 5.0 0.0
0.1 0.0 q.s. 6.5 62 0.01 0.0 25 0.1 0.0 0.1 0.0 q.s. 6.5 63 200 0.0
200 5.0 0.0 0.1 0.0 q.s. 6.5 64 200 0.0 200 0.1 0.0 0.1 0.0 q.s.
6.5 65 0.01 25 0.0 0.0 0.0 200 0.0 q.s. 6.5 66 0.01 200 0.0 0.0 0.0
200 0.0 q.s. 6.5 67 200 25 0.0 0.0 0.0 200 0.0 q.s. 6.5 68 200 200
0.0 0.0 0.0 200 0.0 q.s. 6.5 69 0.01 25 0.0 5.0 0.0 200 0.0 q.s.
6.5 70 0.01 25 0.0 0.1 0.0 200 0.0 q.s. 6.5 71 200 200 0.0 5.0 0.0
200 0.0 q.s. 6.5 72 200 200 0.0 0.1 0.0 200 0.0 q.s. 6.5 73 0.01
0.0 25 0.0 0.0 200 0.0 q.s. 6.5 74 0.01 0.0 200 0.0 0.0 200 0.0
q.s. 6.5 75 200 0.0 25 0.0 0.0 200 0.0 q.s. 6.5 76 200 0.0 200 0.0
0.0 200 0.0 q.s. 6.5 77 0.01 0.0 25 5.0 0.0 200 0.0 q.s. 6.5 78
0.01 0.0 25 0.1 0.0 200 0.0 q.s. 6.5 79 200 0.0 200 5.0 0.0 200 0.0
q.s. 6.5 80 200 0.0 200 0.1 0.0 200 0.0 q.s. 6.5 81 0.01 25 0.0 0.0
0.0 0.0 0.1 q.s. 5.0 82 0.01 200 0.0 0.0 0.0 0.0 0.1 q.s. 5.0 83
200 25 0.0 0.0 0.0 0.0 0.1 q.s. 5.0 84 200 200 0.0 0.0 0.0 0.0 0.1
q.s. 5.0 85 0.01 25 0.0 5.0 0.0 0.0 0.1 q.s. 5.0 86 0.01 25 0.0 0.1
0.0 0.0 0.1 q.s. 5.0 87 200 200 0.0 5.0 0.0 0.0 0.1 q.s. 5.0 88 200
200 0.0 0.1 0.0 0.0 0.1 q.s. 5.0 89 0.01 0.0 25 0.0 0.0 0.0 0.1
q.s. 5.0 90 0.01 0.0 200 0.0 0.0 0.0 0.1 q.s. 5.0 91 200 0.0 25 0.0
0.0 0.0 0.1 q.s. 5.0 92 200 0.0 200 0.0 0.0 0.0 0.1 q.s. 5.0 93
0.01 0.0 25 5.0 0.0 0.0 0.1 q.s. 5.0 94 0.01 0.0 25 0.1 0.0 0.0 0.1
q.s. 5.0 95 200 0.0 200 5.0 0.0 0.0 0.1 q.s. 5.0 96 200 0.0 200 0.1
0.0 0.0 0.1 q.s. 5.0 97 0.01 25 0.0 0.0 0.0 0.0 200 q.s. 5.0 98
0.01 200 0.0 0.0 0.0 0.0 200 q.s. 5.0 99 200 25 0.0 0.0 0.0 0.0 200
q.s. 5.0 100 200 200 0.0 0.0 0.0 0.0 200 q.s. 5.0 101 0.01 25 0.0
5.0 0.0 0.0 200 q.s. 5.0 102 0.01 25 0.0 0.1 0.0 0.0 200 q.s. 5.0
103 200 200 0.0 5.0 0.0 0.0 200 q.s. 5.0 104 200 200 0.0 0.1 0.0
0.0 200 q.s. 5.0 105 0.01 0.0 25 0.0 0.0 0.0 200 q.s. 5.0 106 0.01
0.0 200 0.0 0.0 0.0 200 q.s. 5.0 107 200 0.0 25 0.0 0.0 0.0 200
q.s. 5.0 108 200 0.0 200 0.0 0.0 0.0 200 q.s. 5.0 109 0.01 0.0 25
5.0 0.0 0.0 200 q.s. 5.0 110 0.01 0.0 25 0.1 0.0 0.0 200 q.s. 5.0
111 200 0.0 200 5.0 0.0 0.0 200 q.s. 5.0 112 200 0.0 200 0.1 0.0
0.0 200 q.s. 5.0 .sup.aMilligram/milliliter imatinib
TABLE-US-00023 TABLE 11e Sorafenib tosylate formulations Sorafenib
Sodium Sodium Sodium Citrate Phosphate Fumarate pH Formu- Tosylate
Chloride Bromide Saccharin Buffer Buffer Buffer (+/- lation
(mg/mL).sup.a (mM) (mM) (mM) (mM) (mM (mM) Water 2.0) 1 0.01 25 0.0
0.0 0.0 0.0 0.0 q.s. 4.5 2 0.01 200 0.0 0.0 0.0 0.0 0.0 q.s. 4.5 3
200 25 0.0 0.0 0.0 0.0 0.0 q.s. 4.5 4 200 200 0.0 0.0 0.0 0.0 0.0
q.s. 4.5 5 0.01 25 0.0 5.0 0.0 0.0 0.0 q.s. 4.5 6 0.01 25 0.0 0.1
0.0 0.0 0.0 q.s. 4.5 7 200 200 0.0 5.0 0.0 0.0 0.0 q.s. 4.5 8 200
200 0.0 0.1 0.0 0.0 0.0 q.s. 4.5 9 0.01 0.0 25 0.0 0.0 0.0 0.0 q.s.
4.5 10 0.01 0.0 200 0.0 0.0 0.0 0.0 q.s. 4.5 11 200 0.0 25 0.0 0.0
0.0 0.0 q.s. 4.5 12 200 0.0 200 0.0 0.0 0.0 0.0 q.s. 4.5 13 0.01
0.0 25 5.0 0.0 0.0 0.0 q.s. 4.5 14 0.01 0.0 25 0.1 0.0 0.0 0.0 q.s.
4.5 15 200 0.0 200 5.0 0.0 0.0 0.0 q.s. 4.5 16 200 0.0 200 0.1 0.0
0.0 0.0 q.s. 4.5 17 0.01 25 0.0 0.0 0.1 0.0 0.0 q.s. 5.0 18 0.01
200 0.0 0.0 0.1 0.0 0.0 q.s. 5.0 19 200 25 0.0 0.0 0.1 0.0 0.0 q.s.
5.0 20 200 200 0.0 0.0 0.1 0.0 0.0 q.s. 5.0 21 0.01 25 0.0 5.0 0.1
0.0 0.0 q.s. 5.0 22 0.01 25 0.0 0.1 0.1 0.0 0.0 q.s. 5.0 23 200 200
0.0 5.0 0.1 0.0 0.0 q.s. 5.0 24 200 200 0.0 0.1 0.1 0.0 0.0 q.s.
5.0 25 0.01 0.0 25 0.0 0.1 0.0 0.0 q.s. 5.0 26 0.01 0.0 200 0.0 0.1
0.0 0.0 q.s. 5.0 27 200 0.0 25 0.0 0.1 0.0 0.0 q.s. 5.0 28 200 0.0
200 0.0 0.1 0.0 0.0 q.s. 5.0 29 0.01 0.0 25 5.0 0.1 0.0 0.0 q.s.
5.0 30 0.01 0.0 25 0.1 0.1 0.0 0.0 q.s. 5.0 31 200 0.0 200 5.0 0.1
0.0 0.0 q.s. 5.0 32 200 0.0 200 0.1 0.1 0.0 0.0 q.s. 5.0 33 0.01 25
0.0 0.0 200 0.0 0.0 q.s. 5.0 34 0.01 200 0.0 0.0 200 0.0 0.0 q.s.
5.0 35 200 25 0.0 0.0 200 0.0 0.0 q.s. 5.0 36 200 200 0.0 0.0 200
0.0 0.0 q.s. 5.0 37 0.01 25 0.0 5.0 200 0.0 0.0 q.s. 5.0 38 0.01 25
0.0 0.1 200 0.0 0.0 q.s. 5.0 39 200 200 0.0 5.0 200 0.0 0.0 q.s.
5.0 40 200 200 0.0 0.1 200 0.0 0.0 q.s. 5.0 41 0.01 0.0 25 0.0 200
0.0 0.0 q.s. 5.0 42 0.01 0.0 200 0.0 200 0.0 0.0 q.s. 5.0 43 200
0.0 25 0.0 200 0.0 0.0 q.s. 5.0 44 200 0.0 200 0.0 200 0.0 0.0 q.s.
5.0 45 0.01 0.0 25 5.0 200 0.0 0.0 q.s. 5.0 46 0.01 0.0 25 0.1 200
0.0 0.0 q.s. 5.0 47 200 0.0 200 5.0 200 0.0 0.0 q.s. 5.0 48 200 0.0
200 0.1 200 0.0 0.0 q.s. 5.0 49 0.01 25 0.0 0.0 0.0 0.1 0.0 q.s.
6.5 50 0.01 200 0.0 0.0 0.0 0.1 0.0 q.s. 6.5 51 200 25 0.0 0.0 0.0
0.1 0.0 q.s. 6.5 52 200 200 0.0 0.0 0.0 0.1 0.0 q.s. 6.5 53 0.01 25
0.0 5.0 0.0 0.1 0.0 q.s. 6.5 54 0.01 25 0.0 0.1 0.0 0.1 0.0 q.s.
6.5 55 200 200 0.0 5.0 0.0 0.1 0.0 q.s. 6.5 56 200 200 0.0 0.1 0.0
0.1 0.0 q.s. 6.5 57 0.01 0.0 25 0.0 0.0 0.1 0.0 q.s. 6.5 58 0.01
0.0 200 0.0 0.0 0.1 0.0 q.s. 6.5 59 200 0.0 25 0.0 0.0 0.1 0.0 q.s.
6.5 60 200 0.0 200 0.0 0.0 0.1 0.0 q.s. 6.5 61 0.01 0.0 25 5.0 0.0
0.1 0.0 q.s. 6.5 62 0.01 0.0 25 0.1 0.0 0.1 0.0 q.s. 6.5 63 200 0.0
200 5.0 0.0 0.1 0.0 q.s. 6.5 64 200 0.0 200 0.1 0.0 0.1 0.0 q.s.
6.5 65 0.01 25 0.0 0.0 0.0 200 0.0 q.s. 6.5 66 0.01 200 0.0 0.0 0.0
200 0.0 q.s. 6.5 67 200 25 0.0 0.0 0.0 200 0.0 q.s. 6.5 68 200 200
0.0 0.0 0.0 200 0.0 q.s. 6.5 69 0.01 25 0.0 5.0 0.0 200 0.0 q.s.
6.5 70 0.01 25 0.0 0.1 0.0 200 0.0 q.s. 6.5 71 200 200 0.0 5.0 0.0
200 0.0 q.s. 6.5 72 200 200 0.0 0.1 0.0 200 0.0 q.s. 6.5 73 0.01
0.0 25 0.0 0.0 200 0.0 q.s. 6.5 74 0.01 0.0 200 0.0 0.0 200 0.0
q.s. 6.5 75 200 0.0 25 0.0 0.0 200 0.0 q.s. 6.5 76 200 0.0 200 0.0
0.0 200 0.0 q.s. 6.5 77 0.01 0.0 25 5.0 0.0 200 0.0 q.s. 6.5 78
0.01 0.0 25 0.1 0.0 200 0.0 q.s. 6.5 79 200 0.0 200 5.0 0.0 200 0.0
q.s. 6.5 80 200 0.0 200 0.1 0.0 200 0.0 q.s. 6.5 81 0.01 25 0.0 0.0
0.0 0.0 0.1 q.s. 5.0 82 0.01 200 0.0 0.0 0.0 0.0 0.1 q.s. 5.0 83
200 25 0.0 0.0 0.0 0.0 0.1 q.s. 5.0 84 200 200 0.0 0.0 0.0 0.0 0.1
q.s. 5.0 85 0.01 25 0.0 5.0 0.0 0.0 0.1 q.s. 5.0 86 0.01 25 0.0 0.1
0.0 0.0 0.1 q.s. 5.0 87 200 200 0.0 5.0 0.0 0.0 0.1 q.s. 5.0 88 200
200 0.0 0.1 0.0 0.0 0.1 q.s. 5.0 89 0.01 0.0 25 0.0 0.0 0.0 0.1
q.s. 5.0 90 0.01 0.0 200 0.0 0.0 0.0 0.1 q.s. 5.0 91 200 0.0 25 0.0
0.0 0.0 0.1 q.s. 5.0 92 200 0.0 200 0.0 0.0 0.0 0.1 q.s. 5.0 93
0.01 0.0 25 5.0 0.0 0.0 0.1 q.s. 5.0 94 0.01 0.0 25 0.1 0.0 0.0 0.1
q.s. 5.0 95 200 0.0 200 5.0 0.0 0.0 0.1 q.s. 5.0 96 200 0.0 200 0.1
0.0 0.0 0.1 q.s. 5.0 97 0.01 25 0.0 0.0 0.0 0.0 200 q.s. 5.0 98
0.01 200 0.0 0.0 0.0 0.0 200 q.s. 5.0 99 200 25 0.0 0.0 0.0 0.0 200
q.s. 5.0 100 200 200 0.0 0.0 0.0 0.0 200 q.s. 5.0 101 0.01 25 0.0
5.0 0.0 0.0 200 q.s. 5.0 102 0.01 25 0.0 0.1 0.0 0.0 200 q.s. 5.0
103 200 200 0.0 5.0 0.0 0.0 200 q.s. 5.0 104 200 200 0.0 0.1 0.0
0.0 200 q.s. 5.0 105 0.01 0.0 25 0.0 0.0 0.0 200 q.s. 5.0 106 0.01
0.0 200 0.0 0.0 0.0 200 q.s. 5.0 107 200 0.0 25 0.0 0.0 0.0 200
q.s. 5.0 108 200 0.0 200 0.0 0.0 0.0 200 q.s. 5.0 109 0.01 0.0 25
5.0 0.0 0.0 200 q.s. 5.0 110 0.01 0.0 25 0.1 0.0 0.0 200 q.s. 5.0
111 200 0.0 200 5.0 0.0 0.0 200 q.s. 5.0 112 200 0.0 200 0.1 0.0
0.0 200 q.s. 5.0 .sup.aMilligram/milliliter sorafenib
TABLE-US-00024 TABLE 11f Vargatef formulations Sodium Sodium Sodium
Citrate Phosphate Fumarate pH Formu- Vargatef Chloride Bromide
Saccharin Buffer Buffer Buffer (+/- lation (mg/mL).sup.a (mM) (mM)
(mM) (mM) (mM (mM) Water 2.0) 1 0.01 25 0.0 0.0 0.0 0.0 0.0 q.s.
8.0 2 0.01 200 0.0 0.0 0.0 0.0 0.0 q.s. 8.0 3 200 25 0.0 0.0 0.0
0.0 0.0 q.s. 8.0 4 200 200 0.0 0.0 0.0 0.0 0.0 q.s. 8.0 5 0.01 25
0.0 5.0 0.0 0.0 0.0 q.s. 8.0 6 0.01 25 0.0 0.1 0.0 0.0 0.0 q.s. 8.0
7 200 200 0.0 5.0 0.0 0.0 0.0 q.s. 8.0 8 200 200 0.0 0.1 0.0 0.0
0.0 q.s. 8.0 9 0.01 0.0 25 0.0 0.0 0.0 0.0 q.s. 8.0 10 0.01 0.0 200
0.0 0.0 0.0 0.0 q.s. 8.0 11 200 0.0 25 0.0 0.0 0.0 0.0 q.s. 8.0 12
200 0.0 200 0.0 0.0 0.0 0.0 q.s. 8.0 13 0.01 0.0 25 5.0 0.0 0.0 0.0
q.s. 8.0 14 0.01 0.0 25 0.1 0.0 0.0 0.0 q.s. 8.0 15 200 0.0 200 5.0
0.0 0.0 0.0 q.s. 8.0 16 200 0.0 200 0.1 0.0 0.0 0.0 q.s. 8.0 17
0.01 25 0.0 0.0 0.1 0.0 0.0 q.s. 5.0 18 0.01 200 0.0 0.0 0.1 0.0
0.0 q.s. 5.0 19 200 25 0.0 0.0 0.1 0.0 0.0 q.s. 5.0 20 200 200 0.0
0.0 0.1 0.0 0.0 q.s. 5.0 21 0.01 25 0.0 5.0 0.1 0.0 0.0 q.s. 5.0 22
0.01 25 0.0 0.1 0.1 0.0 0.0 q.s. 5.0 23 200 200 0.0 5.0 0.1 0.0 0.0
q.s. 5.0 24 200 200 0.0 0.1 0.1 0.0 0.0 q.s. 5.0 25 0.01 0.0 25 0.0
0.1 0.0 0.0 q.s. 5.0 26 0.01 0.0 200 0.0 0.1 0.0 0.0 q.s. 5.0 27
200 0.0 25 0.0 0.1 0.0 0.0 q.s. 5.0 28 200 0.0 200 0.0 0.1 0.0 0.0
q.s. 5.0 29 0.01 0.0 25 5.0 0.1 0.0 0.0 q.s. 5.0 30 0.01 0.0 25 0.1
0.1 0.0 0.0 q.s. 5.0 31 200 0.0 200 5.0 0.1 0.0 0.0 q.s. 5.0 32 200
0.0 200 0.1 0.1 0.0 0.0 q.s. 5.0 33 0.01 25 0.0 0.0 200 0.0 0.0
q.s. 5.0 34 0.01 200 0.0 0.0 200 0.0 0.0 q.s. 5.0 35 200 25 0.0 0.0
200 0.0 0.0 q.s. 5.0 36 200 200 0.0 0.0 200 0.0 0.0 q.s. 5.0 37
0.01 25 0.0 5.0 200 0.0 0.0 q.s. 5.0 38 0.01 25 0.0 0.1 200 0.0 0.0
q.s. 5.0 39 200 200 0.0 5.0 200 0.0 0.0 q.s. 5.0 40 200 200 0.0 0.1
200 0.0 0.0 q.s. 5.0 41 0.01 0.0 25 0.0 200 0.0 0.0 q.s. 5.0 42
0.01 0.0 200 0.0 200 0.0 0.0 q.s. 5.0 43 200 0.0 25 0.0 200 0.0 0.0
q.s. 5.0 44 200 0.0 200 0.0 200 0.0 0.0 q.s. 5.0 45 0.01 0.0 25 5.0
200 0.0 0.0 q.s. 5.0 46 0.01 0.0 25 0.1 200 0.0 0.0 q.s. 5.0 47 200
0.0 200 5.0 200 0.0 0.0 q.s. 5.0 48 200 0.0 200 0.1 200 0.0 0.0
q.s. 5.0 49 0.01 25 0.0 0.0 0.0 0.1 0.0 q.s. 6.5 50 0.01 200 0.0
0.0 0.0 0.1 0.0 q.s. 6.5 51 200 25 0.0 0.0 0.0 0.1 0.0 q.s. 6.5 52
200 200 0.0 0.0 0.0 0.1 0.0 q.s. 6.5 53 0.01 25 0.0 5.0 0.0 0.1 0.0
q.s. 6.5 54 0.01 25 0.0 0.1 0.0 0.1 0.0 q.s. 6.5 55 200 200 0.0 5.0
0.0 0.1 0.0 q.s. 6.5 56 200 200 0.0 0.1 0.0 0.1 0.0 q.s. 6.5 57
0.01 0.0 25 0.0 0.0 0.1 0.0 q.s. 6.5 58 0.01 0.0 200 0.0 0.0 0.1
0.0 q.s. 6.5 59 200 0.0 25 0.0 0.0 0.1 0.0 q.s. 6.5 60 200 0.0 200
0.0 0.0 0.1 0.0 q.s. 6.5 61 0.01 0.0 25 5.0 0.0 0.1 0.0 q.s. 6.5 62
0.01 0.0 25 0.1 0.0 0.1 0.0 q.s. 6.5 63 200 0.0 200 5.0 0.0 0.1 0.0
q.s. 6.5 64 200 0.0 200 0.1 0.0 0.1 0.0 q.s. 6.5 65 0.01 25 0.0 0.0
0.0 200 0.0 q.s. 6.5 66 0.01 200 0.0 0.0 0.0 200 0.0 q.s. 6.5 67
200 25 0.0 0.0 0.0 200 0.0 q.s. 6.5 68 200 200 0.0 0.0 0.0 200 0.0
q.s. 6.5 69 0.01 25 0.0 5.0 0.0 200 0.0 q.s. 6.5 70 0.01 25 0.0 0.1
0.0 200 0.0 q.s. 6.5 71 200 200 0.0 5.0 0.0 200 0.0 q.s. 6.5 72 200
200 0.0 0.1 0.0 200 0.0 q.s. 6.5 73 0.01 0.0 25 0.0 0.0 200 0.0
q.s. 6.5 74 0.01 0.0 200 0.0 0.0 200 0.0 q.s. 6.5 75 200 0.0 25 0.0
0.0 200 0.0 q.s. 6.5 76 200 0.0 200 0.0 0.0 200 0.0 q.s. 6.5 77
0.01 0.0 25 5.0 0.0 200 0.0 q.s. 6.5 78 0.01 0.0 25 0.1 0.0 200 0.0
q.s. 6.5 79 200 0.0 200 5.0 0.0 200 0.0 q.s. 6.5 80 200 0.0 200 0.1
0.0 200 0.0 q.s. 6.5 81 0.01 25 0.0 0.0 0.0 0.0 0.1 q.s. 5.0 82
0.01 200 0.0 0.0 0.0 0.0 0.1 q.s. 5.0 83 200 25 0.0 0.0 0.0 0.0 0.1
q.s. 5.0 84 200 200 0.0 0.0 0.0 0.0 0.1 q.s. 5.0 85 0.01 25 0.0 5.0
0.0 0.0 0.1 q.s. 5.0 86 0.01 25 0.0 0.1 0.0 0.0 0.1 q.s. 5.0 87 200
200 0.0 5.0 0.0 0.0 0.1 q.s. 5.0 88 200 200 0.0 0.1 0.0 0.0 0.1
q.s. 5.0 89 0.01 0.0 25 0.0 0.0 0.0 0.1 q.s. 5.0 90 0.01 0.0 200
0.0 0.0 0.0 0.1 q.s. 5.0 91 200 0.0 25 0.0 0.0 0.0 0.1 q.s. 5.0 92
200 0.0 200 0.0 0.0 0.0 0.1 q.s. 5.0 93 0.01 0.0 25 5.0 0.0 0.0 0.1
q.s. 5.0 94 0.01 0.0 25 0.1 0.0 0.0 0.1 q.s. 5.0 95 200 0.0 200 5.0
0.0 0.0 0.1 q.s. 5.0 96 200 0.0 200 0.1 0.0 0.0 0.1 q.s. 5.0 97
0.01 25 0.0 0.0 0.0 0.0 200 q.s. 5.0 98 0.01 200 0.0 0.0 0.0 0.0
200 q.s. 5.0 99 200 25 0.0 0.0 0.0 0.0 200 q.s. 5.0 100 200 200 0.0
0.0 0.0 0.0 200 q.s. 5.0 101 0.01 25 0.0 5.0 0.0 0.0 200 q.s. 5.0
102 0.01 25 0.0 0.1 0.0 0.0 200 q.s. 5.0 103 200 200 0.0 5.0 0.0
0.0 200 q.s. 5.0 104 200 200 0.0 0.1 0.0 0.0 200 q.s. 5.0 105 0.01
0.0 25 0.0 0.0 0.0 200 q.s. 5.0 106 0.01 0.0 200 0.0 0.0 0.0 200
q.s. 5.0 107 200 0.0 25 0.0 0.0 0.0 200 q.s. 5.0 108 200 0.0 200
0.0 0.0 0.0 200 q.s. 5.0 109 0.01 0.0 25 5.0 0.0 0.0 200 q.s. 5.0
110 0.01 0.0 25 0.1 0.0 0.0 200 q.s. 5.0 111 200 0.0 200 5.0 0.0
0.0 200 q.s. 5.0 112 200 0.0 200 0.1 0.0 0.0 200 q.s. 5.0
.sup.aMilligram/milliliter vargatef
Example 6: Nebulization Device Performance
[0662] To evaluate aerosol performance, several formulations (Table
11) were tested in the eFlow device. For these studies the standard
eFlow 35L head was used. Particle size distribution was determined
using an Insitec Spraytec Laser Particle Sizer. Breath simulation
was performed using a Servo 1000i ventilator attached to a
respiratory therapy training lung. The European Standard breath
pattern (15 breaths per minute, 500 cc tidal volume and 1:1
inhalation-to-exhalation ratio) was used in determinations. Results
from these studies are shown in Table 12 and 13. Each result is an
average of duplicate trials in each of three devices.
TABLE-US-00025 TABLE 12 Nebulized aerosol particle sizing
Formulation (Table 11b): 1 2 Fill volume: mL 0.5 0.5 Label claim
mg/mL 20.0 4.0 Dv(90).sup.a .mu.m 5.0 8.1 Dv(50).sup.a 2.6 3.1
Dv(10).sup.a 1.2 1.3 Span.sup.b 1.4 2.2 RF.sup.c % <5 .mu.m 88.7
74.7 .sup.aDv(X): Maximum particle diameter below which 90%, 50%
(median population particle size) and 10% of the sample volume
exists.; .sup.bSpan = [Dv(90)-Dv(10)]/Dv(50); .sup.cRespirable
fraction (RF) is the percent of nebulized particles <5
.mu.m.
TABLE-US-00026 TABLE 13 Nebulized aerosol breath simulation
Formulation from Table 11b: 1 2 Fill Volume mL 0.50 0.50 Label
Claim mg/mL 20.00 4.00 Dose Duration min 1.18 1.05 Inhaled Dose mg
6.02 0.83 RDD.sup.a 5.33 0.62 Output, Dose mg/min 5.13 0.78 Output,
RDD 4.52 0.58 Output, Volume mL/min 0.43 0.49 Residual.sup.b mg
1.09 0.39 Neb efficiency % 53.29 31.02 .sup.aRespirable delivered
dose (RDD) calculated by multiplying the inhaled dose (mg) and
respirable fraction (RF; Table 11); .sup.bResidual imatinib
collected from the device and mouth piece.
[0663] These results show that 0.5 mL of a 20 mg/mL imatinib
phosphate formulation will be administered in about 1.2 minutes and
produced a respirable delivered dose (mg dose present within
inhaled aerosol particles less than 5 microns (.mu.m) in diameter;
RDD) of about 5.3 mg; a nebulization efficiency of about 53%. These
results also show that 0.5 mL of a 4 mg/mL imatinib phosphate
formulation will be administered in about 1.1 minutes and produce a
RDD of about 0.8 mg; a nebulization efficiency of about 31%.
Manipulation of the imatinib concentration and device fill volume
will permit optimization of dose delivery time and lung Cmax/plasma
exposure ratio. By example, a high imatinib concentration
formulation will be administered in only a few breaths over a short
time. The result will be a higher lung Cmax with the same plasma
exposure as the same amount of imatinib delivered in a larger
volume over more breaths and longer time. Similarly, if the
resulting plasma Cmax is determined to be of concern, this may be
addressed by either less administered imatinib or a lower
concentration imatinib formulation. Both will reduce lung Cmax, but
permit balancing the two critical parameters.
Example 7: Pharmacokinetics and Lung-Tissue Distribution
[0664] Sprague-Dawley rats (200-250 grams) were administered
imatinib mesylate by oral (gavage) or imatinib phosphate by
direct-lung aerosol delivery (intratracheal Penn Century
MicroSprayer.RTM. nebulizing catheter; IT). For oral
administration, 5.6 mg/kg imatinib mesylate was dissolved in 0.3 mL
saline delivered by gavage. Plasma and lung tissue samples were
taken at pre-dose, and 1, 2, 3, 4, and 8 hours post dose. Imatinib
was extracted and quantitated as .mu.g/mL plasma and .mu.g/gram
lung tissue. For IT aerosol administration, 1.0 mg/kg imatinib
phosphate was dissolved in 0.15 mL saline and delivered by
nebulizing catheter. Plasma and lung tissue samples were taken at
immediate post dose (within one minute), 5, 10, 30, 60 and 240
minutes post dosing. Imatinib was extracted and quantitated as
.mu.g/mL plasma and .mu.g/gram lung tissue. Results from these
studies are shown in FIG. 1 and Table 14.
TABLE-US-00027 TABLE 14 Imatinib pharmacokinetics and tissue
distribution following oral and aerosol administration to rats. IT
Aerosol Oral Gavage Rat dose (mg/kg) 1.0 5.6 Lung Cmax.sup.b 245.5
13.0 T.sub.1/2.sup.c 0.07 1.7 AUC.sup.d 20.4 64.1 Plasma Cmax.sup.b
0.02 1.1 T.sub.1/2.sup.c 1.7 1.7 AUC.sup.d 0.04 4.9
.sup.aIntratracheal (IT) aerosol administration .sup.bC.sub.max:
Maximum concentration. Lung tissue in .mu.g/g, plasma measured in
.mu.g/mL .sup.cT.sub.1/2: Half-life in hours .sup.dAUC:
Area-under-the-curve. Lung tissue in mg hr/kg, plasma in mg
hr/L
[0665] Table 14 results show that a 1.0 mg/kg imatinib phosphate IT
lung dose results in a lung tissue Cmax about 19-fold higher and
plasma AUC about 120-fold lower than following a 5.6 mg/kg imatinb
mesylate oral dose. During the course of the study, no acute
toxicities were observed from animals receiving IT imatinib
phosphate (out to 4 hours). Because imatinib side effects are
largely due to gastrointestinal exposure and drug-blood levels.
Achieving high lung levels in the absence of high blood levels
offers potential for improved pulmonary efficacy with fewer side
effects.
[0666] Although oral imatinib is clinically useful in treating
gastrointestinal and blood disorders, it has shown limited effect
in pulmonary diseases such as IPF, PAH and cancer. It is believed
that significant barriers (such as P-glycoprotein efflux and plasma
alpha-1 acid glycoprotein binding) exist that prevent oral
bioavailability to the lung. Moreover, safety and tolerability
concerns prohibit further dose escalation of the approved oral
product.
[0667] From the above data, about 106-fold less inhaled imatinib
will achieve the same lung Cmax as oral administration. As these
lung-delivered Cmax levels are relatively short-lived, important
for inhaled product success was the Example 2 demonstration that
only short-duration imatinib peak levels are required for maximum
imatinib activity. In some embodiments, an oral-equivalent inhaled
imatinib lung Cmax will result in oral-equivalent efficacy. In some
embodiments, much less drug is required for equivalent efficacy;
small inhaled imatinib dose levels enable improved safety and
tolerability. In some embodiments improving the safety and
tolerability of imatinib by inhalation administration effectively
broadens the imatinib therapeutic index (TI). In some embodiments,
small inhaled imatinib dose levels may be increased to achieve
additional efficacy.
* * * * *