U.S. patent application number 17/576830 was filed with the patent office on 2022-07-14 for aerosol pirfenidone and pyridone analog compounds and uses thereof.
The applicant listed for this patent is AVALYN PHARMA INC.. Invention is credited to Mark William Surber.
Application Number | 20220218683 17/576830 |
Document ID | / |
Family ID | 1000006215073 |
Filed Date | 2022-07-14 |
United States Patent
Application |
20220218683 |
Kind Code |
A1 |
Surber; Mark William |
July 14, 2022 |
AEROSOL PIRFENIDONE AND PYRIDONE ANALOG COMPOUNDS AND USES
THEREOF
Abstract
Disclosed herein are formulations of pirfenidone or pyridone
analog compounds for aerosolization and use of such formulations
for aerosol administration of pirfenidone or pyridone analog
compounds for the prevention or treatment of various fibrotic and
inflammatory diseases, including disease associated with the lung,
heart, kidney, liver, eye and central nervous system. In some
embodiments, pirfenidone or pyridone analog compound formulations
and delivery options described herein allow for efficacious local
delivery of pirfenidone or pyridone analog compound. 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.
Inventors: |
Surber; Mark William; (San
Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AVALYN PHARMA INC. |
Seattle |
WA |
US |
|
|
Family ID: |
1000006215073 |
Appl. No.: |
17/576830 |
Filed: |
January 14, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16151141 |
Oct 3, 2018 |
11224592 |
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17576830 |
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13363311 |
Jan 31, 2012 |
10092552 |
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16151141 |
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61584119 |
Jan 6, 2012 |
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61559670 |
Nov 14, 2011 |
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61508542 |
Jul 15, 2011 |
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61438203 |
Jan 31, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61M 15/009 20130101;
A61K 31/4418 20130101; A61K 9/0078 20130101; A61M 2202/064
20130101 |
International
Class: |
A61K 31/4418 20060101
A61K031/4418; A61K 9/00 20060101 A61K009/00 |
Claims
1. A composition for clinically efficacious treatment of idiopathic
pulmonary fibrosis in an adult human comprising: delivering a
therapeutically effective dose of pirfenidone or a pyridone analog
compound to the lung of the adult human by inhalation of an aerosol
formed by nebulization of an aqueous solution comprising water;
pirfenidone, at a concentration from about 5.0 to about 19.0 mg/mL;
a permeant ion concentration of between about 0.1% and about 5.0%,
wherein the permeant ions are chloride ions, bromide ions, or a
combination thereof; a citrate or phosphate buffer; and a taste
masking agent at a concentration of between 0.1 and 2.0 mM, wherein
a total daily dose of inhaled pirfenidone does not exceed 480 mg,
and wherein the therapeutically effective dose treats idiopathic
pulmonary fibrosis by reducing a decline in forced vital capacity
(FVC) in the lung of the adult human.
2. The composition of claim 1, wherein nebulization of the aqueous
solution: (i) achieves lung deposition of at least 5% of the
pirfenidone administered to the human; (ii) creates: a) a mass
median aerodynamic diameter (MMAD) of droplet size of the aqueous
solution emitted with the high efficiency liquid nebulizer of about
0.5 .mu.m to about 5 .mu.m; and/or b) a volumetric mean diameter
(VMD) of about 0.5 .mu.m to about 5 .mu.m; (iii) creates a
Geometric Standard Deviation (GSD) of emitted droplet size
distribution of the aqueous solution of about 1.0 .mu.m to about
3.4 .mu.m; (iv) creates a fine particle fraction (FPF=% of aerosol
particles less than or equal to 5 microns) of droplets emitted from
the liquid nebulizer of at least about 30%; (v) creates an output
rate of at least 0.1 mL/min; and/or (vi) creates at least about 25%
of the aqueous solution to the human.
3. The composition of claim 1, wherein: the aerosol formed by the
nebulization of the aqueous solution comprises between 0.1 mg and
250 mg of pirfenidone and the aerosol has a median diameter (MMAD)
particle size from about 0.5 to about 5 micron.
4. The composition of claim 1, wherein: the lung Cmax and/or AUC of
pirfenidone of the aerosol obtained after a single administration
of the aqueous solution to the human with a liquid nebulizer is
about the same or greater than the lung Cmax and/or AUC of
pirfenidone obtainable after administration of a single dose of
orally administered pirfenidone to the human at a dose that is from
about 80% to about 120% of the dose administered with the liquid
nebulizer.
5. The composition of claim 1, wherein the aqueous solution further
comprises: one or more additional ingredients selected from
co-solvents, taste masking agents, tonicity agents, sweeteners,
surfactants, wetting agents, chelating agents, anti-oxidants,
salts, and buffers and combinations thereof.
6. The composition of claim 1 further comprising a liquid nebulizer
having an aerosol generator and a medicament chamber containing the
aqueous solution.
7. The composition claim 6, wherein 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 piston nebulizer.
8. The composition of claim 1 contained in a liquid nebulizer
comprising an aerosol generator adapted to receive a liquid storage
container containing a metered single or multidose volume, such
that the received liquid storage container functions as the
medicament container in the nebulizer, or a piston nebulizer.
9. The composition of claim 8, wherein 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 piston nebulizer.
10. The composition of claim 1, wherein the aerosol of the aqueous
solution creates: a) a lung Cmax of pirfenidone obtained in the
adult human lung upon administration of the therapeutically
effective dose is at least equivalent to or greater than a lung
Cmax achievable upon administration of 801 mg of an orally
administered dosage of pirfenidone to the human; and/or b) a blood
AUC.sub.0-24 of pirfenidone obtained in the adult human lung upon
administration of the therapeutically effective dose is less than a
blood AUC.sub.0-24 achievable upon administration of 801 mg of an
orally administered dosage of pirfenidone to the adult human lung.
Description
PRIORITY CLAIM
[0001] This application claims benefit of U.S. Provisional
Application No. 61/438,203, entitled "AEROSOL PIRFENIDONE AND
PYRIDONE ANALOG COMPOUNDS AND USES THEREOF" filed on Jan. 31, 2011;
U.S. Provisional Application No. 61/508,542, entitled "AEROSOL
PIRFENIDONE AND PYRIDONE ANALOG COMPOUNDS AND USES THEREOF" filed
on Jul. 15, 2011; U.S. Provisional Application No. 61/559,670,
entitled "AEROSOL PIRFENIDONE AND PYRIDONE ANALOG COMPOUNDS AND
USES THEREOF" filed on Nov. 14, 2011; U.S. Provisional Application
No. 61/584,119, entitled "AEROSOL PIRFENIDONE AND PYRIDONE ANALOG
COMPOUNDS AND USES THEREOF" filed on Jan. 6 2012; all of which are
herein incorporated by reference in their entirety.
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 pyridone compositions such as pirfenidone 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] A number of undesirable pulmonary diseases such as
interstitial lung disease (ILD; and sub-class diseases therein),
chronic obstructive pulmonary disease (COPD; and sub-class diseases
therein), asthma, and fibrotic indications of the kidney, heart and
eye, the diseases are initiated from an external challenge. By
non-limiting example, these effectors can include infection,
cigarette smoking, environmental exposure, radiation exposure,
surgical procedures and transplant rejection. However, other causes
related to genetic disposition and the effects of aging may also be
attributed. Described herein are compositions of pirfenidone or a
pyridone analog compound that are suitable for inhalation delivery
to the lungs and/or systemic compartment and methods of using such
compositions.
SUMMARY
[0004] According to a certain embodiment of the present invention,
there is provided a pirfenidone or pyridone analog compound
formulation composition for oral pulmonary or intranasal inhalation
delivery, comprising formulations for aerosol administration of
pirfenidone or pyridone analog compounds for the prevention or
treatment of various fibrotic and inflammatory diseases, including
disease associated with the lung, heart, kidney, liver, eye and
central nervous system.
[0005] In one aspect, described herein is an aqueous solution for
nebulized inhalation administration comprising: water; pirfenidone,
or a pyridone analog compound, at a concentration from about 10
mg/mL to about 50 mg/mL; and one or more co-solvents. In another
aspect, described herein is an aqueous solution for nebulized
inhalation administration comprising: water; pirfenidone, or a
pyridone analog compound, at a concentration from about 10 mg/mL to
about 50 mg/mL; optionally one or more buffers to maintain the pH
between about pH 4.0 to about pH 8.0; and one or more co-solvents.
In some embodiments, the pH of the aqueous solution if from about
pH 4.0 to about pH 8.0. In some embodiments, the pH of the aqueous
solution if from about pH 6.0 to about pH 8.0. In some embodiments,
described herein is an aqueous solution for nebulized inhalation
administration comprising: water; pirfenidone, or a pyridone analog
compound, at a concentration from about 0.1 mg/mL to about 60
mg/mL; and one or more co-solvents, wherein the osmolality of the
aqueous solution is from about 50 mOsmol/kg to about 6000
mOsmol/kg. In some embodiments, pirfenidone, or a pyridone analog
compound, is at a concentration from about 10 mg/mL to about 60
mg/mL. In some embodiments, pirfenidone, or a pyridone analog
compound, is at a concentration from about 10 mg/mL to about 50
mg/mL. In some embodiments, pirfenidone, or a pyridone analog
compound, is at a concentration from about 15 mg/mL to about 50
mg/mL. In some embodiments, pirfenidone, or a pyridone analog
compound, is at a concentration from about 20 mg/mL to about 50
mg/mL. In some embodiments, pirfenidone, or a pyridone analog
compound, is at a concentration from about 25 mg/mL to about 50
mg/mL. In some embodiments, pirfenidone, or a pyridone analog
compound, is at a concentration from about 30 mg/mL to about 50
mg/mL. In some embodiments, the osmolality of the aqueous solution
is from about 50 mOsmol/kg to about 6000 mOsmol/kg. In some
embodiments, the osmolality of the aqueous solution is from about
50 mOsmol/kg to about 5000 mOsmol/kg. In some embodiments, the
osmolality of the aqueous solution is from about 100 mOsmol/kg to
about 5000 mOsmol/kg, from about 300 mOsmol/kg to about 5000
mOsmol/kg, from about 400 mOsmol/kg to about 5000 mOsmol/kg, from
about 600 mOsmol/kg to about 5000 mOsmol/kg, from about 1000
mOsmol/kg to about 5000 mOsmol/kg, or from about 2000 mOsmol/kg to
about 5000 mOsmol/kg. In some embodiments, the total concentration
of co-solvents is from about 1% to about 40% v/v. In some
embodiments, the total concentration of co-solvents is from about
1% to about 30% v/v. In some embodiments, the total concentration
of co-solvents is from about 1% to about 25% v/v. In some
embodiments, the one or more co-solvents are selected from ethanol,
propylene glycol, and glycerol. In some embodiments, the one or
more co-solvents are selected from ethanol, and propylene glycol.
In some embodiments, the aqueous solution includes both ethanol and
propylene glycol. In some embodiments, the solution further
comprises one or more additional ingredients selected from
surfactants, taste masking agents/sweeteners and salts. In some
embodiments, the tastemaking agent/sweetener is saccharin, or salt
thereof. In some embodiments, the solution further comprises one or
more additional ingredients selected from surfactants and salts. In
some embodiments, the surfactant is polysorbate 80 or
cetylpyridinium bromide. In some embodiments, the salt is sodium
chloride or magnesium chloride. In some embodiments, the surfactant
is polysorbate 80 or cetylpyridinium bromide, and the salt is
sodium chloride or magnesium chloride. 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,
described herein is from about 0.5 mL to about 6 mL of the aqueous
solution described herein.
[0006] In some embodiments, the solution further comprises one or
more additional ingredients selected from surfactants, buffers and
salts. In some embodiments, the surfactant is polysorbate 80 or
cetylpyridinium bromide; the buffer is a citrate buffer or
phosphate buffer; and the salt is sodium chloride or magnesium
chloride.
[0007] In some embodiments, the aqueous solution comprises: water;
pirfenidone or pyridone analog compound at a concentration from
about 10 mg/mL to about 60 mg/mL; one or more co-solvents, wherein
the total amount of the one or more co-solvents is about 1% to
about 40% v/v, where the one or more co-solvents are selected from
about 1% to about 25% v/v of ethanol, about 1% to about 25% v/v of
propylene glycol, and about 1% to about 25% v/v of glycerol; and
optionally a phosphate buffer that maintains the pH of the solution
from about pH 6.0 to about pH 8.0.
[0008] In some embodiments, the aqueous solution comprises: water;
pirfenidone or pyridone analog compound at a concentration from
about 15 mg/mL to about 50 mg/mL; one or more co-solvents, wherein
the total amount of the one or more co-solvents if about 1 to about
30% v/v, where the one or more co-solvents are selected from about
1% to about 10% v/v of ethanol, and about 1% to about 20% v/v of
propylene glycol; and optionally a phosphate buffer that maintains
the pH of the solution from about pH 6.0 to about pH 8.0; wherein
the osmolality of the aqueous solution is from about 400 mOsmol/kg
to about 6000 mOsmol/kg.
[0009] In some embodiments, the aqueous solution for nebulized
inhalation administration described herein comprises: water;
pirfenidone or pyridone analog compound at a concentration from
about 10 mg/mL to about 50 mg/mL; optionally a phosphate buffer
that maintains the pH of the solution from about pH 6.0 to about pH
8.0; one or more co-solvents selected from about 1% to about 25%
v/v of ethanol and about 1% to about 25% v/v of propylene glycol,
where the total amount of co-solvents is from 1% to 25% v/v. In
some embodiments, the aqueous solution for nebulized inhalation
administration described herein comprises: water; pirfenidone or
pyridone analog compound at a concentration from about 10 mg/mL to
about 50 mg/mL; optionally a phosphate buffer that maintains the pH
of the solution from about pH 6.0 to about pH 8.0; about 8% v/v of
ethanol; and about 16% v/v of propylene glycol. In some
embodiments, the aqueous solution for nebulized inhalation
administration described herein consists essentially of: water;
pirfenidone or pyridone analog compound at a concentration from
about 10 mg/mL to about 50 mg/mL; optionally a phosphate buffer
that maintains the pH of the solution from about pH 6.0 to about pH
8.0; one or more co-solvents selected from about 1% to about 25%
v/v of ethanol and about 1% to about 25% v/v of propylene glycol,
where the total amount of co-solvents is from 1% to 25% v/v. In
some embodiments, the aqueous solution for nebulized inhalation
administration described herein consists essentially of: water;
pirfenidone or pyridone analog compound at a concentration from
about 10 mg/mL to about 50 mg/mL; optionally a phosphate buffer
that maintains the pH of the solution from about pH 6.0 to about pH
8.0; about 8% v/v of ethanol; and about 16% v/v of propylene
glycol. In some embodiments, described herein is from about 0.5 mL
to about 6 mL of the aqueous solution described herein.
[0010] 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 pirfenidone or a pyridone
analog compound, wherein the concentration of pirfenidone or
pyridone analog compound in the aqueous solution is from about 0.1
mg/mL to about 60 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, salts, and buffers; and
the osmolality of the aqueous solution is from about 50 mOsmol/kg
to about 6000 mOsmol/kg. In some embodiments, the aqueous solution
further comprises: one or more co-solvents selected from ethanol,
propylene glycol, and glycerol; and one or both of a citrate buffer
or a phosphate buffer. In some embodiments, the aqueous solution
comprises: pirfenidone or pyridone analog compound dissolved in
water at a concentration from about 15 mg/mL to about 50 mg/mL;
optionally a phosphate buffer that maintains the pH of the solution
from about pH 6.0 to about pH 8.0; one or more co-solvents, wherein
the total amount of the one or more co-solvents if about 1 to about
30% v/v, where the one or more co-solvents are selected from about
1% to about 10% v/v of ethanol, and about 1% to about 20% v/v of
propylene glycol; wherein the osmolality of the aqueous solution is
from about 400 mOsmol/kg to about 6000 mOsmol/kg. In some
embodiments, the aqueous solution is as described herein.
[0011] In some embodiments, described herein is a kit comprising: a
unit dosage of an aqueous solution of pirfenidone or pyridone
analog as described herein in a container that is adapted for use
in a liquid nebulizer.
[0012] In some embodiments, provided herein is an aqueous droplet
of pirfenidone or pyridone analog compound, 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 pirfenidone or pyridone analog
compound. In some embodiments, the aqueous solution of pirfenidone
or pyridone analog compound is as described herein. In some
embodiments, the aqueous solution has concentration of pirfenidone
or pyridone analog compound from 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 is produced by a
nebulizing an aqueous solution of pirfenidone or pyridone analog
compound 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.
[0013] In some embodiments, provided herein is an aqueous aerosol
comprising a plurality of aqueous droplets of pirfenidone or
pyridone analog compound. In some embodiments, described herein is
an aqueous aerosol comprising a plurality of aqueous droplets of
pirfenidone or pyridone analog compound, 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 pirfenidone or pyridone analog compound. In
some embodiments, the aqueous solution has concentration of
pirfenidone or pyridone analog compound from about 10 mg/mL and
about 60 mg/mL and an osmolality from about 50 mOsmol/kg to about
6000 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 pirfenidone or pyridone analog compound 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.
[0014] 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 pirfenidone or pyridone
analog 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.
[0015] 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
pirfenidone or pyridone analog compound 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%.
[0016] 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 pirfenidone
or a pyridone analog compound 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 pirfenidone or a pyridone
analog compound with a liquid nebulizer; wherein the aqueous
solution comprises water; pirfenidone, or a pyridone analog
compound, at a concentration from about 0.1 mg/mL to about 60
mg/mL; and one or more co-solvents, wherein the osmolality of the
aqueous solution is from about 50 mOsmol/kg to about 6000
mOsmol/kg. In some embodiments, the aqueous solution comprises
water; pirfenidone or pyridone analog compound at a concentration
from about 10 mg/mL to about 60 mg/mL; one or more co-solvents,
wherein the total amount of the one or more co-solvents is about 1%
to about 40% v/v, where the one or more co-solvents are selected
from about 1% to about 25% v/v of ethanol, about 1% to about 25%
v/v of propylene glycol, and about 1% to about 25% v/v of glycerol;
and optionally a phosphate buffer that maintains the pH of the
solution from about pH 6.0 to about pH 8.0. In some embodiments,
the aqueous solution comprises water; pirfenidone or pyridone
analog compound at a concentration from about 15 mg/mL to about 50
mg/mL; one or more co-solvents, wherein the total amount of the one
or more co-solvents if about 1 to about 30% v/v, where the one or
more co-solvents are selected from about 1% to about 10% v/v of
ethanol, and about 1% to about 20% v/v of propylene glycol; and
optionally a phosphate buffer that maintains the pH of the solution
from about pH 6.0 to about pH 8.0; wherein the osmolality of the
aqueous solution is from about 400 mOsmol/kg to about 6000
mOsmol/kg. 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 pirfenidone or
pyridone analog 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. 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 liquid nebulizer delivers from about 0.1 mg to
about 360 mg of pirfenidone or pyridone analog 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.
[0017] In some embodiments, the lung tissue Cmax and/or AUC of
pirfenidone or pyridone analog compound that is obtained after a
single administration of the aqueous solution to the mammal with a
liquid nebulizer is about the same or greater than the lung tissue
Cmax and/or AUC of pirfenidone or pyridone analog compound that is
obtained after a single dose of orally administered pirfenidone or
pyridone analog compound at a dose that is from about 80% to about
120% of the dose administered with the liquid nebulizer; and/or the
plasma Cmax and/or AUC of pirfenidone or pyridone analog compound
that is obtained after a single administration of the aqueous
solution to the mammal with a liquid nebulizer is at least 10% or
greater than the plasma Cmax and/or AUC of pirfenidone or pyridone
analog compound that is obtained after a single dose of orally
administered pirfenidone or pyridone analog compound at a dose that
is from about 80% to about 120% of the dose administered with the
liquid nebulizer. In some embodiments, the lung tissue Cmax of
pirfenidone or pyridone analog compound that is obtained after a
single administration of the aqueous solution to the mammal with a
liquid nebulizer is greater than the lung tissue Cmax of
pirfenidone or pyridone analog compound that is obtained after a
single dose of orally administered pirfenidone or pyridone analog
compound at a dose that is from about 80% to about 120% of the dose
administered with the liquid nebulizer. In some embodiments, the
lung tissue AUC of pirfenidone or pyridone analog compound that is
obtained after a single administration of the aqueous solution to
the mammal with a liquid nebulizer is greater than the lung tissue
AUC of pirfenidone or pyridone analog compound that is obtained
after a single dose of orally administered pirfenidone or pyridone
analog compound at a dose that is from about 80% to about 120% of
the dose administered with the liquid nebulizer. In some
embodiments, the plasma Cmax of pirfenidone or pyridone analog
compound that is obtained after a single administration of the
aqueous solution to the mammal with a liquid nebulizer is at least
10% or greater than the plasma Cmax of pirfenidone or pyridone
analog compound that is obtained after a single dose of orally
administered pirfenidone or pyridone analog compound at a dose that
is from about 80% to about 120% of the dose administered with the
liquid nebulizer. In some embodiments, the plasma AUC of
pirfenidone or pyridone analog compound that is obtained after a
single administration of the aqueous solution to the mammal with a
liquid nebulizer is at least 10% or greater than the plasma AUC of
pirfenidone or pyridone analog compound that is obtained after a
single dose of orally administered pirfenidone or pyridone analog
compound at a dose that is from about 80% to about 120% of the dose
administered with the liquid nebulizer.
[0018] In some embodiments, the liquid nebulizer delivers from
about 0.1 mg to about 360 mg of pirfenidone or pyridone analog
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.
[0019] In some embodiments, administration with the liquid
nebulizer does not include an initial dose-escalation period.
[0020] In some embodiments, described herein is a method of
reducing the risk of gastrointestinal (GI) adverse events in the
treatment of a human with pirfenidone or pyridone analog compound,
comprising: administering to the human in need thereof a nebulized
aqueous solution comprising pirfenidone or a pyridone analog
compound with a liquid nebulizer; wherein the aqueous solution
comprises water; pirfenidone, or a pyridone analog compound, at a
concentration from about 0.1 mg/mL to about 60 mg/mL; and one or
more co-solvents, wherein the osmolality of the aqueous solution is
from about 50 mOsmol/kg to about 6000 mOsmol/kg. In some
embodiments, the aqueous solution comprises water; pirfenidone or
pyridone analog compound at a concentration from about 10 mg/mL to
about 60 mg/mL; one or more co-solvents, wherein the total amount
of the one or more co-solvents is about 1% to about 40% v/v, where
the one or more co-solvents are selected from about 1% to about 25%
v/v of ethanol, about 1% to about 25% v/v of propylene glycol, and
about 1% to about 25% v/v of glycerol; and optionally a phosphate
buffer that maintains the pH of the solution from about pH 6.0 to
about pH 8.0.
[0021] In some embodiments, the aqueous solution comprises water;
pirfenidone or pyridone analog compound at a concentration from
about 15 mg/mL to about 50 mg/mL; one or more co-solvents, wherein
the total amount of the one or more co-solvents if about 1 to about
30% v/v, where the one or more co-solvents are selected from about
1% to about 10% v/v of ethanol, and about 1% to about 20% v/v of
propylene glycol; and optionally a phosphate buffer that maintains
the pH of the solution from about pH 6.0 to about pH 8.0; wherein
the osmolality of the aqueous solution is from about 400 mOsmol/kg
to about 6000 mOsmol/kg. In some embodiments, the pirfenidone or
pyridone analog is administered to treat lung disease in the human.
In some embodiments, lung disease is idiopathic pulmonary
fibrosis.
[0022] In some embodiments, the liquid nebulizer delivers about 0.1
mg to about 360 mg of prifenidone or pyridone analog compound to
the lungs in less than about 20 minutes with mass median diameter
(MMAD) particles sizes from about 1 to about 5 micron.
[0023] In some embodiments, administration with the liquid
nebulizer does not include an initial dose-escalation period.
[0024] 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 pirfenidone or
pyridone analog compound from about 0.1 mg/mL to about 60 mg/mL and
the osmolality of the aqueous solution is from about 50 mOsmol/kg
to about 5000 mOsmol/kg; and the liquid nebulizer is a nebulizer
comprising a vibrating mesh or plate with multiple apertures.
[0025] In some embodiments, the liquid nebulizer delivers about 0.1
mg to about 360 mg of prifenidone or pyridone analog 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 aqueous solution has a pH from about 4.0 to about
8.0 and an osmolality from about 400 mOsmol/kg to about 5000
mOsmol/kg.
[0026] In some embodiments, described herein is an inhalation
system for administration of pirfenidone or pyridone analog
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 pirfenidone or pyridone analog compound; 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 pirfenidone or pyridone analog
compound in the aqueous solution is from about 0.1 mg/mL and about
60 mg/mL and the osmolality of the aqueous solution is from about
400 mOsmol/kg to about 6000 mOsmol/kg. In some embodiments, the
aqueous solution comprises: water; pirfenidone, or a pyridone
analog compound, at a concentration from about 10 mg/mL to about 50
mg/mL; optionally a phosphate buffer that maintains the pH of the
solution from about pH 6.0 to about pH 8.0; about 1% to about 8% of
ethanol; and/or about 2% to about 16% of propylene glycol. In some
embodiments, the aqueous solution is as described herein.
[0027] In one aspect, described herein is a method of achieving a
lung tissue Cmax of pirfenidone or pyridone analog 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
801 mg of an orally administered dosage of pirfenidone or pyridone
analog compound, the method comprising nebulizing an aqueous
solution comprising pirfenidone or pyridone analog compound and
administering the nebulized aqueous solution to a human. In some
embodiments, described herein is a method of achieving a lung
tissue Cmax of pirfenidone or pyridone analog compound that is at
least equivalent to or greater than a Cmax of up to 801 mg of an
orally administered dosage of pirfenidone or pyridone analog
compound, the method comprising nebulizing an aqueous solution
comprising pirfenidone or pyridone analog compound and
administering the nebulized aqueous solution to a human.
[0028] In one aspect, described herein is a method of achieving a
lung tissue AUC.sub.0-24 of pirfenidone or pyridone analog 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
AUC.sub.0-24 of up to 801 mg of an orally administered dosage of
pirfenidone or pyridone analog compound, the method comprising
nebulizing an aqueous solution comprising pirfenidone or pyridone
analog 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 pirfenidone or pyridone
analog compound that is at least equivalent to or greater than
AUC.sub.0-24 of up to 801 mg of an orally administered dosage of
pirfenidone or pyridone analog compound, the method comprising
nebulizing an aqueous solution comprising pirfenidone or pyridone
analog compound and administering the nebulized aqueous solution to
a human.
[0029] In one aspect, described herein is a method of administering
pirfenidone or a pyridone analog compound to a human, comprising
administering a nebulized aqueous solution containing the
pirfenidone or pyridone analog, 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 pirfenidone or pyridone analog compound dosage
that is from 80% to 120% of the dose amount of pirfenidone that is
administered by nebulization.
[0030] In one aspect, described herein is a method of administering
pirfenidone or a pyridone analog compound to a human, comprising
administering a nebulized aqueous solution containing the
pirfenidone or pyridone analog, 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 pirfenidone or pyridone analog compound dosage
that is from 80% to 120% of the dosage of pirfenidone or pyridone
analog compound in the nebulized aqueous solution of pirfenidone or
pyridone analog compound. In some embodiments, described herein is
a method of administering pirfenidone or a pyridone analog compound
to a human, comprising administering a nebulized aqueous solution
containing the pirfenidone or pyridone analog, 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 pirfenidone or pyridone analog compound dosage
that is from 80% to 120% of the dosage of pirfenidone or pyridone
analog compound in the nebulized aqueous solution of pirfenidone or
pyridone analog compound that is administered.
[0031] In some embodiments, described herein is a method of
administering pirfenidone or a pyridone analog compound to a human,
comprising administering a nebulized aqueous solution containing
the pirfenidone or pyridone analog, wherein the plasma AUC.sub.0-24
achieved with the nebulized solution is at least 10% or greater
than the plasma AUC.sub.0-24 achieved with an orally administered
pirfenidone or pyridone analog compound dosage that is from 80% to
120% of the dosage of pirfenidone or pyridone analog compound in
the nebulized aqueous solution of pirfenidone or pyridone analog
compound that is administered.
[0032] In one aspect, described herein is a method of administering
pirfenidone or a pyridone analog compound to a human, comprising
administering a nebulized aqueous solution containing the
pirfenidone or pyridone analog, 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 pirfenidone or pyridone analog
compound dosage that is from 80% to 120% of the dosage of
pirfenidone or pyridone analog compound in the nebulized aqueous
solution of pirfenidone or pyridone analog compound. In some
embodiments, described herein is a method of administering
pirfenidone or a pyridone analog compound to a human, comprising
administering a nebulized aqueous solution containing the
pirfenidone or pyridone analog, 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 pirfenidone or pyridone analog compound dosage that is
from 80% to 120% of the dosage of pirfenidone or pyridone analog
compound in the nebulized aqueous solution of pirfenidone or
pyridone analog compound.
[0033] In one aspect, provided herein is a method of improving the
pharmacokinetic profile obtained in a human following a single oral
dose administration of pirfenidone or pyridone analog. In some
embodiments, the human the pirfenidone or pyridone analog 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 801 mg
of pirfenidone or pyridone analog compound. In some embodiments,
the method of improving the pharmacokinetic profile comprises the
step of administering pirfenidone or pryridone analog 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 pirfenidone or pryridone analog is
administered as an aqueous solution with a liquid nebulizer. In
some embodiments, the aqueous solution of pirfenidone or pyridone
analog is as described herein. In some embodimenents, 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, the improvement in
pharmacokinetic profile is subtantially the same as depicted in
FIG. 1. In some embodiments, the initial improvement in
pharmacokinetic profile is subtantially the same as depicted in
FIG. 1, but the pulmonary half-life is extended providing longer
pulmonary residence time.
[0034] In some embodiments, described herein is a pharmaceutical
composition for pulmonary delivery, comprising a solution of
pirfenidone or pyridone analog having a concentration greater than
about 34 mcg/mL, having an osmolality greater than about 100
mOsmol/kg, and having a pH greater than about 4.0. In some
embodiments, the pirfenidone or pyridone analog concentration is
greater than about 1.72 mg/mL. In some embodiments, the pirfenidone
or pyridone analog concentration is greater than about 86 mg/mL. In
some embodiments, the pirfenidone or pyridone analog 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 pirfenidone or pyridone analog solution has a pH
from about 4.0 to about 8.0. In some embodiments, the pirfenidone
or pyridone analog solution has an osmolality from about 100
mOsmol/kg to about 1000 mOsmol/kg. In some embodiments, the
pirfenidone or pyridone analog solution has an osmolality from
about 50 mOsmol/kg to about 5000 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 agent suitable for pulmonary delivery. In some
embodiments, the composition comprises a second anti-inflammatory
agent suitable for pulmonary delivery.
[0035] In some embodiments, described herein is a pharmaceutical
composition for pulmonary delivery, comprising a solution of
pirfenidone or pyridone analog 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
pirfenidone or pyridone analog concentration is greater than about
34 mcg/mL. In some embodiments, the pirfenidone or pyridone analog
concentration is greater than about 1.72 mg/mL. In some
embodiments, the pirfenidone or pyridone analog concentration is
greater than about 86 mg/mL. In some embodiments, the pirfenidone
or pyridone analog 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 pirfenidone or
pyridone analog solution has a pH from about 4.0 to about 8.0. In
some embodiments, the pirfenidone or pyridone analog solution has
an osmolality from about 100 mOsmol/kg to about 1000 mOsmol/kg. In
some embodiments, the pirfenidone or pyridone analog solution has
an osmolality from about 50 mOsmol/kg to about 5000 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 agent suitable for pulmonary delivery. In some
embodiments, the composition comprises a second anti-inflammatory
agent suitable for pulmonary delivery.
[0036] In some embodiments, described herein is a sterile,
single-use container comprising from about 0.1 mL to about 20 mL of
a solution of pirfenidone or pyridone analog having a concentration
greater than about 34 mcg/mL, having an osmolality greater than
about 100 mOsmol/kg, and having a pH greater than about 4.0. In
some embodiments, the pirfenidone or pyridone analog concentration
is greater than about 1.72 mg/mL. In some embodiments, the
pirfenidone or pyridone analog concentration is greater than about
86 mg/mL. In some embodiments, the pirfenidone or pyridone analog
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 pirfenidone or pyridone analog
solution has a pH from about 4.0 to about 8.0. In some embodiments,
the pirfenidone or pyridone analog solution has an osmolality from
about 100 mOsmol/kg to about 1000 mOsmol/kg. In some embodiments,
the pirfenidone or pyridone analog solution has an osmolality from
about 50 mOsmol/kg to about 5000 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 agent suitable for pulmonary
delivery. In some embodiments, the container further comprises a
second anti-inflammatory agent suitable for pulmonary delivery.
[0037] In one aspect, described herein is a method to treat a
pulmonary disease comprising inhaling an aerosol of pirfenidone or
pyridone analog solution having a concentration greater than about
34 mcg/mL, having an osmolality greater than about 100 mOsmol/kg,
and having a pH greater than about 4.0. In some embodiments, the
pirfenidone or pyridone analog concentration is greater than about
1.72 mg/mL. In some embodiments, the pirfenidone or pyridone analog
concentration is greater than about 86 mg/mL. In some embodiments,
the pirfenidone or pyridone analog 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 pirfenidone or pyridone analog solution has a pH
from about 4.0 to about 8.0. In some embodiments, the pirfenidone
or pyridone analog solution has an osmolality from about 100
mOsmol/kg to about 1000 mOsmol/kg. In some embodiments, the
pirfenidone or pyridone analog solution has an osmolality from
about 50 mOsmol/kg to about 5000 mOsmol/kg. In some embodiments,
the pirfenidone or pyridone analog 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 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 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 asthma. 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
a least 6.8 mcg pirfenidone or pyridone analog. In some
embodiments, the inhaling step delivers a dose of a least 340 mcg
pirfenidone or pyridone analog. In some embodiments, the inhaling
step delivers a dose of a least 740 mcg pirfenidone or pyridone
analog. In some embodiments, the inhaling step delivers a dose of a
least 1.7 mg pirfenidone or pyridone analog. In some embodiments,
the inhaling step delivers a dose of a least 93 mg pirfenidone or
pyridone analog. In some embodiments, the inhaling step delivers a
dose of a least 463 mg pirfenidone or pyridone analog. 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.
[0038] 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 pirfenidone or pyridone analog solution having a
concentration greater than about 34 mcg/mL, having an osmolality
greater than about 100 mOsmol/kg, and having a pH greater than
about 4.0. In another aspect, described herein is a method to
administer an anti-inflammatory agent to lungs of a patient,
comprising: introducing in a nebulizer a pirfenidone or pyridone
analog solution having a concentration greater than about 34
mcg/mL, having an osmolality greater than about 100 mOsmol/kg, and
having a pH greater than about 4.0. In some embodiments, the
pirfenidone or pyridone analog concentration is greater than about
1.72 mg/mL. In some embodiments, the pirfenidone or pyridone analog
concentration is greater than about 86 mg/mL. In some embodiments,
the pirfenidone or pyridone analog 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 pirfenidone or pyridone analog solution has a pH
from about 4.0 to about 8.0. In some embodiments, the pirfenidone
or pyridone analog solution has an osmolality from about 100
mOsmol/kg to about 1000 mOsmol/kg. In some embodiments, the
pirfenidone or pyridone analog solution has an osmolality from
about 50 mOsmol/kg to about 5000 mOsmol/kg. In some embodiments,
the pirfenidone or pyridone analog 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 pirfenidone or pyridone analog
solution. In some embodiments, the method further comprises
administering a second anti-fibrotic agent suitable for pulmonary
delivery. In some embodiments, the method further comprises
administering a second anti-inflammatory agent suitable for
pulmonary delivery.
[0039] In one aspect, described herein is a method to treat an
extrapulmonary disease target comprising inhaling an aerosol of
pirfenidone or pyridone analog solution having a concentration
greater than about 34 mcg/mL, having an osmolality greater than
about 100 mOsmol/kg, and having a pH greater than about 4.0 for the
purpose of absorbing into the pulmonary vasculature and exposing
downstream disease targets to delivered pirfenidone or pyridone
analog. In some embodiments, the pirfenidone or pyridone analog
concentration is greater than about 1.72 mg/mL. In some
embodiments, the pirfenidone or pyridone analog concentration is
greater than about 86 mg/mL. In some embodiments, the pirfenidone
or pyridone analog 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 pirfenidone or
pyridone analog solution has a pH from about 4.0 to about 8.0. In
some embodiments, the pirfenidone or pyridone analog solution has
an osmolality from about 100 mOsmol/kg to about 1000 mOsmol/kg. In
some embodiments, the pirfenidone or pyridone analog solution has
an osmolality from about 50 mOsmol/kg to about 5000 mOsmol/kg. In
some embodiments, the pirfenidone or pyridone analog 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
pirfenidone or pyridone analog solution. In some embodiments, the
method further comprises administering a second anti-fibrotic 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 the kidney. In some
embodiments, the extrapulmonary disease target is the liver.
[0040] In any of the methods described herein using an aerosol or
nebeulizer to deliver a pirfenidone or pyridone analog 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
a least 6.8 mcg pirfenidone or pyridone analog. In some
embodiments, the inhaling step delivers a dose of a least 340 mcg
pirfenidone or pyridone analog. In some embodiments, the inhaling
step delivers a dose of a least 740 mcg pirfenidone or pyridone
analog. In some embodiments, the inhaling step delivers a dose of a
least 17 mg pirfenidone or pyridone analog. In some embodiments,
the inhaling step delivers a dose of a least 93 mg pirfenidone or
pyridone analog. In some embodiments, the inhaling step delivers a
dose of a least 463 mg pirfenidone or pyridone analog. 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.
[0041] In one aspect, described herein is a method to treat a
neurologic disease comprising intranasal inhalation of an aerosol
of pirfenidone or pyridone analog solution having a concentration
greater than about 34 mcg/mL, having an osmolality greater than
about 100 mOsmol/kg, and having a pH greater than about 4.0. In
some embodiments, the pirfenidone or pyridone analog concentration
is greater than about 1.72 mg/mL. In some embodiments, the
pirfenidone or pyridone analog concentration is greater than about
86 mg/mL. In some embodiments, the pirfenidone or pyridone analog
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 pirfenidone or pyridone analog
solution has a pH from about 4.0 to about 8.0. In some embodiments,
the pirfenidone or pyridone analog solution has an osmolality from
about 100 mOsmol/kg to about 1000 mOsmol/kg. In some embodiments,
the pirfenidone or pyridone analog solution has an osmolality from
about 50 mOsmol/kg to about 5000 mOsmol/kg. In some embodiments,
the aerosol 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 method
further comprises administering a mucolytic agent suitable for
intranasal delivery. In some embodiments, the method further
comprises administering a second anti-fibrotic agent suitable for
intranasal delivery. In some embodiments, the method further
comprises administering a second anti-inflammatory agent suitable
for intranasal delivery. In some embodiments, the neurologic
disease is multiple sclerosis. 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 a least 6.8 mcg pirfenidone or
pyridone analog. In some embodiments, the inhaling step delivers a
dose of a least 340 mcg pirfenidone or pyridone analog. In some
embodiments, the inhaling step delivers a dose of a least 740 mcg
pirfenidone or pyridone analog. In some embodiments, the inhaling
step delivers a dose of a least 1.7 mg pirfenidone or pyridone
analog. In some embodiments, the inhaling step delivers a dose of a
least 93 mg pirfenidone or pyridone analog. In some embodiments,
the inhaling step delivers a dose of a least 463 mg pirfenidone or
pyridone analog. 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.
[0042] 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 pirfenidone or pyridone
analog solution having a concentration greater than about 34
mcg/mL, having an osmolality greater than about 100 mOsmol/kg, and
having a pH greater than about 4.0. In some embodiments, the
pirfenidone or pyridone analog concentration is greater than about
1.72 mg/mL. In some embodiments, the pirfenidone or pyridone analog
concentration is greater than about 86 mg/mL. In some embodiments,
the pirfenidone or pyridone analog 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 pirfenidone or pyridone analog solution has a pH
from about 4.0 to about 8.0. In some embodiments, the pirfenidone
or pyridone analog solution has an osmolality from about 100
mOsmol/kg to about 1000 mOsmol/kg. In some embodiments, the
pirfenidone or pyridone analog solution has an osmolality from
about 50 mOsmol/kg to about 5000 mOsmol/kg. In some embodiments,
the solution 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 method
further comprises administering a mucolytic agent suitable for
intranasal delivery. In some embodiments, the mucolytic agent is
inhaled separately from the pirfenidone or pyridone analog
solution. In some embodiments, the method further comprises
administering a second agent suitable for intranasal delivery.
[0043] In any of the methods described herein involving introducing
in a nebulizer a pirfenidone or pyridone analog 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
pirfenidone or pyridone analog solution for introduction into a
nebulizer.
[0044] 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 a least 6.8 mcg pirfenidone or pyridone analog. In some
embodiments, the inhaling step delivers a dose of a least 340 mcg
pirfenidone or pyridone analog. In some embodiments, the inhaling
step delivers a dose of a least 740 mcg pirfenidone or pyridone
analog. In some embodiments, the inhaling step delivers a dose of a
least 1.7 mg pirfenidone or pyridone analog. In some embodiments,
the inhaling step delivers a dose of a least 93 mg pirfenidone or
pyridone analog. In some embodiments, the inhaling step delivers a
dose of a least 463 mg pirfenidone or pyridone analog. 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
one breath.
[0045] In one aspect, provided herein is a kit comprising: a
pharmaceutical composition comprising a pirfenidone or pyridone
analog solution in a sterile container, wherein the pirfenidone or
pyridone analog solution has a concentration greater than about 34
mcg/mL, an osmolality greater than about 100 mOsmol/kg, and a pH
greater than about 4.0, and a nebulizer adapted to aerosolize the
pirfenidone or pyridone analog solution for delivery to the middle
to lower respiratory tract through oral inhalation. In some
embodiments, the pirfenidone or pyridone analog concentration is
greater than about 1.72 mg/mL. In some embodiments, the pirfenidone
or pyridone analog concentration is greater than about 86 mg/mL. In
some embodiments, the pirfenidone or pyridone analog 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 pirfenidone or pyridone analog solution has a pH
from about 4.0 to about 8.0. In some embodiments, the pirfenidone
or pyridone analog solution has an osmolality from about 100
mOsmol/kg to about 1000 mOsmol/kg. In some embodiments, the
pirfenidone or pyridone analog solution has an osmolality from
about 50 mOsmol/kg to about 5000 mOsmol/kg. In some embodiments,
the solution 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 kit
further comprises a mucolytic agent suitable for pulmonary
delivery. In some embodiments, the kit further comprises a second
anti-fibrotic agent suitable for pulmonary delivery. In some
embodiments, the kit further comprises a second anti-inflammatory
agent suitable for pulmonary delivery.
[0046] In another aspect, provided herein is a kit comprising: a
pharmaceutical composition comprising a pirfenidone or pyridone
analog solution in a sterile container, wherein the pirfenidone or
pyridone analog solution has a concentration greater than about 34
mcg/mL, an osmolality greater than about 100 mOsmol/kg, and a pH
greater than about 4.0, and a nebulizer adapted to aerosolize the
pirfenidone or pyridone analog solution for delivery to the nasal
cavity through intranasal inhalation.
[0047] In some embodiments, the pirfenidone or pyridone analog
concentration is greater than about 1.72 mg/mL. In some
embodiments, the pirfenidone or pyridone analog concentration is
greater than about 86 mg/mL. In some embodiments, the pirfenidone
or pyridone analog 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 pirfenidone or
pyridone analog solution has a pH from about 4.0 to about 8.0. In
some embodiments, the pirfenidone or pyridone analog solution has
an osmolality from about 100 mOsmol/kg to about 1000 mOsmol/kg. In
some embodiments, the pirfenidone or pyridone analog solution has
an osmolality from about 50 mOsmol/kg to about 5000 mOsmol/kg. In
some embodiments, the solution 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 kit further comprises a mucolytic agent suitable for intranasal
delivery. In some embodiments, the kit further comprises a second
anti-fibrotic agent suitable for intranasal delivery. In some
embodiments, the kit further comprises a second anti-inflammatory
agent suitable for intranasal delivery.
[0048] In one aspect, described herein is a method for treating
lung disease, comprising administering pirfenidone or pyridone
analog 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 pirfenidone or pyridone analog,
wherein the disease is selected from interstitial lung disease,
including idiopathic pulmonary fibrosis and radiation
therapy-induced fibrosis; chronic obstructive pulmonary disease;
and asthma. 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 obstructive pulmonary
disease. In some embodiments, the subject is identified as having
chronic bronchitis. In some embodiments, the subject is identified
as having asthma. In some embodiments, the subject is a subject
being mechanically ventilated.
[0049] A method for treating extrapulmonary disease, comprising
administering pirfenidone or pyridone analog 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
pirfenidone or pyridone analog 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 a subject being mechanically ventilated.
[0050] In one aspect, described herein is a method for treating
neurologic disease, comprising administering pirfenidone or
pyridone analog to the nasal cavity of a subject having or
suspected of having neurologic disease through intranasal
inhalation of an aerosol comprising pirfenidone or pyridone analog
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.
[0051] In one aspect, described herein is a pharmaceutical
composition for pulmonary delivery, comprising a dry powder
containing pirfenidone or pyridone analog having a dosage content
greater than about 1%. In some embodiments, the pirfenidone or
pyridone analog dose content is greater than about 6.8 mcg. In some
embodiments, the pirfenidone or pyridone analog content is greater
than about 340 mcg. In some embodiments, the pirfenidone or
pyridone analog content is greater than about 17 mg. In some
embodiments, the pirfenidone or pyridone analog content is greater
than about 463 mg. In some embodiments, the powder further
comprises a blending agent. In some embodiments, the blending agent
is selected from the group consisting of lactose.
[0052] In one aspect, described herein is a pharmaceutical
composition for pulmonary delivery, comprising a dry powder
containing pirfenidone or pyridone analog having a dosage content
greater than about 1%. In yet another aspect, described herein is a
sterile, single-use container comprising from about 0.5 mg to about
100 mg dry powder containing pirfenidone or pyridone analog 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 pirfenidone or
pyridone dosage content greater than about 1%. In some embodiments,
the pirfenidone or pyridone analog dose content is greater than
about 6.8 mcg. In some embodiments, the pirfenidone or pyridone
analog content is greater than about 340 mcg. In some embodiments,
the pirfenidone or pyridone analog content is greater than about 17
mg. In some embodiments, the pirfenidone or pyridone analog content
is greater than about 463 mg. In some embodiments, the dry powder
further comprises a blending agent. In some embodiments, the
blending agent is lactose. 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 asthma. 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
a least 6.8 mcg pirfenidone or pyidone analog. In some embodiments,
the inhaling step delivers a dose of a least 340 mcg pirfenidone or
pyidone analog. In some embodiments, the inhaling step delivers a
dose of a least 740 mcg pirfenidone or pyidone analog. In some
embodiments, the inhaling step delivers a dose of a least 1.7 mg
pirfenidone or pyidone analog. In some embodiments, the inhaling
step delivers a dose of a least 93 mg pirfenidone or pyidone
analog. In some embodiments, the inhaling step delivers a dose of a
least 463 mg pirfenidone or pyidone analog. 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.
[0053] 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 a pirfenidone or pyridone analog dry powder
formulation having a dosage content greater than about 1%. In
another aspect, provided herein is a method to administer an
anti-inflammatory agent to lungs of a subject, comprising:
introducing in a dry powder inhaler a pirfenidone or pyridone
analog 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 pirfenidone or pyridone 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 yet
another aspect, provided herein is a method to treat a neurologic
disease comprising intranasal inhalation of a dry powder aerosol
containing pirfenidone or pyridone 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 a pirfenidone or
pyridone analog dry powder formulation having a dosage content
greater than about 1%. In some embodiments, the pirfenidone or
pyridone analog dose content is greater than about 6.8 mcg. In some
embodiments, the pirfenidone or pyridone analog content is greater
than about 340 mcg. In some embodiments, the pirfenidone or
pyridone analog content is greater than about 17 mg. In some
embodiments, the pirfenidone or pyridone analog content is greater
than about 463 mg. In some embodiments, the dry powder comprises a
blending agent. In some embodiments, the blending 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 a least 6.8 mcg pirfenidone or pyidone analog. In some
embodiments, the inhaling step delivers a dose of a least 340 mcg
pirfenidone or pyidone analog. In some embodiments, the inhaling
step delivers a dose of a least 740 mcg pirfenidone or pyidone
analog. In some embodiments, the inhaling step delivers a dose of a
least 1.7 mg pirfenidone or pyidone analog. In some embodiments,
the inhaling step delivers a dose of a least 17 mg pirfenidone or
pyidone analog. In some embodiments, the inhaling step delivers a
dose of a least 93 mg pirfenidone or pyidone analog. In some
embodiments, the inhaling step delivers a dose of a least 463 mg
pirfenidone or pyidone analog. 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 0.5 mg to about 10 mg dry powder formulation
containing pirfenidone or pyridone analog for introduction into a
dry powder inhaler.
[0054] In one aspect, described herein is a kit comprising: a
pharmaceutical composition comprising a dry powder pirfenidone or
pyridone analog formulation in a container, wherein the pirfenidone
or pyridone analog dosage content is greater than about 1%; and a
dry powder inhaler adapted to aerosolize the pirfenidone or
pyridone analog 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 pirfenidone or pyridone analog
formulation in a container, wherein the pirfenidone or pyridone
analog dosage content is greater than about 1%, and a dry powder
inhaler adapted to aerosolize the pirfenidone or pyridone analog
dry powder formulation for delivery to the nasal cavity through
intranasal inhalation. In some embodiments, the pirfenidone or
pyridone analog dose content is greater than about 6.8 mcg. In some
embodiments, the pirfenidone or pyridone analog content is greater
than about 340 mcg. In some embodiments, the pirfenidone or
pyridone analog content is greater than about 17 mg. In some
embodiments, the pirfenidone or pyridone analog content is greater
than about 463 mg. In some embodiments, the powder further
comprises a blending agent. In some embodiments, the blending agent
is lactose.
[0055] In one aspect, described herein is a method for treating
lung disease, comprising administering pirfenidone or pyridone
analog 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 pirfenidone or pyridone analog,
wherein the disease is selected from interstitial lung disease,
including idiopathic pulmonary fibrosis and radiation
therapy-induced fibrosis; chronic obstructive pulmonary disease;
and asthma. 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 obstructive pulmonary
disease. In some embodiments, the subject is identified as having
chronic bronchitis. In some embodiments, the subject is identified
as having asthma. In some embodiments, the subject is a subject
being mechanically ventilated.
[0056] In one aspect, described herein is a method for treating
extrapulmonary disease, comprising administering pirfenidone or
pyridone analog 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 pirfenidone or pyridone analog 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.
[0057] 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.
[0058] In one aspect, described herein is a method for treating
neurologic disease, comprising administering pirfenidone or
pyridone analog to the nasal cavity of a subject having or
suspected of having neurologic disease through intranasal
inhalation of an aerosol comprising pirfenidone or pyridone analog
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.
[0059] In one aspect, described herein is a method of administering
pirfenidone or pyridone analog to treat a patient with idiopathic
pulmonary fibrosis (IPF), 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 pirfenidone or pyridone analog administration, comprising
administering to said patient pirfenidone or pyridone analog at
doses less than 300 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 pirfenidone or pyridone analog 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 pirfenidone
or pyridone analog is less than 10 mcg/mL. In some embodiments, the
blood Cmax following administration of pirfenidone or pyridone
analog is greater than 10 mcg/mL.
[0060] In one aspect, described herein is a method of administering
pirfenidone or pyridone analog to treat a patient with idiopathic
pulmonary fibrosis (IPF), wherein the patient avoids the incidence
of photosensitivity reaction observed following oral
administration, comprising administering to said patient
pirfenidone or pyridone analog at doses less than 360 mg per day.
In some embodiments, the pirfenidone or pyridone analog is
delivered to the patient by oral inhalation or intranasal
inhalation. In some embodiments, the incidence of photosensitivity
reaction adverse events is less than about 12%. In some
embodiments, the blood Cmax following administration of pirfenidone
or pyridone analog is less than 10 mcg/mL. In some embodiments, the
blood Cmax following administration of pirfenidone or pyridone
analog is greater than 10 mcg/mL.
[0061] In one aspect, described herein is a method of administering
pirfenidone or pyridone analog to treat a patient with idiopathic
pulmonary fibrosis (IPF), wherein the patient avoids the incidence
of phototoxicity observed following oral administration, comprising
administering to said patient pirfenidone or pyridone analog at
doses less than 360 mg per day. In some embodiments, the
pirfenidone or pyridone analog is delivered to the patient by oral
inhalation or intranasal inhalation. In some embodiments, the
incidence of photosensitivity reaction adverse events is less than
about 12%. In some embodiments, the blood Cmax following
administration of pirfenidone or pyridone analog is less than 10
mcg/mL. In some embodiments, the blood Cmax following
administration of pirfenidone or pyridone analog is greater than 10
mcg/mL.
[0062] In one aspect, described herein is a method of administering
pirfenidone or pyridone analog to treat a patient with idiopathic
pulmonary fibrosis (IPF), wherein the patient avoids the incidence
of gastrointestinal adverse events observed following oral
administration, by delivering pirfenidone or pyridone analog
directly to the lung by oral inhalation or intranasal inhalation.
In some embodiments, gastrointestinal adverse events observed
following oral administration of pirfenidone or pyridone analog
include, but are not limited to any one or more of the following:
dyspepsia, nausea, diarrhea, gastroesophageal reflux disease (GERD)
and vomiting. In some embodiments, less than 360 mg per day of
pirfenidone or pyridone analog is delivered to the patient by
inhalation. In some embodiments, less than 1000 mg, less than 900
mg, less 600 mg, or less than 300 mg per day of pirfenidone or
pyridone analog is delivered to the patient by inhalation. In some
embodiments, less than 300 mg per day of pirfenidone or pyridone
analog is delivered per dose to the patient by inhlaltion. In some
embodiments, pirfenidone or pyridone analog is delivered by
inhalaltion once per day, twice per day, three time a day, or four
time a day.
[0063] In some embodiments, up to about 360 mg of pirfenidone or
pyridone analog is delivered to the patient by inhalation per dose.
In some embodiments, about lmg to about 360 mg, about 10 mg to
about 360 mg, about 20 mg to about 360 mg, about 30 mg to about 360
mg, about 40 mg to about 360 mg, about 50 mg to about 360 mg, about
60 mg to about 70 mg, about 80 mg to about 360 mg, about 90 mg to
about 360 mg, about 100 mg to about 360 mg, about 120 mg to about
360 mg, about 140 mg to about 360 mg, about 160 mg to about 360 mg,
about 180 mg to about 360 mg, or about 200 mg to about 360 mg, of
pirfenidone or pyridone analog is delivered to the patient by
inhalation per dose. In some embodiments, pirfenidone or pyridone
analog is delivered by inhalaltion once per day, twice per day,
three time a day, or four time a day.
[0064] In one aspect, described herein is a pharmaceutical
composition comprising a therapeutically effective amount of an
inhaled agent, wherein the agent is pirfenidone or pyridone analog,
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 1 mcg pirfenidone or pyridone analog
compound per gram of adult human lung tissue.
[0065] In one aspect, described herein is a pharmaceutical
composition for aerosol delivery to the lung, comprising a solution
of pirfenidone or pyridone analog containing a divalent cation. In
some embodiments, the divalent cation is selected from the group
consisting of calcium, iron, magnesium, and beryllium. In some
embodiments, the ratio of pirfenidone or pyridone analog to
divalent cation is within the molar range of 1 to about 0.1 to 10,
in unit increments of about 0.01. By example, 1 to about 10, 1 to
about 9, 1 to about 8, 1 to about 7, 1 to about 6, 1 to about 5, 1
to about 4, 1 to about 3, 1 to about 2, 1 to about 1.5, 1 to about
1, 1 to about 0.75, 1 to about 0.5, 1 to about 0.25, and 1 to about
0.1. In some embodiments, the active pharmaceutical ingredient is
pirfenidone or pyridone analog concentration is between 0.1 mg/mL
and 50 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, and about 60 mg/mL. In some
embodiments, the active pharmaceutical ingredient is not a salt of
pirfenidone or pyridone analog. 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, about 2000 mOsmol/kg, about 2500 mOsmol/kg,
greater than about 3000 mOsmol/kg, about 3500 mOsmol/kg, about 4000
mOsmol/kg, greater than about 4500 mOsmol/kg, about 5000 mOsmol/kg,
about 5500 mOsmol/kg, about 6000 mOsmol/kg, or greater than about
6000 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 pirfenidone or pyridone analog 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. By examples, 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.
[0066] 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.
[0067] 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.
[0068] 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.
[0069] In some embodiments, oxygen exposure is reduced by inserting
the primary packaging into a gas-impermeable secondary packaging
container.
[0070] 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.
[0071] 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 0.1 mg to about 360 mgs prifenidone or pyridone analog, in
0.1 mg increments. By example, about 0.1 mg, about 0.5 mg, 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 150
mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about
280 mg, about 300 mg, about 320 mg, about 340 mg, or about 360
mg.
[0072] 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 agent suitable for pulmonary delivery. In some
embodiments, the compositions further comprise a second
anti-inflammatory agent suitable for pulmonary delivery.
[0073] 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
[0074] FIG. 1 shows a modeled nebulized aerosol administration of
pirfenidone and oral administration of pirfenidone to a human
subject.
DETAILED DESCRIPTION
[0075] A number of undesirable pulmonary diseases such as
interstitial lung disease (ILD; and sub-class diseases therein),
chronic obstructive pulmonary disease (COPD; and sub-class diseases
therein), asthma, and fibrotic indications of the lungs, kidney,
heart and eye, are initiated from an external challenge. By
non-limiting example, these effectors can include infection,
cigarette smoking, environmental exposure, radiation exposure,
surgical procedures and transplant rejection. However, other causes
related to genetic disposition and the effects of aging may also be
attributed.
[0076] In epithelium, scarring serves a valuable healing role
following injury. However, epithelium 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.
[0077] In neurologic disease, inflammatory destruction of myelin
(demylination) is considered the initial event in diseases such as
multiple sclerosis. Demyelination causes scarring and hardening
(sclerosis) of nerve tissue in the spinal cord, brain, and optic
nerves. Demyelination slows conduction of nerve impulses, which
results in weakness, numbness, pain, and vision loss.
[0078] 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), endothelin, 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. In the case of demylination, abnormal TNF
expression or activity is considered a primary cause of multiple
sclerosis and other neurologic disorders, such as rheumatoid
disease.
[0079] In conditions such as pulmonary, kidney, cardiac and ocular
fibrosis, multiple sclerosis and rheumatoid disease, physiological
responses characterized by control of pro-inflammatory and
pro-fibrotic factors with pyridone analogs, such as pirfenidone may
be beneficial to attenuate and/or reverse fibrosis and
demyelination. Therapeutic strategies exploiting such pyridone
analog and/or pirfenidone effects in these and other indications
are contemplated herein.
[0080] TNF-alpha is expressed in asthmatic airways and may play a
key role in amplifying asthmatic inflammation through the
activation of NF-kappaB, AP-1 and other transcription factors. IgE
receptor activation induces TNF-alpha release from human lung
tissue and upregulates eosinophil TNF mRNA levels. TNF-alpha causes
transient bronchial hyper-responsiveness likely through a
muscarinic receptor expression-mediated response.
[0081] TNF-alpha is also believed to play a central role in the
pathophysiology of COPD. It is produced by alveolar macrophages,
neutrophils, T cells, mast cells and epithelial cells following
contact with different pollutants including cigarette smoke.
TNF-alpha has been shown in animal models to induce pathological
features associated with COPD, such as an inflammatory cell
infiltrate into the lungs, pulmonary fibrosis and emphysema.
Intriguingly, TNF-alpha levels in sputum increase significantly
during acute exacerbations of COPD.
[0082] The mechanism of action for pyridone analogs, such as
pirfenidone is believed to be both anti-inflammatory and
anti-fibrotic. Pirfenidone inhibits synthesis and release of
pro-inflammatory cytokines and reduces the accumulation of
inflammatory cells in response to various stimuli. Pirfenidone also
attenuates fibroblast proliferation, production of fibrosis
associated proteins and cytokines, and the increased biosynthesis
and accumulation of extracellular matrix in response to cytokine
growth factors such as TGF-beta and platelet-derived growth factor
(PDGF).
[0083] In in vitro cell-based assays, pirfenidone suppressed the
proliferation of fibroblasts; inhibited lipopolysaccharide
(LPS)-stimulated release of PDGF, tumor necrosis factor alpha
(TNF-alpha), and TGF-beta1; and inhibited collagen synthesis.
Depending on the assay conditions, these in vitro activities were
evident at pirfenidone concentrations of about 30 microM to about
10 mM (about 5.5 mcg/mL to about 1.85 mg/mL). Given that the oral
Cmax of pirfenidone in IPF patients is about 42 microM in the
recommended fed-state to about 84 microM in the fasting-state (or
about 7.9 mcg/mL to about 15.7 mcg/mL, respectively), these same
activities may be promoted in vivo, albeit in the lower range of
observed efficacy.
[0084] Oral administration of pirfenidone to LPS-challenged mice
resulted in dose-dependent decreased mortality, reduced serum
levels of the pro-inflammatory cytokines TNF-alpha, interleukin
(IL-12) and interferon gamma, and increased serum levels of the
anti-inflammatory cytokine, IL-10. Pirfenidone treatment also
prevented LPS-related hemorrhagic necrosis and apoptosis in the
liver, and suppressed increases in TGF-beta.
[0085] In vitro studies suggest that pirfenidone may also suppress
fibrogenesis through selective inhibition of p38 mitogen-activated
protein kinase (MAPK). These observations have been associated with
an attenuation of TGF-beta-induced collagen synthesis. The parallel
observation that silencing p38 may also restore sensitivity to
coriticosteroids in COPD is also promising for this and other
disease populations. Unfortunately, compounds that inhibit p38 MAPK
have also proven toxic and have been withdrawn from the clinical
setting. These compounds have each employed oral
administration.
[0086] In rat, hamster, and mouse models of bleomycin-induced lung
fibrosis, prophylactic administration of pirfenidone reduced
pulmonary fibrosis assessed by both histopathological analysis and
quantitative determination of collagen content. Pirfenidone
treatment also reduced pulmonary edema and pulmonary levels of
TGF-beta, basic fibroblast growth factor (bFGF), and various
pro-inflammatory cytokines.
[0087] In rat, pirfenidone decreased collagen production and
deposition in hepatic fibrosis, reversed cardiac and renal
fibrosis, and attenuated the increase in diastolic stiffness of
diabetic hearts from streptozotocin-treated animals without
normalizing cardiac contractility or renal function. In DOCA-salt
hypertensive rats, pirfenidone also reversed and prevented cardiac
remodeling, and reversed and prevented increased cardiac stiffness
without reversing the increased vascular responses to
noradrenaline.
[0088] Human studies have shown some clinical anti-inflammatory and
anti-fibrotic benefit of oral pirfenidone. Phototoxicity,
gastrointestinal disorders and abnormal liver function test values
may result in human populations following oral administration of
pirfenidone. As a consequence patient dosing must be closely
monitored. In Phase 3 clinical studies with orally administered
pirfenidone, initial dose escalation was required to establish
gastrointestinal tolerance. However, dose levels are also limited
during or following escalation due to occurrence of nausea, rash,
dyspepsia, dizziness, vomiting, photosensitivity reaction,
anorexia, and elevated AST and ALT serum transaminases. In some
cases, oral administration of pirfendione may result in dose
de-escalation or discontinuation of pirfenidone administration.
[0089] In addition to required pirfenidone dose escalation to
establish gastrointestinal tolerance, dose de-escalation and the
use of food has been employed to enable oral administration to
individuals unable to achieve tolerance and would otherwise be
removed from therapy, for example, dose de-escalation of up to and
greater than 50%. Further, clinical studies utilizing the use of
food to enable dose tolerability may also be attempted. In both
cases, the plasma Cmax is reduced dose-proportionately. More
specifically, the fed-state results in about a 50% reduction in
Cmax, about a seven-fold increase in Tmax and a reduction in
overall exposure of 10-15%. Both fed and fasted state resulted in a
plasma half-life of about 2.5 hours. While this approach may reduce
gastrointestinal-related adverse events, the lack of
clinically-significant efficacy in recent orally-administered
clinical studies may have been influenced by these approaches.
[0090] Based upon clinical observations and adverse events as well
as observed toxicities, oral pirfenidone therapy is limited to
doses up to about 1800 mg/day to about 2400 mg/day (from 600 mg TID
or 801 mg TID, respectively). Thus, while pirfenidone exhibits a
wide range of non-human efficacy, human adverse events and
toxicities have limited oral dosing to the lower end of this
range.
[0091] Regulatory risk-benefit analysis between observed efficacy
and associated adverse events of orally administered pirfendione
has led to concerns that these doses do not provide sufficient
efficacy to warrant the safety risk; even in a terminal population
of unmet clinical need. Provided herein in certain embodiments, is
a method of administering an equivalent or increased pirfenidone or
pyridone analog dose directly to the disease site (e.g., inhalation
delivery to the lung) would provide equivalent or improved efficacy
over oral routes. In certain embodiments, these doses require less
administered drug. In certain embodiments, this approach of
administering pirfenidone by inhalation may also benefit from
reduced systemic exposure and an increased safety margin when
compared to oral administration of pirfenidone. Described herein
are compositions of pirfenidone or a pyridone analog compound that
are suitable for delivery to a mammal by inhalation and methods of
using such compositions.
[0092] It is unclear from the existing data whether pirfenidone
anti-inflammatory or anti-fibrotic mechanism or mechanisms of
action are driven by Cmax or exposure (area under the curve, AUC).
In some embodiments, low to moderately-observed clinical efficacy
may be associated with pirfenidone plasma levels about or greater
than 5 mcg/mL, exposures (AUCO-infinitiy) about or greater than 50
mghr/L, and/or a plasma elimination rate of about 2.5 hours.
[0093] In some embodiments, intravenous or oral administration of
pirfenidone may result in lung epithelial lining fluid (ELF) levels
comparable to that observed in plasma, and thus, in some
embodiments, clinically-measured plasma Cmax of about or greater
than 5 mcg/mL are directly associated with low to
moderately-observed clinical pulmonary efficacy. In some
embodiments, plasma levels of pirfendione resulting from oral
administration are associated with lower efficacy, and thus is some
embodiments the resultant ELF and lung tissue levels are also
associated with lower efficacy. In other embodiments, intravenous
or oral administration of pirfenidone may result in lung epithelial
lining fluid (ELF) levels less than that observed as efficacious
from the plasma. In some embodiments, ELF levels corresponding with
oral or intravenous-delivered, plasma-observed efficacious levels
may be 0.1 mcg/mL to about 5 mcg/mL. In some embodiments, ELF
levels corresponding with plasma-observed efficacious levels may be
0.1 mcg/mL to about 1 mcg/mL. In some embodiments, ELF levels
corresponding with oral or intravenous-delivered, plasma-observed
efficacious levels may be 0.5 mcg/mL to about 5 mcg/mL. In some
embodiments, ELF levels corresponding with oral or
intravenous-delivered, plasma-observed efficacious levels may be
0.3 mcg/mL to about 3 mcg/mL. In some embodiments, direct
administration of pirfenidone to the lung, results in delivery of
about or greater than 5 mcg pirfenidone to one mL ELF, and may
result in equivalent pulmonary efficacy without elevated systemic
levels associated with adverse events and toxicities observed with
administration. By non-limiting example, this may be accomplished
by oral or intranasal inhaled delivery of aerosolized pirfenidone
or pyridone analog to the lung providing about or greater than 0.1
mcg/mL, for example greater than about 0.2 mcg/mL, 0.4 mcg/mL, 0.6
mcg/mL, 0.8 mcg/mL, 1.0 mcg/mL, 2 mcg/mL, 3 mcg/mL, 4 mcg/mL, 5
mcg/mL, 6 mcg/mL, 7 mcg/mL, 8 mcg/mL, 9 mcg/mL, or greater than 10
mcg/mL of pirfenidone or pyridone analog to the ELF. Once in the
ELF, pirfenidone or pyridone analog will in some embodiments
penetrate lung tissue resulting in between about 0.004 mcg and 0.7
mcg pirfenidone or pyridone analog to one gram lung tissue (about
0.1 mcg/mL in about 25 mL ELF to about 5 mcg/mL in about 75 mL ELF,
about 600 grams adult human lung tissue weight).
[0094] In some embodiments, pirfenidone may readily equilibrate
between the plasma and lung, and/or other organs. In some
embodiments, organ pirfenidone levels may also mimic that of
plasma, such as for example, the lung, heart, kidney or nervous
system. In some embodiments, delivery of about or greater than
0.004 mcg to 0.7 mcg pirfenidone to one gram tissue may provide a
similar therapeutic benefit to other organs. In some embodiments,
providing additional pirfenidone or pyridone analog may provide
additional efficacy. In some embodiments, this may be accomplished
by inhalation (i.e. oral inhalation or intranasal inhalation)
delivery of aerosolized pirfenidone or pyridone analog to the lung.
In some embodiments, pirfenidone or pyridone analog delivered to
the lung may, in some embodiments, become readily available to the
heart. In some embodiments, providing about 0.1 mcg/mL to about 5
mcg/mL ELF or 0.004 mcg/gram to about 0.7 mcg/gram lung tissue
pirfenidone or pyridone analog pyridone analog to the ELF or 0.2 to
0.7 mcg/gram lung tissue pirfenidone or pyridine analog may result
in a similar efficacious dose to the heart in the absence of
elevated systemic adverse events or toxicities observed with oral
dosing. In some embodiments, intranasal inhalation or oral
inhalation delivery of aerosolized pirfenidone or pyridone analog
to the lung may result in efficacious delivery of pirfenidone or
pyridone analog to the liver. In some embodiments, pirfenidone or
pyridone analog delivered to the lung will become available to the
liver. In some embodiments, providing about 0.1 mcg/mL to about 5
mcg/mL ELF or 0.004 mcg/gram to about 0.7 mcg/gram lung tissue
pirfenidone or pyridone analog pyridone analog may result in a
similar efficacious dose to the liver in the absence of elevated
systemic adverse events or toxicities observed with oral dosing. In
some embodiments, intranasal or oral inhalation delivery of
aerosolized pirfenidone or pyridone analog to the lung may result
in efficacious delivery of pirfenidone or pyridone analog to the
kidney. In some embodiments, pirfenidone or pyridone analog
delivered to the lung will become available to the kidney. In some
embodiments, providing about 0.1 mcg/mL to about 5 mcg/mL ELF or
0.004 mcg/gram to about 0.7 mcg/gram lung tissue pirfenidone or
pyridone analog pyridone analog may result in a similar efficacious
dose to the kidney in the absence of elevated systemic adverse
events or toxicities observed with oral dosing. In some
embodiments, intranasal inhalation delivery of aerosolized
pirfenidone or pyridone analog to the nasal cavity may result in
efficacious delivery of pirfenidone or pyridone analog to the
central nervous system (CNS). In some embodiments, inhalation
delivery of pirfenidone or pyridone analog to the nasal cavity will
become readily available to the CNS. In some embodiments, providing
a nasal cavity-delivered dose equivalent to about 0.1 mcg/mL to
about 5 mcg/mL ELF or 0.004 mcg/gram to about 0.7 mcg/gram lung
tissue pirfenidone or pyridone analog may result in similar
efficacy in the CNS in the absence elevated systemic adverse events
or toxicities observed with oral dosing.
[0095] In some embodiments, topical delivery of aerosolized, liquid
or cream pirfenidone or pyridone analog to a site of desired effect
providing about 0.004 mcg/gram to about 0.7 mcg/gram tissue weight
may result in a similar efficacious dose in the absence of systemic
adverse events or toxicities. In some embodiments, topical delivery
of aerosolized, liquid or cream pirfenidone or pyridone analog to
damaged skin epithelium may prevent or reverse scarring, fibrosis
and/or inflammation. This damage could be the result of infection,
burn, surgery, acute of chronic injury (such as bed soars), or
other event. In some embodiments, topical delivery of liquid or dry
powder pirfenidone or pyridone analog to the bladder may prevent
scarring, fibrosis and/or inflammation associated with bladder
infection, bladder cancer, in-dwelling catheter or other event. In
some embodiments, topical delivery of liquid pirfenidone or
pyridone analog to the eye may prevent development of
post-operative fibrosis in the conjunctiva and/or episclera
following glaucoma surgery.
[0096] In some embodiments, injection delivery of liquid
pirfenidone or pyridone analog to a site of desired effect
providing about 0.004 mcg/gram to about 0.7 mcg/gram tissue weight
pirfenidone or pyridone analog may result in a similar efficacious
dose in the absence of systemic adverse events or toxicities. In
some embodiments, injection delivery of liquid pirfenidone or
pyridone analog to skeletal joints may prevent scarring, fibrosis
and/or inflammation associated with autoimmune diseases, arthritis,
rheumatoid arthritis, infection or other event.
[0097] In some embodiments, in addition to Cmax, and in additional
embodiments, pirfenidone exposure (AUC) to the disease site may
also be critical for efficacy. In some embodiments, plasma
AUC0-infinity about or greater than 50 mghr/L is also associated
with pulmonary efficacy. In some embodiments, partial or ready
equilibrium of pirfenidone between the plasma and lung ELF and
between the plasma and lung tissue, in some embodiments, may
provide that AUC may also be mimicked in the lung. In other
embodiments, lung ELF and tissue AUC may be less.
[0098] In some embodiments, individually or in combination Cmax,
AUC and/or half-life are required for efficacy, and thus in some
embodiments are provided a conservative model with all three
parameters (Cmax, AUC and half-life) required for efficacy. In some
embodiments, and by non-limiting example, direct inhalation
delivery of about 0.1 mcg to about 5 mcg pirfenidone or pyridone
analog to one mL lung ELF, providing an ELF AUCO-infinity about 1.0
mghr/L or about 50 mghr/L, and maintaining these levels for the
same period of time as that delivered via the oral route are
equivalently efficacious. Similarly, in other embodiments, direct
inhalation delivery of about or greater than 0.2004 to 0.7 mcg
pirfenidone or pyridone analog to one gram lung tissue, provides a
tissue AUCO-infinity less than to equivalent or substantially
equivalent to that of the plasma following oral delivery, and in
further embodiments, maintaining these levels for the same period
of time as that delivered via the oral route is equivalently
efficacious. In some embodiments, the following assumptions and
theoretical calculations are described for inhalation therapy:
[0099] ELF Delivery Assumptions:
[0100] 1. The total volume of human ELF is 25 mL;
[0101] 2. The inhaled route of administration is dependent upon a
respirable delivered dose (RDD); RDD is the fraction of drug
inhaled in aerosol particles less than 5 microns in diameter;
[0102] 3. RDD of typical dry powder, liquid nebulization or
meter-dose inhalation devices ranges from 10% to 70%. In some
embodiments, higher and lower efficiency devices with RDDs greater
than 70% and less than 10% are contemplated.
[0103] 4. Plasma pirfenidone or pyridone analog half-life following
oral administration is around 2.5 hours. In some embodiments,
intestinal absorption affects this yule but for exemplary purposes
of this model the lung ELF pirfenidone half-life following
inhalation delivery is assumed to be one-half that following oral
administration (e.g. 2.5 hours/2=1.25 hours). Half-life values may
be supported by measurements indicating intravenous administration
of pirfenidone results in a lung ELF half-life of around one-half
that following oral administration;
[0104] 5. In some embodiments, a lung ELF level of 5 mcg/mL may be
the lower limit of efficacy; and
[0105] 6. 801 mg oral pirfenidone results in a plasma level at or
greater than 5 mcg/mL for 4 hours (human-measured value). For
purposes of comparing routes, this model will assume lung ELF
pirfenidone levels following oral administration remain at or above
5 mcg/mL lung ELF for the same duration as plasma.
[0106] Exemplary ELF Calculations: [0107] 1. Mcg pirfenidone
delivered to 25 mL ELF to make 5 mcg/mL=125 mcg; [0108] 2. Based
upon an RDD efficiency of 30%, the unit dose required is 416 mcg
(125 mcg/0.3=416 mcg); [0109] 3. Based upon an RDD efficiency of
50%, the unit dose required is 250 mcg (125 mcg/0.5=250 mcg);
[0110] 4. Based upon an RDD efficiency of 70%, the unit dose
required is 179 mcg (125 mcg/0.7 =179 mcg); and
[0111] Compensating to maintain at or above these levels for 3.2
half lives of 1.25 hours each (4 hours at or above 5 mcg/mL with a
lung half-life of 1.25 hours=3.2 half lives): [0112] 5. For an RDD
efficiency of 30%, the unit dose required to maintain the lower
limit of clinically-observed efficacy (in this case 416 mcg) for
3.2 half lives is 3994 mcg; [0113] 6. For an RDD efficiency of 50%,
the unit dose required to maintain the lower limit of
clinically-observed efficacy (in this case 250 mcg) for 3.2 half
lives 2400 mcg; and [0114] 7. For an RDD efficiency of 70%, the
unit dose required to maintain the lower limit of
clinically-observed efficacy (in this case 179 mcg) for 3.2 half
lives 1718 mcg.
[0115] By non-limiting example, based upon the above assumptions
and in certain embodiments, a dose of approximately 4 mg in a
device delivering pirfenidone or pyridone analog with 30%
efficiency may result in lung ELF levels at or above 5 mcg/mL for
the same duration as that obtained following 801 mg administered
orally. Moreover, while the minimally efficacious pirfenidone dose
may be maintained for this duration, local pirfenidone levels may
also exhibit significantly higher ELF Cmax levels providing
improved efficacy. In some embodiments, delivery of 4 mg
pirfenidone or pyridone analog with a 30% efficiency device may
result in a lung ELF Cmax up to about 48 mcg/mL (4 mg.times.30%=1.2
mg. 1.2 mg/25 mL ELF=48 mcg/mL). In some embodiments, based upon
the above assumptions a dose of approximately 66 mg in a device
delivering pirfenidone or pyridone analog with 70% efficiency may
result in a lung ELF Cmax up to 1.85 mg/mL (66 mg.times.70%=46.2
mg. 46.2 mg/25 mL ELF=1.85 mg/mL). In some embodiments, based upon
the above assumptions a dose of approximately 154 mg in a device
delivering pirfenidone or pyridone analog with 30% efficiency may
also result in a lung ELF Cmax up to 1.85 mg/mL (154
mg.times.30%=46.2 mg. 46.2 mg/25 mL ELF=1.85 mg/mL). In some
embodiments, based upon the above assumptions a dose of
approximately 12 mg in a device delivering pirfenidone or pyridone
analog with 70% efficiency may result in a lung ELF Cmax up to 336
mcg/mL (12 mg.times.70%=8.4 mg. 8.4 mg/25 mL ELF=336 mcg/mL). In
some embodiments, based upon the above assumptions a dose of
approximately 28 mg in a device delivering pirfenidone or pyridone
analog with 30% efficiency may also result in a lung ELF Cmax up to
336 mcg/mL (28 mg.times.30%=8.4 mg. 8.4 mg/25 mL ELF=336 mcg/mL).
In some embodiments, this dose may result in maintaining at or
above the 5 mcg/mL minimally efficacious dose for about 6
half-lifes, or about 15 hours. In some embodiments, the embodiments
described for inhalation therapy provide beneficial efficacy
through an increased Cmax and maintaining drug exposure at or above
the 5 mcg/mL minimal efficacy range for a longer duration than that
currently limited by oral dosing. In some embodiments, prolonged
exposure may enable a reduced dosing interval (by example
once-a-day or twice-a-day versus the current three times a day oral
dosing regimen). In some embodiments, while delivery is directly to
the lung, these doses may result in very low systemic plasma levels
(e.g. around 2 mcg/mL pirfenidone). In some embodiments, although
about 28 mg pirfenidone or pyridone analog delivered with a 30%
efficiency aerosol device may initially result in elevated levels
in vasculature and tissues immediately downstream of the lung (or
nasal cavity), the dilute systemic plasma concentration may be
around 1.7 mcg/mL (28 mg.times.30%=8.4 mg. 8.4 mg/5 L total body
blood=1.7 mcg/mL). In some embodiments, delivery of about 46 mg
pirfenidone or pyridone analog may result in a dilute systemic
plasma concentration of about 9.3 mcg/mL.
[0116] One of skill in the art whill recognize from the discussions
herein that doses calculated in the above model will change if the
actual measured lung ELF half-life of pirfenidone or pyridone
analog elimination changes. If the half-life is shorter, more
administered pirfenidone or pyridone analog will be required to
maintain the lung ELF concentration above that considered the
minimal efficacious level. Additional increases in administered
pirfenidone or pyridone analog may be desired to further improve
efficacy. Further, in addition to delivering desired lung tissue
Cmax and AUC, oral inhaled or intranasal inhaled delivery of
aerosol pirfenidone or pyridone analog may also serve an efficient
route for systemic delivery. In some embodiments, dosing schemes
are contemplated that enable inhaled delivery of pirfenidone or
pyridone analog to initially achieve desired lung tissue Cmax and
AUC, with plasma half-life slower than that of the lung ELF, and
targeting the delivery of specific plasma concentrations may in
turn prolong lung ELF-pirfenidone or pyridone analog exposure.
[0117] Exemplary Lung Tissue Delivery Assumptions:
[0118] 1. The total wet weight of the adult human lung is about 685
to 1,050 grams (for calculations, conservatively about 1,000
grams);
[0119] 2. The adult human lung blood volume is about 450 mL;
[0120] 3. The tissue weight of the adult human lung is
conservatively 1,050 grams wet weight minus 450 mL blood weight
(assuming density of 1.0), equals 600 grams;
[0121] 4. In some embodiments, following intravenous push of
pirfenidone to a mouse: [0122] plasma pirfenidone Tmax is
equivalent to lung Tmax [0123] 40 mg/kg intravenous dose results in
plasma Cmax of about 55 mcg/mL and a lung Cmax of 30 mcg/gram wet
tissue [0124] Conservatively, blood makes up about 40% of the wet
lung weight. Given that the plasma and lung Tmax are, in some
embodiments, equivalent, it follows that much of the 30 mcg/g
pirfenidone measured in the wet lung is due to the presence of
blood. Conservatively, if blood makes up about 40% of the wet lung
weight, then 40% of the plasma Cmax (or 55 mcg/mL.times.40%) is
about 22 mcg/gram pirfenidone in the measured lung weight is due to
blood. Taking the difference between the wet lung Cmax and this
number (or 30 mcg/g minus 22 mcg/g), about 8 mcg/g is in the lung
tissue. [0125] a measured wet lung half-life that is about 45%
longer than the plasma half-life may be considered. Taking the
argument above that about 40% of the wet lung pirfenidone is in the
blood, the actual lung tissue half-life is much greater then 45%
longer than plasma;
[0126] 5. From the above observations and calculations that 55
mcg/mL plasma Cmax results in a lung tissue Cmax of about 8
mcg/gram, the following comparison to humans can be made: [0127]
Taking an early assumption, the lower end of human efficacy is 5
mcg/mL plasma pirfenidone. [0128] Assuming the above ratio (55
mcg/mL plasma results in 8 mcg/gram lung tissue) is true for
humans, 5 mcg/mL divided by 55 mcg/mL is about 9.1%. 9.1% of 8
mcg/gram is about 0.7 mcg/gram. [0129] Taken together, 5 mcg/mL
plasma pirfenidone may result in 0.7 mcg/gram lung tissue
pirfenidone. Thus, about 0.7 mcg/gram lung tissue pirfenidone is
the lower end of efficacy.
[0130] 6. The inhaled route of administration is dependent upon a
respirable delivered dose (RDD). The RDD is the fraction of drug
inhaled in aerosol particles less than 5 microns in diameter;
[0131] 7. RDD of typical dry powder, liquid nebulization or
meter-dose inhalation devices ranges from 10% to 70%. Higher and
lower efficiency devices with RDDs greater than 70% and less than
10% also exist;
[0132] 8. As discussed above, lung tissue pirfenidone half-life is
much longer than the intravenously delivered plasma pirfenidone
half-life (by as much or greater than 2-4.times.). Plasma
pirfenidone half-life following oral administration is around 2.5
hours. However, continued intestinal absorption affects this number
and hence is much longer than that following intravenous delivery.
Therefore, for purposes of this model the lung tissue pirfenidone
half-life following inhalation delivery will be considered
equivalent to that following oral administration (e.g. 2.5
hours);
[0133] 9. From the above observations and calculations, the lower
limit of efficacy in lung tissue is 8 mcg/gram; and
[0134] 10. Incorporating that 801 mg oral pirfenidone results in a
human plasma level at or greater than 5 mcg/mL for 4 hours and that
5 mcg/mL plasma results in 0.7 mcg/gram lung tissue pirfenidone,
what is delivered by oral or intranasal inhalation must be at or
above 0.7 mcg/gram lung tissue pirfenidone for at least 4 hours for
equivalent lung fibrosis efficacy to the oral dose.
[0135] Exemplary Lung Tissue Calculations: [0136] 1. Mcg
pirfenidone delivered to 1000 grams wet lung tissue (blood plus
lung tissue) to make 0.7 mcg/gram=700 mcg; [0137] 2. Based upon an
RDD efficiency of 30%, the unit dose required is 2,333 mcg (700
mcg/0.3=2,333 mcg); [0138] 3. Based upon an RDD efficiency of 50%,
the unit dose required is 1,400 mcg (700 mcg/0.5=1,400 mcg); [0139]
4. Based upon an RDD efficiency of 70%, the unit dose required is
1,000 mcg (700 mcg/0.7=1,000 mcg); and
[0140] Compensating to maintain at or above these levels for 2 half
lives of 2.5 hours each (4 hours at or above 0.7 mcg/gram wet lung
tissue with a lung half-life of 2.5 hours=1.6 half lives): [0141]
5. For an RDD efficiency of 30%, the unit dose required to match
the lower limit of clinically-observed oral route efficacy (in this
case 2,333 mcg) for 1.6 half lives is 3,733 mcg; [0142] 6. For an
RDD efficiency of 50%, the unit dose required to match the lower
limit of clinically-observed oral route efficacy (in this case
1,400 mcg) for 1.6 half lives 2,240 mcg; and [0143] 7. For an RDD
efficiency of 70%, the unit dose required to match the lower limit
of clinically-observed oral route efficacy (in this case 1,000 mcg)
for 1.6 half lives 1,600 mcg.
[0144] By non-limiting example, based upon the above assumptions a
dose of approximately 3.7 mg in a device delivering pirfenidone or
pyridone analog with 30% efficiency may result in wet lung tissue
levels at or above 0.7 mcg/gram for the same duration as that
obtained following 801 mg administered orally. Moreover, while the
minimally efficacious pirfenidone dose is maintained for this
duration, local pirfenidone levels may exhibit significantly higher
wet lung tissue Cmax levels providing improved efficacy. By
non-limiting example, delivery of 3.7 mg pirfenidone or pyridone
analog with a 30% efficiency device may result in a wet lung tissue
Cmax up to about 1.1 mcg/gram (3.7 mg.times.30%=1.1 mg. 1.1
mg/1,050 grams wet lung weight=1.1 mcg/gram). This number is near
about 1.5-fold higher than that delivered following oral delivery.
By another non-limiting example, based upon the above assumptions a
dose of approximately 50 mg in a device delivering pirfenidone or
pyridone analog with 30% efficiency may result in a wet lung tissue
Cmax up to 14.3 mcg/mL (50 mg.times.30%=15 mg. 15 mg/1,050 grams
wet lung weight=14.3 mcg/gram), or about 20-fold higher than that
delivered following oral delivery. Under this scenario, this dose
may result in maintaining at or above the 0.7 mcg/gram wet lung
tissue minimally efficacious dose for at least about 5 half-lifes,
or about 12.5 hours; compared to 4 hours following 801 mg oral dose
administration. Similarly, by another non-limiting example, based
upon the above assumptions a dose of approximately 15 mg in a
device delivering pirfenidone or pyridone analog with 70%
efficiency may result in a wet lung tissue Cmax up to 10 mcg/mL (15
mg.times.70%=10.5 mg. 10.5 mg/1,050 grams wet lung weight=10
mcg/gram), or about 14-fold higher than that delivered following
oral delivery. Under this scenario, this dose may result in
maintaining at or above the 0.7 mcg/gram wet lung tissue minimally
efficacious dose for about 4.5 half-lifes, or at least about 11
hours; compared to 4 hours following 801 mg oral dose
administration. Such duration over 0.7 mcg/gram lung tissue may
permit twice a day dosing (BID). Similarly, by another non-limiting
example, based upon the above assumptions a dose of approximately
75 mg in a device delivering pirfenidone or pyridone analog with
70% efficiency may result in a wet lung tissue Cmax up to 50 mcg/mL
(75 mg.times.70%=52.5 mg. 52.5 mg/1,050 grams wet lung weight=50
mcg/gram), or about 71-fold higher than that delivered following
oral delivery. Under this scenario, this dose may result in
maintaining at or above the 0.7 mcg/gram wet lung tissue minimally
efficacious dose for at least about 6 half-lifes, or about 15
hours; compared to 4 hours following 801 mg oral dose
administration. Such duration over 0.7 mcg/gram lung tissue may
permit BID dosing. Similary, by another non-limiting example, based
upon the above assumptions a dose of approximately 15 mg in a
device delivering pirfenidone or pyridone analog with 30%
efficiency may result in a wet lung tissue Cmax up to 4.3 mcg/mL
(15 mg.times.30%=4.5 mg. 4.5 mg/1,050 grams wet lung weight=4.3
mcg/gram), or about 6-fold higher than that delivered following
oral delivery. Under this scenario, this dose may result in
maintaining at or above the 0.7 mcg/gram wet lung tissue minimally
efficacious dose for at least about 3 half-lifes, or about 7.5
hours; compared to 4 hours following 801 mg oral dose
administration. Similarly, by another non-limiting example, based
upon the above assumptions a dose of approximately 75 mg in a
device delivering pirfenidone or pyridone analog with 30%
efficiency may result in a wet lung tissue Cmax up to 21 mcg/mL (75
mg.times.30%=22.5 mg. 52.5 mg/1,050 grams wet lung weight=21
mcg/gram), or about 31-fold higher than that delivered following
oral delivery. Under this scenario, this dose may result in
maintaining at or above the 0.7 mcg/gram wet lung tissue minimally
efficacious dose for at least about 5 half-lifes, or about 12.5
hours; compared to 4 hours following 801 mg oral dose
administration. Such duration over 0.7 mcg/gram lung tissue may
permit BID dosing. Similary, by another non-limiting example, based
upon the above assumptions a dose of approximately 15 mg in a
device delivering pirfenidone or pyridone analog with 10%
efficiency may result in a wet lung tissue Cmax up to 1.4 mcg/mL
(15 mg.times.10%=1.5 mg. 1.5 mg/1,050 grams wet lung weight=1.4
mcg/gram), or about 2-fold higher than that delivered following
oral delivery. Under this scenario, this dose may result in
maintaining at or above the 0.7 mcg/gram wet lung tissue minimally
efficacious dose for about 1 half-lifes, or at least about 2.5
hours; compared to 4 hours following 801 mg oral dose
administration. Similarly, by another non-limiting example, based
upon the above assumptions a dose of approximately 75 mg in a
device delivering pirfenidone or pyridone analog with 10%
efficiency may result in a wet lung tissue Cmax up to 21 mcg/mL (75
mg.times.10%=7.5 mg. 7.5 mg/1,050 grams wet lung weight=7.1
mcg/gram), or about 10-fold higher than that delivered following
oral delivery. Under this scenario, this dose may result in
maintaining at or above the 0.7 mcg/gram wet lung tissue minimally
efficacious dose for about 3.5 half-lifes, or at least about 8.8
hours; compared to 4 hours following 801 mg oral dose
administration. Such duration over 0.7 mcg/gram lung tissue may
permit TID dosing. Such an approach could benefit efficacy through
an increased Cmax and maintaining drug exposure at or above the 0.7
mcg/gram wet lung tissue minimal efficacy range for a longer
duration than that currently limited by oral dosing. Such prolonged
exposure may enable a reduced dosing interval (by example
once-a-day or twice-a-day versus the current three times a day oral
dosing regimen). Moreover, while this approach delivers directly to
the lung, using the above non-limiting examples these doses may
result in reduced systemic plasma levels (e.g. Cmax from less than
0.6 mcg/mL pirfenidone from a 4.5 mg delivered dose to 5,000 mL
blood to less than 2 mcg/mL pirfenidone from a 15 mg delivered dose
to less than 10 mcg/mL from a 75 mg dose).
[0145] Doses calculated in the above model will change considerably
if the actual measured lung tissue half-life of pirfenidone or
pyridone analog elimination changes. If the half-life is faster,
more inhaled pirfenidone or pyridone analog will be required to
maintain the lung tissue concentration above that considered the
minimal efficacious level. Additional increases in inhaled
pirfenidone or pyridone analog may be desired to further improve
efficacy. Further, in addition to delivering desired lung tissue
Cmax and AUC, inhaled delivery of aerosol pirfenidone or pyridone
analog may also serve an efficient route for systemic delivery. In
some embodiments, dosing schemes are contemplated that enable
inhaled delivery of pirfenidone or pyridone analog to initially
achieve desired lung tissue Cmax and AUC, and as plasma half-life
is predicted to be slower than that of the lung tissue, targeting
the delivery of specific plasma concentrations may in turn prolong
lung tissue-pirfenidone or pyridone analog exposure.
[0146] As scarring is irreversible, IPF efficacy is the act of
protecting native lung tissue against invading fibrosis. Therefore,
maintaining regular efficacious drug levels in unaffected tissue is
critical for improved patient survival. Clinical and nonclinical
studies have suggested pirfenidone efficacy is dose-responsive
ranging from slowed-disease progression to improvement.
Unfortunately, substantial gastrointestinal (GI) side effects and
systemic toxicity have forced an approved oral dose that is limited
to the lower end of this range. Complicating matters,
recommendations for dose-absorbing food and frequent triggering of
dose-reduction/discontinuation protocols addressing these issues
further reduce lung dose and interrupt required maintenance therapy
of this otherwise promising drug. Inhalation delivery of aerosol
pirfenidone or pyridone analog directly to the lung will reduce or
eliminate these safety or tolerability limitations associated with
the oral route of delivery.
[0147] Oral pirfenidone efficacy has been moderately demonstrated
in human clinical studies and the data suggests that this effect
increases with higher doses. Unfortunately, significant side
effects and toxicity have limited the oral dose to the lower end of
this efficacy range (Esbriet approved up to 2403 mg/d).
Jeopardizing this already low efficacy dose, the Esbriet
prescription requires an initial dose-escalation scheme and
recommended administration with food to acquire minimal GI
tolerance and an acceptable side-effect/toxicity profile (range up
to three 267 mg capsules, or 801 mg three times a day (TID)).
Unfortunately, not all patients reach this recommended dose and
food further reduces bioavailability (food reduces Cmax and AUC
.about.50% and .about.20%, respectively). Further, elevated liver
enzyme levels and skin photoreactivity initiate a physician-guided
dose-reduction and stoppage protocol that in Phase 3 studies
permitted up to a 50% dose reduction before discontinuation (in
these studies between 48% and 67% of patient doses were reduced).
As chronic lung tissue dosing of effective drug levels is critical
for maintenance protection against invading fibrosis, it is likely
that oral pirfenidone prescription and practice result in
sub-efficacious dosing of this otherwise promising drug; a
hypothesis that may in part explain the moderate efficacy observed
in Phase 3 studies.
[0148] 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
pirfenidone or pyridone analog improves pirfenidone treatment
effectiveness through increased lung dose and improved compliance.
In one embodiment, inhalation of pirfenidone or pyridone analog
(e.g. with a nebulizer) delivers pirfenidone or pyridone analog
directly to the lung and whole-body dilution of the delivered dose
is minimized. In some embodiments, inhalation of pirfenidone
reduces or eliminates GI exposure and/or systemic toxicities that
are common with oral administration of pirfenidone or pyridone
analog. In some embodiments, inhalation delivery of pirfenidone or
pyridone analog provided herein provides higher lung tissue levels
of pirfenidone than is possible through oral administration. In
some embodiments, inhalation delivery of pirfenidone or pyridone
analog serves as an efficient means of delivering pirfenidone or
pyridone analog to the systemic compartment. In some embodiments,
inhalation delivery of pirfenidone or pyridone analog provides Cmax
and AUC benefits over the oral route. In some embodiments,
inhalation delivery of pirfenidone or pyridone analog provides Cmax
and AUC benefits over the oral route, wherein plasma re-circulated,
aerosol-delivered pirfenidone or pyridone analog 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 gastrointestinal, phototoxic or liver
enzyme-associated 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 gastrointestinal, phototoxic or liver
enzyme-associated 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 with mild-to-moderate IPF without
the need to initially dose-escalate the patient. In some
embodiments, the methods described herein may be used provide a
prophylactic therapy to 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 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 gastrointestinal, phototoxic or liver enzyme-associated 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 gastrointestinal, phototoxic or liver
enzyme-associated 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 gastrointestinal,
phototoxic or liver enzyme-associated 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
gastrointestinal, phototoxic or liver enzyme-associated adverse
events. By non-limiting example, clincal 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 MMPI, and
CCL18. In some embodiments, a comparison of oral and inhaled
aerosol properties that may be observed is shown in Table A.
TABLE-US-00001 TABLE A Advantages of inhaling pirfenidone Oral
Pirfenidone Inhaled Pirfenidone High oral dose =
minimally-effective Lower inhaled dose = superior lung levels lung
levels Oral route = significant GI side effects Inhaled route =
no/reduced GI side effects High dose = toxicity Lower dose =
reduced toxicity Low efficacy: High efficacy: 1. Pirfenidone is a
low potency drug. 1. Inhaled route permits use of smaller The oral
route requires a very high pirfenidone doses to deliver superior
dose to deliver sufficient lung levels. initial pirfenidone lung
tissue Cmax Significant GI side effects and to a and AUC in the
absence of GI side- lesser extent systemic toxicities limit
effects. In some embodiments, inhaled the oral dose to the lower
end of the administration also serves as non-oral efficacy and
dose-response curve. route for systemic delivery; enabling 2.
Initial dose escalation required to sufficient circulating plasma
obtain maximum-tolerated pirfenidone levels to extend the
maintenance dose. Due to poor duration of superior efficacy.
tolerability, this maintenance dose is 2. Good tolerability permits
establishing often set below the approved dose the maintenance dose
a the approved level level 3. Continued intolerability and safety
3. Strong adherence to maintenance concerns reduce adherence to
therapy maintenance therapy Dose and chronic therapy maintained
Dose reduced and interrupted Inhaled drug unaffected by food
Recommended food absorbs Safe & well-tolerated; no need for
drug special protocols Side effects and toxicity trigger dose
reduction/stoppage protocols
[0149] In some embodiments the methods described herein provide for
delivery of high concentration, readily bioavailable pirfenidone or
pyridone analog compound which in turn provides improved efficacy
over pirfenidone or pyridone analog compound admininstered 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 pirfenidone or pyridone
analog described and contemplated herein for administration by
inhalation are completely homogeneous and soluble.
[0150] In some embodiments, an obstacle to patient compliance with
oral pirfenidone therapy is GI intolerability. Pirfenidone 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 to 801 mg
three times a day. While elevated liver enzymes, photosensitivity
reaction and phototoxicity occur at this dose, they occur with
higher frequency and greater severity with higher doses. Secondly,
pirfenidone is primarily metabolised by CYP1A2. In vitro metabolism
studies with hepatic microsomes indicate that approximately 48% of
pirfenidone is metabolised via CYP1A2 with other CYP isoenzymes
including CYP2C9, 2C19, 2D6, and 2E1 each contributing less than
13%. Thus, inhibiting these enzyme systems results in elevated
pirfenidone blood levels, resulting in increased incidence and
severity of toxicity. To this end, items such as grapefruit juice,
fluvoxamine and other inhibitors of CYP1A2 should be avoided during
oral treatment with pirfenidone.
[0151] Oral administration of pirfenidoen is contraindicated in
patients with concomitant use of fluvoxamine. Fluvoxamine should be
discontinued prior to the initiation of Esbriet therapy and avoided
during Esbriet therapy due to the reduced clearance of pirfenidone.
Other therapies that are inhibitors of both CYP1A2 and one or more
other CYP isoenzymes involved in the metabolism of pirfenidone
(e.g. CYP2C9, 2C19, and 2D6) should also be avoided during
pirfenidone treatment.
[0152] Also for the oral administration, special care should also
be exercised if CYP inhibitors are being used concomitantly with
potent inhibitors of one or more other CYP isoenzymes involved in
the metabolism of pirfenidone such as CYP2C9 (e.g amiodarone,
fluconazole), 2C19 (e.g. chloramphenicol) and 2D6 (e.g. fluoxetine,
paroxetine).
[0153] The oral product should be used with caution in patients
treated with other moderate or strong inhibitors of CYP1A2 (e.g.
ciprofloxacin, amiodarone, propafenone).
[0154] 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 pirfenidone blood levels and increases the
rate and severity of the toxic events described herein. In some
embodiments oral inhalation and intranasal inhalation delivery of
pirfenidone or pyridone analogs 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 pirfenidone or pyridone
analog.
[0155] The primary metabolite of pirfenidone is
5-carboxy-pirfenidone. Following oral or intravenous
administration, this metabolite appears quickly at at high
concetrations in blood. 5-carboxy-pirfenidone does not appear to
have anti-fibrotic or anti-inflammatory activity, its high blood
levels occur at the loss of pirfenidone blood concentrations. Thus,
while the oral product is dosed at the highest possible level, once
pirfenidone enters the blood it is rapidly metabolized to a
non-active species further reducing the drugs potential to achieve
sufficient lung levels required for substantital efficacy. In some
embodiments, because oral inhalation and intranasal inhalation
delivery of pirfenidone or pyridone analogs can achieve effective
lung tissue levels directly, extra-lung metabolism is
minimized.
[0156] In some embodiments, administration of pirfenidone or
pyridone analog 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
pirfenidone or pyridone analog by inhalation avoids or
substantially avoids the gastronintestinal tract and therefore
effects observed with oral administration of pirfenidone or
pyridone analog 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.
[0157] 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, asthma, chronic obstructive pulmonary disease (COPD),
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.
[0158] Pulmonary Fibrosis
[0159] In some embodiments, the compositions and methods described
herein can treat or slow down the progression of or prevent
pulmonary fibrosis. In some embodiments, pulmonary fibrosis
includes interstitial pulmonary fibrosis. 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
[0160] 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.
[0161] 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, pirfenidone inhibits
fibroblast proliferation and differentiation related to collagen
synthesis, inhibits the production and activity of TGF-beta,
reduces production of fibronectiv 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 pirfenidone methods
and compositions described herein may provide tolerability and
usefulness in patients with advanced idiopathic pulmonary fibrosis
and other lung diseases. In some embodiments, pirfenidone 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
pirfenidone treatment. In some embodiments inhaled delivery of
pirfenidone or pyridone analog may be an effective means to
prevent, manage or treat idiopathic pulmonary fibrosis or other
pulmonary fibrotic diseases.
[0162] 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.
[0163] Exemplary 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, chronic obstructive pulmonary disease (COPD),
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).
[0164] Kidney Fibrosis
[0165] In some embodiments, the compositions and methods described
herein can treat or slow down the progression of or prevent kidney
fibrosis. 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 pirfenidone provides protective effect against
heavy metal challenge and fibrosis reversal following diabetic
challenge in rats. Additionally, the antifibrotic action of
pirfenidone in renal fibrosis following partial nephrectomy in rats
has also been shown. Moreover, clinical studies administering oral
pirfenidone 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 pirfenidone or pyridone analog 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.
[0166] 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.
[0167] Heart and Kidney Toxicity
[0168] In some embodiments, the compositions and methods described
herein can treat or slow down the progression of or prevent heart
and/or kidney toxicity. 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 pirfenidone 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 pirfenidone or pyridone analog 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 pirfenidone or pyridone
analog compound is used in the treatment of heart toxicity and/or
kidney toxicity associated with chemotherapy or other therapeutic
agents in a human.
[0169] 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.
[0170] 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.
[0171] Cardiac Fibrosis
[0172] In some embodiments, the compositions and methods described
herein can treat or slow down the progression of or prevent cardiac
fibrosis. 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.
[0173] Treatment of DOCA-salt hypertensive rats with pirfenidone
reversed and prevented fibrosis. Suggesting that pirfenidone or
pyridone analog 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 pirfenidone 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 pirfenidone or pyridone
analog 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.
[0174] 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.
[0175] Hepatic Fibrosis
[0176] In some embodiments, the compositions and methods described
herein can treat or slow down the progression of or prevent hepatic
fibrosis. 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 pirfenidone 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 pirfenidone treatment. Additionally, clinical
studies administering oral pirfenidone 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 pirfenidone or pyridone analog 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.
[0177] 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.
[0178] Multiple Sclerosis
[0179] In some embodiments, the compositions and methods described
herein can treat or slow down the progression of or prevent
multiple sclerosis. Multiple sclerosis is a demyelinating disorder
that is characterized by neurological deficits attributable to
demyelinating lesions and progressive axonal loss in the white
matter. The evidence that TNF-alpha plays a pivotal role in the
pathogenesis of multiple sclerosis led to evaluation of pirfenidone
in this indication. In a clinical study, oral pirfenidone improved
the Scripps Neurological Rating Scale scores over placebo. Further,
pirfenidone reduced the incidence of relapses and was associated
with a marked improvement in bladder dysfunction. Together, and
because the central nervous system vasculature is immediately
downstream of the lung, these results suggest that inhaled delivery
of pirfenidone or pyridone analog may be an effective means to
prevent, manage or treat multiple sclerosis without exposing the
systemic compartment to otherwise toxic drug levels associated with
oral administration.
[0180] The term "multiple sclerosis" is a demyelinating disorder
that is characterized by neurological deficits attributable to
demyelinating lesions and progressive axonal loss in the white
matter.
[0181] Chronic Obstructive Pulmonary Disease (COPD)
[0182] In some embodiments, the compositions and methods described
herein can treat or slow down the progression of or prevent COPD.
Oxidants and oxidative stress due to, by non-limiting example,
cigarette smoking promote lung inflammation, which is mediated, at
least in part, by activation of the transcription factors nuclear
factor (NF)-KB and activator protein (AP)-1. These coordinate the
expression of several genes thought to be important in COPD, such
as interleukin (IL)-8 and TNF.alpha.. These pro-inflammatory
cytokines and chemokines, together with IL-1.beta., strongly
activate the p38 subgroup of mitogen-activated protein kinases
(MAPKs), a family of signal transduction enzymes that also include
extracellular signal-regulated kinases (ERK) and c-jun NH2-terminal
kinases (INK). JNK and p38 members are activated mainly by
cytokines implicated in inflammation and apoptosis. Within the MAPK
family, both the JNK and the p38 subgroups are involved in
mediating pro-inflammatory responses, though p38 seems to play a
prominent role in COPD. Pirfenidone has been shown to inhibit both
TNF-alpha and p38-gamma MAPK. Moreover, silencing p38-gamma MAPK
has been demonstrated to have potential to restore COPD sensitivity
to corticosteroids (Mercado et al., 2007). In some embodiments,
inhaled delivery of pirfenidone or pyridone analog compound is used
in the treatment of COPD in a human. In some embodiments, inhaled
delivery of pirfenidone or pyridone analog may be an effective
means to prevent, manage or treat COPD or associated illness
without exposing the systemic compartment to otherwise toxic drug
levels associated with oral administration. Moreover, inhaled
delivery of pirfenidone or pyridone analog may serve as conjunctive
therapy with corticosteroids to restore their usefulness in this
indication.
[0183] The term "chronic obstructive pulmonary disesase" or "COPD"
by non-limiting example may be associated with or caused by
exposure to tobacco smoke and preexisting asthma. COPD describes a
wide range of airway disorders that range from simple chronic
bronchitis (smokers cough) to the more severe chronic obstructive
bronchitis. The addition of episodes of airway hyper-reactivity to
the above syndrome establishes the diagnosis of chronic asthmatic
bronchitis. Chronic obstructive pulmonary disease includes, but is
not limited to, chronic bronchitis, emphysema, and/or pulmonary
hypertension.
[0184] Asthma
[0185] In some embodiments, the compositions and methods described
herein can treat or slow down the progression of or prevent asthma.
TNF-alpha has been shown to be a highly pro-inflammatory cytokine
in asthma, as it upregulates adhesion molecules, increases mucin
secretion, and promotes airway remodeling. TNF-alpha is produced by
a large number of cells in the airways, including mast cells,
smooth muscle cells, epithelial cells, monocytes, and macrophages.
This cytokine has been shown to be relevant and increased in
patients with asthma. Clinical studies using anti-TNF-alpha therapy
have produced encouraging results. In one set of studies using a
soluble form of recombinant human TNF-alpha receptor (etanercept)
the medication improved FEV1 and improved quality of life. Another
clinical study administering an anti-TNF-alpha antibody reduced
asthma exacerbation (infliximab). However, because of concerns
associated with adverse events future investigation of these
therapies in asthma is unlikely. Because pirfenidone has been shown
to inhibit TNF-alpha, inhaled delivery of pirfenidone or pyridone
analog may be an effective means to manage or treat asthma or
associated illness without exposing the systemic compartment to
otherwise toxic drug levels associated with oral administration. In
some embodiments, inhaled delivery of pirfenidone or pyridone
analog compound is used in the treatment of asthma in a human.
Moreover, inhaled delivery of pirfenidone or pyridone analog may
serve as conjunctive therapy with corticosteroids to restore their
usefulness in asthma patients exhibiting steroid resistance.
[0186] The term "asthma" is associated with or caused by
environmental and genetic factors. Asthma is a common chronic
inflammatory disease of the airways characterized by variable and
recurring symptoms, reversible airflow obstruction, and
bronchospasm. Symptoms include wheezing, coughing, chest tightness,
and shortness of breath. The term asthma may be used with one or
more adjectives to indicate cause. Non-limiting examples of asthma
include, but are not limited to, allergic asthma, non-allergic
asthma, acute severe asthma, chronic asthma, clinical asthma,
nocturnal asthma, allergen-induced asthma, aspirin-sensitive
asthma, exercise-induced asthma, child-onset asthma, adult-onset
asthma, cough-variant asthma, occupational asthma,
steroid-resistant asthma, or seasonal asthma.
[0187] Lung Inflammation
[0188] In some embodiments, the compositions and methods described
herein can treat or slow down the progression of or prevent lung
inflammation. Pirfenidone therapy has shown to have
anti-inflammatory effects in addition to anti-fibrotic effects. In
some embodiments, pirfenidone or pyridone analog compound is
administered to a human to treat lung inflammation. Lung
inflammation is associated with or contributes to the symptoms of
bronchitis, asthma, lung fibrosis, chronic obstructive pulmonary
disorder (COPD), and pneumonitis.
[0189] Glaucoma Surgery Post-Operative Fibrosis
[0190] 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 pirfenidone or pyridone analog may prove beneficial.
[0191] The present invention provides, in several embodiments as
herein disclosed, compositions and methods for pirfenidone and
pyridone analog compound formulations that offer unprecedented
advantages with respect to localized delivery of pirfenidone or
pyridone analog in a manner that permits both rapid and sustained
availability of therapeutically useful pirfenidone or pyridone
analog levels to one or more desired tissues.
[0192] In certain preferred embodiments, and as described in
greater detail below, delivery of the pirfenidone or pyridone
analog 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 lungmay be
achieved by inhalation therapy of a pirfenidone or pyridone analog
compound formulation as described herein.
[0193] These and related embodiments will usefully provide
therapeutic and/or prophylactic benefit, by making therapeutically
effective pirfenidone or pyridone analog 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 pirfenidone or
pyridone analog is available for a prolonged therapeutic
effect.
[0194] The compositions and methods disclosed herein provide for
such rapid and sustained localized delivery of a pirfenidone or
pirfenidone or pyridone analog pyridone analog compound to a wide
variety of tissues. Contemplated are embodiments for the treatment
of numerous clinically significant conditions including pulmonary
fibrosis, chronic obstructive pulmonary disease (COPD), asthma,
cystic fibrosis, cardiac fibrosis, transplantation (e.g., lung,
liver, kidney, heart, etc.), vascular grafts, and/or other
conditions such as multiple sclerosis for which rapid and sustained
bioavailable pirfenidone or pyridone analog therapy may be
indicated.
[0195] 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
a pirfenidone or pyridone analog.
[0196] Without wishing to be bound by theory, according to certain
of these and related embodiments as described in greater detail
herein, a pirfenidone or pyridone analog is provided in a
formulation having components that are selected to deliver an
efficacious dose of pirfenidone or pyridone analog following
aerosolization of a liquid, dry powder or metered-dose formulation
providing rapid and sustained localized delivery of pirfenidone or
pyridone analog to the site of desired effect.
[0197] According to certain related embodiments, regulation of the
total amount of dissolved solutes in a pirfenidone or pyridone
analog compound formulation is believed, according to non-limiting
theory, to result in aqueous pirfenidone or pyridone analog
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 pirfenidone or pyridone analog
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.
[0198] An unexpected observation is that exposure of inhaled
pirfenidone 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 pirfenidone's ability
to chelate ions such as iron(III) in a ratio of three pirfenidone
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 prifenidone
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 pirfenidone was found to
chlate magnesium at a ratio of two pirfenidone molecules to one
magnesium ion. Thus, formulation of between about two and ten
pirfenidone molecules with one magnesium molecule results in
filling or saturating the chelation capacity of prifenidone and
reduces pirfenidone'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 pirfenidone reduces pirfenidone'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, a
pirfenidone or pyridone analog compound formulation that comprises
pirfenidone or a pyridone analog 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, pirfenidone or pyridone analog concentration,
total osmolality and potential taste-masking agent, provides
certain therapeutic and other advantages.
[0199] In certain such embodiments, for example, a pirfenidone or
pyridone analog compound formulation that comprises pirfenidone or
a pyridone analog 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, pirfenidone or pyridone analog stability
(including, by non-limiting example polymorph, amorphic content and
water content), pirfenidone or pyridone analog amount and potential
taste-masking agent, provides certain therapeutic and other
advantages.
[0200] In certain such embodiments, for example, a pirfenidone or
pyridone analog compound formulation that comprises pirfenidone or
a pyridone analog 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, pirfenidone or pyridone analog
stability provides certain therapeutic and other advantages.
[0201] In certain preferred embodiments, a pirfenidone or pyridone
analog 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 a pirfenidone or pyridone analog 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 pirfenidone or pyridone analog
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 pirfenidone or pyridone analog
compound to the pulmonary vasculature.
[0202] 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 preferably include a pirfenidone or
pyridone analog compound such as pirfenidone or pyridone analog
alone or a salt thereof As noted above, however, the invention is
not intended to be so limited and may relate, according to
particularly preferred embodiments, to pirfenidone or a salt
thereof Other contemplated embodiments may relate to another
pyridone analog compound such as those disclosed herein.
[0203] As a non-limiting example, in a preferred embodiment, a
pyridone analog compound as provided herein (e.g., pirfenidone)
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.
[0204] 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.
[0205] 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 pirfenidone or
pyridone analog compound formulations and methods described herein
may be used with commercially available inhalation devices, or with
other devices for aerosol therapeutic product administration.
[0206] As a non-limiting example, in a preferred embodiment, a
pyridone analog compound as provided herein (e.g., pirfenidone)
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 pirfenidone or pyridone analog compound to the pulmonary
vasculature immediately upstream of the left atrium and hence, to
the coronary arterial system with interlumenal atrial and
ventricular exposure.
[0207] 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.
[0208] As a non-limiting example, in a preferred embodiment, a
pyridone analog compound as provided herein (e.g., pirfenidone)
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 pirfenidone or pyridone analog
compound to the pulmonary vasculature immediately upstream of the
left atrium, left ventical and hence, to the kidney
vasculature.
[0209] 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.
[0210] As a non-limiting example, in a preferred embodiment, a
pyridone analog compound as provided herein (e.g., pirfenidone)
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
pirfenidone or pyridone analog compound to the pulmonary
vasculature immediately upstream of the left atrium, left ventical,
and hence, to the heart and kidney vasculature.
[0211] 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.
[0212] As a non-limiting example, in a preferred embodiment, a
pyridone analog compound as provided herein (e.g., pirfenidone)
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 pirfenidone or pyridone analog
compound to the pulmonary vasculature immediately upstream of the
left atrium, left ventical and hence, to the hepatic
vasculature.
[0213] 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.
[0214] As a non-limiting example, in a preferred embodiment, a
pyridone analog compound as provided herein (e.g., pirfenidone)
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-inflammatory and/or anti-demylination benefits, for instance,
to prevent, manage or treat multiple sclerosis. If by oral
inhalation, such embodiments provide for direct and high
concentration delivery of the pirfenidone or pyridone analog
compound 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
pirfenidone or pyridone analog compound to the nasal and sinus
vasculature immediately upstream of the central nervous system.
[0215] 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 multiple sclerosis associated.
[0216] As a non-limiting example, in a preferred embodiment, a
pyridone analog compound as provided herein (e.g., pirfenidone)
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 diseases associated with chronic obstructive
pulmonary disease (COPD), including emphysema and chronic
bronchitis.
[0217] 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 COPD associated, by non-limiting example with
exposure to pipe, cigar and cigarette smoke, secondhand smoke, air
pollution, and chemical fumes or dust, and/or alpha-1 antitrypsin
deficiency.
[0218] As a non-limiting example, in a preferred embodiment, a
pyridone analog compound as provided herein (e.g., pirfenidone)
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 patients with asthma.
[0219] 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 asthma associated, by non-limiting example with
exercise, genetics, airborne allergens, inhaled irritants such as
pipe, cigar and cigarette smoke, and childhood respiratory
infection.
[0220] As a non-limiting example, in a preferred embodiment, a
pyridone analog compound as provided herein (e.g., pirfenidone)
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 pyridone analog compound
with an antibiotic, steroid, hyperosmolar solution, DNAse or other
mucus thinning agent, or other agent.
[0221] 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.
[0222] For the applications described herein, liquid nebulized, dry
powder or metered-dose aerosol pirfenidone or pyridone analog
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, 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-la (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.
[0223] 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 pirfenidone or pyridone analog 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 fibrotic or inflammatory disease. By
non-limiting example, pirfenidone or pyridone analog is
administered either in fixed combination, co-administered,
adminstered 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 and/or fibrosis. By another
non-limiting example, pirfenidone or pyridone analog is
administered either in fixed combination, co-administered,
adminstered sequentially, or co-prescribed with IW001 (Type V
collagen), analog or other collagen targeting immunogenic tolerance
to reduce inflammation and/or fibrosis. By another non-limiting
example, pirfenidone or pyridone analog is administered either in
fixed combination, co-administered, adminstered sequentially, or
co-prescribed with PRM-151 (recombinant pentraxin-2), analog or
other molecule targeting regulation of the injury response to
reduce inflammation and/or fibrosis. By another non-limiting
example, pirfenidone or pyridone analog is administered either in
fixed combination, co-administered, adminstered sequentially, or
co-prescribed with CC-903 (Jun kinase inhibitor), analog or other
Jun kinase inhibitor to reduce the inflammatory response. By
another non-limiting example, pirfenidone or pyridone analog is
administered either in fixed combination, co-administered,
adminstered 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 fibrosis. By another non-limiting example, pirfenidone or
pyridone analog is administered either in fixed combination,
co-administered, adminstered sequentially, or co-prescribed with
QAX576 (monoclonal antibody targeting interleukin 13 [IL-13]),
analog or other antibody targeting IL-13 to reduce inflammation. By
another non-limiting example, pirfenidone or pyridone analog is
administered either in fixed combination, co-administered,
adminstered sequentially, or co-prescribed with FG-3019 (monoclonal
antibody targeting connective tissue growth factor [CTGF]), analog
or other antibody targeting CTGF to reduce fibrosis. By another
non-limiting example, pirfenidone or pyridone analog is
administered either in fixed combination, co-administered,
adminstered 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
fibrosis. By another non-limiting example, pirfenidone or pyridone
analog is administered either in fixed combination,
co-administered, adminstered sequentially, or co-prescribed with
Esbriet, Pirespa or Pirfenex (trade names for pirfenidone), or
analog targeting inflammation and fibrosis. By another non-limiting
example, pirfenidone or pyridone analog is administered either in
fixed combination, co-administered, adminstered 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 and/or inflammation.
[0224] As with administration of pirfenidone, oral and parenteral
routes of administration (by non-limiting example, intravenous and
subcutaneous) of other compounds, molecules and antibodies
targeting the reduction of inflammation 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 pirfenidone or
pyridone analogs, 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 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-903 (Jun kinase
inhibitor), analog or other Jun kinase inhibitor to reduce 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, 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 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 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 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
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 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.
[0225] 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 pyridone compound
(e.g., pirfenidone) 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 a pirfenidone or pyridone
analog 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.
[0226] In addition to the clinical and pharmacological criteria
according to which any composition intended for therapeutic
administration (such as the herein described pirfenidone or
pyridone analog 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 (LogP), predicted stability in various formulations,
osmolality, surface tension, pH, pKa, pKb, dissolution rate, sputum
permeability, sputum binding/inactivation, taste, throat
irritability and acute tolerability.
[0227] Other factors to consider when selecting the particular
product form include physical chemistry of the formulation (e.g., a
pirfenidone or pyridone analog 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 pirfenidone or pyridone analog 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
pirfenidone or pyridone analog compound with non-encapsulating
soluble excipients/salts), a complex liquid such as an aqueous
liquid (e.g., pirfenidone or pyridone analog compound encapsulated
or complexed with soluble excipients such as lipids, liposomes,
cyclodextrins, microencapsulations, and emulsions), a complex
suspension (e.g., pirfenidone or pyridone analog compound 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 pirfenidone or pyridone analog 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.
[0228] Selection of a particular pirfenidone or pyridone analog
compound formulation or pirfenidone or pyridone analog compound
formulation composition 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.
[0229] Packaged agents may be manufactured in such a way as to be
provide a pirfenidone or pyridone analog compound formulation
composition for pulmonary delivery that comprises a solution which
is provided as a pirfenidone or pyridone analog 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 0.1
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.
[0230] In some embodiments, the present invention relates to the
aerosol and/or topical delivery of a pyridone analog compound
(e.g., pirfenidone). Pirfenidone 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.
[0231] In a preferred embodiment, the method treats or serves as
prophylaxis against interstitial lung disease (ILD) by
administering a pirfenidone or pyridone analog 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, hypersensitity pneumonitis and infection), and
other forms of ILD (e.g., lymphangioleiomyomatosis, pulmonary
Langerhans' cell histocytosis, eosinophilic pneumonia and pulmonary
alveolar proteinosis).
[0232] 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 pirfenidone or pyridone analog 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.
[0233] 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 pirfenidone or
pyridone analog 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.
[0234] 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 pirfenidone or
pyridone analog 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.
[0235] In another embodiment, liquid nebulized, dry powder or
metered-dose aerosol pirfenidone or pyridone analog 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.
[0236] As a non-limiting example, in a preferred embodiment, a
pyridone analog compound as provided herein (e.g., pirfenidone)
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), COPD
and asthma 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 pirfenidone or
pyridone analog. 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 pirfenidone or pyridone analog.
[0237] As a non-limiting example, in a preferred embodiment, a
pyridone analog compound as provided herein (e.g., pirfenidone)
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 pirfenidone or pyridone analog. 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 pirfenidone or
pyridone analog.
[0238] In another embodiment, a method is provided for acute or
prophylactic treatment of a patient through non-oral or non-nasal
topical administration of pirfenidone or pyridone analog (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.
[0239] In another embodiment, a method is provided for acute or
prophylactic treatment of a patient through non-oral or non-nasal
topical administration of pirfenidone or pyridone analog (or a 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.
[0240] In another embodiment, a pyridone analog compound as
provided herein (e.g., pirfenidone) 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.
[0241] As a non-limiting example, in a preferred embodiment, a
pyridone analog compound as provided herein (e.g., pirfenidone)
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 pirfenidone or pyridone analog 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.
[0242] As a non-limiting example, in a preferred embodiment, a
pyridone analog compound as provided herein (e.g., pirfenidone 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 pirfenidone or pyridone analog 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.
[0243] In some embodiments, delivery sites such as a pulmonary
site, the a pirfenidone or pyridone analog compound formulation as
provided herein is administered in one or more administrations so
as to achieve a respirable delivered dose daily of pirfenidone or
pyridone analog 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,
a pirfenidone or pyridone analog compound formulation as provided
herein is administered in one or more administrations so as to
achieve a respirable delivered dose daily of pirfenidone or
pyridone analog 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, 205, 210, 215, 220,
225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285,
290, 295, 300 milligrams. The pirfenidone or pyridone analog
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,
pirfenidone or pyridone analog 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.
[0244] In some embodiments, delivery sites such as the nasal cavity
or sinus, pirfenidone or pyridone analog (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 pirfenidone
or pyridone analog 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,
pirfenidone or pyridone analog (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 pirfenidone
or pyridone analog 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, 205,
210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270,
275, 280, 285, 290, 295, 300 milligrams. The pirfenidone or
pyridone analog 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, pirfenidone or pyridone analog 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.
[0245] 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.
[0246] 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.
[0247] 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.
[0248] 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.
[0249] 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.
[0250] 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.
[0251] 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 COPD therapy. In some
embodiments of the methods describe above, the human subject may be
mechanically ventilated.
[0252] 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 asthma therapy. In some
embodiments of the methods describe above, the human subject may be
mechanically ventilated.
[0253] 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 multiple sclerosis therapy.
In some embodiments of the methods describe above, the human
subject may be mechanically ventilated.
[0254] In another embodiment, a pharmaceutical composition is
provided that includes a simple liquid pirfenidone or pyridone
analog (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.
[0255] In another embodiment, a pharmaceutical composition is
provided that includes a simple liquid pirfenidone or pyridone
analog (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.
[0256] In another embodiment, a pharmaceutical composition is
provided that includes a complex liquid pirfenidone or pyridone
analog (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.
[0257] In another embodiment, a pharmaceutical composition is
provided that includes a complex liquid pirfenidone or pyridone
analog (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.
[0258] In another embodiment, a pharmaceutical composition is
provided that includes a complex liquid pirfenidone or pyridone
analog (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.
[0259] In another embodiment, a pharmaceutical composition is
provided that includes a simple liquid formulation of pirfenidone
or pyridone analog (or salt thereof) compound formulation having a
prifenidone or pyridone analog to multivalent cation positive
charge molar ratio between about two pirfenidone or pyridone analog
compounds to about 0.1 to about 4 multivalent cation positive
charges. By non-limiting example, two pirfenidone or pyridone
analog compounds to one magnesium ion (two cation positive
charges), three prifenidone or pyridone analog compounds to one
magnesium ions, four pirfenidone or pyridone analog compounds to
one magnesium ions, and two pirfenidone or pyridone analog
compounds to two magnesium ions.
[0260] An unexpected finding was that divalent cations, by
non-limiting example magnesium, reduced pirfenidone dissolution
time and increased pirfenidone aqueous solubility in a molar
ratio-dependent manner. This increased saturation solubility is
enabling to deliver predicted-sufficient quantities of inhaled
liquid-nebulized pirfenidone to the lung. By example, one
pirfenidone molecules to three magnesium molecules exhibited a
slower dissolution time and reduced saturation solubility than one
pirfenidone molecule to one magnesium molecule. Moreover, one
pirfenidone molecules to one magnesium molecule exhibited a faster
dissolution time and greater aqueous solubility than an equal-molar
ratio of pirfenidone to sodium.
[0261] In another embodiment, a pharmaceutical conmposition is
provided that includes a complex liquid formulation of pirfenidone
or pyridone analog (or salt thereof) compound formulation having a
prifenidone or pyridone analog to to about 0.1 to about 4
multivalent cation positive charges. By non-limiting example, two
pirfenidone or pyridone analog compounds to one magnesium ion (two
cation positive charges), three prifenidone or pyridone analog
compounds to one magnesium ions, four pirfenidone or pyridone
analog compounds to one magnesium ions, and two pirfenidone or
pyridone analog compounds to two magnesium ions.
[0262] In another embodiment, a pharmaceutical composition is
provided that includes a complex liquid pirfenidone or pyridone
analog (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.
[0263] In another embodiment, a pharmaceutical composition is
provided that includes a complex suspension of a pirfenidone or
pyridone analog (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.
[0264] In another embodiment, a pharmaceutical composition is
provided that includes a complex suspension of a pirfenidone or
pyridone analog (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.
[0265] In another embodiment, a pharmaceutical composition is
provided that includes a complex suspension of pirfenidone or
pyridone analog (or salt thereof) compound formulation having a
pirfenidone or pyridone analog to multivalent cation positive
charge molar ratio between about one pirfenidone or pyridone analog
compounds to about 0.1 to about 4 multivalent cation positive
charges. By non-limiting example, two pirfenidone or pyridone
analog compounds to one magnesium ion (two cation positive
charges), three prifenidone or pyridone analog compounds to one
magnesium ions, four pirfenidone or pyridone analog compounds to
one magnesium ions, and two pirfenidone or pyridone analog
compounds to two magnesium ions.
[0266] In other embodiments, a pirfenidone or pyridone analog (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 a pirfenidone or pyridone analog (or salt
thereof) compound.
[0267] In certain preferred embodiments that relate to the
pirfenidone or pyridone analog (or salt thereof) compound
formulations disclosed herein, the formulation comprises a
pirfenidone or pyridone analog (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 pirfenidone of
pyridone analog. 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 a pirfenidone or pyridone
analog (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 pirfenidone or pyridone analog
(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 a pirfenidone or pyridone analog (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 pirfenidone or pyridone analog (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
pirfenidone or pyridone analog. By example, 1 mol divalent ion to 2
mols pirfenidone or pyridone analog, 1.5 mols divalent ion to 2
mols pirfenidone or pyridone analog, 2 mols divalent ion to 2 mols
pirfenidone or pyridone analog, 3 mols divalent ion to 2 mols
pirfenidone or pyridone analog, or 4 mols divalent ion to 2 mols
pirfenidone or pyridone analog. 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.
[0268] In another embodiment, while the inclusion of the correct
molar ratio of magnesium to pirfenidone 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.
[0269] 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.
[0270] 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.
[0271] In another embodiment, pirfenidone or pyridone analog
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 2-pyridone structure of
pirfenidone. It is known that pirfenidone chelates Fe(III) at a
ratio of 3 pirfenidone molecules to 1 Fe(III). From this it follows
that pirfenidone will chelate magnesium at 2 pirfenidone 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 pirfenidone or pyridone analog. By non-limiting
example, 2 pirfenidone molecules to 0.1 magnesium molecules, 2
pirfenidone molecules to 0.25 magnesium molecules, 2 pirfenidone
molecules to 0.5 magnesium molecules, 2 pirfenidone molecules to
0.75 magnesium molecules, 2 pirfenidone molecules to 1 magnesium
molecules, 2 pirfenidone molecules to 1.5 magnesium molecules, 2
pirfenidone molecules to 2 magnesium molecules, 2 pirfenidone
molecules to 3 magnesium molecules, 2 pirfenidone molecules to 4
magnesium molecules, 2 pirfenidone molecules to 5 magnesium
molecules, 2 pirfenidone molecules to 6 magnesium molecules, 2
pirfenidone molecules to 7 magnesium molecules, 2 pirfenidone
molecules to 8 magnesium molecules, 2 pirfenidone molecules to 9
magnesium molecules, 2 pirfenidone molecules to 10 magnesium
molecules, 2 pirfenidone molecules to 12 magnesium molecules, 2
pirfenidone molecules to 14 magnesium molecules, 2 pirfenidone
molecules to 16 magnesium molecules, 2 pirfenidone molecules to 18
magnesium molecules, or 2 pirfenidone 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.
[0272] In another embodiment, a pharmaceutical composition of
liquid pirfenidone or pyridone analog 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.
[0273] In another embodiment, a pharmaceutical composition of
liquid or dry powder pirfenidone or pyridone analog may contain a
chelated metal ion to assist in solubility and/or dissolution of
pirfenidone or pyridone analog. By non-limiting example, these may
include iron, magnesium, or calcium.
[0274] In another embodiment, a pharmaceutical composition of
liquid or dry powder pirfenidone or pyridone analog 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 pirfenidone or pyridone analog. By non-limiting example,
2 pirfenidone molecules to 0.1 magnesium molecules, 2 pirfenidone
molecules to 0.25 magnesium molecules, 2 pirfenidone molecules to
0.5 magnesium molecules, 2 pirfenidone molecules to 0.75 magnesium
molecules, 2 pirfenidone molecules to 1 magnesium molecules, 2
pirfenidone molecules to 1.5 magnesium molecules, 2 pirfenidone
molecules to 2 magnesium molecules, 2 pirfenidone molecules to 3
magnesium molecules, 2 pirfenidone molecules to 4 magnesium
molecules, 2 pirfenidone molecules to 5 magnesium molecules, 2
pirfenidone molecules to 6 magnesium molecules, 2 pirfenidone
molecules to 7 magnesium molecules, 2 pirfenidone molecules to 8
magnesium molecules, 2 pirfenidone molecules to 9 magnesium
molecules, 2 pirfenidone molecules to 10 magnesium molecules, 2
pirfenidone molecules to 12 magnesium molecules, 2 pirfenidone
molecules to 14 magnesium molecules, 2 pirfenidone molecules to 16
magnesium molecules, 2 pirfenidone molecules to 18 magnesium
molecules, or 2 pirfenidone 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.
[0275] In some embodiments, described herein is a pharmaceutical
composition that includes: pirfenidone; water; phosphate buffer or
citrate buffer; and optionally sodium chloride or magnesium
chloride. In other embodiments, described herein is a
pharmaceutical composition that includes: pirfenidone; 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 pirfenidone,
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 1-1 to Table 1-11 of Example 1.
[0276] Solutions of pirfenidone should remain protected from light
as the API in solution is subject to degradation
[0277] In another embodiment, a pharmaceutical composition is
provided that includes a simple dry powder pirfenidone or pyridone
analog (or salt thereof) compound alone in dry powder form with or
without a blending agent such as lactose.
[0278] In another embodiment, the pharmaceutical composition used
in a liquid, dry powder or meter-dose inhalation device is provided
such that pirfenidone or pyridone analog is not in a salt form.
[0279] In another embodiment, a pharmaceutical composition is
provided that includes a complex dry powder pirfenidone or pyridone
analog (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
blending agent such as lactose.
[0280] In another embodiment, a system is provided for
administering a pirfenidone or pyridone analog (or salt thereof)
compound that includes a container comprising a solution of a
pirfenidone or pyridone analog (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.
[0281] In another embodiment, a system is provided for
administering a pirfenidone or pyridone analog (or salt thereof)
compound that includes a container comprising a dry powder of a
pirfenidone or pyridone analog (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.
[0282] In another embodiment, a kit is provided that includes a
container comprising a pharmaceutical formulation comprising a
pirfenidone or pyridone analog (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.
[0283] In another embodiment, a kit is provided that includes a
container comprising a pharmaceutical formulation comprising a
pirfenidone or pyridone analog (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.
[0284] It should be understood that many carriers and excipients
may serve several functions, even within the same formulation.
[0285] Contemplated pharmaceutical compositions provide a
therapeutically effective amount of pirfendione or pyridone analog
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 pirfendione or pyridone analog compound
enabling once-a-day dosing. In some embodiments, pharmaceutical
compositions for inhaled delivery provide an effective amount of
pirfendione or pyridone analog compound enabling twice-a-day
dosing. In some embodiments, pharmaceutical compositions for
inhaled delivery provide an effective amount of pirfendione or
pyridone analog compound enabling three times-a-day dosing.
[0286] 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
[0287] The term "mg" refers to milligram.
[0288] The term "mcg" refers to microgram.
[0289] The term "microM" refers to micromolar.
[0290] The term "QD" refers to once a day dosing.
[0291] The term "BID" refers to twice a day dosing.
[0292] The term "TID" refers to three times a day dosing.
[0293] The term "QID" refers to four times a day dosing.
[0294] 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.
[0295] As used herein, the terms "comprising," "including," "such
as," and "for example" are used in their open, non-limiting
sense.
[0296] 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 a pirfenidone or
pyridone analog (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.
[0297] 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 a pirfenidone or pyridone analog (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.
[0298] The terms "intranasal inhalation administration" and
"intranasal inhalation delivery" refer to a method of giving to a
mammal a dosage of a pirfenidone or pyridone analog (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.
[0299] 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 a pirfenidone or
pyridone analog (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.
[0300] 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 a pirfenidone or
pyridone analog (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.
[0301] "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.
[0302] The terms "oral inhalation administration" or "oral
inhalation delivery" or "oral inhalation" refer to a method of
giving to a mammal a dosage of a pirfenidone or pyridone analog (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.
[0303] 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.
[0304] "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.
[0305] "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.
[0306] 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.
[0307] 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.
[0308] "Patient" or "subject" are used interchangeably and refer to
a mammal.
[0309] The term "mammal" is used in its usual biological sense. In
some embodiments, a mammal is a human.
[0310] The term "ex vivo" refers to experimentation or manipulation
done in or on living tissue in an artificial environment outside
the organism.
[0311] 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.
[0312] 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.
[0313] 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.
[0314] According to certain herein disclosed embodiments a
pirfenidone or a pyridone analog 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.
[0315] 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.
[0316] 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 a pirfenidone or
pyridone analog compound formulation, and greater than about pH 8.0
for a pirfenidone or pyridone analog compound aqueous solution.
[0317] 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 a
pirfenidone or pyridone analog 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.).
[0318] 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 ((pKal) 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.
[0319] "Solvate" refers to the compound formed by the interaction
of a solvent and pirfenidone or a pyridone analog compound, a
metabolite, or salt thereof. Suitable solvates are pharmaceutically
acceptable solvates including hydrates.
[0320] By "therapeutically effective amount" or "pharmaceutically
effective amount" is meant pirfenidone or a pyridone analog
compound, as disclosed for this invention, which has a therapeutic
effect. The doses of pirfenidone or a pyridone analog compound
which are useful in treatment are therapeutically effective
amounts. Thus, as used herein, a therapeutically effective amount
means those amounts of pirfenidone or a pyridone analog 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, multiple sclerosis, COPD or asthma. In particular
embodiments, the pirfenidone or pyridone analog 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 pirfenidone or pyridone analog
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.
[0321] 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 COPD, a "therapeutic effect" is defined as a
patient-reported improvement in quality of life and/or a
statistically significant 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. For asthma, a "therapeutic effect" is defined
as a patient-reported improvement in quality of life and/or a
statistically significantly improved exercise capacity, improved
FEV1 and/or FVC, and/or reduced incidence or acute exacerbation.
For multiple sclerosis, a "therapeutic effect" is defined as a
patient-reported improvement in quality of life and/or a
statistically significantly improved Scripps Neurological Rating
Scale score, improvement in bladder dysfunction, improved
Disability Status Socres, MRI lesion count, and/or an slowed or
halted progression of disease.
[0322] "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 pirfenidone or a pyridone analog compound.
[0323] "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 pirfenidone or a pyridone analog compound.
[0324] The term "dosing interval" refers to the time between
administrations of the two sequential doses of a pharmaceutical's
during multiple dosing regimens.
[0325] The "respirable delivered dose" is the amount of aerosolized
pirfenidone or a pyridone analog compound particles inhaled during
the inspiratory phase of the breath simulator that is equal to or
less than 5 microns.
[0326] "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.
[0327] "Nominal dose," or "loaded dose" refers to the amount of
drug that is placed in the nebuluzer prior to administration to a
mammal. The volume of solution containing the nominal dose is
referred to as the "fill volume."
[0328] "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).
[0329] "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.
[0330] "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, chronic
obstructive pulmonary disease (COPD), bronchitis, chronic
bronchitis, emphysema, or asthma.
[0331] "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.
[0332] "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.
Pirfenidone and Pyridone Analog Compounds
[0333] As also noted elsewhere herein, in preferred embodiments the
pyridone compound for use in a pyridone compound formulation as
described herein comprises pirfenidone
(5-methyl-1-phenyl-2-(1H)-pyridone) or a salt thereof. Although
various embodiments are described with the use of pirfenidone, it
is noted that other pyridone analog compounds, or salts thereof,
may be used in place of pirfenidone.
[0334] Pirfenidone is also known as
5-methyl-1-phenyl-2-(1H)-pyridone and has the structure:
##STR00001##
[0335] "Pyridone analog" or "pyridone compound" refers to compounds
that have the same type of biological activity and effectiveness as
pirfenidone. Such pyridone analog compounds are those that upon
administration to a mammal produce anti-inflammatory, anti-fibrotic
and/or anti-demylination activity for therapeutic or prophylactic
purposes. In some embodiments, a pyridone analog is a compound that
has a substituted 2-(1H)pyridone or 3-(1H)pyridone core structure.
In some embodiments, a pyridone analog is a compound that has a
substituted 2-(1H)pyridone core structure.
[0336] 1-Phenyl-2-(1H)pyridone,
5-methyl-1-(4-methylphenyl)-2-(1H)-pyridone,
5-methyl-1-(4-hydroxyphenyl)-2-(1H)-pyridone,
5-methyl-1-(4-methoxyphenyl)-2-(1H)-pyridone,
5-Methyl-1-(2'-pyridyl)-2-(1H)pyridone,
6-Methyl-1-phenyl-3-(1H)pyridone, 6-Methyl-1-phenyl-2-(1H)pyridone,
5-Methyl-1-p-tolyl-3-(1H)pyridone,
5-Methyl-3-phenyl-1-(2'-thienyl)-2-(1H)pyridone,
5-Methyl-1-(2'-naphthyl)-3-(1H)pyridone,
5-Methyl-1-(2'-naphthyl)-2-(1H)pyridone,
5-Methyl-1-phenyl-3-(1H)pyridone,
5-Methyl-1-p-tolyl-2-(1H)pyridone,
5-Methyl-1-(1'naphthyl)-2-(1H)pyridone,
5-Methyl-1-(5'-quinolyl)-3-(1H)pyridone,
5-Ethyl-1-phenyl-2-(1H)pyridone, 5-Ethyl-1-phenyl-3-(1H)pyridone,
5-Methyl-1-(5'-quinolyl)-2-(1H)pyridone,
5-Methyl-1-(4'-methoxyphenyl)-3-(1H)pyridone,
5-Methyl-1-(4'-quinolyl)-2-(1H)pyridone,
4-Methyl-1-phenyl-3-(1H)pyridone,
5-Methyl-1-(4'-pyridyl)-2-(1H)pyridone,
5-Methyl-1-(3'-pyridyl)-3-(1H)pyridone,
3-Methyl-1-phenyl-2-(1H)pyridone,
5-Methyl-1-(4'-methoxyphenyl)-2-(1H)pyridone,
5-Methyl-1-(2'-Thienyl)-3-(1H)pyridone,
5-Methyl-1-(2'-pyridyl)-3-(1H)pyridone,
1,3-Diphenyl-2-(1H)pyridone, 1,3-Diphenyl-5-methyl-2-(1H)pyridone,
5-Methyl-1-(2'-quino lyl)-3-(1H)pyridone,
5-Methyl-1-(3'-trifluoromethylphenyl)-2-(1H)pyridone,
1-Phenyl-3-(1H)pyridone, 1-(2'-Furyl)-5-methyl-3-(1H)-pyridone,
3-Ethyl-1-phenyl-2-(1H)pyridone,
1-(4'-Chlorophenyl)-5-methyl-(1H)pyridone,
5-Methyl-1-(3'-pyridyl)-2-3-(1H)pyridone,
5-Methyl-1-(3-nitrophenyl)-2-(1H)pyridone,
3-(4'-Chlorophenyl)-5-Methyl-1-phenyl-2-(1H)pyridone,
5-Methyl-1-(2'-Thienyl)-2-(1H)pyridone,
5-Methyl-1-(2'-thiazolyl)-2-(1H)pyridone,
3,6-Dimethyl-1-phenyl-2-(1H)pyridone,
1-(4'Chlorophenyl)-5-Methyl-2-(1H)pyridone,
1-(2'-Imidazolyl)-5-Methyl-2-(1H)pyridone,
1-(4'-Nitrophenyl)-2-(1H)pyridone,
1-(2'-Furyl)-5-Methyl-2-(1H)pyridone,
1-Phenyl-3-(4'-chlorophenyl)-2-(1H)pyridone.
[0337] In some embodiments, a pyridone analog compound is a
compound described in US patent publication no. US20090005424; US
patent publication no. 20070092488; U.S. Pat. Nos. 8,022,087;
6,090,822; 5,716,632; 5,518,729; 5,310,562; 4,052,509; 4,042,699;
3,839,346; or 3,974,281.
[0338] In some embodiments, a pyridone analog is a deuterated
pirfenidone compound, where 1 or more hydrogen atoms of pirfenidone
are replced with deuterium.
According to certain other distinct embodiments of the compositions
and methods described herein, the pyridone compound is selected
from the group consisting of bis(2-hydroxyethyl)azanium;
2-(3,5-diiodo-4-oxopyridin-1-yl)acetate, propyl
2-(3,5-diiodo-4-oxopyridin-1-yl)acetate,
2-[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl][1,2,4]triazolo[4,3-a]pyrid-
in-3-one hydrochloride,
2-[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl]-[1,2,4]triazolo[4,3-a]pyri-
din-3-one, 3-anilino-1-phenylpropan-1-one,
2-[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl]-[1,2,4]triazolo[4,3-a]pyri-
din-3-one hydrochloride,
2-[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl]-[1,2,4]triazolo[4,3
a]pyridin-3-one,
2S)-2-amino-3-(3-hydroxy-4-oxopyridin-1-yl)propanoic acid, 2-[3-[4
(3-chlorophenyl)piperazin-1-yl]propyl]-[1,2,4]triazolo[4,3-a]pyridin-3-on-
e,
2-[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl]-[1,2,4]triazolo[4,3-a]py-
ridin-3-one hydrochloride,
2-[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl]-[1,2,4]triazolo[4,3-a]pyri-
din-3-one hydrochloride,
(2S)-2-[(3-hydroxy-4-oxopyridin-1-yl)amino]propanoic acid,
2-[3-[4-(3
chlorophenyl)piperazin-1-yl]propyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one
hydrochloride, 2-amino-3-(3-hydroxy-4-oxopyridin-1-yl)propanoic
acid,
2-[3-[4-(3chlorophenyl)piperazin-1-yl]propyl]-[1,2,4]triazolo[4,3-a]pyrid-
in-3-one hydrochloride, propyl
2-(3,5-diiodo-4-oxopyridin-1-yl)acetate,
2-(3,5-diiodo-4-oxopyridin-1-yl)acetic acid; 2-(2
hydroxyethylamino)ethanol,
(2S)-2-amino-3-(3-hydroxy-4-oxopyridin-1-yl)propanoic acid,
(2R)-2-amino-3-(3-hydroxy-4-oxopyridin-1-yl)propanoic acid,
2-amino-3-(3-hydroxy-4-oxopyridin-1-yl)propanoic acid,
5-cyano-6-methyl-N-[4
(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropy-
ridine-3-carboxamide,
6-methyl-N-[4-(methylsulfonyl)benzyl]-5-nitro-2-oxo-1-[3-(trifluoromethyl-
)phenyl]-1,2-dihydropyridine-3-carboxamide,
5-(1-butoxyvinyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifl-
uoromethyl) phenyl]-1,2-dihydropyridine-3-carboxamide,
5-acetyl-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethy-
l)phenyl]-1,2-dihydropyridine-3-carboxamide,
5-[(1E)-N-methoxyethanimidoyl]-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-ox-
o-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
5-[(1E)-N-hydroxyethanimidoyl]-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-ox-
o-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-(pyridin-3-yle
thynyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-(2-pyridin-3-ylethyl)-1-[3--
(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-
-5-vinyl-1,2-dihydropyridine-3-carboxamide, ethyl
2-methyl-5-({[4(methylsulfonyl)benzyl]amino}carbonyl)-6-oxo-1-[3-(trifluo-
romethyl)phenyl]-1,6-dihydropyridine-3-carboxylate,
5-(4-methanesulfonyl-benzylcarbamoyl)-2-methyl-6-oxo-1-(3-trifluoromethyl-
-phenyl)-1,6-dihydro-pyridine-3-carboxylic acid,
6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dica-
rboxylic acid 5-dimethylamide 3-(4-methanesulfonyl-benzylamide),
6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dica-
rboxylic acid 5-amide 3-(4-methanesulfonyl-benzylamide),
6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dica-
rboxylic acid 3-(4-methanesulfonyl-benzylamide)5-methylamide,
6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydropyridine-3,5-dicar-
boxylic acid
5-[(2-hydroxy-ethyl)-methyl-amide]3-(4-methanesulfonyl-benzylamide),
6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dica-
rboxylic acid
3-(4-methanesulfonyl-benzylamide)5-(methyl-propyl-amide),
6-methyl-2-oxo-5-(pyrrolidine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1,-
2-dihydro-pyridine-3,5-dicarboxylic acid
3-(4-methanesulfonyl-benzylamide),
6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dica-
rboxylic acid
5-[(2-dimethylamino-ethyl)-methyl-amide]3-(4-methanesulfonyl-benzylamide)-
,
5-((2R)-2-hydroxymethyl-pyrrolidine-1-carbonyl)-6-methyl-2-oxo-1-(3-trif-
luoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid
3-(4-methanesulfonyl-benzylamide),
5-(3-hydroxy-pyrrolidine-1-carbonyl)-6-methyl-2-oxo-1-(3-trifluoromethyl--
phenyl)-1,2-dihydro-pyridine-3,5-dicarboxylic acid
3-(4-methanesulfonyl-benzylamide), N
3-[(1,1-dioxido-2,3-dihydro-1-benzothien-5-yl)methyl]-N 5,N
5,6-trimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-
-dicarboxamide, 5-(N
1-acetyl-hydrazinocarbonyl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1-
,2-dihydro-pyridine-3-carboxylic acid
4-methanesulfonyl-benzylamide, 5-[N
1-(2-cyano-acetyl)-hydrazinocarbonyl]-6-methyl-2-oxo-1-(3-trifluoromethyl-
-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid
4-methanesulfonyl-benzylamide,
5-{[2-(aminocarbonothioyl)hydrazino]carbonyl}-6-methyl-N-[4-(methylsulfon-
yl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carbo-
xamide,
5-hydrazinocarbonyl-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,-
2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide,
5-({2-[(ethylamino)carbonyl]hydrazino}carbonyl)-6-methyl-N-[4-(methylsulf-
onyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-car-
boxamide,
5-({2-[(N,N-dimethylamino)carbonyl]hydrazino}carbonyl)-6-methyl--
N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihyd-
ropyridine-3-carboxamide,
5-(3,3-dimethyl-ureido)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-d-
ihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide,
6-methyl-5-(3-methyl-ureido)-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihyd-
ro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide,
6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-5-ureido-1,2-dihydro-pyridine-
-3-carboxylic acid 4-methanesulfonyl-benzylamide,
5-amino-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine--
3-carboxylic acid 4-methanesulfonyl-benzylamide,
6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-propionyl-1-[3-(trifluorome-
thyl) phenyl]-1,2-dihydropyridine-3-carboxamide,
5-formyl-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethy-
l)phenyl]-1,2-dihydropyridine-3-carboxamide,
6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-(3-oxobutyl)-1-[3-(trifluor-
omethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
5-acetyl-N-[4-(isopropylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluorome-
thyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
5-acetyl-1-(3-cyano-phenyl)-6-methyl-2-oxo-1,2-dihydro-pyridine-3-carboxy-
lic acid 4-methanesulfonyl-benzylamide,
5-acetyl-1-(3-chloro-phenyl)-6-methyl-2-oxo-1,2-dihydro-pyridine-3-carbox-
ylic acid 4-methanesulfonyl-benzylamide,
5-acetyl-6-methyl-2-oxo-1-m-tolyl-1,2-dihydro-pyridine-3-carboxylic
acid 4-methanesulfonyl-benzylamide,
5-(1-hydroxyethyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trif-
luoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
5-(1-azidoethyl)-6-methyl-N-[4-(methylsulfonyl)
benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxa-
mide,
6-methyl-N-[4-(methylsulfonyl)benzyl]-5-(1-morpholin-4-ylethyl)-2-ox-
o-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
5-(1-hydroxypropyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(tri-
fluoromethyl)phenyl]-1,2-dihydropyridine-3-carb oxamide,
5-(1-hydroxyethyl)-N-[4-(isopropylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(t-
rifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
N-[4-(cyclopropylsulfonyl)benzyl]-5-formyl-6-methyl-2-oxo
1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
5-[(E)-(methoxyimino)methyl]-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo--
1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
5-(hydroxymethyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifl-
uoromethyl)phenyl]-1,2-dihydropyridine-3-carbox amide,
5-[(dimethylamino)methyl]-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[-
3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
6-methyl-5-[(methylamino)methyl]-N-[4-(methylsulfonyl)benzyl]-2-oxo
1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
6-methyl-N-[4-(methylsulfonyl)benzyl]-5-(morpholin-4-ylmethyl)-2-oxo-1-[3-
-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
5-{[(2-furylmethyl)amino]methyl}-6-methyl-N-[4-(methylsulfonyl)benzyl]-2--
oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
5-[(cyclopropylamino)methyl]-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo--
1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
5-{[(2-hydroxypropyl)amino]methyl}-6-methyl-N-[4-(methylsulfonyl)benzyl]--
2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
5-[(cyclopentylamino)methyl]-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo--
1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
5-{[(2-hydroxyethyl)(methyl)amino]methyl}-6-methyl-N-[4-(methylsulfonyl)b-
enzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxami-
de,
6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-(pyrrolidin-1-ylmethyl)--
1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
5-{[methoxy(methyl)amino]methyl}-6-methyl-N-[4-(methylsulfonyl)
benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxa-
mide,
5-{[(cyanomethyl)amino]methyl}-6-methyl-N-[4-(methylsulfonyl)benzyl]-
-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
5-{[(cyclopropylmethyl)amino]methyl}-6-methyl-N-[4-(methylsulfonyl)benzyl-
]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
5-[(3-hydroxypyrrolidin-1-yl)methyl]-6-methyl-N-[4-(methylsulfonyl)benzyl-
]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
5-(2-hydroxyethoxy)-N-[4-(isopropylsulfonyl)benzyl]-6-methyl
-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
2-methyl-5-({[4-(methylsulfonyl)benzyl]amino}carbonyl)-6-oxo-1-[3-(triflu-
oromethyl)phenyl]-1,6-dihydropyridin-3-yl acetate,
5-methoxy-6-methyl-N-[4-(methylsulfonyl)
benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxa-
mide,
5-(3-methoxypropoxy)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[-
3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
2-methyl-5-({[4-(methylsulfonyl)benzyl]amino}carbonyl)-6-oxo-1-[3-(triflu-
oromethyl)phenyl]-1,6-dihydropyridin-3-ylmethanesulfonate,
5-ethoxy-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethy-
l)phenyl]-1,2-dihydropyridine-3-carboxamide,
5-(2-hydroxyethoxy)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(tri-
fluoro methyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
5-(cyanomethoxy)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(triflu-
oromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
2-({2-methyl-5-({[4-(methylsulfonyl)benzyl]amino}carbonyl)-6-oxo-1-[3-(tr-
ifluoromethyl)phenyl]-1,6-dihydropyridin-3-yl}oxy)ethylacetate,
5-[2-(dimethylamino)-2-oxoethoxy]-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-
-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
5-(2-aminoethoxy)-N-[4-(isopropylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(tr-
ifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
5-(acetylamino)-6-methyl-N-[4-(methylsulfonyl)
benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxa-
mide,
N-[4-(isopropylsulfonyl)benzyl]-6-methyl-5-[3-(methylamino)propoxy]--
2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
5-(1-methoxyethyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trif-
luoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
5-(2-bromo-1-methoxyethyl)-6-methyl-N-[4-(methylsulfonyl)ben
zyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamid-
e,
5-(1-isopropoxyethyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3--
(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-(N
1-isobutyryl-hydrazinocarbonyl)-6-methyl-2-oxo-1-(3-trifluoromethyl-pheny-
l)-1,2-dihydro-pyridine-3-carboxylic acid
4-methanesulfonyl-benzylamide, N 5-methoxy-6-methyl-N
3-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihy-
dropyridine-3,5-dicarboxamide, N 5-methoxy-N 5,6-dimethyl-N
3-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihy-
dropyridine-3,5-dicarboxamide,
5-[(2,5-dimethyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-6-methyl-N-[4-(meth-
ylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-
-3-carboxamide, 6-methyl-N 3-[4-(methylsulfonyl)benzyl]-2-oxo-N
5-pyrrolidin-1-yl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-d-
icarboxamide,
6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-(piperidin-1-ylcarbonyl)-1--
[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
6-methyl-N 3-[4-(methylsulfonyl)benzyl]-N
5-morpholin-4-yl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine--
3,5-dicarboxamide,
6-methyl-5-[(4-methylpiperidin-1-yl)carbonyl]-N-[4-(methylsulfonyl)benzyl-
]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihyd
ropyridine-3-carboxamide, 6-methyl-N
3-[4-(methylsulfonyl)benzyl]-2-oxo-N
5-piperidin-1-yl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-di-
carboxamide, N 5-(tert-butyl)-N 5,6-dimethyl-N
3-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihy-
dropyridine-3,5-dicarboxamide, N 5-butyl-N 5,6-dimethyl-N
3-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihy-
dropyridine-3,5-dicarboxamide, N 5-ethyl-N 5-isopropyl-6-methyl-N
3-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihy-
dropyridine-3,5-dicarboxamide, 5-[N
1-(formyl-hydrazinocarbonyl]-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)--
1,2-dihydro-pyridine-3-carboxylic acid
4-methanesulfonyl-benzylamide, N
1-[5-(4-methanesulfonyl-benzylcarbamoyl)-2-methyl-6-oxo-1-(3-trifluoromet-
hyl-phenyl)-1,6-dihydro-pyridine-3-carbonyl]-hydrazinecarboxylic
acid ethyl ester,
5-({2-[(ethylamino)carbonothioyl]hydrazino}carbonyl)-6-methyl-N-[4-(methy-
lsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine--
3-carboxamide,
5-(isoxazolidin-2-ylcarbonyl)-6-methyl-N-[4-(methylsulfonyl)
benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxa-
mide,
6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-
-dicarboxylic acid
5-(methoxy-methyl-amide)3-[4-(propane-2-sulfonyl)-benzylamide],
6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dica-
rboxylic acid
3-(4-ethanesulfonyl-benzylamide)5-(methoxy-methyl-amide),
6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dica-
rboxylic acid
3-(4-cyclopropanesulfonyl-benzylamide)5-(methoxy-methyl-amide),
6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dica-
rboxylic acid
5-[(2-hydroxy-ethyl)-amide]3-(4-methanesulfonyl-benzylamide,
5-(isoxazolidine-2-carbonyl)-6-methyl-2-oxo-1-(3-trifluorome
thyl-phenyl)1,2-dihydro-pyridine -3-carboxylic acid
4-ethanesulfonyl-benzylamide,
5-(isoxazolidine-2-carbonyl)-6-methyl-2-oxo-1-(3-trifluorome
thylphenyl) 1,2dihydropyridine-3-carboxylic acid 4-cyclopropane
sulfonylbenzylamide,
5-(N-hydroxycarbamimidoyl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,-
2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide,
N 3-(cyclohexylmethyl)-N 5,N 5,6-trimethyl-2-oxo-1-[3-(trifluoro
methyl)phenyl]-1,2-dihydropyridine-3,5-dicarboxamide, N 5 N
5,6-trimethyl-2-oxo-N
3-(pyridin-3-ylmethyl)-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-
-3,5-dicarboxamide, N 5,N 5,6-trimethyl-N
3-(2-morpholin-4-ylethyl)-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydr-
opyridine-3,5-dicarboxamide, N 5,N 5,6-trimethyl-N
3-(3-morpholin-4-ylpropyl)-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihyd-
ropyridine-3,5-dicarboxamide, N 3-benzyl-N 5,N
5,6-trimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydro-pyridine-3,-
5-dicarboxamide, N 3-[2-(1H-indol-3-yl)ethyl]-N 5,N
5,6-trimethyl-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3,-
5-dicarboxamide, N 5,N 5,6-trimethyl-2-oxo-N
3-(1-phenylethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-d-
icarboxamide, N 5,N 5,6-trimethyl-2-oxo-N
3-(2-phenylethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-d-
icarboxamide, N 5,N 5,6-trimethyl-2-oxo-N
3-[(2R)-2-phenylcyclopropyl]-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropy-
ridine-3,5-dicarboxamide, N 3-(2,3-dihydro-1H-inden-2-yl)-N 5,N
5,6-trimethyl-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3,-
5-dicarboxamide, N 3-[2-(1,3-benzodioxol-5-yl)ethyl]-N 5,N
5,6-trimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-
-dicarboxamide,
5-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}-N,N,2-trimethyl-6-oxo-1-[3-
-(trifluoromethyl)phenyl]-1,6-dihydropyridine-3-carboxamide, N
3-[(1-ethylpyrrolidin-2-yl)methyl]-N 5,N
5,6-trimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-
-dicarboxamide, N 5,N 5,6-trimethyl-N
3-[3-(2-methylpiperidin-1-yl)propyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]--
1,2-dihydropyridine-3,5-dicarboxamide, N 5,N 5,6-trimethyl-N
3-(1-naphthylmethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyrid-
ine-3,5-dicarboxamide, N 3-(1,3-benzodioxol-5-ylmethyl)-N 5,N
5,6-trimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-
-dicarboxamide, N 3-(3,4-difluorobenzyl)-N 5,N 5,
6-trimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-d-
icarboxamide, N 3-(2-chloro-4-fluorobenzyl)-N 5,N
5,6-trimethyl-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3,-
5-dicarboxamide, N 5,N 5,6-trimethyl-2-oxo-N
3-(2-thienylmethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-
-dicarboxamide, N 3-(3,4-dichlorobenzyl)-N 5,N
5,6-trimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-
-dicarboxamide, N 3-[2-(2,4-dichlorophenyl)ethyl]-N 5,N
5,6-trimethyl-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3,-
5-dicarboxamide, N 3-(2-cyclohex-1-en-1-ylethyl)-N 5,N
5,6-trimethyl-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3,-
5-dicarboxamide, N 3-[1-(4-chlorophenyl)ethyl]-N 5,N
5,6-trimethyl-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3,-
5-dicarboxamide, N 5,N 5,6-trimethyl-2-oxo-N
3-[3-(2-oxopyrrolidin-1-yl)propyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihy-
dropyridine-3,5-dicarboxamide, N 5,N 5,6-trimethyl-2-oxo-N
3-(pyridin-4-ylmethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine--
3,5-dicarboxamide,
N,N,2-trimethyl-6-oxo-5-[(4-phenylpiperazin-1-yl)carbonyl]-1-[3-(trifluor-
omethyl) phenyl]-1,6-dihydropyridine-3-carboxamide,
N,N,2-trimethyl-6-oxo-5-[(4-pyridin-2-ylpiperazin-1-yl)carbonyl]-1-[3-(tr-
ifluoromethyl)phenyl]-1,6-dihydropyridine-3-carboxamide, N
3-(2,3-dihydro-1-benzofuran-5-ylmethyl)-N 5,N
5,6-trimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-
-dicarboxamide, methyl
4-{[({5-[(dimethylamino)carbonyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)ph-
enyl]-1,2-dihydropyridin-3-yl}carbonyl)amino]methyl}benzoate,
5-{[3-(dimethylamino)
pyrrolidin-1-yl]carbonyl}-N,N,2-trimethyl-6-oxo-1-[3-(trifluoromethyl)phe-
nyl]-1,6-dihydropyridine-3-carboxamide, N 5,N 5,6-trimethyl-2-oxo-N
3-[2-(2-thienyl)ethyl]-1-[3-(trifluoromethyl)phenyl]-1,
2-dihydropyridine-3,5-dicarboxamide, N 5,N 5,6-trimethyl-2-oxo-N
3-(4-phenoxybenzyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-
-dicarboxamide, N 5,N 5,6-trimethyl-2-oxo-N
3-(3-thienylmethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-
-dicarboxamide, N 3-[2-(4-tert-butylphenyl)ethyl]-N 5,N
5,6-trimethyl-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3,-
5-dicarboxamide, N 3-{2-[4-(aminosulfonyl)phenyl]ethyl}-N 5,N
5,6-trimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-
-dicarboxamide, N 5,N 5,6-trimethyl-2-oxo-N
3-[4-(1H-pyrazol-1-yl)benzyl]-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydrop-
yridine-3,5-dicarboxamide, N 5,N 5,6-trimethyl-2-oxo-N
3-phenoxy-1-[3-(trifluoromethyl)phenyl]-1,2-dihydro-pyridine-3,5-dicarbox-
amide, N 3-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-N 5,N
5,6-trimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-
-dicarboxamide, N 3-[(6-fluoro-4H-1,3-benzodioxin-8-yl)methyl]-N
5,N
5,6-trimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-
-dicarboxamide, N 3-(1-benzothien-3-ylmethyl)-N 5,N
5,6-trimethyl-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3,-
5-dicarboxamide, N 5,N 5,6-trimethyl-2-oxo-N
3-[2-(tetrahydro-2H-pyran-4-yl)ethyl]-1-[3-(trifluoromethyl)phenyl]-1,2-d-
ihydropyridine-3,5-dicarboxamide, N 5,N 5,6-trimethyl-N
3-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]--
1,2-dihydropyridine-3,5-dicarboxamide, N 5,N 5,6-trimethyl-2-oxo-N
3-[(1-phenyl-1H-pyrazol-4-yl)methyl]-1-[3-(trifluoromethyl)phenyl]-1,2-di-
hydropyridine-3,5-dicarboxamide, N
3-[(5-methoxy-4-oxo-4H-pyran-2-yl)methyl]-N 5,N
5,6-trimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-
-dicarboxamide, N 3-(3-azepan-1-ylpropyl)-N 5,N
5,6-trimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-
-dicarboxamide, N 3-(4-cyanobenzyl)-N 5,N
5,6-trimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-
-dicarboxamide, N 5,N 5,6-trimethyl-2-oxo-N
3-[3-(5-oxo-4,5-dihydro-1H-pyrazol-4-yl)propyl]-1-[3-(trifluoromethyl)phe-
nyl]-1,2-dihydropyridine-3,5-dicarboxamide, N
3-{[(2R)-1-ethylpyrrolidin-2-yl]methyl}-N 5,N
5,6-trimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-
-dicarboxamide,
5-cyclopropyl-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoro-
methyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
6-methyl-5-(2-methyl-1,3-dioxolan-2-yl)-N-[4-(methylsulfonyl)benzyl]-2-ox-
o-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
5-(4,5-dihydro-oxazol-2-yl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1-
,2-dihydro-pyridine-3-carboxylic acid
4-methanesulfonyl-benzylamide,
5-cyclopropyl-6-methyl-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1-
-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide,
2-amino-3-(3-hydroxy-4-oxopyridin-1-yl)propanoic acid,
(2S)-2-amino-3-(3-hydroxy-4-oxopyridin-1-yl)propanoic acid,
2-amino-3-(3-hydroxy-4-oxopyridin-1-yl)propanoic acid,
(2S)-2-amino-3-(3-hydroxy-4-oxopyridin-1-yl)propanoic acid,
2-amino-3-(3-hydroxy-4-oxopyridin-1-yl)propanoic acid,
2-amino-3-(3-hydroxy-4-oxopyridin-1-yl)propanoic acid, propyl
2-(3,5-diiodo-4-oxopyridin-1-yl)acetate,
(2S)-2-azaniumyl-3-(3-hydroxy-4-oxopyridin-1-yl)propanoate, propyl
2-(3,5-diiodo-4-oxopyridin-1-yl)acetate, 2-(4-aminophenyl)ethanol,
4-hydroxy-5-(3-methylanilino)-1H-pyrimidin-6-one,
6-cyclohexyl-1-hydroxy-4-methylpyridin-2-one,
1,6-dimethyl-2-oxo-5-pyridin-4-ylpyridine-3-carbonitrile,
(2-oxo-1H-pyridin-3-yl) acetate,
3-methyl-1-(2,4,6-trimethylphenyl)butan-1-one,
5-methyl-1-phenylpyridin-2-one,
6-cyclohexyl-1-hydroxy-4-methylpyridin-2-one, 2-amino ethanol;
6-cyclohexyl-1-hydroxy-4-methylpyridin-2-one,
4-[(3,5-diiodo-4-oxopyridin-1-yl)methyl]benzoic acid, 2-amino
ethanol;
3-[(6-hydroxy-5-methyl-2-oxo-1H-pyridin-3-yl)imino]-5-methylpyridine-2,6--
dione,
5-ethyl-3-[(5-ethyl-2-methoxy-6-methylpyridin-3-yl)methylamino]-6-m-
ethyl-1H-pyridin-2-one, 6-cyclohexyl-1-hydroxy-4-methyl
pyridin-2-one, 5-(2,5-dihydroxyphenyl)-1H-pyridin-2-one,
6-(4,4-dimethyl-5-oxofuran-2-yl)-1H-pyridin-2-one,
N[0339]'-(6-oxo-1H-pyridin-2-yl)-N,N-dipropyl methanimidamide,
[6-oxo-1-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxylmethyl)oxan-2-yl]p-
yridin-2-yl]acetic acid, 5-(2,5-dihydroxyphenyl)-1H-pyridin-2-one,
3-[(6-hydroxy-5-methyl-2-oxo-1H-pyridin-3-yl)imino]-5-methylpyridine-2,6--
dione, 5-(4-cyanophenyl)-6-methyl-2-oxo-1H-pyridine-3-carbonitrile,
3,3-diethyl-1-[(piperazin-1-ylamino)methyl]pyridine-2,4-dione,
5-ethyl-3-[(5-ethyl-2-methoxy-6-methylpyridin-3-yl)methylamino]-6-methyl--
1H-pyridin-2-one and pharmaceutically acceptable salts thereof.
[0340] In some embodiments, the pirfendione or pyridone analog
compound is used in compositions and methods described herein in
free-base or free-acid form. In other embodiments, the pirfendione
or pyridone analog compound is used as pharmaceutically acceptable
salts. In some embodiments, pharmaceutically acceptable salts are
obtained by reacting the compound with an acid or with a base. The
type of pharmaceutical acceptable salts, include, but are not
limited to: (1) acid addition salts, formed by reacting the free
base form of the compound with a pharmaceutically acceptable: (1)
acid such as, for example, hydrochloric acid, hydrobromic acid,
sulfuric acid, phosphoric acid, metaphosphoric acid, acetic acid,
propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic
acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic
acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric
acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,
cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic
acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,
benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic
acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid,
glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic
acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary
butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic
acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic
acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic
acid, and the like; or (2) base, where an acidic proton present in
the parent compound is replaced by a metal ion, e.g., an alkali
metal ion (e.g. lithium, sodium, potassium), an alkaline earth ion
(e.g. magnesium, or calcium), or an aluminum ion. In some cases,
the pirfendione or pyridone analog compound is reacted with an
organic base, such as, but not limited to, ethanolamine,
diethanolamine, triethanolamine, tromethamine, N-methylglucamine,
dicyclohexylamine, tris(hydroxymethyl)methylamine or with an amino
acid such as, but not limited to, arginine, lysine, and the
like.
Advantages of Inhaled Aerosol and Topical (Non-Oral) Drug
Delivery
[0341] Inhalation therapy of aerosolized pirfenidone or a pyridone
analog 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
pirfenidone or a pyridone analog compound directly upstream of the
CNS compartment.
[0342] 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
pirfenidone or a pyridone analog 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.
[0343] Pharmaceutical Compositions
[0344] For purposes of the method described herein, a pyridone
analog compound, most preferably pirfenidone may be administered
using a liquid nebulization, dry powder or metered-dose inhaler. In
some embodiments, pirfenidone or a pyridone analog 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.
[0345] In some embodiments, the isoform content of the manufactured
pyridone analog compound, most preferably pirfenidone 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).
[0346] Manufacture
[0347] In some embodiments, pirfenidone drug product (DP) includes
pirfenidone 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 salts (NaCl and/or MgCl.sub.2 and/or MgSO.sub.4). In some
embodiments, the pirfenidone 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).
[0348] To achieve pirfenidone concentrations above 3 mg/mL,
manufacturing process are described. In one embodiment, the
manufacturing process includes high temperature pirfenidone 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 pirfenidone during the cooling
process and provide a stable, high-concentration,
ambient-temperature formulation of pirfenidone. 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 pirfenidone drug product includes co-solvent(s) in
the concentration range of 0% to 100% in otherwise buffered aqueous
solution. In some embodiments, the pirfenidone 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 pirfenidone drug product
includes surfactant(s) in the concentration range of 0% to 100% in
otherwise buffered aqueous solution. In some embodiments, the
pirfenidone 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 pirfenidone 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 pirfenidone 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 pirfenidone 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.
[0349] In another embodiment, the manufacturing process includes
excess co-solvent and/or surfactant and/or cation addition to a
super-saturated pirfenidone 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.
[0350] In some embodiments, the manufacturing process is as
described in Example 5.
Administration
[0351] The pyridone analog compound, most preferably pirfenidone 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. Generally, for example, a
daily aerosol dose of pirfenidone in a pirfenidone compound
formulation may be from about 0.001 mg to about 6.6 mg
pirfenidone/kg of body weigh per dose. Thus, for administration to
a 70 kg person, the dosage range would be about 0.07 mg to about
463 mg pirfenidone per dose or up to about 0.280 mg to about 1852
mg pirfenidone 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 pirfenidone in preferred embodiments, or
in other embodiments of pyridone analog compound, would be about
0.28 to 1852 mg per day.
[0352] Another unexpected observation is that inhalation delivery
of aerosol pirfenidone to the lung exhibits less metabolism of
pirfenidone observed with oral administration. Thus, oral or
intranasal inhalation of pirfenidone or pyridone analog will permit
maximum levels of active substance to the pulmonary tissue in the
absence of substantial metabolism to inactive agents.
[0353] Inhibitors of CYP enzymes reduce pirfenidone metabolism
resulting in elevated blood levels and associated toxicity. 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 pirfenidone blood levels and increases the rate and
severity of the toxic events described herein. Because oral and
intranasal inhalation delivery of pirfenidone or pyridone analogs
can achieve effective 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.
[0354] The primary metabolite of pirfenidone is
5-carboxy-pirfenidone. Following oral or intravenous
administration, this metabolite appears quickly at at high
concetrations in blood. 5-carboxy-pirfenidone does not appear to
have anti-fibrotic or anti-inflammatory activity, its high blood
levels occur at the loss of pirfenidone blood concentrations. Thus,
while the oral product is dosed at the highest possible level, once
pirfenidone enters the blood it is rapidly metabolized to a
non-active species further reducing the drugs potential to achieve
sufficient lung levels required for substantital efficacy. Because
oral and intranasal inhalation delivery of pirfenidone or pyridone
analogs can achieve effective lung tissue levels directly
extra-lung metabolism is not a factor.
[0355] Administration of the pyridone analog compound, most
preferably pirfenidone 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.
[0356] 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.
[0357] The pyridone analog compound, most preferably pirfenidone 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.
[0358] 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.
[0359] 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.
[0360] Pirfenidone or pyridone analog 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 pirfenidone
or pyridone analog 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 pirfenidone or pyridone analog 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 pirfenidone or pyridone
analog compound alone or with either water soluble or organic
soluble non-encapsulating excipients with or without a blending
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
pirfenidone or pyridone analog 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
pirfenidone or pyridone analog 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 pirfenidone or pyridone analog 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
pirfenidone or pyridone analog 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 pirfenidone or pyridone analog 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 blending agent such as lactose. Specific methods for
simple and complex formulation preparation are described
herein.
Aerosol Delivery
[0361] Pirfenidone or pyridone analog compounds as described herein
are preferably directly administered as an aerosol to a site of
pulmonary pathology including pulmonary fibrosis, COPD or asthma.
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 fibrosis and
inflammatory diseases of the heart, kidney and liver, or pulmonary
or intra-nasal delivery for extra-pulmonary or extra-nasal cavity
demylination diseases associated with the central nervous
system.
[0362] 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. Pirfenidone or pyridone analog compounds disclosed herein
range in solubility, are generally stable and have a range of
tastes. In one such embodiment, pirfenidone or pyridone analog
compounds are water soluble at pH 4 to pH 8, are stable in aqueous
solution and have limited to no taste. Such a pyridone includes
pirfenidone.
[0363] Accordingly, in one embodiment, a particular formulation of
the pirfenidone or pyridone analog 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, 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
[0364] The distribution of aerosol particle/droplet size can be
expressed in terms of either: [0365] 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; [0366] volumetric mean diameter (VMD); [0367] mass median
diameter (MMD); [0368] the fine particle fraction (FPF)--the
percentage of particles that are <5 .mu.m in diameter.
[0369] 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.
[0370] 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.
[0371] 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 impator 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.
[0372] In some embodiments, the particle size of the aerosol is
optimized to maximize the pirfenidone or pyridone analog 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 gm) 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.
[0373] In some embodiments, the pirfenidone or pyridone analog
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.
[0374] 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
pirfenidone or a pyridone analog compound with a liquid nebulizer.
In some embodiments, the liquid nebulizer is a high effieciency
liquid nebulizer. In some embodiments a lung deposition of
pirfenidone or a pyridone analog 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 pirfenidone or a pyridone analog compound is
acheived.
[0375] There are two main methods used to measure aerosol
deposition in the lungs. First, .gamma.-scintigraphy is performed
by radio labeling 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.
[0376] In some embodiments, administration of the pirfenidone or
pyridone analog 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.
[0377] 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 pirfenidone or pyridone
analog 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%.
[0378] 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 formaulations 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%.
[0379] 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.
[0380] In one embodiment, described herein an aqueous droplet
containing pirfenidone or pyridone analog 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 colsolvents. 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 dioplet was produced
from a liquid nebulizer and an aqueous solution of pirfenidone or
pyridone analog compound as described herein. In some embodiments,
the aqueous droplet was produced from an aqueous solution that has
concentration of pirfenidone or pyridone analog compound 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
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.
[0381] Also described are aqueous aerosols comprising a plurality
of aqueous droplets of pirfenidone or pyridone analog 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
[0382] In one embodiment, a nebulizer is selected on the basis of
allowing the formation of an aerosol of a pirfenidone or pyridone
analog compound disclosed herein having an MMAD predominantly
between about 1 to about 5 microns. In one embodiment, the
delivered amount of pirfenidone or pyridone analog compound
provides a therapeutic effect for pulmonary pathology and/or
extra-pulmonary, systemic, tissue or central nervous system
distribution.
[0383] 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
nebuluzer 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.
[0384] Accordingly, in one embodiment, a vibrating mesh nebulizer
is used to deliver in preferred embodiments an aerosol of the
pirfenidone compound as disclosed herein, or in other embodiments,
a pyridone analog 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 1 to about 6 ml of the pirfenidone compound
formulation (or in another related embodiment, of a pyridone analog
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 pirfenidone compound
formulation (or in another related embodiment, of a pyridone analog
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 pirfenidone compound
formulation (or in another related embodiment, of a pyridone analog
compound formulation) that is originally placed in the storage
container and the aerosol generator is replaced to increase the
administered dose size.
[0385] In some embodiments a pirfenidone or pyridone analog
compound formulation as disclosed herein, is placed in a liquid
nebulization inhaler and prepared in dosages to deliver from about
34 mcg to about 463 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.
[0386] In some embodiments a pirfenidone or pyridone analog
compound formulation as disclosed herein, is placed in a liquid
nebulization inhaler and prepared in dosages to deliver from about
34 mcg to about 463 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.
[0387] By non-limiting example, a nebulized pirfenidone or pyridone
analog 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, or less than about 2 min.
[0388] By non-limiting example, a nebulized pirfenidone or pyridone
analog 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.
[0389] By non-limiting example, in other circumstances, a nebulized
pirfenidone or pyridone analog 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 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.
[0390] As disclosed herein, there is provided a pyridone analog
compound formulation composition comprising a pirfenidone compound
aqueous solution having a pH from about 4.0 to about pH 8.0 where
the pirfenidone compound is present at a concentration from about
34 mcg/mL to about 463 mg/mL pirfenidone. In certain other
embodiments the pirfenidone compound formulation is provided as an
aqueous solution having a pH of from about 4.0 to about 8.0, the
solution comprising a pirfenidone compound at a concentration of
from about 34 mcg/mL to about 463 mg/mL pirfenidone; and citrate
buffer or phosphate buffer at a concentration of from about 0 mM to
about 50 mM. In certain other embodiments the pirfenidone compound
formulation is provided as an aqueous solution having a pH of from
about 4.0 to about 8.0, the solution comprising a pirfenidone
compound at a concentration of from about 34 mcg/mL to about 463
mg/mL pirfenidone; 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.
[0391] In some embodiments, described herein is a pharmaceutical
composition that includes: pirfenidone; water; phosphate buffer or
citrate buffer; and optionally sodium chloride or magnesium
chloride. In other embodiments, described herein is a
pharmaceutical composition that includes: pirfenidone; 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 pirfenidone,
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 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 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 nebulized
pharmaceutical composition may deliver between about 0.0001 mg and
about 25 mg pirfenidone or pryridone analog in aerosol particles
with a MMAD between 1 and 5 microns in each inhaled breath. In some
embodiments, 1 mg pirfenidone or pyridone analog delivered in 10
breaths over 1 minute, whereby 50% of the inhaled particles are
between 1 and 5 microns, 0.05 mg pirfenidone or pyridine analog
will be delivered in each breath. In some embodiments, 1 mg
pirfenidone or pyridone analog delivered in 15 breaths per minute
over 10 minutes, whereby 50% of the inhaled particles are between 1
and 5 microns, 0.0033 mg pirfenidone or pyridone analog will be
delivered in each breath. In some embodiments, 1 mg pirfenidone or
pyridone analog delivered in 20 breaths per minute over 20 minutes,
whereby 50% of the inhaled particles are between 1 and 5 microns,
0.00125 mg pirfenidone or pyridone analog will be delivered in each
breath. In some embodiments, 200 mg pirfenidone or pyridone analog
delivered in 10 breaths over 1 minute, whereby 50% of the inhaled
particles are between 1 and 5 microns, 10 mg pirfenidone or
pyridone analog will be delivered in each breath. In some
embodiments, 200 mg pirfenidone or pyridone analog delivered in 15
breaths per minute over 10 minutes, whereby 50% of the inhaled
particles are between 1 and 5 microns, 0.67 mg pirfenidone or
pyridone analog will be delivered in each breath. By another
non-limiting example, In some embodiments, 200 mg pirfenidone or
pyridone analog delivered in 20 breaths per minute over 20 minutes,
whereby 50% of the inhaled particles are between 1 and 5 microns,
0.25 mg pirfenidone or pyridone analog will be delivered in each
breath. In some embodiments, 500 mg pirfenidone or pyridine analog
delivered in 10 breaths over 1 minute, whereby 50% of the inhaled
particles are between 1 and 5 microns, 25 mg pirfenidone or
pyridone analog will be delivered in each breath. In some
embodiments, 500 mg pirfenidone or pyridone analog delivered in 15
breaths per minute over 10 minutes, whereby 50% of the inhaled
particles are between 1 and 5 microns, 1.67 mg pirfenidone or
pyridone analog will be delivered in each breath. In some
embodiments, 500 mg pirfenidone or pyridone analog delivered in 20
breaths per minute over 20 minutes, whereby 50% of the inhaled
particles are between 1 and 5 microns, 0.625 mg pirfenidone or
pyridone analog will be delivered in each breath.
[0392] In some embodiments, a nebulized pirfenidone or pyridone
analog 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, or less than about 2 min.
[0393] 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 pirfenidone or pyridone analogs 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.
[0394] 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, CA), 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.
[0395] 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.
[0396] 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
PulmoMate.
[0397] 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.
[0398] 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.
[0399] 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.
[0400] 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.
[0401] 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.
[0402] 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.
[0403] 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.
[0404] 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.
[0405] 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.
[0406] 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.
[0407] 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 pirfenidone or pyridone analog
compound and excipient are unstable for storage, yet desired in the
same mixture for administration.
[0408] 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.
[0409] 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.
[0410] 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.
[0411] 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.
[0412] 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.
[0413] 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.
[0414] 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.
[0415] 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.
[0416] 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
[0417] 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.
[0418] 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.
[0419] 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.
[0420] 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.
[0421] 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 pirfenidone or pyridone analog compound
administered to the mammal.
[0422] 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.
[0423] 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.
[0424] 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%.
[0425] 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.
[0426] 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.
[0427] 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%.
[0428] 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).
[0429] 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.
[0430] 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
(Galaway, Ireland) utilizing the OnQ.RTM. nebulizer technology.
Meter Dose Inhaler (MDI)
[0431] 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).
[0432] 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.
[0433] By non-limiting example, metered-dose inhalers (MDI), the
pirfenidone or pyridone analog 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
pirfenidone or pyridone analog 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.
[0434] By non-limiting example, a metered-dose pirfenidone or
pyridone analog compound may be administered in the described
respirable delivered dose in 10 or fewer inhalation breaths, more
preferably in 8 or fewer inhalation breaths, more preferably in 6
or fewer inhalation breaths, more preferably in 8 or fewer
inhalation breaths, more preferably in 4 or fewer inhalation
breaths, more preferably in 2 or fewer inhalation breaths.
[0435] The propellants for use with the MDIs may be any propellants
known in the art. Examples of propellants include
chlorofluorocarbons (CFCs) such as dichlorodifluoromethane,
trichlorofluorometbane, 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.
[0436] 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.
[0437] 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.
[0438] 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)
[0439] 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.
[0440] As with liquid nebulization and MDIs, particle size of the
pirfenidone or pyridone analog 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.
[0441] By non-limiting example, in dry powder inhalers, the
pirfenidone or pyridone analog compound disclosed herein are
prepared in dosages to disperse and deliver from about 34 mcg to
about 463 mg from a dry powder formulation.
[0442] By non-limiting example, a dry powder pirfenidone or
pyridone analog compound may be administered in the described
respirable delivered dose in 10 or fewer inhalation breaths, more
preferably in 8 or fewer inhalation breaths, more preferably in 6
or fewer inhalation breaths, more preferably in 8 or fewer
inhalation breaths, more preferably in 4 or fewer inhalation
breaths, more preferably in 2 or fewer inhalation breaths.
[0443] In some embodiments, a dry powder inhaler (DPI) is used to
dispense the pirfenidone or pyridone analog 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.
[0444] There are three common types of DPIs, all of which may be
used with the pirfenidone or pyridone analog 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.
[0445] 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.
[0446] 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.
[0447] 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.
[0448] 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.
[0449] Commercial examples of dry powder inhalers that can be used
with the pirfenidone or pyridone analog compound formulations
described herein include the Aerolizer, Turohaler, Handihaler and
Discus.
Solution/Dispersion Formulations
[0450] 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, or about 15 mg/mL to about 50 mg/mL, or
about 20 mg/mL to about 50 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, pirfenidone or pyridone analog
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.
[0451] In some embodiments, described herein is an aqueous
pharmaceutical composition comprising pirfenidone or pyridone
analog compound, water and one or more additional ingredients
selected from co-solvents, tonicity agents, sweeteners,
surfactants, wetting agents, chelating agents, anti-oxidants,
salts, and buffers. It should be understood that many excipients
may serve several functions, even within the same formulation.
[0452] In some embodiments, pharmaceutical compositions described
herein do not include any thickening agents.
[0453] In some embodiments, the concentration of pirfenidone or
pyridone analog compound in the aqueous pharmaceutical composition
is between about 0.1 mg/mL and about 100 mg/mL. In some
embodiments, the concentration of pirfenidone or pyridone analog
compound in the pharmaceutical composition is between about 1 mg/mL
and about 100 mg/mL, between about 10 mg/mL and about 100 mg/mL
between about 20 mg/mL and about 100 mg/mL, between about 25 mg/mL
and about 100 mg/mL, between about 30 mg/mL and about 100 mg/mL,
between about 15 mg/mL and about 50 mg/mL, between about 20 mg/mL
and about 50 mg/mL, between about 25 mg/mL and about 50 mg/mL, or
between about 30 mg/mL and about 50 mg/mL.
[0454] 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.
[0455] 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.
[0456] 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.
[0457] 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.
[0458] In some embodiments, the aqueous pharmaceutical composition
consists essentially of pirfenidone or pyridone analog 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-maksing agents). In
some embodiments, the one or more salts are selected from tonicity
agents. In some embodiments, the one or more salts are selected
from sodium chloride and magnesium chloride.
[0459] In some embodiments, the aqueous pharmaceutical composition
consists essentially of pirfenidone or pyridone analog compound at
a concentration of about 10 mg/mL to about 50 mg/mL, water, one or
two coslovents (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 salts,
surfactants, and sweeteners (taste-maksing agents).
[0460] 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.
[0461] 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.
[0462] 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.
[0463] 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.
[0464] In some embodiments, the osmolality of aqueous solutions of
the pirfenidone or pyridone analog 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 pirfenidone or pyridone analog
compound.
[0465] In some embodiments, the osmolality of aqueous solutions of
the pirfenidone or pyridone analog compound disclosed herein is
greater than 100 mOsmol/kg. In some embodiments, the osmolality of
aqueous solutions of the pirfenidone or pyridone analog compound
disclosed herein is greater than 300 mOsmol/kg. In some
embodiments, the osmolality of aqueous solutions of the pirfenidone
or pyridone analog 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.
[0466] In some embodiments, the osmolality of aqueous solutions of
the pirfenidone or pyridone analog 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 pirfenidone
or pyridone analog compound
[0467] In some embodiments, the formulation for an aerosol
pirfenidone or pyridone analog compound may comprise from about 34
mcg to about 463 mg pirfenidone or pyridone analog compound per
about 1 to about 5 ml of dilute saline (between 1/10 to 2/1 normal
saline). Accordingly, the concentration of a pirfenidone or
pyridone analog 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.
[0468] 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.
[0469] 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
[0470] 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.
[0471] 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.
[0472] 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.
[0473] 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.
[0474] 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.
[0475] 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.
[0476] 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.
[0477] 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.
[0478] 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.
[0479] 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.
[0480] 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.
[0481] 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.
[0482] For aqueous aerosol formulations, the nanoparticulate
pirfenidone or pyridone analog 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.
[0483] 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.
[0484] 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.
[0485] Another method of forming nanoparticle dispersion is by
microprecipitation. This is a method of preparing stable
dispersions of drugs in the 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.
[0486] 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 dichlorotetafluoroethane (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.
[0487] 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.
[0488] 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.
[0489] 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.
[0490] 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.
[0491] 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.
[0492] 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.
[0493] 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
[0494] In some embodiments, pirfenidone or pyridone analog
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.
[0495] 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.
[0496] 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).
[0497] 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.
[0498] 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
[0499] Pirfenidone or pyridone analog 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.
[0500] 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)-phenolpolymer 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); poloxamnines
(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.
[0501] 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
[0502] 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.
[0503] In the present invention, the optimal ratio of drug to
surface modifier is .about.0.1% to .about.99.9% pirfenidone or
pyridone analog compound, more preferably about 10% to about
90%.
Microspheres
[0504] Microspheres can be used for pulmonary delivery of
pirfenidone or pyridone analog compounds by first adding an
appropriate amount of drug compound to be solubilzed in water. For
example, an aqueous pirfenidone or pyridone analog 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,
a pirfenidone or pyridone analog 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 pirfenidone or
pyridone analog compound microparticles will be stored at
-20.degree. C.
[0505] By non-limiting example, a spray drying approach will be
employed to prepare pirfenidone or pyridone analog compound
microspheres. An appropriate amount of pirfenidone or pyridone
analog compound will be solubilized in methylene chloride
containing PLGA (0.1-1%). This solution will be spray dried to
obtain the microspheres.
[0506] By non-limiting example, pirfenidone or pyridone analog
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.
[0507] 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 pirfenidone or
pyridone analog compounds or salt forms for nanoparticle-based
formulations.
[0508] A certain amount of pirfenidone or pyridone analog 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
[0509] Preparation of pirfenidone or pyridone analog 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 pirfenidone or
pyridone analog compounds or salt forms for nanoparticle-based
formulations.
Melt-Extrusion AUC Shape-Enhancing Formulation
[0510] Melt-Extrusion AUC shape-enhancing pirfenidone or pyridone
analog 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 pirfenidone or pyridone analog
compound, hydroxypropyl-b-cyclodextrin (HP-b-CD), and
hydroxypropylmethylcellulose (HPMC), in order to, by non-limiting
example create a AUC shape-enhancing formulation of pirfenidone or
pyridone analog 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
pirfenidone or pyridone analog compounds or salt forms for
nanoparticle-based formulations.
Co-Precipitates
[0511] Co-precipitate pirfenidone or pyridone analog 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 pirfenidone or pyridone analog
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 pirfenidone or
pyridone analog compounds or salt forms for nanoparticle-based
formulations.
Dispersion-Enhancing Peptides
[0512] 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.
[0513] 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.
[0514] 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.
[0515] 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.
[0516] 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.
[0517] 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.
[0518] 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.
[0519] 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
[0520] 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
[0521] 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
[0522] 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.
[0523] 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.
[0524] 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).
[0525] 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.
[0526] 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.
[0527] 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.
[0528] 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 %.
[0529] 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
[0530] As also described above, pirfenidone or pyridone analog
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
pyridone analog compound such as pirfenidone), 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).
[0531] By way of non-limiting example, taste-masking agents in
pirfenidone or pyridone analog 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 pyridone
analog compound such as pirfenidone), 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.
[0532] 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 a pirfenidone or pyridone analog compound
solubility are described herein, for example, through the use in
formulation of particular salt forms of pyridone analog 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.
[0533] 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 a pirfenidone or pyridone
analog compound according to certain embodiments or, in other
embodiments, non-dissolved forms of a pirfenidone or pyridone
analog 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.
[0534] An alternative according to certain other preferred
embodiments is to include taste-modifying agents in the pirfenidone
or pyridone analog compound formulation. These embodments
contemplate including in the formulation a taste-masking substance
that is mixed with, coated onto or otherwise combined with the
active medicament pirfenidone or pyridone analog 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 pirfenidone or pyridone analog 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 pirfenidone
or pyridone analog compound (or a salt thereof) or, in separate
embodiments, pirfenidone or pyridone analog compound for aerosol
administration.
Mucolytic Agents
[0535] Methods to produce formulations that combine agents to
reduce sputum viscosity during aerosol treatment with a pirfenidone
or pyridone analog compound include the following. These agents can
be prepared in fixed combination or be administered in succession
with aerosol pirfenidone or pyridone analog compound therapy.
[0536] 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), chronic obstructive
pulmonary disease (COPD) 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.
[0537] 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.
[0538] 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 a pirfenidone or
pyridone analog compound for either co-administration or fixed
combination therapy.
[0539] 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.
[0540] 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 Hl. 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.
[0541] 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 pirfenidone or pyridone analog 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
[0542] 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.
[0543] 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
[0544] 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:
[0545] Cmax: The maximum plasma concentration in a patient.
[0546] AUC: area under the curve
[0547] TOE: time of exposure
[0548] T1/2: period of time it takes for the amount in a patient of
drug to decrease by half
[0549] T.sub.max: The time to reach maximum plasma concentration in
a patient
[0550] Pharmacokinetics (PK) is concerned with the time course of a
therapeutic agent, such as pirfenidone, or a pyridone analog
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.
[0551] Any standard pharmacokinetic protocol can be used to
determine blood plasma concentration profile in humans following
administration of a formulation comprising pirfenidone or a
pyridone analog 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 pirfenidone or
a pyridone analog 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.
[0552] 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.
[0553] Any aqueous inhalable mixture giving the desired
pharmacokinetic profile may be suitable for administration
according to the present methods.
[0554] 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
pirfenidone or a pyridone analog compound dosing.
[0555] 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 pirfenidone or pyridone
analog compound as compared to oral administration.
[0556] In some embodiments, a delayed appearance of
5-carboxy-pirfenidone (the primary pirfenidone liver metabolite)
has been observed from the methods and systems described herein. In
some embodiments, rapid elimination of pirfenidone from the lung
tissue has been observed. Comparing the initial rapid elimination
of pirfenidone from the lung tissue and parallel appearance of
pirfenidone in the plasma suggest that direct pulmonary
administration may be a good route for systemic administration of
pirfenidone. The delayed appearance of 5-carboxy-pirfenidone
metabolite supports this hypothesis in that this metabolite serves
as a marker for re-circulation of pirfenidone to the lung and other
tissues following direct aerosol administration to the lung. In
some embodiments, re-circulated pirfenidone is likely important to
support long-term, elevated pirfenidone levels in the lung and
other tissues of potential efficacy.
[0557] In some embodiments, the amount of pirfenidone or pyridone
analog compound that is administered to a human by inhalation may
be calculated by measuring the amount of pirfenidone or pyridone
analog compound and associated metabolites that are found in the
urine. In some embodiments, about 80% of administered pirfenidone
is excreted in the urine (with 95% being the primary metabolite,
5-carboxy-pirfenidone). 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 pirfenidone or pyridone analog compound delivered to the
human is the sum of measured pirfenidone and its metabolites. By
non-limiting example, knowing that 80% of pirfenidone is excreted,
a 50 mg sum urinary measurement of pirfenidone 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 pirfenidone 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.
[0558] In some embodiments, method or systems described herein
provide pharmacokinetic profiles of pirfenidone or puridone anlog
compounds as described herein. In some embodiments, method or
systems described herein provide pharmacokinetic profiles of
pirfenidone or pyridone anlog compounds as in Examples 6 and 7.
EXAMPLES
Example 1
Pirfenidone Formulations
[0559] Non-limiting examples of compositions of pirfenidone include
those described in Table 1-1 through Table 1-11.
TABLE-US-00002 TABLE 1-1 Ingredient and Amount Phosphate Phosphate
Citrate Buffer Buffer Buffer (acid/sodium Sodium Magnesium
Composition (sodium salt), (sodium salt), salt), pH 5.8 Chloride
Chloride no. Pirfenidone pH 6.2 (mM) pH 7.3 (mM) (mM) (.mu.mols)
(.mu.mols) Water 1 1 mg to -- -- 0.01 mM to -- -- q.s. to 500 mg
500 mM 5 mL (5 .mu.mols to 3 mmols) 2 1 mg to 0.01 mM to -- -- --
-- q.s. to 500 mg 500 mM 5 mL (5 .mu.mols to 3 mmols) 3 1 mg to --
0.01 mM to -- -- -- q.s. to 500 mg 500 mM 5 mL (5 .mu.mols to 3
mmols) 4 54 .mu.mols 0.01 to 500 -- -- 150 -- q.s. to 5 mL 5 54
.mu.mols -- 0.01 to 500 -- 150 -- q.s. to 5 mL 6 54 .mu.mols -- --
0.01 to 500 150 -- q.s. to 5 mL 7 54 .mu.mols 0.01 to 500 -- -- --
150 q.s. to 5 mL 8 54 .mu.mols -- 0.01 to 500 -- -- 150 q.s. to 5
mL 9 54 .mu.mols -- -- 0.01 to 500 -- 150 q.s. to 5 mL 10 54
.mu.mols 0.01 to 500 -- -- 13.5 -- q.s. to 5 mL 11 54 .mu.mols --
0.01 to 500 -- 13.5 -- q.s. to 5 mL 12 54 .mu.mols -- -- 0.01 to
500 13.5 -- q.s. to 5 mL 13 54 .mu.mols 0.01 to 500 -- -- -- 13.5
q.s. to 5 mL 14 54 .mu.mols -- 0.01 to 500 -- -- 13.5 q.s. to 5 mL
15 54 .mu.mols -- -- 0.01 to 500 -- 13.5 q.s. to 5 mL 16 54
.mu.mols 0.01 to 500 -- -- 54 -- q.s. to 5 mL 17 54 .mu.mols --
0.01 to 500 -- 54 -- q.s. to 5 mL 18 54 .mu.mols -- -- 0.01 to 500
54 -- q.s. to 5 mL 19 54 .mu.mols 0.01 to 500 -- -- -- 54 .mu.mols
q.s. to 5 mL 20 54 .mu.mols -- 0.01 to 500 -- -- 54 .mu.mols q.s.
to 5 mL 21 54 .mu.mols -- -- 0.01 to 500 -- 54 .mu.mols q.s. to 5
mL 22 54 .mu.mols 0.01 to 500 -- -- 27 -- q.s. to 5 mL 23 54
.mu.mols -- 0.01 to 500 -- 27 -- q.s. to 5 mL 24 54 .mu.mols -- --
0.01 to 500 27 -- q.s. to 5 mL 25 54 .mu.mols 0.01 to 500 -- -- --
27 q.s. to 5 mL 26 54 .mu.mols -- 0.01 to 500 -- -- 27 q.s. to 5 mL
27 54 .mu.mols -- -- 0.01 to 500 -- 27 q.s. to 5 mL
TABLE-US-00003 TABLE 1-2 Ingredient and Amount Phosphate Citrate
Buffer Buffer (acid/ (monobasic/ sodium salt), dibasicsodium Sodium
Saccharin Composition pH 2.0 to salts), pH 2.0 Chloride Magnesium
(sodium salt) no. Pirfenidone 9.0 (mM) to 9.0 (mM) (.mu.mols)
Chloride (mM) Water 28 5 .mu.mols to 0.01 to 500 -- -- 1 .mu.mols
to 0.01 to 10.0 q.s. to 3 mmols 15 mmols 5 mL 29 5 .mu.mols to --
0.01 to 500 -- 1 .mu.mols to 0.01 to 10.0 q.s. to 3 mmols 15 mmols
5 mL 30 5 .mu.mols to 0.01 to 500 -- 1 .mu.mols to -- 0.01 to 10.0
q.s. to 3 mmols 15 mmols 5 mL 31 5 .mu.mols to -- 0.01 to 500 1
.mu.mols to -- 0.01 to 10.0 q.s. to 3 mmols 15 mmols 5 mL
TABLE-US-00004 TABLE 1-3 Ingredient and Amount Phosphate Phosphate
Buffer Buffer Citrate (monobasic/ (monobasic/ Buffer (acid/ dibasic
dibasic Saccharin Composition sodium salt), sodium salts), sodium
salts), (sodium salt) no. Pirfenidone pH 5.8 (mM) pH 6.2 (mM) pH
7.3 (mM) (mM) Water 32 1 mg to 500 mg 0.01 to 500 -- -- 0.01 to
10.0 q.s. to (5 .mu.mols to 5 mL 3 mmols) 33 1 mg to 500 mg -- 0.01
to 500 -- 0.01 to 10.0 q.s. to (5 .mu.mols to 5 mL 3 mmols) 34 1 mg
to 500 mg 0.01 to 500 0.01 to 10.0 q.s. to (5 .mu.mols to 5 mL 3
mmols)
[0560] In some embodiments, pirfenidone exhibited aqueous
solubility to .about.17 mg/mL across a pH range of about 4.0 to
about 8.0. However, at this (and lower) concentration it was
determined that salt addition was required to improve acute
tolerability upon inhalation of a nebulized solution (otherwise a
hypotonic solution). To address tonicity, NaCl or MgCl.sub.2 were
added. In some embodiments, addition of NaCl improved acute
tolerability, but destabilized the formulation and resulted in
precipitation upon ambient storage. In some embodiments, it was
determined that addition of MgCl.sub.2 maintained a stable, soluble
solution at this concentration with an osmolality in a tolerable
range. By non-limiting example, 81 mM MgCl.sub.2 provides a 1:1
mole ratio of magnesium to pirfenidone where pirfenidone is at 15
mg/mL (or 81 mM). This effect was also observed at various
pirfenidone concentrations with 1:1 and 1:2 mole ratios of
magnesium to pirfenidone, but not at ratios less than or equal to
0.25:1 or greater than or equal to 1:0.33 magnesium to pirfenidone,
respectively. This effect was observed in 5 mM to 50 mM citrate
buffer at pH 4.0 and pH 5.8, and 5 mM to 50 mM phosphate buffer at
pH 6.2, pH 7.3 and pH 7.8. Other observations included: 1)
Formulations of both buffer systems exhibited a metallic, bitter
flavor and throat irritation; 2) From 0.1 to 0.7 mM sodium
saccharin was required to taste mask these formulations; 3) 0.6 mM
sodium saccharin was the best concentration and improved the flavor
of 2:1 mol ratio pirfenidone to magnesium in phosphate buffer more
so than the 1:1 mol ratio; 4) The taste of 2:1 mol ratio
pirfenidone to magnesium in citrate buffer without sodium saccharin
was equivalent to the 1:1 mol ratio pirfenidone to magnesium in
phosphate buffer with 0.6 mM sodium saccharin; 5) The taste of 2:1
mol ratio pirfenidone to magnesium in citrate buffer with 0.2 mM
sodium saccharin was equivalent to the 2:1 mol ratio pirfenidone to
magnesium in phosphate buffer with 0.6 mM sodium saccharin; 6) The
taste of 1:1 mol ratio pirfenidone to magnesium in citrate buffer
with 0.6 mM sodium saccharin was equivalent to 2:1 mol ratio
pirfenidone to magnesium in phosphate buffer 0.6 mM sodium
saccharin; and 7) 1:1 mol ratio pirfenidone to magnesium dissolved
in up to 40% the time required to dissolve 2:1 mol ratio
pirfenidone to magnesium in either buffer system at .about.pH 6.
This effect was not observed at .about.pH 8.
TABLE-US-00005 TABLE 1-4 Ingredient and Amount Phosphate Buffer
(monobasic/ Cetylpyridinium dibasic sodium Propylene Bromide
Composition Pirfenidone salts), pH 5.5 Ethanol Glycol Glycerol
Polysorbate (or chloride) Osmolality no. (mg) to 8.5 (mM) (% v/v)
(% v/v) (% v/v) 80 (% v/v) (%) (mOsmo/kg) Water 35 1 to 500 0.01 to
500 0.001 -- -- -- -- 50 to 5000 q.s. to to 25 5 mL 36 * 1 to 500
0.01 to 500 -- 0.001 -- -- -- 50 to 5000 q.s. to to 25 5 mL 37 1 to
500 0.01 to 500 -- -- 0.001 -- -- 50 to 5000 q.s. to to 25 5 mL 38
1 to 500 0.01 to 500 -- -- -- 0.0001 -- 50 to 5000 q.s. to to 1.0 5
mL 39 * 1 to 500 0.01 to 500 -- -- -- -- 0.0001 to 5.0 50 to 5000
q.s. to 5 mL 40 1 to 500 0.01 to 500 0.001 0.001 -- -- -- 50 to
5000 q.s. to to 25 to 25 5 mL 41 1 to 500 0.01 to 500 0.001 --
0.001 -- -- 50 to 5000 q.s. to to 25 to 25 5 mL 42 1 to 500 0.01 to
500 0.001 -- -- 0.0001 -- 50 to 5000 q.s. to to 25 to 1.0 5 mL 43 1
to 500 0.01 to 500 0.001 -- -- -- 0.0001 to 5.0 50 to 5000 q.s. to
to 25 5 mL 44 1 to 500 0.01 to 500 0.001 0.001 0.001 -- -- 50 to
5000 q.s. to to 25 to 25 to 25 5 mL 45 1 to 500 0.01 to 500 0.001
0.001 -- 0.0001 -- 50 to 5000 q.s. to to 25 to 25 to 1.0 5 mL 46 1
to 500 0.01 to 500 0.001 0.001 -- -- 0.0001 to 5.0 50 to 5000 q.s.
to to 25 to 25 5 mL 47 1 to 500 0.01 to 500 0.001 0.001 0.001
0.0001 -- 50 to 5000 q.s. to to 25 to 25 to 25 to 1.0 5 mL 48 1 to
500 0.01 to 500 0.001 0.001 -- 0.0001 -- 50 to 5000 q.s. to to 25
to 25 to 1.0 5 mL 49 1 to 500 0.01 to 500 0.001 0.001 0.001 --
0.0001 to 5.0 50 to 5000 q.s. to to 25 to 25 to 25 5 mL 50 1 to 500
0.01 to 500 0.001 0.001 -- -- 0.0001 to 5.0 50 to 5000 q.s. to to
25 to 25 5 mL * Phosphate Buffer (monobasic/dibasic sodium salts),
pH 6.2
TABLE-US-00006 TABLE 1-5 Ingredient and Amount Citrate Buffer
(citric Cetylpyridinium acid/sodium Propylene Bromide Composition
Pirfenidone citrate), pH 3.5 Ethanol Glycol Glycerol Polysorbate
(or chloride) Osmolality no. (mg) to pH 6.5 (mM) (% v/v) (% v/v) (%
v/v) 80 (% v/v) (%) (mOsmo/kg) Water 51 1 to 500 0.01 to 500 0.001
-- -- -- -- 50 to 5000 q.s. to to 25 5 mL 52 1 to 500 0.01 to 500
-- 0.001 -- -- -- 50 to 5000 q.s. to to 25 5 mL 53 1 to 500 0.01 to
500 -- -- 0.001 -- -- 50 to 5000 q.s. to to 25 5 mL 54 1 to 500
0.01 to 500 -- -- -- 0.0001 -- 50 to 5000 q.s. to to 1.0 5 mL 55 1
to 500 0.01 to 500 -- -- -- -- 0.0001 to 5.0 50 to 5000 q.s. to 5
mL 56 1 to 500 0.01 to 500 0.001 0.001 -- -- -- 50 to 5000 q.s. to
to 25 to 25 5 mL 57 1 to 500 0.01 to 500 0.001 -- 0.001 -- -- 50 to
5000 q.s. to to 25 to 25 5 mL 58 1 to 500 0.01 to 500 0.001 -- --
0.0001 -- 50 to 5000 q.s. to to 25 to 1.0 5 mL 59 1 to 500 0.01 to
500 0.001 -- -- -- 0.0001 to 5.0 50 to 5000 q.s. to to 25 5 mL 60 1
to 500 0.01 to 500 0.001 0.001 0.001 -- -- 50 to 5000 q.s. to to 25
to 25 to 25 5 mL 61 1 to 500 0.01 to 500 0.001 0.001 -- 0.0001 --
50 to 5000 q.s. to to 25 to 25 to 1.0 5 mL 62 1 to 500 0.01 to 500
0.001 0.001 -- -- 0.0001 to 5.0 50 to 5000 q.s. to to 25 to 25 5 mL
63 1 to 500 0.01 to 500 0.001 0.001 0.001 0.0001 -- 50 to 5000 q.s.
to to 25 to 25 to 25 to 1.0 5 mL 64 1 to 500 0.01 to 500 0.001
0.001 -- 0.0001 -- 50 to 5000 q.s. to to 25 to 25 to 1.0 5 mL 65 1
to 500 0.01 to 500 0.001 0.001 0.001 -- 0.0001 to 5.0 50 to 5000
q.s. to to 25 to 25 to 25 5 mL 66 1 to 500 0.01 to 500 0.001 0.001
-- -- 0.0001 to 5.0 50 to 5000 q.s. to to 25 to 25 5 mL
TABLE-US-00007 TABLE 1-6 Ingredient and Amount Phosphate Buffer
Chloride ion (monobasic/ (sodium, dibasic sodium Propylene
Cetylpyridinium magnesium Composition Pirfenidone salts), pH 5.5
Ethanol Glycol Glycerol Polysorbate Bromide (or or calcium
Osmolality no. (mg) to 8.5 (mM) (% v/v) (% v/v) (% v/v) 80 (%)
chloride) (%) salts) (%) (mOsmo/kg) Water 67 1 to 500 0.01 to 500
0.001 -- -- -- -- 0.01 to 5 50 to 5000 q.s. to 25 to 5 mL 68 * 1 to
500 0.01 to 500 -- 0.001 -- -- -- 0.01 to 5 50 to 5000 q.s. to 25
to 5 mL 69 1 to 500 0.01 to 500 -- -- 0.001 -- -- 0.01 to 5 50 to
5000 q.s. to 25 to 5 mL 70 1 to 500 0.01 to 500 -- -- -- 0.0001 --
0.01 to 5 50 to 5000 q.s. to 1.0 to 5 mL 71 * 1 to 500 0.01 to 500
-- -- -- -- 0.0001 to 5.0 0.01 to 5 50 to 5000 q.s. to 5 mL 72 1 to
500 0.01 to 500 0.001 0.001 -- -- -- 0.01 to 5 50 to 5000 q.s. to
25 to 25 to 5 mL 73 1 to 500 0.01 to 500 0.001 -- 0.001 -- -- 0.01
to 5 50 to 5000 q.s. to 25 to 25 to 5 mL 74 1 to 500 0.01 to 500
0.001 -- -- 0.0001 -- 0.01 to 5 50 to 5000 q.s. to 25 to 1.0 to 5
mL 75 1 to 500 0.01 to 500 0.001 -- -- -- 0.0001 to 5.0 0.01 to 5
50 to 5000 q.s. to 25 to 5 mL 76 1 to 500 0.01 to 500 0.001 0.001
0.001 -- -- 0.01 to 5 50 to 5000 q.s. to 25 to 25 to 25 to 5 mL 77
1 to 500 0.01 to 500 0.001 0.001 -- 0.0001 -- 0.01 to 5 50 to 5000
q.s. to 25 to 25 to 1.0 to 5 mL 78 1 to 500 0.01 to 500 0.001 0.001
-- -- 0.0001 to 5.0 0.01 to 5 50 to 5000 q.s. to 25 to 25 to 5 mL
79 1 to 500 0.01 to 500 0.001 0.001 0.001 0.0001 -- 0.01 to 5 50 to
5000 q.s. to 25 to 25 to 25 to 1.0 to 5 mL 80 1 to 500 0.01 to 500
0.001 0.001 -- 0.0001 -- 0.01 to 5 50 to 5000 q.s. to 25 to 25 to
1.0 to 5 mL 81 1 to 500 0.01 to 500 0.001 0.001 0.001 -- 0.0001 to
5.0 0.01 to 5 50 to 5000 q.s. to 25 to 25 to 25 to 5 mL 82 1 to 500
0.01 to 500 0.001 0.001 -- -- 0.0001 to 5.0 0.01 to 5 50 to 5000
q.s. to 25 to 25 to 5 mL * Phosphate Buffer (monobasic/dibasic
sodium salts), pH 6.2
TABLE-US-00008 TABLE 1-7 Ingredient and Amount Citrate Chloride ion
Buffer (citric (sodium, acid/sodium Propylene Cetylpyridinium
magnesium Composition Pirfenidone citrate), pH 3.5 Ethanol Glycol
Glycerol Polysorbate Bromide (or or calcium Osmolality no. (mg) to
pH 6.5 (mM) (% v/v) (% v/v) (% v/v) 80 (%) chloride) (%) salts) (%)
(mOsmo/kg) Water 83 1 to 500 0.01 to 500 0.001 -- -- -- -- 0.01 to
5 50 to 5000 q.s. to 25 to 5 mL 84 1 to 500 0.01 to 500 -- 0.001 --
-- -- 0.01 to 5 50 to 5000 q.s. to 25 to 5 mL 85 1 to 500 0.01 to
500 -- -- 0.001 -- -- 0.01 to 5 50 to 5000 q.s. to 25 to 5 mL 86 1
to 500 0.01 to 500 -- -- -- 0.0001 -- 0.01% 50 to 5000 q.s. to 1.0
to 5% to 5 mL 87 1 to 500 0.01 to 500 -- -- -- -- 0.0001 to 5.0
0.01 to 5 50 to 5000 q.s. to 5 mL 88 1 to 500 0.01 to 500 0.001
0.001 -- -- -- 0.01 to 5 50 to 5000 q.s. to 25 to 25 to 5 mL 89 1
to 500 0.01 to 500 0.001 -- 0.001 -- -- 0.01 to 5 50 to 5000 q.s.
to 25 to 25 to 5 mL 90 1 to 500 0.01 to 500 0.001 -- -- 0.0001 --
0.01 to 5 50 to 5000 q.s. to 25 to 1.0 to 5 mL 91 1 to 500 0.01 to
500 0.001 -- -- -- 0.0001 to 5.0 0.01 to 5 50 to 5000 q.s. to 25 to
5 mL 92 1 to 500 0.01 to 500 0.001 0.001 0.001 -- -- 0.01 to 5 50
to 5000 q.s. to 25 to 25 to 25 to 5 mL 93 1 to 500 0.01 to 500
0.001 0.001 -- 0.0001 -- 0.01 to 5 50 to 5000 q.s. to 25 to 25 to
1.0 to 5 mL 94 1 to 500 0.01 to 500 0.001 0.001 -- -- 0.0001 to 5.0
0.01 to 5 50 to 5000 q.s. to 25 to 25 to 5 mL 95 1 to 500 0.01 to
500 0.001 0.001 0.001 0.0001 -- 0.01 to 5 50 to 5000 q.s. to 25 to
25 to 25 to 1.0 to 5 mL 96 1 to 500 0.01 to 500 0.001 0.001 --
0.0001 -- 0.01 to 5 50 to 5000 q.s. to 25 to 25 to 1.0 to 5 mL 97 1
to 500 0.01 to 500 0.001 0.001 0.001 -- 0.0001 to 5.0 0.01 to 5 50
to 5000 q.s. to 25 to 25 to 25 to 5 mL 98 1 to 500 0.01 to 500
0.001 0.001 -- -- 0.0001 to 5.0 0.01 to 5 50 to 5000 q.s. to 25 to
25 to 5 mL
TABLE-US-00009 TABLE 1-8 Ingredient and Amount Citrate Buffer
(citric acid/sodium Propylene Composition Pirfenidone citrate), pH
4.0 Ethanol Glycol Osmolality no. (mg) to pH 5.0 (mM) (% v/v/) (%
v/v) (mOsmo/kg) Water 99 5 mg 5 0.5% 1.0% 200 to 400 q.s. to 5 mL
(27 .mu.mols) 100 5 mg 5 1.0% 2.0% 400 to 600 q.s. to 5 mL (27
.mu.mols) 101 10 mg 5 1.0% 2.0% 400 to 600 q.s. to 5 mL (54
.mu.mols) 102 15 5 1.0% 2.0% 400 to 600 q.s. to 5 mL (81 .mu.mols)
103 25 mg 5 1.0% 2.0% 400 to 600 q.s. to 5 mL (135 .mu.mols) 104
37.5 mg 5 1.0% 2.0% 400 to 600 q.s. to 5 mL (202 .mu.mols) 105 75
mg 5 1.0% 2.0% 400 to 600 q.s. to 5 mL (405 .mu.mols) 106 100 mg 5
2.0% 4.0% 900 to 1100 q.s. to 5 mL (541 .mu.mols) 107 115 mg 5 4.0%
8.0% 1800 to 2100 q.s. to 5 mL (621 .mu.mols) 108 150 mg 5 6.0%
12.0% 1800 to 2100 q.s. to 5 mL (810 .mu.mols) 109 190 mg 5 8.0%
16.0% 3500 to 3900 q.s. to 5 mL (1027 .mu.mols) 110 220 mg 5 8.0%
16.0% 3600 to 4000 q.s. to 5 mL (1189 .mu.mols)
TABLE-US-00010 TABLE 1-9 Ingredient and Amount Phosphate Buffer
(monobasic/ dibasic sodium Propylene Composition Pirfenidone
salts), pH 6.0 to Ethanol Glycol Osmolality no. (mg) pH 7.0 (mM) (%
v/v) (% v/v) (mOsmo/kg) Water 111 5 mg 5 0.5% 1.0% 200 to 400 q.s.
to 5 mL (27 .mu.mols) 112 5 mg 5 1.0% 2.0% 200 to 600 q.s. to 5 mL
(27 .mu.mols) 113 10 mg 5 1.0% 2.0% 400 to 600 q.s. to 5 mL (54
.mu.mols) 114 15 5 1.0% 2.0% 400 to 600 q.s. to 5 mL (81 .mu.mols)
115 25 mg 5 1.0% 2.0% 400 to 600 q.s. to 5 mL (135 .mu.mols) 116
37.5 mg 5 1.0% 2.0% 400 to 600 q.s. to 5 mL (202 .mu.mols) 117 75
mg 5 1.0% 2.0% 400 to 600 q.s. to 5 mL (405 .mu.mols) 118 100 mg 5
2.0% 4.0% 900 to 1100 q.s. to 5 mL (541 .mu.mols) 119 115 mg 5 4.0%
8.0% 1800 to 2100 q.s. to 5 mL (621 .mu.mols) 120 150 mg 5 6.0%
12.0% 1800 to 2100 q.s. to 5 mL (810 .mu.mols) 121 190 mg 5 8.0%
16.0% 3500 to 3900 q.s. to 5 mL (1027 .mu.mols) 122 220 mg 5 8.0%
16.0% 3600 to 4000 q.s. to 5 mL (1189 .mu.mols)
TABLE-US-00011 TABLE 1-10 Ingredient and Amount Phosphate Buffer
(citric adic/ Chloride ion sodium citrate), Propylene (sodium,
Composition Pirfenidone pH 4.0 to Ethanol Glycol magnesium or
Osmolality no. (mg) pH 5.0 (mM) (% v/v) (% v/v) calcium salts)
(mOsmo/kg) Water 123 5 mg 5 0.5% 1.0% 0.1% to 0.9% 200 to 500 q.s.
to 5 mL (27 .mu.mols) 124 5 mg 5 1.0% 2.0% 0.1% to 0.9% 400 to 700
q.s. to 5 mL (27 .mu.mols) 125 10 mg 5 1.0% 2.0% 0.1% to 0.9% 400
to 700 q.s. to 5 mL (54 .mu.mols) 126 15 5 1.0% 2.0% 0.1% to 0.9%
400 to 700 q.s. to 5 mL (81 .mu.mols) 127 25 mg 5 1.0% 2.0% 0.1% to
0.9% 400 to 700 q.s. to 5 mL (135 .mu.mols) 128 37.5 mg 5 1.0% 2.0%
0.1% to 0.9% 400 to 700 q.s. to 5 mL (202 .mu.mols) 129 75 mg 5
1.0% 2.0% 0.1% to 0.9% 400 to 700 q.s. to 5 mL (405 .mu.mols) 130
100 mg 5 2.0% 4.0% 0.1% to 0.9% 900 to 1200 q.s. to 5 mL (541
.mu.mols) 131 115 mg 5 4.0% 8.0% 0.1% to 0.9% 1800 to 2200 q.s. to
5 mL (621 .mu.mols) 132 150 mg 5 6.0% 12.0% 0.1% to 0.9% 1800 to
2200 q.s. to 5 mL (810 .mu.mols) 133 190 mg 5 8.0% 16.0% 0.1% to
0.9% 3500 to 4000 q.s. to 5 mL (1027 .mu.mols) 134 220 mg 5 8.0%
16.0% 0.1% to 0.9% 3600 to 4100 q.s. to 5 mL (1189 .mu.mols)
TABLE-US-00012 TABLE 1-11 Ingredient and Amount Phosphate Buffer
(monobasic/ Chloride ion dibasic sodium (sodium, Composition
Pirfenidone salts), pH 6.0 to Propylene magnesium or Osmolality no.
(mg) pH 7.0 (mM) Ethanol Glycol calcium salts) (mOsmo/kg) Water 135
5 mg 5 0.5% 1.0% 0.1% to 0.9% 200 to 500 q.s. to 5 mL (27 .mu.mols)
136 5 mg 5 1.0% 2.0% 0.1% to 0.9% 200 to 700 q.s. to 5 mL (27
.mu.mols) 137 10 mg 5 1.0% 2.0% 0.1% to 0.9% 400 to 700 q.s. to 5
mL (54 .mu.mols) 138 15 5 1.0% 2.0% 0.1% to 0.9% 400 to 700 q.s. to
5 mL (81 .mu.mols) 139 25 mg 5 1.0% 2.0% 0.1% to 0.9% 400 to 700
q.s. to 5 mL (135 .mu.mols) 140 37.5 mg 5 1.0% 2.0% 0.1% to 0.9%
400 to 700 q.s. to 5 mL (202 .mu.mols) 141 75 mg 5 1.0% 2.0% -- 400
to 700 q.s. to 5 mL (405 .mu.mols) 142 100 mg 5 2.0% 4.0% 0.1% to
0.9% 900 to 1200 q.s. to 5 mL (541 .mu.mols) 143 115 mg 5 4.0% 8.0%
0.1% to 0.9% 1800 to 2200 q.s. to 5 mL (621 .mu.mols) 144 150 mg 5
6.0% 12.0% 0.1% to 0.9% 1800 to 2200 q.s. to 5 mL (810 .mu.mols)
145 190 mg 5 8.0% 16.0% 0.1% to 0.9% 3500 to 4000 q.s. to 5 mL
(1027 .mu.mols) 146 220 mg 5 8.0% 16.0% 0.1% to 0.9% 3600 to 4100
q.s. to 5 mL (1189 .mu.mols)
Example 2
Buffer and pH Effects Development Study
[0561] Pirfenidone solubility in citrate and phosphate buffers were
investigated (Table 2). Pirfenidone (250 mg) was reconstituted with
5 mL of buffer in water or water alone and mixed thoroughly with
sonication and vortexing. The sample was agitated at ambient
temperature overnight. The sample was visually inspected,
appearance recorded, centrifuged to sediment any un-dissolved
material, and the supernatant withdrawn via syringe through a 0.22
gm PVDF filter. The filtered sample was tested with respect to:
appearance, pH (USP <791>), osmolality (USP <785>), and
Pirfenidone concentration and Pirfenidone % purity by RP-HPLC. The
remaining filtered sample was split into three equal volumes in
glass vials and placed at 25.degree. C./60RH, 40.degree. C./75RH
and refrigeration. Samples were wrapped in aluminum foil to reduce
light exposure. After the first night of incubation, samples were
briefly visually inspected for any signs of discoloration or
precipitate formation.
TABLE-US-00013 TABLE 2 Buffer/pH Effects Study Results Pirfenidone
Saturation Buffer Buffer(mM) pH Solubility (mg/mL) Citrate 5 4 18.4
Citrate 50 4 18.1 Citrate 5 6 18.4 Citrate 50 6 16.4 Phosphate 5 6
18.3 Phosphate 50 6 17.2 Phosphate 5 7.5 19.0 Phosphate 50 7.5 16.3
Water 0 7.9 18.4
[0562] Table 2 shows the observed solubility of pirfenidone under
the conditions described.
Example 3
Co-Solvent and Surfactant Effects
[0563] Pirfenidone solubility in the presence of added co-solvent
(ethanol, propylene glycol, or glycerin) and surfactant
(polysorbate 80 or cetylpyridinium bromide) were investigated. The
buffer type, strength, and pH of the aqueous vehicle are selected
based on results from the Buffer/pH Effects study results (Example
2). Pirfenidone (375 mg) is reconstituted with 5 mL of each sovent
system shown in Table 3.
TABLE-US-00014 TABLE 3 Co-Solvent/Surfactant Effects Study Results
Pirfenidone % Citrate % Phosphate Saturation Added Co-Solvent
and/or Surfactant, % % Buffer Buffer Solubility EtOH PG Gly PS80
CPB Water (10 mM) (5 mM) pH (mg/mL) 0 0 0 0.04 0 100.0 0 0 6.5 19.9
0 0 0 0 0.1 99.9 0 0 6.2 20.0 0 0 0 0.04 0 100.0 0 0 4.8 8.3 0 0 0
0 0.1 99.9 0 0 4.6 19.3 0 0 0 0.04 0 0 100.0 0 4.5 19.1 0 0 0 0 0.1
0 99.9 0 4.5 19.3 4 0 0 0 0 96.0 0 0 6.9 24.3 0 8 0 0 0 92.0 0 0
6.8 24.6 0 0 4 0 0 96.0 0 0 6.7 20.1 4 0 0 0 0 96.0 0 0 5.0 22.8 0
8 0 0 0 92.0 0 0 5.0 24.3 0 0 4 0 0 96.0 0 0 4.8 20.1 4 0 0 0 0 0
96.0 0 4.5 22.3 0 8 0 0 0 0 92.0 0 4.4 23.2 0 0 4 0 0 0 96.0 0 4.4
19.8 4 0 0 0.04 0 96.0 0 0 6.7 24.5 0 8 0 0.04 0 92.0 0 0 6.6 23.2
0 0 4 0.04 0 96.0 0 0 6.5 20.2 4 0 0 0.04 0 96.0 0 0 4.7 22.5 0 8 0
0.04 0 92.0 0 0 4.6 23.4 0 0 4 0.04 0 96.0 0 0 4.9 20.0 4 0 0 0.04
0 0 96.0 0 4.5 21.9 0 8 0 0.04 0 0 92.0 0 4.5 23.2 0 0 4 0.04 0 0
96.0 0 4.4 17.6 4 0 0 0 0.1 95.9 0 0 6.1 23.9 0 8 0 0 0.1 91.9 0 0
6.2 23.4 0 0 4 0 0.1 95.9 0 0 ND ND 4 0 0 0 0.1 95.9 0 0 4.9 20.2 0
8 0 0 0.1 91.9 0 0 5.0 22.3 0 0 4 0 0.1 95.9 0 0 ND ND 4 0 0 0 0.1
0 95.9 0 4.5 20.4 0 8 0 0 0.1 0 91.9 0 4.5 21.0 0 0 4 0 0.1 0 95.9
0 ND ND 4 8 0 0 0 88.0 0 0 6.2 30.0 4 8 0 0.04 0 88.0 0 0 5.8 28.9
4 8 0 0 0 0 0 88.0 6.6 27.2 4 8 0 0.04 0 0 0 88.0 6.6 29.4 6 12 0 0
0 0 0 82.0 7.0 34.7 8 16 0 0 0 0 0 76.0 7.0 43.7 8 0 0 0 0 0 0 92
6.6 26.7 8 4 0 0 0 0 0 88 6.8 30.4 8 8 0 0 0 0 0 84 6.8 35.0 8 12 0
0 0 0 0 80 6.7 37.7 8 16 0 0 0 0 0 76 6.8 45.4 6 16 0 0 0 0 0 78
6.9 40.9 4 16 0 0 0 0 0 80 6.9 36.8 2 16 0 0 0 0 0 82 6.8 31.0 0 16
0 0 0 0 0 84 6.8 29.3 *Buffer type, buffer strength, and pH chosen
on the basis of Buffer/pH study results (Example 2). EtOH: ethanol,
PG: propylene glycol, Gly: glycerol, PS80: polysorbate 80 (Tween
80), CPB: Cetylpyridinium chloride. % in Table 3 refers to
volume/volume.
[0564] Each sample was agitated at ambient temperature overnight.
The samples were visually inspected and appearance recorded.
Samples were centrifuged to sediment any un-dissolved material and
the supernatant withdrawn via syringe through a 0.22 .mu.m PVDF
filter. The filtered sample was tested with respect to: appearance,
pH (USP <791>), osmolality (USP <785>), and Pirfenidone
concentration and Pirfenidone % purity by RP-HPLC. The remaining
filtered sample was split into three equal volumes in glass vials
and placed at 25.degree. C./60RH, 40.degree. C./75RH and
refrigeration. Samples are wrapped in aluminum foil to reduce light
exposure. After the first night of incubation, samples are briefly
visually inspected for any signs of discoloration or precipitate
formation.
[0565] Both ethanol (EtOH) and propylene glycol (PG) increase the
saturation solubility of pirfenidone. Ethanol and propylene glycol
together have an additive effect in increasing the saturation
solubility of pirfenidone.
[0566] Selected formulations were subjected to osmolality
determination and nebulization for taste testing and throat
irritation and or cough response. Table 4 shows these results.
TABLE-US-00015 TABLE 4 Compositions and Additional Analysis Added
Co-Solvent and/or Surfactant Sodium % Phosphate (%).sup.a Saccharin
Buffer Pirfenidone Osmolality Throat Cough EtOH PG (mM) (5 mM) pH
(mg/mL) (mOsmo/Kg) Taste Irritation? Response? 4 8 0 88 6.6 27.2
~1830* 4.5 micron aerosol particle: No No Mild taste, unremarkable
flavor 6 12 0 82 7.0 34.7 ~2750* 4.5 micron aerosol particle: No No
Mild taste, slight sweet flavor, slight bitter after- taste 8 16 0
76 7.0 43.7 3672 4.5 micron aerosol particle: No No Mild taste,
moderate sweet flavor, moderate bitter after-taste 3.5 micron
aerosol particle: Mild taste, similar sweet flavor and bitter
after-taste as 6% EtOH + 12% PG 8 16 0.3 76 7.0 43.7 3672 3.5
micron aerosol particle: No No Mild taste, similar sweet flavor and
slightly bitter after-taste similar to 6% EtOH + 12% PG 8 16 0 76
4.5 0 3672 3.5 micron aerosol particle: No No Mild taste, slightly
sweeter than 6% EtOH + 12% PG, with similar bitter after- taste
*Calculated. .sup.a% volume/volume
[0567] Results from Table 4 show that co-solvent-containing
formulations contain a relatively high osmolality. Unexpectedly,
these high osmolar solutions do not exhibit poor inhalation
tolerability. Solutions containing up to 8% (v/v) ethanol plus 16%
(v/v) propylene glycol are well-tolerated, have a slight sweet
flavor with minimal bitter after-taste, minimal throat irritation
and minimal stimulation of cough response. Formulations lacking
co-solvents are limited to about 15 mg/mL. These same formulations
exhibited a bitter, slightly metallic taste. Unexpectedly,
co-solvent-enabling high concentration pirfenidone formulations (by
non-limiting example up to 44 mg/mL) do not exhibit these poor
taste characteristics.
[0568] Saturated pirfenidone formulations appeared stable out to
2-5 days under the tested conditions. However, in all cases
pirfenidone eventually re-crystallized. This re-crystallization was
not inhibited by pre-filtration of the sample. From this
observation, pirfenidone concentrations less then saturation were
explored. 85% saturation pirfenidone concentrations were exposed to
several temperatures. These results are shown in Table 5.
TABLE-US-00016 TABLE 5 Compositions and Additional Analysis Added
Co-Solvent % Phosphate (%) Buffer Pirfenidone Recrystallization
upon storage.sup.a EtOH PG (5 mM) pH (mg/mL) 25.degree. C.
15.degree. C. 4.degree. C. -20.degree. C. 4 8 88 6.6 27.2.sup.b Yes
ND.sup.d ND ND 4 8 88 6.6 23.0.sup.e No No No Yes 6 12 82 7.0 34.7
Yes ND ND ND 6 12 82 7.0 29.5 No No No Yes.sup.f 8 16 76 7.0 43.7
Yes ND ND ND 8 16 76 7.0 37.0 No No No Yes.sup.f .sup.aObservation
after overnight storage at designated temperature .sup.bPirfenidone
saturation solubility at given formulation .sup.cCalculated
.sup.dNot determined .sup.ePirfenidone concentration at 85%
saturation solubility .sup.fCrystals re-dissolved at 25.degree. C.
without agitation % refers to % v/v
[0569] Results from Table 5 show that these 85% pirfenidone
saturation formulations do not re-crystallize down to 4.degree. C.
(at least following overnight incubation). These results suggest
that these formulations will survive periodic exposures down to
4.degree. C., and even upon freezing will re-dissolve without
agitation.
[0570] Additional studies examined pirfenidone stability in 5 mM
sodium phosphate buffer, pH 6.5, as a function of optimized
co-solvent strength for stability assessment. The target
concentrations represent roughly 85% of the saturated concentration
possible at each specified co-solvent concentration. Two additional
formulations examined pirfenidone stability at 1 mg/mL in specific
formulations. Pirfenidone (amounts are outlined in Table 6) was
reconstituted with 100 mL vehicle as described and mixed thoroughly
by agitation. The sample was agitated until completely dissolved.
Once dissolved, samples were filtered via syringe through a 0.22
.mu.m PVDF filter.
[0571] Samples were refrigerated to reduce evaporative loss of
volatile co-solvents (ethanol) during filtration and dispensing. An
approximate 5.0-mL aliquot of each formulation was transferred to
class A glass 6 ml containers with suitable closures (20 mm
stopper). At least 8 containers are being maintained in the upright
orientation at 25.degree. C./60RH, and another 8 containers
maintained at 40 .degree. C./75RH. One container for each
formulation was used for the initial evaluation, t=0, with testing
for: appearance, pH, osmolality, HPLC=RP-HPLC for pirfenidone assay
(reported as % label claim) and individual impurities (reported as
% pirfenidone and RRT). Stability time point testing will evaluate
for appearance, and HPLC=RP-HPLC for pirfenidone assay (reported as
% label claim) and individual impurities (reported as % pirfenidone
and RRT).
TABLE-US-00017 TABLE 6 Representative Pirfenidone Formulations for
Stability Assessment Target 5 mM Phosphate Target Add Add Add Add
Buffer, pH 6.5, Pirfenidone Pirfenidone Buffer Ethanol PG plus
(mg/mL) (mg) (mL) (mL) (mL) 8% (v/v) EtOH, 38 3800 20 8.0 16.0 16%
(v/v) PG 8% (v/v) EtOH, 1 100 20 8.0 16.0 16% (v/v) PG 6% (v/v)
EtOH, 30 300 20 6.0 12.0 12% (v/v) PG 4% (v/v) EtOH, 23 230 20 4.0
8.0 8% (v/v) PG 1% (v/v) EtOH, 15 150 20 1.0 2.0 2% (v/v) PG 1%
(v/v) EtOH, 1 100 20 1.0 2.0 2% (v/v) PG
[0572] For each variant Formulation, samples are tested according
to the schedule shown in Table 7.
TABLE-US-00018 TABLE 7 Stability Schedule Tests* Performed at Time
Point (mo) = Condition 0 0.5** 1 3 6 9 12 contingency total
25.degree. C./60% RH 1 1 1 1 1 1 1 2 9 40.degree. C./75% RH 1 1 1 1
1 1 2 8 *all samples will be tested for appearance by visual
observation, pH, HPLC = RP-HPLC for pirfenidone assay (reported as
% label claim), and individual impurities (reported as %
pirfenidone and RRT). At t = 0, testing will also include
osmolality. **Appearance only
TABLE-US-00019 TABLE 8 Time-Zero Stability Assessment Target 5 mM
Phosphate Target Measured Buffer, pH Pirfenidone Pirfenidone
mOsmol/ 6.5, plus (mg/mL) (mg/mL) pH kg App. 8% (v/v) EtOH, 38 38.9
7.04 3750 * 16% (v/v) PG 8% (v/v) EtOH, 1 1.0 6.98 3590 * 16% (v/v)
PG 6% (v/v) EtOH, 30 30.3 6.90 2863 * 12% (v/v) PG 4% (v/v) EtOH,
23 24.1 6.78 1928 * 8% (v/v) PG 1% (v/v) EtOH, 15 16.1 6.65 512 *
2% (v/v) PG 1% (v/v) EtOH, 1 1.0 6.69 452 * 2% (v/v) PG * All
solutions are clear and colorless without visible signs of
crystallization.
[0573] Selected formulations were prepared for pharmacokinetic
analysis following aerosol delivery to rat lung. In these studies,
lung, heart, kidney and plasma tissue samples were analyzed for
pirfenidone and metabolite content (Tables 16-19). Formulations
prepared for this study are outlined in Table 9. Briefly, this
study prepared pirfenidone in 5 mM sodium phosphate buffer, pH 6.5,
as a function of optimized co-solvent strength. The target
concentration in each formulation is 12.5 mg/mL. Pirfenidone
(amounts as described in Table 9) were reconstituted with 30 mL
vehicle as described and mixed thoroughly by agitation. The sample
was agitated until completely dissolved. Once pirfenidone had
dissolved completely, formulations were filtered via syringe
through a 0.22 .mu.m PVDF filter. Filtered samples were analyzed by
HPLC.
[0574] The samples were then refrigerated to reduce evaporative
loss of volatile co-solvents (ethanol) during filtration and
dispensing. Formulations were transferred to class A glass
containers (approximately 10 mL) with suitable closures (20 mm
stopper).
TABLE-US-00020 TABLE 9 Formulations for Co-Solvent Effects
Pharmacokinetic and Tissue Distribution Study Target 5 mM Phosphate
Target Add Add Add Add Add Dosing Buffer, pH Vol. Pirfenidone
Pirfenidone Buffer** EtOH PG NaCl Group 6.5, plus (mL)* (mg/mL)
(mg) (mL) (mL) (mL) (g) 1 8% (v/v) 30 12.5 375 6 2.4 4.8 0 EtOH,
16% (v/v) PG 2 6% (v/v) 30 12.5 375 6 1.8 3.6 0 EtOH, 12% (v/v) PG
3 4% (v/v) EtOH, 8% (v/v) PG 30 12.5 375 6 1.2 2.4 0 4 2% (v/v) 30
12.5 375 6 0.6 1.2 0 EtOH, 4% (v/v) PG 5 1% (v/v) 30 12.5 375 6 0.3
0.6 0 EtOH, 2% (v/v) PG 6 0.4% NaCl 30 12.5 375 6 0 0 0.12
*Pirfenidone was reconstituted with 30 mL of the indicated Vehicle
by QS'ing the remaining volume with water. **25 mM NaPO4, pH 6.5
(5X solution)
Example 4
Nebulization Device Perfomance
[0575] Selected formulations were prepared for nebulization device
aerosol characterization. Briefly, this study prepared pirfenidone
in 5 mM sodium phosphate buffer, pH 6.5, as a function of optimized
co-solvent strength. These formulations are outlined in Table 10.
Pirfenidone (amounts as listed in Table 10) were reconstituted as
described and mixed thoroughly by agitation. Each sample was
agitated until completely dissolved. Once dissolved completely,
formulations were filtered via syringe through a 0.45 .mu.m PVDF
filter. Filtered samples were analyzed by HPLC.
[0576] Each sample was refrigerated to reduce evaporative loss of
volatile co-solvents (ethanol) during filtration and dispensing. As
described in Table 10, each formulation was transferred to class A
glass containers with suitable closures.
TABLE-US-00021 TABLE 10 Formulations for Nebulization Device
Aerosol Performance Studies Target 5 mM Phosphate Target Add Add
Add Add Add Test Buffer, pH Vol. Pirfenidone Pirfenidone Buffer*
Ethanol PG NaCl Article 6.5, plus (mL) (mg/mL) (mg) (mL) (mL) (mL)
(g) 1 8% (v/v) 200 38** 7600 40 16 32 0 EtOH, 16% (v/v) PG 2 8%
(v/v) 200 0 0 40 16 32 0 EtOH, 16% (v/v) PG 3 1% (v/v) 200 0 0 40 2
4 0 EtOH, 2% (v/v) PG 4 0.2% (v/v) NA 0.475 Diluted Test Articles 1
and 3 EtOH, 0.4% (v/v) PG 5 0.4% NaCl 200 0 0 40 0 0 0.8 *25 mM
NaPO4, pH 6.5 (5X solution) **Active formulations were diluted with
water and vehicle by the device characterization facility as
necessary to characterize lower pirfenidone concentrations.
[0577] Philips I-neb.RTM. AAD System
[0578] For aerosol analysis, three units of each I-neb
breath-actuated nebulizer were studied in triplicate for each
device/formulation combination. Using Malvern Mastersizer aerosol
particle sizer, the particle size and distribution was
characterized. Parameters reported were mass median diameter (MMD),
span, fine particle fraction (FPF=%.ltoreq.5 microns), output rate
(mg formulation per second), nebulized volume, delivered volume
(volume of dose in range of FPF), respirable delivered dose (mg
pirfenidone delivered volume). Aerosol output was measured using a
5 second inhalation, 2 second exhalation breathing pattern with a
1.25 L tidal volume. The results are shown in Table 11.
TABLE-US-00022 TABLE 11 Nebulization of Pirfenidone Formulations
using the Philips I-neb Device Test Test Test Test Test Article
Article Article Article Article Parameter 1 2 3 4 5 MMD (micron)
3.31 3.64 4.95 5.52 4.95 Span (micron) 1.13 1.36 1.21 1.14 1.20 FPF
(% < 5 microns) 84.41 74.70 51.40 42.01 51.11 Output rate
(mg/sec) 0.96 1.31 3.52 6.92 4.60 Nebulized vol (mg) 776.63 810.42
846.42 853.30 814.51 Delivered vol (mg) 653.44 605.83 436.19 345.55
417.12 RDD (mg)* 24.83 NA NA 0.16 NA *Exemplary (RDD = FPF .times.
Nebulized Volume .times. loaded dose)
[0579] PARI eFlow.RTM.--35 Head
[0580] For aerosol analysis, three units of each eFlow nebulizer
containing a 35-head were studied in duplicate for each
device/formulation combination. Using an Insitec Spraytec Laser
Particle sizer, the particle size and distribution was
characterized. Parameters reported were volumetric mean diameter
(VMD), geometric standard deviation (GSD), time to nebulize dose
(duration), remaining dose following nebulization (dead volume),
and fine particle fraction (FPF=%.ltoreq.5 microns). 4 mL of each
formulation was tested. The results are shown in Table 12.
TABLE-US-00023 TABLE 12 Nebulization of Pirfenidone Formulations
using the PARI eFlow Device Test Test Test Test Test Article
Article Article Article Article Parameter 1 2 3 4 5 Loaded Dose
(mg) 152 0 0 1.9 0 VMD (micron) 2.60 2.84 3.60 3.88 3.81 GSD
(micron) 1.86 1.85 1.74 1.68 1.68 FPF (% < 5 microns) 85.47
81.81 71.26 67.70 68.78 Duration (min) 9.87 8.85 6.26 5.99 5.86
Dead volume (mL) 0.15 0.16 0.19 0.18 0.16 Output rate (mL/min) 0.40
0.44 0.61 0.64 0.67 Nebulized vol (mL) 3.85 3.84 3.81 3.82 3.84 RDD
(mg)* 87.04 NA NA 0.86 NA RDD (mg)/minute 8.82 NA NA 0.14 NA
*Exemplary (RDD = FPF .times. Inhaled Mass .times. Loaded Dose).
For the exemplary calculation, assume a 67% delivered dose (i.e.
inhaled mass). (Representative of a 1:1 inhalation:exhalation
breathing pattern using the eFlow device with 35 head.)
[0581] Aerogen Aeroneb.RTM. Solo
[0582] For aerosol analysis, between two and four units of each
Aeroneb.RTM. Solo nebulizer with Aeroneb.RTM. Pro-X controller were
studied with each formulation. Using a Malvern Spraytech aerosol
particle sizer, the particle size and distribution were
characterized. Parameters reported were volumetric mean diameter
(VMD), geometric standard deviation (GSD), time to nebulize dose
(duration), remaining dose following nebulization (dead volume),
and fine particle fraction (FPF=%.ltoreq.5 microns). 1 mL of each
formulation was tested. The results are shown in Table 13.
TABLE-US-00024 TABLE 13 Nebulization of Pirfenidone Formulations
using the Aeroneb Solo Device Test Test Test Test Parameter Article
1 Article 2 Article 3 Article 5 Loaded Dose (mg) 38 0 0 0 VMD
(micron) 9.73 5.49 4.31 4.76 GSD (micron) 3.21 3.43 2.25 2.23 FPF
(% < 5 microns) 38.97 48.13 59.09 53.77 Duration (min) 5.88 5.56
4.17 2.17 Output rate (mL/min) 0.17 0.18 0.24 0.46 RDD (mg)* 9.9 NA
NA NA RDD (mg)*/minute 1.68 NA NA NA *Exemplary (RDD = FPF .times.
Inhaled Mass .times. Loaded Dose). For the exemplary calculation,
assume a 67% inhaled mass.
Example 5
Process temperature Development Study
[0583] This study examined the above-ambient temperature stability
of pirfenidone in aqueous solution to best understand stability at
this temperature and saturation solubility. This information may be
utilized with manufacturing process embodiments of the present
invention wherein high temperature pirfenidone aqueous dissolution,
in the presence of or followed by co-solvent and/or surfactant
and/or cation addition, and subsequent cooling to ambient
temperature provide higher pirfenidone saturation solubility then
ambient temperature dissolution alone. In this process, added
co-solvent and/or surfactant and/or cation may stabilize the
high-temperature-dissolved pirfenidone during the cooling process
and provide a stable, high-concentration, ambient-temperature
formulation for long-term storage. Alternatively, the added
co-solvent and/or surfactant and/or cation may provide access to
greater soluble pirfenidone for which to maintain in solution then
ambient temperature dissolution alone. Alternatively,
high-temperature dissolution may be integrated into manufacturing
process embodiments to reduce dissolution time and/or reduce the
effects of lot-to-lot crystal structure, amorphic content and
polymorph variability on dissolution time and degree of
dissolution.
[0584] Formulations were prepared as described in Table 11.
Briefly, this study prepared 250 mg pirfenidone in 5 mM sodium
phosphate buffer, pH 6.5, in the presence of ethanol, propylene
glycol and/or polysorbate 80. The final volume of each formulation
was 5 mL. Pirfenidone (amounts as listed in Table 11) were
reconstituted as described and mixed thoroughly by agitation. Each
sample was mixed thoroughly and agitated overnight at 60.degree. C.
Rapid cooling and step-wise cooling from 60.degree. C. to
25.degree. C. was performed. HPLC analysis was performed on samples
taken after overnight incubation and after cooling to 25.degree. C.
Prior to HPLC analysis, formulations were filtered via syringe
through a 0.45 .mu.m PVDF filter. Results for this evaluation are
shown in Table 14.
TABLE-US-00025 TABLE 14 Formulations for Process Temperature Study
Added Co-Solvent Pirfenidone and/or Surfactant % Phosphate (mg/mL)
(% v/v) Buffer >Re- EtOH PG PS80 (5 mM) pH >60.degree.
C..sup.a crystal.sup.b Observations 4 8 0 88 6.7 50.34 27.6 Fully
dissolved after overnight at 60.degree. C. Stable at 25.degree. C.
for >4 hours before re-crystallization 4 8 0.04 88 6.7 51.8 26.8
Fully dissolved after overnight at 60.degree. C. Stable at
25.degree. C. for >4 hours before re-crystallization 4 0 0.04 96
6.6 50.7 22.4 Fully dissolved after overnight at 60.degree. C.
Stable at 25.degree. C. for >4 hours before re-crystallization 0
8 0.04 92 6.7 52.8 22.3 Fully dissolved after overnight at
60.degree. C. Stable at 25.degree. C. for >4 hours before
re-crystallization 0 8 0 92 6.6 54.6 18.6 Fully dissolved after
overnight at 60.degree. C. Stable at 25.degree. C. for >4 hours
before re-crystallization .sup.aPirfenidone assay content after
stepwise cooling to 25.degree. C. .sup.bPirfenidone assay content
after stepwise cooling to 25.degree. C. and then later
re-crystallization .sup.cCalculated .sup.dNot determined
.sup.ePirfenidone concentration at 85% saturation solubility
.sup.fCrystals re-dissolved at 25.degree. C. without agitation
[0585] The results in Table 14 show that heating pirfenidone to
60.degree. C. enables full dissolution up to or potentially greater
than 50 mg/mL. Rapid cooling to 25.degree. C. of this dissolved
material led to rapid recrystallization (data not shown). Slow
cooling to 25.degree. C. (step-wise from 60.degree. C. to
40.degree. C. to 30.degree. C. then 25.degree. C., with temperature
equilibration occurring at each step prior to further reducing the
temperature) enabled pirfenidone to stay in solution at about 50
mg/mL for several hours before each solution ultimately
re-crystallized. Filtering each formulation prior to
re-crystallization (either at 30.degree. C. or after equilibrium at
25.degree. C.) did not noticeably extend or prevent
re-crystallization. Pirfenidone dissolution time is reduced by
heating and appears to be stable at this temperature during the
dissolution process. Thus, heating pirfenidone formulations can be
beneficial in a manufacturing process embodiments to overcome the
slower dissolution observed at ambient temperature.
Example 6
Pharmacokinetics and Lung-Tissue Distribution
[0586] Sprague-Dawley rats (300-350 grams) were administered
pirfenidone by either the oral (gavage) or aerosol (intratracheal
Penn Century nebulizing catheter) routes. For oral administration,
50 mg pirfenidone was dissolved in 3.33 mL distilled water
containing 0.5% CMC to a final concentration of 15 mg/mL. Solutions
were vortexed until all crystals dissolved. Rats were administered
70 mg/kg pirfenidone (.about.1.4 mL). Plasma samples were taken at
pre-dose, 0.08, 0.16, 0.25, 0.5, 0.75, 1.0, 1.5, 2, 4, and 6 hours
post dosing. For lung tissue samples, eight additional rats were
also dosed 70 mg/kg by the oral route. Lungs were taken at pre-dose
0.08, 0.5, 2, and 4 hours post dosing. Materials were extracted and
pirfenidone quantitated as .mu.g/mL plasma and .mu.g/gram lung
tissue. For aerosol administration, 60 mg pirfenidone was dissolved
in 10 mM phosphate buffer, pH 6.2 containing 81 mM MgCl.sub.2 (1:1
pirfenidone to magnesium). Rats were administered 5 mg/kg
pirfenidone (.about.100 .mu.L) by nebulizing catheter. Plasma
samples were taken at pre-dose, 0.08, 0.16, 0.25, 0.5, 0.75, 1.0,
1.5, 2, 4, and 6 hours post dosing. For lung tissue samples, eight
additional rats were also dosed 70 mg/kg by the oral route. Lungs
were taken at pre-dose 0.08, 0.5, 2, and 4 hours post dosing.
Materials were extracted and pirfenidone quantitated as .mu.g/mL
plasma and .mu.g/gram lung tissue. Results from these studies are
shown in Table 15.
TABLE-US-00026 TABLE 15 Pirfenidone pharmacokinetics and tissue
distribution following oral and aerosol administration to rats.
Aerosol Measured.sup.a Oral Rat dose (mg/kg) 1 5 70 Lung Cmax.sup.b
101 508 3.6 T.sub.1/2.sup.c <1, 45 <1, 45 45 AUC.sup.d 5.2
25.4 4.3 TOE.sup.e 5 84 89 Plasma Cmax.sup.f 1.1 7.0 8.1 T.sub.1/2
30 30 30 AUC.sub.0-6 hrs.sup.g 0.9 4.5 13.5 .sup.aBolus aerosol
intratracheal delivery .sup.bC.sub.max: Lung tissue (.mu.g/g)
immediate post-dose calculated from the direct-lung delivered dose.
All other time points measured. Plasma measured (.mu.g/mL)
.sup.cT.sub.1/2: Minutes (aerosol = .alpha., .beta.; oral = .alpha.
only observed) .sup.dAUC: Lung tissue (mg hr/kg for time >1
.mu.g/g) .sup.eTOE: Time of exposure as minutes over 1 .mu.g/g lung
tissue) .sup.fCmax: Plasma (.mu.g/mL) .sup.gAUC.sub.0-6 hrs: Plasma
(mg hr/L)
Example 7
Pharmacokinetics and Tissue Distribution of Co-Solvent
Formulations
[0587] To assess the pharmacokinetics and tissue distribution of
co-solvent formulations (described in Table 9), Sprague-Dawley rats
(350-400 grams) in triplicate were administered pirfenidone by
bolus aerosol (intratracheal Penn Century nebulizing catheter).
Rats were dosed about 4 mg/kg pirfenidone (.about.150 .mu.L) by
nebulizing catheter. Plasma samples, and entire lungs, hearts and
kidneys were taken at pre-dose, 0.033, 0.067, 0.1, 0.167, 0.333,
0.667, 1.0, 1.5, 2, and 2.5 hours post dosing. Materials were
extracted and pirfenidone quantitated as .mu.g/mL plasma and
.mu.g/gram lung, heart or kidney tissue. Results from these studies
are shown in Table 16 thru 19. No adverse events were noted in
these studies.
TABLE-US-00027 TABLE 16 Pirfenidone Pharmacokinetics and Lung
Tissue Distribution - Co-Solvent-Based Formulation Study (Dosing
group formulations listed in Table 9) Group 1 Group 2 Group 3 Group
4 Group 5 Group 6 Time Mean Mean Mean Mean Mean Mean Analyte (hr)
.mu.g/gram .mu.g/gram .mu.g/gram .mu.g/gram .mu.g/gram .mu.g/gram
PIRFENIDONE 0.sup.A 107.58 0.0333 3.57 3.93 5.56 3.16 5.24 2.25
0.0667 2.66 2.16 2.29 1.94 2.68 2.06 0.1 1.93 1.49 1.84 1.87 1.51
1.71 0.167 1.38 1.43 1.54 1.31 1.45 1.31 0.333 1.07 0.95 0.95 1.00
1.27 0.96 0.667 0.52 0.60 0.61 0.62 0.48 0.57 1 0.38 0.31 0.26 0.34
0.36 0.31 1.5 0.15 0.18 0.11 0.17 0.12 0.09 2 0.07 0.09 0.08 0.05
0.07 0.08 2.5 0.02 0.03 0.03 0.03 0.02 0.05 5-CARBOXY-N- 0 MIN 0.00
phenyl-5-1H-pyridone 0.0333 H 0.03 NOT 0.03 NOT 0.07 0.04 0.0667 H
0.03 TESTED 0.10 TESTED 0.10 0.11 0.100 H 0.12 0.14 0.09 0.09 0.167
H 0.13 0.22 0.14 0.16 0.333 H 0.25 0.27 0.36 0.24 0.667 H 0.24 0.20
0.24 0.23 1 H 0.18 0.17 0.19 0.20 1.50 H 0.12 0.13 0.11 0.11 2 H
0.05 0.08 0.05 0.06 2.50 H 0.03 0.03 0.02 0.04 .sup.aAverage of 18
immediate post-dose measurements
TABLE-US-00028 TABLE 17 Pirfenidone Plasma Pharmacokinetics -
Co-Solvent-Based Formulation Study (Dosing group formulations
listed in Table 9) Group 1 Group 2 Group 3 Group 4 Group 5 Group 6
Time Mean Mean Mean Mean Mean Mean Analyte (hr) .mu.g/mL .mu.g/mL
.mu.g/mL .mu.g/mL .mu.g/mL .mu.g/mL PIRFENIDONE 0 0.03 0.01 0.06
0.01 0.02 0.06 0.0333 6.80 6.20 7.47 7.23 7.72 6.84 0.0667 6.09
6.04 6.52 7.43 7.05 7.31 0.1 5.72 5.12 5.39 3.98 5.55 5.75 0.167
5.56 5.60 5.51 4.75 4.59 5.31 0.333 3.94 4.53 4.53 3.98 3.84 4.26
0.667 2.74 3.02 2.54 2.41 2.24 2.87 1 1.93 1.65 1.39 1.45 1.68 1.49
1.5 0.67 0.80 0.54 0.85 0.59 0.43 2 0.29 0.37 0.36 0.22 0.29 0.33
2.5 0.09 0.12 0.11 0.11 0.08 0.13
TABLE-US-00029 TABLE 18 Pirfenidone Pharmacokinetics and Heart
Tissue Distribution - Co-Solvent-Based Formulation Study (Dosing
group formulations listed in Table 9) Group 1 Group 2 Group 3 Group
4 Group 5 Group 6 Time Mean Mean Mean Mean Mean Mean Analyte (hr)
.mu.g/gram .mu.g/gram .mu.g/gram .mu.g/gram .mu.g/gram .mu.g/gram
PIRFENIDONE 0 0.00 0.05 NOT TESTED 0.02 0.0667 1.97 1.48 1.58 0.167
1.23 1.02 1.24 0.333 0.96 0.78 0.86 0.667 0.45 0.55 0.55 1 0.35
0.27 0.31 1.5 0.15 0.17 0.09 2.5 0.02 0.03 0.03
TABLE-US-00030 TABLE 19 Pirfenidone Pharmacokinetics and Kidney
Tissue Distribution - Co-Solvent-Based Formulation Study (Dosing
group formulations listed in Table 9) Group 1 Group 2 Group 3 Group
4 Group 5 Group 6 Time Mean Mean Mean Mean Mean Mean Analyte (hr)
.mu.g/gram .mu.g/gram .mu.g/gram .mu.g/gram .mu.g/gram .mu.g/gram
PIRFENIDONE 0 0.00 0.13 NOT TESTED 0.08 0.0667 2.65 2.87 3.42 0.167
1.70 2.21 1.74 0.333 1.30 2.02 1.23 0.667 0.74 0.84 0.88 1 0.51
0.46 0.43 1.5 0.26 0.24 0.15 2.5 0.05 0.05 0.05
[0588] Results from the co-solvent effects tissue distribution
studies show that the presence of up to 8% ethanol with 16%
propylene glycol to change the tissue or plasma pharmacokinetic
profile compared to a 0.4% sodium chloride formulation. Further,
these results show a delayed appearance of 5-Carboxy-pirfenidone
(the primary pirfenidone liver metabolite). Comparing the initial
rapid elimination of pirfenidone from the lung tissue and parallel
appearance of pirfenidone in the plasma suggest that direct
pulmonary administration may be a good route for systemic
administration of pirfenidone. The delayed appearance of
5-Carboxy-pirfenidone metabolite supports this hypothesis in that
this metabolite serves as a marker for re-circulation of
pirfenidone to the lung and other tissues following direct aerosol
administration to the lung. Further, as suggested in Tables 15 and
16 and supported by the modeled data in FIG. 1 and Table 20,
re-circulated pirfenidone is likely important to support long-term,
elevated pirfenidone levels in the lung and other tissues of
potential efficacy.
[0589] To understand pirfenidone human lung tissue distribution and
associated pharmacokinetics following a 10-12 minute aerosol
administration from a nebulizer, measured rat pharmacokinetic and
lung tissue distribution data following bolus nebulizing catheter
administration was scaled. Briefly, using allometric scaling, rat
aerosol lung data and plasma delivery was scaled to humans. Rat
data was taken from Table 16 and 17. Allometric scaling used
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. July,
2005, and Caldwell et al., European Journal of Drug Metabolism and
Pharmacokinetics, 2004, Vol. 29, No. 2, pp. 133-143. For
comparative purposes, human plasma pharmacokinetic data resulting
from oral administration was taken directly Rubino et al., 2009.
For oral data, fed-state human data was used. To model plasma
pirfenidone pharmacokinetics where plasma pirfenidone was delivered
from aerosol administration, pharmacokinetics data from
fasting-state humans was used (Rubino et al., 2009). Inhaled
aerosol-derived plasma pirfenidone levels were calculated based
upon an assumed 100% bioavailability of inhaled,
respirable-deposited pirfenidone to a 5,000 mL total blood volume.
The contribution of plasma-derived pirfenidone (whether from oral
or aerosol inhalation dosing) to lung tissue distribution and
pharmacokinetics assumed at any given time 50% of plasma
pirfenidone was delivered to the lung tissue. By example, a plasma
level of 10 .mu.g/mL contributed 5 .mu.g/gram pirfenidone to the
lung tissue. Results of this analysis are shown in FIG. 1 and Table
20.
[0590] Aerosol deliver parameters based on Table 10 formulation
characterization in high-efficiency, mesh-based nebulizers (Tables
11-13). Respirable delivered dose (RDD) calculated by the product
of fine particle fraction (FPF, %<5 microns) and inhaled mass.
An about 110 mg RDD was calculated from a 5 mL device-loaded dose
of a 40 mg/mL pirfenidone formulation (200 mg loaded dose). The FPF
and inhaled mass were 85% and 67%, respectively. Inhaled mass was
calculated based upon breathing pattern. A 1:1
inhalation:exhalation breathing pattern (e.g. a 2 second inhalation
followed by a 2 second exhalation) using the eFlow device and
35-head is predicted to produce an inhaled mass of about 67%. From
this, a 2:1 breathing pattern (e.g., a 4 second inhalation followed
by a 2 second exhalation) may produce an inhaled mass between about
74% and about 80%. Using the inhaled mass of 74% and the FPF of
85%, a 200 mg device-loaded dose may produce an RDD of about 125
mg. Similarly, the inhaled mass of 80% may produce an RDD of about
136 mg from a 200 mg device-loaded dose. Continuing, a 3:1
breathing pattern (e.g., a 6 second inhalation followed by a 2
second exhalation) may produce an inhaled mass between about 80%
and about 87%. Using the inhaled mass of 87% and the FPF of 85%, a
200 mg device-loaded dose may produce an RDD of about 148 mg. In
some embodiments, the RDD may be further increased or decreased by
additional means: by non-limiting example, changing the
device-loaded volume and/or changing the formulation pirfenidone
concentration. In some embodiments, increasing the formulation
concentration to 50 mg/mL and using the 5 mL device-loaded volume
will provide a 250 mg device-loaded dose. Using the FPF of 85% and
inhaled mass of about 67%, a 250 mg device-loaded dose may produce
an RDD of about 142 mg, a 74% inhaled mass may produce an RDD of
about 157 mg, a 80% inhaled mass may produce an RDD of about 170
mg, and a 87% inhaled mass may produce an RDD of about 185 mg.
Additional dose escalations are possible with increased co-solvent
addition to the pirfenidone formulation. Similarly, dose
de-escalations are possible with reduced device-loaded dose
(reduced volume and/or reduced pirfenidone formulation
concentration) and/or less-efficient breathing pattern. While
allometric scaling is an established means to predict
pharmacokinetic parameters and dose scaling between animals and
humans, precedent exists that supports human-inhaled therapies
remaining in the lung significantly longer than the duration
predicted by allometric scaling. This possibility may also result
in longer lung pirfenidone residence time and may also translate to
reduced plasma exposure.
TABLE-US-00031 TABLE 20 Modeled human pirfenidone pharmacokinetics
and tissue distribution. Aerosol (RDD.sup.a) Oral (801 mg) 110 mg
154 mg 185 mg Fed-State Fasted-State Parameter LT P LT P LT P LT P
LT P Cmax.sup.b 57.5 17.7 71.2 24.8 85.8 30.0 3.9 7.9 7.1 14.2
AUC.sup.c 43.4 68.9 61.0 96.8 75.1 118.3 22.1 58.9 33.9 67.7
TOE.sup.d 8.7 -- 9.9 -- 10.4 -- 10.4 -- 10.0 -- T.sub.1/2 alpha
(min) 5 -- 5 -- 5 -- -- -- -- -- T.sub.1/2 beta (hr).sup.e 2.5 2.5
2.5 2.5 2.5 2.5 2.4 2.4 2.5 2.5 T.sub.1/2 Absorption -- 0.1 -- 0.1
-- 0.1 -- 1.8 -- 0.4 (hr).sup.f LT = lung tissue; P = plasma.
.sup.aRDD: respirable delivered dose = fine particle fraction (FPF;
% particles <5 microns) X inhaled mass .sup.bCmax: Lung tissue =
microgram/gram; plasma = microgram/mL .sup.cAUC: Expressed as AUC
over 0-18 hours, Lung tissue in mg hr/kg and plasma expressed in mg
hr/L. .sup.dTOE: Time of exposure measured as minutes over 1
microgram/gram lung tissue .sup.eT.sub.1/2 beta: Lung tissue
pirfenidone levels and associated beta phase lung tissue T.sub.1/2
derived solely from plasma-pirfenidone and hence, plasma
pirfenidone T.sub.1/2. Aerosol = Rubino et al., 2009 fasted-state;
Oral = Rubino et al., 2009 .sup.fT.sub.1/2 absorption: Aerosol =
modeled from allometrically-scaled bolus aerosol rat data; Oral =
Rubino et al., 2009.
[0591] 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.
* * * * *