U.S. patent application number 16/576487 was filed with the patent office on 2020-05-21 for cromolyn compositions for treatment of chronic cough due to idiopathic pulmonary fibrosis.
This patent application is currently assigned to Respivant Sciences GmbH. The applicant listed for this patent is Respivant Sciences GmbH. Invention is credited to William Gerhart, Pravin Soni, Ahmet Tutuncu.
Application Number | 20200155452 16/576487 |
Document ID | / |
Family ID | 61301476 |
Filed Date | 2020-05-21 |
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United States Patent
Application |
20200155452 |
Kind Code |
A1 |
Soni; Pravin ; et
al. |
May 21, 2020 |
Cromolyn Compositions for Treatment of Chronic Cough Due to
Idiopathic Pulmonary Fibrosis
Abstract
The disclosure provides a method of treating chronic cough in a
subject having idiopathic pulmonary fibrosis (IPF) comprising
administering to the subject a pharmaceutical composition
comprising from about 2% by weight to about 6% by weight of
cromolyn sodium and an ionic osmotic agent with a nebulizer.
Inventors: |
Soni; Pravin; (Sunnyvale,
CA) ; Gerhart; William; (Del Mar, CA) ;
Tutuncu; Ahmet; (Del Mar, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Respivant Sciences GmbH |
Basel |
|
CH |
|
|
Assignee: |
Respivant Sciences GmbH
Basel
CH
|
Family ID: |
61301476 |
Appl. No.: |
16/576487 |
Filed: |
September 19, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16277689 |
Feb 15, 2019 |
10463613 |
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16576487 |
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15887830 |
Feb 2, 2018 |
10265267 |
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16277689 |
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PCT/US2017/049205 |
Aug 29, 2017 |
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15887830 |
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62417898 |
Nov 4, 2016 |
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62381914 |
Aug 31, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 37/08 20180101;
A61K 9/008 20130101; A61K 9/0075 20130101; A61K 31/35 20130101;
A61K 47/183 20130101; A61K 31/352 20130101; A61M 11/005 20130101;
A61P 11/14 20180101; A61P 11/00 20180101; A61K 9/0078 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61P 37/08 20060101 A61P037/08; A61K 31/35 20060101
A61K031/35; A61P 11/00 20060101 A61P011/00; A61K 31/352 20060101
A61K031/352; A61K 47/18 20060101 A61K047/18; A61P 11/14 20060101
A61P011/14 |
Claims
1.-30. (canceled)
31. A method of reducing chronic cough in a subject having
idiopathic pulmonary fibrosis, comprising administering to the
subject a therapeutically effective amount of a pharmaceutical
composition comprising cromolyn, or a pharmaceutically acceptable
salt thereof; with an inhalation device; wherein the subject has
been diagnosed as having idiopathic pulmonary fibrosis prior to
administration of the pharmaceutical composition; and wherein the
24 hour cough count decreases by about 10% to about 80%, relative
to a baseline cough count.
32. The method of claim 31, wherein the 24 hour cough count
decreases by about 10% to about 70%, relative to a baseline cough
count.
33. The method of claim 31, wherein the 24 hour cough count
decreases by about 10% to about 60%, relative to a baseline cough
count.
34. The method of claim 31, wherein the 24 hour cough count
decreases by about 10% to about 50%, relative to a baseline cough
count.
35. The method of claim 31, wherein the 24 hour cough count
decreases by about 10% to about 40%, relative to a baseline cough
count.
36. The method of claim 31, wherein the 24 hour cough count
decreases by about 10% to about 30%, relative to a baseline cough
count.
37. The method of claim 31, wherein the 24 hour cough count
decreases by about 10% to about 20%, relative to a baseline cough
count.
38. The method of claim 31, wherein the inhalation device is a
nebulizer or a dry powder inhaler.
39. The method of claim 38, wherein the inhalation device is a
nebulizer.
40. The method of claim 39, wherein the nebulizer is a jet
nebulizer.
41. The method of claim 39, wherein the nebulizer is a
high-efficiency nebulizer.
42. The method of claim 41, wherein the high-efficiency nebulizer
is a vibrating mesh nebulizer.
43. The method of claim 38, wherein the inhalation device is a dry
powder inhaler.
44. The method of claim 31, wherein the composition comprises a
pharmaceutically acceptable salt of cromolyn.
45. The method of claim 44, wherein the composition comprises
cromolyn sodium.
46. The method of claim 31, wherein the pharmaceutical composition
comprises between about 2% and about 99% by weight of a
pharmaceutically acceptable salt of cromolyn.
47. The method of claim 46, wherein the composition comprises
comprises between about 2% and about 99% by weight cromolyn
sodium.
48. The method according to claim 31, wherein the pharmaceutical
composition is administered to the subject from once per day to
five times per day.
49. The method according to claim 31, wherein the pharmaceutical
composition is administered to the subject three times per day.
50. The method of claim 38, wherein administration of the
pharmaceutical composition to the subject with the inhalation
device provides in the subject a bioavailability of cromolyn
between about 5% and about 60%.
51. The method of claim 38, wherein each of the doses of the
pharmaceutical composition comprises from about 10 mg to about 80
mg of cromolyn sodium, and administration of the pharmaceutical
composition provides in the subject an AUC.sub.(0-.infin.) of the
cromolyn sodium of between about 100 ng*hr/mL and about 500
ng*hr/mL.
52. The method of claim 38, wherein each of the doses of the
pharmaceutical composition comprises from about 20 mg to about 80
mg of cromolyn sodium, and administration of the pharmaceutical
composition provides in the subject a Cmax of the cromolyn sodium
between about 50 ng/mL and about 230 ng/mL.
53. The method of claim 38, wherein the nebulizer produces an
aerosol of the pharmaceutical composition that exhibits a
respirable fraction (.ltoreq.5 .mu.m) as measured by USP
<1601> of between about 60% and about 90%.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation Application of U.S.
application Ser. No. 15/887,830 filed on Feb. 2, 2018, which is a
Continuation Application of PCT/US17/49205, filed on Aug. 29, 2017
which claims the priority benefit of U.S. provisional application
No. 62/381,914, filed on Aug. 31, 2016, and 62/417,898, filed on
Nov. 4, 2016, each of which is incorporated by reference herein in
their entirety.
FIELD OF THE DISCLOSURE
[0002] The disclosure is directed to the field of medicine and, in,
particular the use of compositions comprising cromolyn for the
treatment of chronic cough due to idiopathic pulmonary
fibrosis.
BACKGROUND
[0003] There has been a long-felt but unmet need in the art for an
effective treatment of chronic cough due to idiopathic pulmonary
fibrosis (IPF), as the majority of individuals with condition are
unresponsive to currently available treatment. The disclosure
provides a solution to this long-felt but unmet need.
SUMMARY
[0004] The disclosure provides compositions and methods for the
treatment of chronic cough due to IPF. Subjects treated with the
compositions and formulations provided in the disclosure
demonstrate a statistically significant and medically relevant
improvement in objective cough rates after 14 days of treatment
compared to those subjects who received a placebo. These subjects
had refractory chronic cough associated with IPF and are unable to
find relief with the currently-available treatments (not including
the compositions or methods disclosed herein).
[0005] Specifically, the disclosure provides a method of treating
chronic cough in a subject having idiopathic pulmonary fibrosis
(IPF) comprising administering to the subject a pharmaceutical
composition comprising from about 1% by weight to about 10% by
weight of cromolyn sodium and an ionic osmotic agent with a
nebulizer. In certain embodiments, the pharmaceutical composition
comprises about 1%, about 2%, about 3%, about 4%, about 5%, about
6%, about 7%, about 8%, about 9%, or about 10% by weight of
cromolyn sodium. In certain embodiments, the pharmaceutical
composition comprises about 2% by weight of cromolyn sodium. In
certain embodiments, the pharmaceutical composition comprises about
4% by weight of cromolyn sodium. In certain embodiments, the
pharmaceutical composition comprises about 6% by weight of cromolyn
sodium.
[0006] The disclosure provies a pharmaceutically acceptable aerosol
for the treatment of chronic cough in a subject having idiopathic
pulmonary fibrosis (IPF), comprising droplets of an aqueous
solution comprising (i) from about 2% to about 6% by weight of
cromolyn sodium and (ii) an osmolarity adjusting agent comprising
(a) between about 0.1% and about 0.5% by weight of sodium chloride,
inclusive of the endpoints, and (b) optionally salts of
ethylenediaminetetraacetic acid (EDTA), wherein said aerosol has a
respirable fraction (.ltoreq.3.3 .mu.m) as measured by USP
<1601> of at least about 30%, and wherein said treatment of
said chronic cough in said subject is achieved via delivery of a
therapeutically effective amount of cromolyn sodium to the lungs of
the subject by said subject orally inhaling said pharmaceutically
acceptable aerosol.
[0007] The disclosure provides a pharmaceutically acceptable
aerosol for the treatment of chronic cough in a subject having
idiopathic pulmonary fibrosis (IPF), consisting of droplets of an
aqueous solution consisting of (i) from about 2% to about 6% by
weight of cromolyn sodium and (ii) an osmolarity adjusting agent
consisting of (a) between about 0.1% and about 0.5% by weight of
sodium chloride, inclusive of the endpoints, and (b) optionally
salts of ethylenediaminetetraacetic acid (EDTA), wherein said
aerosol has a respirable fraction (.ltoreq.3.3 .mu.m) as measured
by USP <1601> of at least about 30%, and wherein said
treatment of said chronic cough in said subject is achieved via
delivery of a therapeutically effective amount of cromolyn sodium
to the lungs of the subject by said subject orally inhaling said
pharmaceutically acceptable aerosol.
[0008] The disclosure provides a pharmaceutically acceptable
solution, comprising from about 1% to about 10% by weight of
cromolyn sodium and an osmotic agent, wherein an aerosol created
from the pharmaceutically acceptable solution is suitable for
inhalation by a subject having chronic cough due to idiopathic
pulmonary fibrosis. In certain embodiments, the aerosol has a
respirable fraction (.ltoreq.3.3 .mu.m) as measured by USP
<1601> of at least about 30%. In certain embodiments, the
aerosol has a respirable fraction (.ltoreq.3.3 .mu.m) as measured
by USP <1601> of at least about 30% and a respirable fraction
(.ltoreq.5 .mu.m) as measured by USP <1601> of at least about
75%.
[0009] The disclosure provides a dosage form for the treatment of
chronic cough in a subject having idiopathic pulmonary fibrosis
(IPF) comprising: [0010] (a) an aqueous pharmaceutical composition
comprising (i) from about 2% to about 6% by weight of cromolyn
sodium, and (ii) an osmolarity adjusting agent consisting of (A)
between about 0.1% to about 0.5% sodium chloride, inclusive of the
endpoints; and (B) optionally salts of EDTA; and (b) an inhalation
device that forms an aerosol of said pharmaceutical composition,
said aerosol exhibiting a respirable fraction of said
pharmaceutical composition (.ltoreq.5 .mu.m) as measured by USP
<1601> of at least about 60%. In certain embodiments, the
pharmaceutical composition further comprises purified water and
sodium EDTA. In certain embodiments, the pharmaceutical composition
comprises from about 5 mg to about 80 mg of cromolyn sodium. In
certain embodiments, the pharmaceutical composition comprises from
about 36 mg to about 44 mg of cromolyn sodium. In certain
embodiments, the aerosol has a respirable fraction (.ltoreq.3.3
.mu.m) as measured by USP <1601> of at least about 30%. In
certain embodiments, the aerosol has a respirable fraction
(.ltoreq.3.3 .mu.m) as measured by USP <1601> of at least
about 30% and a respirable fraction (.ltoreq.5 .mu.m) as measured
by USP <1601> of at least about 75%. In certain embodiments,
wherein the osmolarity adjusting agent consists of between 0.1% to
0.2% sodium chloride, inclusive of the endpoints.
[0011] The terms pharmaceutical composition, composition, solution,
and formulation are used interchangeably throughout the
disclosure.
[0012] In certain embodiments of the compositions and formulations
of the disclosure, the ionic osmotic agent may comprise or consist
of an ionic osmotic agent. In certain embodiments of the
compositions and formulations of the disclosure, the ionic osmotic
agent may comprise or consist of sodium chloride. The ionic osmotic
agent of the compositions of the disclosure may comprise between
0.1% and 0.7%, by weight, of the composition, inclusive of the
endpoints. In certain embodiments, the compositions of the
disclosure may comprise between 0.1% and 0.2%, by weight of the
composition, of the ionic osmotic agent inclusive of the endpoints.
In certain embodiments, the compositions of the disclosure may
comprise 0.2%, by weight, of the composition, of the ionic osmotic
agent.
[0013] Compositions and formulations of the disclosure may further
comprise a chelating agent. In certain embodiments, the chelating
agent may comprise about 0.01%, or about 0.02%, or about 0.03%, or
about 0.04%, or about 0.05%, or about 0.06%, or about 0.07%, or
about 0.08%, or about 0.09%, or about 0.1%, or about 0.2%, or about
0.3%, or about 0.4%, or about 0.5%, or about 0.6%, or about 0.7%,
or about 0.8% or about 0.9%, or about 1% by weight, of the
composition. In certain embodiments, the chelating agent comprises
ethylenediaminetetraacetic acid (EDTA), sodium-EDTA, or sodium
citrate. In certain embodiments, the chelating agent comprises
EDTA. In certain embodiments, the chelating agent comprises
sodium-EDTA. In certain embodiments, the chelating agent comprises
sodium citrate.
[0014] Compositions and formulations of the disclosure may further
comprise a non-ionic osmotic agent, preferably, wherein the
non-ionic osmotic agent comprises or consists of mannitol.
[0015] Compositions and formulations of the disclosure may exclude,
or, may not comprise a non-ionic osmotic agent. In certain
embodiments, compositions of the disclosure may not comprise a
non-ionic osmotic agent comprising or consisting of mannitol, a
sugar alcohol and/or propylene glycol. In certain embodiments,
compositions of the disclosure do not comprise propylene glycol,
regardless of any potential functional role of the propylene
glycol.
[0016] Compositions and formulations of the disclosure may exclude,
or, may not comprise a non-ionic osmotic agent. In certain
embodiments, compositions of the disclosure may not comprise a
non-ionic osmotic agent comprising or consisting of mannitol, any
other sugar alcohol and/or propylene glycol. In certain
embodiments, compositions of the disclosure do not comprise
mannitol, any other sugar alcohol and/or propylene glycol,
regardless of any potential functional role, chemical property or
use of mannitol, any other sugar alcohol and/or propylene glycol
known to those of ordinary skill in the art.
[0017] Compositions and formulations of the disclosure may have a
surface tension effective for deposition, penetration or retention
of the composition primarily in the peripheral lung regions,
including the bronchioles and alveoli. In certain embodiments, the
compositions and formulations of the disclosure may have a surface
tension in the range similar to that or water or higher. In certain
embodiments, the compositions and formulations according to the
present disclosure has a surface tension of at least about 30 mN/m,
or at least about 40 mN/m, or at least about 50 mN/m, or at least
about 60 mN/m, or at least about 70 mN/m, such as in the range of
about 30 mN/m to about 75 mN/m, or about 50 mN/m to about 75 mN/m,
or about 70 mN/m to about 75 mN/m.
[0018] Compositions and formulations of the disclosure may exclude,
or, may not comprise a surfactant. In certain embodiments,
compositions of the disclosure may not comprise any dispersing
agent, solubilizing agent, or spreading agent. Some examples of
surfactants that are excluded from the present compositions and
formulations include: PEG (polyethylene glycol) 400; Sodium lauryl
sulfate sorbitan laurate, sorbitan palmitate, sorbitan stearate
available under the tradename Span.RTM. (20-40-60 etc.);
polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20)
sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate
available under the tradename Tween (polysorbates, 20-40-60 etc.);
tyloxapol; propylene glycol; and Benzalkoniumrn chloride,
vitamin-TPGS and lecithins, (Exosurf.RTM., GlaxoSmithKline),
surfactant proteins. In certain embodiments, surfactants that are
excluded from the present compositions and formulations include any
compound or agent that lowers the surface tension of a
composition.
[0019] Compositions and formulations of the disclosure may further
comprise purified water for injection. The amount of the water may
vary depending upon, for example, a fill volume required for the
particular high-efficiency nebulizer used. In certain embodiments,
compositions of the disclosure comprise purified water for
injection in a quantum sufficiat (q.s.).
[0020] Compositions and formulations of the disclosure may have an
osmolality of between about 100 mOsm/kg and about 200 mOsm/kg,
inclusive of the endpoints. Compositions and formulations of the
disclosure may have an osmolality of between about 125 mOsm/kg and
about 135 mOsm/kg, inclusive of the endpoints. Compositions and
formulations of the disclosure may have an osmolality of between
about 100 mOsm/kg and about 125 mOsm/kg, inclusive of the
endpoints. Compositions and formulations of the disclosure may have
an osmolality of between about 100 mOsm/kg and about 135 mOsm/kg,
inclusive of the endpoints. Compositions and formulations of the
disclosure may have an osmolality of about 100 mOsm/kg.
Compositions and formulations of the disclosure may have an
osmolality of about 125 mOsm/kg. Compositions and formulations of
the disclosure may have an osmolality of about 135 mOsm/kg.
Compositions and formulations of the disclosure may have an
osmolality of about 200 mOsm/kg.
[0021] Compositions and formulations of the disclosure may be in
the form of a solution having a fill volume of about 0.1 mL to
about 5 mL. Compositions and formulations of the disclosure may be
in the form of an aqeuous solution having a fill volume of about
0.1 mL, about 0.5 mL, about 1 mL, about 1.5 mL, about 2 mL, about
2.5 mL, about 3 mL, about 3.5 mL, about 4 mL, about 4.5 mL, or
about 5 mL.
[0022] Compositions and formulations of the disclosure may comprise
from about 5 mg to about 80 mg of cromolyn sodium, inclusive of the
endpoints. Compositions and formulations of the disclosure may
comprise from about 36 mg to about 44 mg of cromolyn sodium,
inclusive of the endpoints.
[0023] Nebulizers administering a composition or formulation of the
disclosure may provide an aerosol having a respirable fraction
.ltoreq.3.3 .mu.m as measured by USP <1601> of at least about
30% and a respirable fraction .ltoreq.5 .mu.m as measured by USP
<1601> of at least about 65%. Nebulizers administering a
composition or formulation of the disclosure may provide an aerosol
having a respirable fraction .ltoreq.3.3 .mu.m as measured by USP
<1601> of at least about 45% and a respirable fraction
.ltoreq.5 .mu.m as measured by USP <1601> of at least about
75%.
[0024] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure with a nebulizer
may result in primarily lung deposition, and minimal deposition in
other respiratory tracts, of the administered aerosol. In certain
embodiments, sedimentation is the major mechanism of deposition of
the aerosol. In certain embodiments, administration of
pharmaceutical compositions of the disclosure with a nebulizer
provides a lung deposition (deposited lung dose) of 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%, about 20% to
about 40%, about 25% to about 35%, about 25% to about 30%, about
25% to about 75%, about 30% to about 50%, about 35% to about 90%,
about 40% to about 80%, about 40% to about 60%, about 50% to about
60%, about 50% to about 70%, or about 60% to about 75% based on the
nominal dose of the composition.
[0025] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure with a nebulizer
may produce in the subject an AUC.sub.(0-.infin.) of the cromolyn
sodium greater than about 150 ng*hr/mL, a C.sub.max of the cromolyn
sodium greater than about 50 ng/mL, and a deposited lung dose of
cromolyn sodium greater than about 4 mg. According to the methods
of the disclosure, administration of pharmaceutical compositions of
the disclosure with a nebulizer may produce in the subject an
AUC.sub.(0-.infin.) of the cromolyn sodium greater than about 175
ng*hr/mL, a C.sub.max of the cromolyn sodium greater than about 60
ng/mL, and a deposited lung dose of the cromolyn sodium greater
than about 4 mg. According to the methods of the disclosure,
administration of pharmaceutical compositions of the disclosure
with a nebulizer may produce in the subject an AUC.sub.(0-.infin.)
of the cromolyn sodium greater than about 100 ng*hr/mL, a C.sub.max
of the cromolyn sodium greater than about 40 ng/mL, and a deposited
lung dose of the cromolyn sodium greater than about 4 mg.
[0026] Lung Deposited Percentage
[0027] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
40 mg of cromolyn sodium with a nebulizer may produce in a subject
an AUC.sub.(0-.infin.) of the cromolyn sodium that is between about
120 ng*hr/mL and about 350 ng*hr/mL.
[0028] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
40 mg of cromolyn sodium with a nebulizer may produce in a subject
an AUC.sub.(0-.infin.) of the cromolyn sodium that is within 80% to
125% of about 340 ng*hr/mL.
[0029] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
40 mg of cromolyn sodium with a nebulizer may produce in a subject
an AUC.sub.(0-6) of the cromolyn sodium that is between about 120
ng*hr/mL and about 350 ng*hr/mL.
[0030] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
40 mg of cromolyn sodium with a nebulizer may produce in a subject
an AUC.sub.(0-6) of the cromolyn sodium that is within 80% to 125%
of about 237 ng*hr/mL.
[0031] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
40 mg of cromolyn sodium with a nebulizer may produce in a subject
a C.sub.max of the cromolyn sodium of between about 40 ng/mL and
about 150 ng/mL.
[0032] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
40 mg of cromolyn sodium with a nebulizer may produce in a subject
a C.sub.max of the cromolyn sodium that is within 80% to 125% of
about 85 ng/mL, or about 75 ng/mL, or about 82 ng/mL, or about 93
ng/mL.
[0033] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
60 mg of cromolyn sodium with a nebulizer may produce in a subject
an AUC.sub.(0-.infin.) of the cromolyn sodium that is between about
250 ng*hr/mL and about 1000 ng*hr/mL.
[0034] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
60 mg of cromolyn sodium with a nebulizer may produce in a subject
an AUC.sub.(0-.infin.) of the cromolyn sodium that is within 80% to
125% of about 542 ng*hr/mL.
[0035] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
60 mg of cromolyn sodium with a nebulizer may produce in a subject
an AUC.sub.(0-6) of the cromolyn sodium that is between about 200
ng*hr/mL and about 700 ng*hr/mL.
[0036] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
60 mg of cromolyn sodium with a nebulizer may produce in a subject
an AUC.sub.(0-6) of the cromolyn sodium that is within 80% to 125%
of about 389 ng*hr/mL.
[0037] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
60 mg of cromolyn sodium with a nebulizer may produce in a subject
a C.sub.max of the cromolyn sodium of between about 50 ng/mL and
about 250 ng/mL.
[0038] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
60 mg of cromolyn sodium with a nebulizer may produce in a subject
C.sub.max of the cromolyn sodium that is within 80% to 125% of
about 134 ng/mL, or about 119 ng/mL, or about 148 ng/mL, or about
157 ng/mL.
[0039] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
80 mg of cromolyn sodium with a nebulizer may produce in a subject
an AUC.sub.(0-.infin.) of the cromolyn sodium that is between about
300 ng*hr/mL and about 800 ng*hr/mL.
[0040] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
80 mg of cromolyn sodium with a nebulizer may produce in a subject
an AUC.sub.(0-.infin.) of the cromolyn sodium that is within 80% to
125% of about 526 ng*hr/mL.
[0041] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
80 mg of cromolyn sodium with a nebulizer may produce in a subject
a C.sub.max of the cromolyn sodium of between about 90 ng/mL and
about 450 ng/mL.
[0042] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure with a dry powder
inhaler may produce in the subject an AUC.sub.(0-.infin.) of the
cromolyn sodium greater than about 150 ng*hr/mL, a C.sub.max of the
cromolyn sodium greater than about 50 ng/mL, and a deposited lung
dose of cromolyn sodium greater than about 4 mg.
[0043] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure with a nebulizer
may produce in the subject an AUC.sub.(0-.infin.) of the cromolyn
sodium greater than about 175 ng*hr/mL, a C.sub.max of the cromolyn
sodium greater than about 60 ng/mL, and a deposited lung dose of
the cromolyn sodium greater than about 4 mg.
[0044] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure with a nebulizer
may produce in the subject an AUC.sub.(0-.infin.) of the cromolyn
sodium greater than about 100 ng*hr/mL, a C.sub.max of the cromolyn
sodium greater than about 40 ng/mL, and a deposited lung dose of
the cromolyn sodium greater than about 4 mg.
[0045] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
40 mg of cromolyn sodium with a dry powder inhaler may produce in a
subject an AUC.sub.(0-.infin.) of the cromolyn sodium that is
between about 120 ng*hr/mL and about 350 ng*hr/mL.
[0046] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
40 mg of cromolyn sodium with a dry powder inhaler may produce in a
subject an AUC.sub.(0-.infin.) of the cromolyn sodium that is
within 80% to 125% of about 340 ng*hr/mL.
[0047] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
40 mg of cromolyn sodium with a dry powder inhaler may produce in a
subject an AUC.sub.(0-6) of the cromolyn sodium that is between
about 120 ng*hr/mL and about 350 ng*hr/mL.
[0048] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
40 mg of cromolyn sodium with a dry powder inhaler may produce in a
subject an AUC.sub.(0-6) of the cromolyn sodium that is within 80%
to 125% of about 237 ng*hr/mL.
[0049] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
40 mg of cromolyn sodium with a dry powder inhaler may produce in a
subject a Cma of the cromolyn sodium of between about 40 ng/mL and
about 150 ng/mL.
[0050] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
40 mg of cromolyn sodium with a dry powder inhaler may produce in a
subject a C.sub.max of the cromolyn sodium that is within 80% to
125% of about 85 ng/mL, or about 75 ng/mL, or about 82 ng/mL, or
about 93 ng/mL.
[0051] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
60 mg of cromolyn sodium with a dry powder inhaler may produce in a
subject an AUC.sub.(0-.infin.) of the cromolyn sodium that is
between about 250 ng*hr/mL and about 1000 ng*hr/mL.
[0052] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
60 mg of cromolyn sodium with a dry powder inhaler may produce in a
subject an AUC.sub.(0-.infin.) of the cromolyn sodium that is
within 80% to 125% of about 542 ng*hr/mL.
[0053] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
60 mg of cromolyn sodium with a dry powder inhaler may produce in a
subject an AUC.sub.(0-6) of the cromolyn sodium that is between
about 200 ng*hr/mL and about 700 ng*hr/mL.
[0054] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
60 mg of cromolyn sodium with a dry powder inhaler may produce in a
subject an AUC.sub.(0-6) of the cromolyn sodium that is within 80%
to 125% of about 389 ng*hr/mL.
[0055] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
60 mg of cromolyn sodium with a dry powder inhaler may produce in a
subject a Cma of the cromolyn sodium of between about 50 ng/mL and
about 250 ng/mL.
[0056] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
60 mg of cromolyn sodium with a dry powder inhaler may produce in a
subject C.sub.max of the cromolyn sodium that is within 80% to 125%
of about 134 ng/mL, or about 119 ng/mL, or about 148 ng/mL, or
about 157 ng/mL.
[0057] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
80 mg of cromolyn sodium with a dry powder inhaler may produce in a
subject an AUC.sub.(0-.infin.) of the cromolyn sodium that is
between about 300 ng*hr/mL and about 800 ng*hr/mL.
[0058] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
80 mg of cromolyn sodium with a dry powder inhaler may produce in a
subject an AUC.sub.(0-.infin.) of the cromolyn sodium that is
within 80% to 125% of about 526 ng*hr/mL.
[0059] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
80 mg of cromolyn sodium with a dry powder inhaler may produce in a
subject a C.sub.max of the cromolyn sodium of between about 90
ng/mL and about 450 ng/mL.
[0060] According to the methods of the disclosure, administration
of pharmaceutical compositions of the disclosure comprising about
80 mg of cromolyn sodium with a dry powder inhaler may produce in a
subject a C.sub.max of the cromolyn sodium that is within 80% to
125% of about 236 ng/mL.
[0061] According to the methods of the disclosure, in certain
embodiments, the pharmaceutical composition is administered daily.
In certain embodiments, the pharmaceutical composition is
administered once per day. In certain embodiments, the
pharmaceutical composition is administered twice per day. In
certain embodiments, the pharmaceutical composition is administered
three times per day. In certain embodiments, the pharmaceutical
composition is administered four times per day. In certain
embodiments, the pharmaceutical composition is administered five
times per day.
[0062] According to the methods of the disclosure, in certain
embodiments, the pharmaceutical composition is administered three
times per day for at least 7 days. In certain embodiments, the
pharmaceutical composition is administered three times per day for
at least 14 days. In certain embodiments, the pharmaceutical
composition is administered three times per day as a daily
maintenance therapy (e.g. at least 7 or at least 14 days without a
limit for the total length of treatment).
[0063] According to the methods of the disclosure, in certain
embodiments, the pharmaceutical composition may be administered as
a combination therapy with any other therapeutic composition for
the treatment of chronic cough associated or due to a diagnosis of
IPF in a subject.
BRIEF DESCRIPTION OF THE DRAWINGS
[0064] FIG. 1 is a series of graphs showing the average number of
daytime coughs for each subject in Example 1 following treatment
with either PA101 or with one of two placebo treatments.
[0065] FIG. 2 is a series of graphs showing the total number of
daytime coughs for each subject in Example 1 following treatment
with either PA101 or with one of two placebo treatments.
[0066] FIG. 3 is a graph depicting pulmonary function (measured as
Forced Expiratory Volume in One Second (FEV1)) as a function of
time for each of the treatment groups described in Example 1.
[0067] FIG. 4 is a schematic diagram of the design of the Phase II
study described in Example 4.
[0068] FIG. 5 is a graph showing the average number of daytime
coughs (coughs/hour) as a function of time in both placebo-treated
(n=21) and PA101-treated subjects (n=23) at baseline, Day 7, and
Day 14 of the study described in Example 4. The average number of
daytime coughs per hour is a primary efficacy endpoint of this
phase II study.
[0069] FIG. 6 is a graph showing the mean change from baseline of
the average number of daytime coughs per hour as a function of time
in both placebo-treated and PA101-treated subjects at baseline, Day
7, and Day 14 of the study described in Example 4. At Day 7 and Day
14, the mean change from baseline in the PA101-treated group (the
closed circles) was statistically significant (p=0.03). At Day 14,
the mean change from baseline in the PA101-treated group (the
closed circles) was statistically significant (p=0.04).
[0070] FIG. 7 is a pair of graphs demonstrating a placebo-adjusted
reduction in cough (left-hand graph), expressed as a percent change
from baseline in the daytime average cough/hour at Day 14 for
placebo versus PA101-treated subjects of the study described in
Example 4 and a PA101/placebo LS mean ratio (95% CI) for this
reduction in cough (right-hand graph), expressed as a change in the
log transformed daytime average cough/hour at Day 14 for placebo
versus PA101-treated subjects of the study described in Example 4.
At Day 14, the change in the log transformed daytime average
cough/hour in the PA101-treated group was statistically significant
(p=0.02).
[0071] FIG. 8 is a graph showing the PA101/placebo LS mean ratio
(95% CI) for the reduction in daytime cough in PA101-treated
subjects at Days 7 and 14 (see Example 4). At Day 7, the change in
the log transformed daytime average cough/hour in the PA101-treated
group was statistically significant (p=0.03). At Day 14, the change
in the log transformed daytime average cough/hour in the
PA101-treated group was statistically significant (p=0.02).
[0072] FIG. 9 is a pair of graphs depicting the average daytime
coughs per hour for each subject in each of the placebo and PA101
treated groups at either baseline or day 14 of the study described
in Example 4.
[0073] FIG. 10 is a graph providing the results of a responder
analysis for daytime cough, expressed as the percentage (%) of
subjects in the study described in Example 4 who experienced a
percentage (%) reduction in daytime average coughs/hour compared to
baseline. Greater than 30% responders: n=8 with PA101 (3 subjects
concomitantly taking one or more other IPF treatments vs. 5
subjects without conconmitant administration of one or more other
IPF treatments) and n=4 with placebo (1 subject concomitantly
taking one or more other IPF treatments vs. 3 subjects without
concomitant administration of one or more other IPF treatments). By
"conconmitantly taking" or "conconmitant administration" is meant
that a particular subject is being administered one or more other
IPF treatments, such as pirfenidone or nintedanib esylate while
being administered at least one formulation disclosed herein that
comprises cromolyn sodium.
[0074] FIG. 11 is a graph providing the results of a responder
analysis for 24-hour cough, expressed as the percentage (%) of
subjects in the study described in Example 4 who experienced a
percentage (%) reduction in 24-hour average coughs/hour compared to
baseline. Greater than 30% responders: n=8 with PA101 (3 subjects
concomitantly taking one or more other IPF treatments vs. 5
subjects without conconmitant administration of one or more other
IPF treatments) and n=4 with placebo (1 subject concomitantly
taking one or more other IPF treatments vs. 3 subjects without
conconmitant administration of one or more other IPF treatments).
By "conconmitantly taking" or "conconmitant administration" is
meant that a particular subject is being administered one or more
other IPF treatments, such as pirfenidone or nintedanib esylate
while being administered at least one formulation disclosed herein
that comprises cromolyn sodium.
[0075] FIG. 12 is a graph showing the nighttime average coughs per
hour in (coughs/hour) as a function of time in both placebo-treated
and PA101-treated subjects at baseline, Day 7, and Day 14 of the
study described in Example 4. The average number of nighttime
coughs per hour is a secondary efficacy endpoint of this phase II
study.
[0076] FIG. 13 is a graph showing the mean change from baseline of
the average number of nighttime coughs per hour as a function of
time in both placebo-treated and PA101-treated subjects at Day 14
of the study described in Example 4.
[0077] FIG. 14 is a graph showing the average number of coughs
(coughs/hour) in a 24-hour period as a function of time in both
placebo-treated and PA101-treated subjects at baseline, Day 7, and
Day 14 of the study described in Example 4. The average number of
coughs per hour in a 24-hour period is a secondary efficacy
endpoint of this phase II study.
[0078] FIG. 15 is a graph demonstrating placebo-adjusted reduction
in coughs during a 24-hour period, expressed as a percent change
from baseline in the average coughs/hour during a 24-hour period at
Days 7 and 14 for placebo versus PA101-treated subjects of the
study described in Example 4.
[0079] FIG. 16 is a graph showing the PA101/placebo LS mean ratio
(95% CI) for the placebo-adjusted reduction in coughs, expressed as
a change in the log transformed average coughs/hour during a
24-hour period at Days 7 and 14 for placebo versus PA101-treated
subjects of the study described in Example 4. At Day 7, the change
in the log transformed average coughs/hour during a 24-hour period
in the PA101-treated group was statistically significant (p=0.016).
At Day 14, the change in the log transformed average coughs/hour
during a 24-hour period in the PA101-treated group was
statistically significant (p=0.025).
[0080] FIG. 17 is a pair of graphs demonstrating a placebo-adjusted
reduction in cough (left-hand graph), expressed as a percent change
from baseline in the 24-hour average cough/hour at Day 14 for
placebo versus PA101-treated subjects of the study described in
Example 4 and a PA101/placebo LS mean ratio (95% CI) for this
reduction in cough (right-hand graph), expressed as a change in the
log transformed 24-hour average cough/hour at Day 14 for placebo
versus PA101-treated subjects of the study described in Example 4.
At Day 14, the change in the log transformed 24-hour average
cough/hour in the PA101-treated group was statistically significant
(p=0.025).
[0081] FIG. 18 is a pair of graphs depicting a 24-hour cough
profile for a subject with chronic cough due to IPF receiving
either placebo or PAl01 as part of the Phase II study described in
Example 4.
[0082] FIG. 19 is a pair of graphs showing the results of the
Responder Analysis from Example 4. LCQ and VAS scores were compared
in Responders from this study at baseline and day 14 of treatment
with PA101.
[0083] FIG. 20 is a schematic diagram of the design of the study
described in Example 5.
[0084] FIG. 21 is a pair of graphs depicting the average daytime
coughs per hour for each subject in each of the placebo and PA101
treated groups at either baseline or day 14 of the study described
in Example 5.
[0085] FIG. 22 is a graph showing the average number of 24-hour
coughs (coughs/hour) as a function of time in both placebo-treated
and PA101-treated subjects at baseline, Day 7, and Day 14 of the
study described in Example 5. The average number of 24-hour coughs
per hour is a secondary efficacy endpoint of this phase II
study.
[0086] FIG. 23 is a graph showing the PA101/placebo LS mean ratio
(95% CI) for the reduction in daytime cough in PA101-treated
subjects at Days 7 and 14 (see Example 5). At Day 7, the change in
the log transformed daytime average cough/hour in the PA101-treated
group was statistically significant (p=0.038). At Day 14, the
change in the log transformed daytime average cough/hour in the
PA101-treated group was not statistically significant (p=0.33).
[0087] FIG. 24 is a graph providing the results of a responder
analysis for daytime cough, expressed as the percentage (%) of
subjects in the study described in Example 5 who experienced a
percentage (%) reduction in daytime average coughs/hour compared to
baseline.
[0088] FIG. 25 is a graph showing the PA101/placebo LS mean ratio
(95% CI) for the reduction in cough during a 24-hour period in
PA101-treated subjects at Days 7 and 14 (see Example 5).
[0089] FIG. 26 is a pair of graphs showing a Responder Analysis for
daytime average cough/hour for subjects with chronic cough due to
IPF (Example 4) versus subjects with chronic idiopathic cough (CIC)
(Example 5).
[0090] FIG. 27 is a pair of graphs showing a Responder Analysis for
24-hour average cough/hour for subjects with chronic cough due to
IPF (Example 4) versus subjects with chronic idiopathic cough (CIC)
(Example 5).
[0091] FIG. 28 is a graph showing the log transformed daytime
average cough/hour subjects with chronic cough due to IPF (Example
4) versus subjects with chronic idiopathic cough (CIC) (Example
5).
[0092] FIG. 29 is a graph showing the log transformed 24-hour
average cough/hour subjects with chronic cough due to IPF (Example
4) versus subjects with chronic idiopathic cough (CIC) (Example
5).
DETAILED DESCRIPTION
[0093] Compositions of the disclosure comprising cromolyn sodium
and an ionic osmotic agent are safe and efficacious for the
treatment of chronic cough due to IPF. Subjects treated with the
compositions and formulations provided in the disclosure
demonstrate a statistically significant and medically relevant
improvement in objective cough rates after 14 days of treatment
compared to those subjects who received a placebo. These subjects
had refractory chronic cough associated with IPF, each of them
unable to find relief with the currently-available treatments (not
including the formulations and methods of the present
disclosure).
Chronic Cough
[0094] In the United States, cough is the most common complaint for
which subjects seek medical attention and is the second most common
reason for a general medical examination, accounting for more than
26 million office visits annually (National Center for Health
Statistics. National Ambulatory Medical Care Survey: 2008). Upper
respiratory tract infection (i.e. the common cold) is by far the
most common cause of cough, but post-infectious cough, unexplained
chronic cough, and cough due to pulmonary disorders, such as
asthma, chronic obstructive pulmonary disease (COPD), idiopathic
pulmonary fibrosis (IPF), and lung cancer are also common.
[0095] Cough serves a potentially beneficial purpose by clearing
the airways of excessive mucus, irritants, or abnormal substances
such as edema fluid or pus. But while productive cough may serve a
useful function, coughing can also lead to a variety of problems,
including exhaustion (57%), feeling self, conscious (55%), insomnia
(45%), changes in lifestyle (45%), musculoskeletal pain (45%),
hoarseness (43%), excessive perspiration (42%), and urinary
incontinence (39%). These problems are more likely to be prominent
in the setting of chronic versus acute cough. As a consequence,
chronic cough is responsible for up to 38% of pulmonary outsubject
visits. There is a significant economic cost for the individual
with cough and for society, for example absence from work and lost
productivity.
[0096] Cough results from activation of myelinated cough receptors
and unmyelinated C fibers whose cell bodies are in the jugular and
nodose ganglia. Extensive C fiber endings are found under the
airway epithelium while cough receptors endings terminate in the
mucosa between the epithelium and smooth muscle. Mast cells play an
important role in cough, as degranulated mast cells release
mediators which can activate C fibers, causing release of Substance
P, histamine, serotonin, and proteases. Release of Substance P
results in inflammation, vasodilatation, sensitization of nerves,
and a hyperactive cough reflex.
Idiopathic Pulmonary Fibrosis (IPF)
[0097] IPF is a progressive life threatening disease that is
characterized anatomically by scarring of the lungs and
symptomatically by exertional dyspnea. Its etiology is unknown, and
the pathogenic mechanisms involved in its initiation and
progression are poorly understood. IPF is characterized by the
accumulation of lung fibroblasts and extracellular matrix
deposition, ultimately leading to compromised tissue architecture
and lung function capacity. Clinical features of IPF include dry
cough, breathlessness, restrictive respiratory physiology, end
inspiratory crackles, reduced oxygenation, and finger clubbing
High-resolution computer tomography (HRCT) shows a distinctive
pattern of subpleural shadowing and honeycomb fibrosis later in the
disease.
Chronic Cough in IPF (Also Referred to as Refractory Chronic Cough
in IPF)
[0098] IPF is a rare lung disorder of unknown etiology impacting
approximately 135,000 people in the United States. One common
characteristic of IPF appears to be aberrant wound healing that
leads to fibrosis. As of the date of this disclosure, no curative
therapy exists. The median survival of a subject with IPF is
between three and five years.
[0099] As used herein, chronic cough associated with IPF may be
defined as a dry non-productive cough (up to 100 coughs per hour)
that persists for more than eight weeks despite treatment with
standard care. Chronic cough associated with IPF significantly
impacts quality of life resulting in, for example, one or more of
headache, dizziness, sweating, incontinence, fractured ribs,
laryngeal trauma, vomiting, exacerbation of respiratory diseases,
loss of sleep, exhaustion, and anxiety. Moreover, chronic cough
associated with IPF significantly impacts psychosocial factors,
including, but not limited to, job loss, reluctance to attend
public events, and depression.
[0100] Chronic cough associated with IPF may be an independent
predictor of IPF disease progression. Approximately 80% of IPF
subjects have a chronic cough. Of those 80%, approximately 40% of
those subjects have a form of chronic cough that is refractory to
available treatments (available treatments do not include the
formulations, compositions or methods of the disclosure).
[0101] Available treatments options for cough have significant
limitations. Over-the-counter drugs provide negligible efficacy.
Prescription drugs are opioid-based and only occasionally
effective, but frequently associated with constipation, drowsiness,
respiratory depression and risk of addiction. No new non-opioid
products have been approved for cough in the last 50 years.
[0102] Individuals with chronic cough due to IPF may have frequent
coughing during the day with relatively little nocturnal cough.
Cough rates may be wide ranging and do not appear to be influenced
by the subject's age or gender.
Cromolyn, and Analogs, Derivatives, and Pharmaceutically Acceptable
Salts Thereof
[0103] As used herein, cromolyn refers to disodium
5,5'-(2-hydroxypropane-1,3-diyl)bis(oxy)bis(4-oxo-4H-chromene-2-carboxyla-
te) and has the following structure:
##STR00001##
[0104] Cromolyn is also known as sodium cromolyn, cromoglicic acid,
disodium cromoglicate (DSCG), sodium cromoglicate, and
cromoglicate. Pharmaceutically acceptable salts of cromolyn include
but are not limited to cromolyn sodium, cromolyn lysinate, ammonium
cromonglycate, and magnesium cromoglycate. Cromolyn sodium is also
known as disodium
5,5'-[(2-hydroxytrimethylene)dioxy]bis[4-oxo-4H-1-benzopyran-2-carboxylat-
e].
[0105] Cromolyn and the pharmaceutically acceptable salts described
herein may be prepared as prodrugs. A "prodrug" refers to an agent
that is converted into the parent drug in vivo. The prodrug can be
designed to alter the metabolic stability or the transport
characteristics of a drug, to mask side effects or toxicity, to
improve the flavor of a drug, or to alter other characteristics or
properties of a drug. In certain embodiments, the prodrug has
improved bioavailability relative to the parent drug. In certain
embodiments, the prodrug has improved solubility in pharmaceutical
compositions over the parent drug. In certain embodiments, prodrugs
may be designed as reversible drug derivatives, for use as
modifiers to enhance drug transport to site-specific tissues. In
certain embodiments, a prodrug of cromolyn is an ester of cromolyn,
which is hydrolyzed to the carboxylic acid, the parent compound. In
certain embodiments, a prodrug comprises a short peptide
(polyaminoacid) bonded to an acid group, wherein the peptide is
metabolized in vivo to reveal the parent drug. In certain
embodiments, upon in vivo administration, a prodrug is chemically
converted to the biologically, pharmaceutically or therapeutically
active form of cromolyn. In certain embodiments, a prodrug is
enzymatically metabolized by one or more steps or processes to the
parent compound. In certain embodiments, prodrug of cromolyn is
used. In a specific embodiment, the prodrug of cromolyn is
cromoglicate lisetil.
[0106] To produce a prodrug, a pharmaceutically active cromolyn is
modified such that the active compound will be regenerated upon in
vivo administration. In certain embodiments, prodrugs of cromolyn
are designed by virtue of knowledge of pharmacodynamic processes
and drug metabolism in vivo. See, e.g., Nogrady (1985) Medicinal
Chemistry A Biochemical Approach, Oxford University Press, New
York, pages 388-392; Silverman (1992), The Organic Chemistry of
Drug Design and Drug Action, Academic Press, Inc., San Diego, pages
352-401, Saulnier et al., (1994), Bioorganic and Medicinal
Chemistry Letters, Vol. 4, p. 1985; Rooseboom et al.,
Pharmacological Reviews, 56:53-102, 2004; Miller et al., J. Med.
Chem. Vol. 46, no. 24, 5097-5116, 2003; Aesop Cho, "Recent Advances
in Oral Prodrug Discovery", Annual Reports in Medicinal Chemistry,
Vol. 41, 395-407, 2006.
[0107] In certain embodiments, cromolyn and pharmaceutically
acceptable salts thereof disclosed herein are isotopically-labeled
compounds, which are identical to those recited herein, but for the
fact that one or more atoms are replaced by an atom having an
atomic mass or mass number different from the atomic mass or mass
number usually found in nature. Examples of isotopes that can be
incorporated into the present compounds include isotopes of
hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as,
for example, .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N,
.sup.18O, .sup.17O, .sup.35S, .sup.18F, .sup.36Cl, respectively.
Certain isotopically labeled compounds described herein, for
example those with isotopes such as deuterium, i.e., .sup.2H, can
afford certain therapeutic advantages resulting from greater
metabolic stability, such as, for example, increased in vivo
half-life or reduced dosage requirements. In certain embodiments,
isotopically labeled cromolyn is co-administered. In some, the
pharmaceutically acceptable salt of cromolyn, such as cromolyn
sodium, is isotopically labeled. In certain embodiments, the
pharmaceutically acceptable salt of cromolyn is deuterium-labeled
cromolyn sodium.
[0108] In certain embodiments, cromolyn and the pharmaceutically
acceptable salt thereof described herein are pegylated, wherein one
or more polyethylene glycol (PEG) polymers are covalently attached
to cromolyn or the pharmaceutically acceptable salt thereof. In
certain embodiments, pegylation increases the half-life of the
pegylated compound in the body. In certain embodiments, pegylation
increases the hydrodynamic size of the pegylated compound and
reduces renal clearance. In certain embodiments, pegylation
increases the solubility of the pegylated compound. In certain
embodiments, protects the pegylated compound from proteolytic
degradation.
[0109] Cromolyn and pharmaceutically acceptable salts, prodrugs,
and adducts thereof, may be prepared by methods known in the
art.
[0110] Cromolyn or a pharmaceutically acceptable salt thereof may
be administered in the methods disclosed herein in a suitable dose
or nominal dose as determined by one of ordinary skill in the art.
In certain embodiments, cromolyn or a pharmaceutically acceptable
salt thereof is administered at a dosage or nominal dosage of less
than about 1 mg/dose, about 1 mg/dose to about 100 mg/dose, about 1
mg/dose to about 120 mg/dose, about 5 mg/dose to about 80 mg/dose,
about 20 mg/dose to about 60 mg/dose, about 30 mg/dose to about 50
mg/dose, or greater than about 100 mg/dose. In certain embodiments,
cromolyn or a pharmaceutically acceptable salt thereof is
administered in less than about 1 mg, about 1 mg, about 5 mg, about
10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35
mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60
mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85
mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110
mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg doses,
about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 200
mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about
450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg,
about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900
mg, about 950 mg, or about 1000 mg doses. In certain embodiments,
cromolyn or a pharmaceutically acceptable salt thereof is
administered in about 30 mg. In certain embodiments, cromolyn or a
pharmaceutically acceptable salt thereof is administered in about
40 mg. In certain embodiments, cromolyn or a pharmaceutically
acceptable salt thereof is administered in about 50 mg. In certain
embodiments, cromolyn or a pharmaceutically acceptable salt thereof
is administered in about 60 mg. In certain embodiments, cromolyn or
a pharmaceutically acceptable salt thereof is administered in about
70 mg. In certain embodiments, cromolyn or a pharmaceutically
acceptable salt thereof is administered in about 80 mg.
[0111] In certain embodiments of the methods disclosed herein,
cromolyn sodium is administered at a dosage or nominal dosage of
less than about 1 mg/dose, about 1 mg/dose to about 100 mg/dose,
about 1 mg/dose to about 120 mg/dose, about 5 mg/dose to about 80
mg/dose, about 20 mg/dose to about 60 mg/dose, or about 30 mg/dose
to about 50 mg/dose, or greater than about 100 mg/dose. In other
embodiments, cromolyn sodium is administered in less than about 1
mg, about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg,
about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg,
about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg,
about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg,
about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120
mg, about 125 mg, about 130 mg doses, about 135 mg, about 140 mg,
about 145 mg, about 150 mg, about 200 mg, about 250 mg, about 300
mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about
550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg,
about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about
1000 mg doses. In certain embodiments, cromolyn or a
pharmaceutically acceptable salt thereof is administered in about
30 mg. In certain embodiments, cromolyn or a pharmaceutically
acceptable salt thereof is administered in about 40 mg. In certain
embodiments, cromolyn or a pharmaceutically acceptable salt thereof
is administered in about 50 mg. In certain embodiments, cromolyn or
a pharmaceutically acceptable salt thereof is administered in about
60 mg. In certain embodiments, cromolyn or a pharmaceutically
acceptable salt thereof is administered in about 70 mg. In certain
embodiments, cromolyn or a pharmaceutically acceptable salt thereof
is administered in about 80 mg.
Formulations
[0112] DSCG has a long history of use for its anti-allergy,
anti-inflammatory, and immune-modulating properties as well as its
exceptional safety profile. However, the available formulations of
DSCG (that do not include the compositions of the disclosure) are
not suitable for use in chronic cough associated with IPF, because
the available formulations of DSCG are too limited by poor delivery
efficiency and very low bioavailability (approximately 1%).
[0113] The compositions and formulations of the disclosure enhance
bioavailability and provide efficacious treatment of the
debilitating symptoms of chronic cough associated with IPF. The
compositions and formulations of the disclosure achieve
significantly higher lung and peripheral distribution than
currently available formulations, parameters that are both required
for efficacy in treatment of chronic cough associated with IPF.
[0114] Table 1a provides exemplary, nonlimiting, formulations of
the compositions of the disclosure, wherein the amounts of each
component of the formulations are expressed as weight percent of
the total weight of the formulation.
TABLE-US-00001 PA101 PA101B PA101B PA101B Component Function (wt %)
(wt %) (wt %) (wt %) Cromolyn Active Substance 4 2 4 6 Sodium
Chloride Osmotic Agent 0.2 0.2 0.2 0.2 EDTA Chelating Agent 0.02
0.02 0.02 0.02 Mannitol Non-ionic Osmotic Agent 1.25 0 0 0 Water
for Injection (WFI) Quantum sufficiat (q.s.) q.s. q.s. q.s. q.s.
Osmolality (mOsm/kg) Tonicity 200 106 125 135
[0115] Table 1b provides further exemplary, nonlimiting,
formulations of the compositions of the disclosure, wherein the
amounts of each component of the formulations are expressed as
weight percent of the total weight of the formulation.
TABLE-US-00002 Cromolyn Sodium sodium Mannitol chloride EDTA
Osmolality Formulation (%) (%) (%) (%) (mOsm/kg) 1 2 0 0 0.02 42 2
2 0 0.2 0.02 106 3 2 0 0.4 0.02 170 4 2 0 0.6 0.02 235 5 2 0 0.8
0.02 299 6 4 1.25 0.2 0.02 199 7 4 1 0.2 0.02 183 8 4 0.75 0.2 0.02
169 9 4 0.5 0.2 0.02 154 10 4 0.25 0.2 0.02 139 11 4 0 0.2 0.02 125
12 5 1.25 0.2 0.02 207 13 5 0 0.2 0.02 131 14 5 0 0.25 0.02 147 15
6 1.25 0.2 0.02 214 16 6 0 0.2 0.02 138 17 6 0 0.25 0.02 154
[0116] PA101B formulations 4% by weight and 6% by weight, are each
highly concentrated, well-tolerated, room-temperature stable
formulations of disodium cromoglycate optimized for delivery via an
electronic nebulizer.
[0117] In certain embodiments, compositions of the disclosure may
comprise an ionic osmolarity or osmolality adjusting agent but, do
not comprise a non-ionic osmolarity or osmolality adjusting agent.
Ionic osmolarity or osmolality adjusting agents can be selected
from, for example, alkali metal salts, such as sodium and potassium
salts. Examples of such salts include, but are not limited to,
sodium chloride, sodium gluconate, sodium pyruvate, and potassium
chloride. It is possible to use a single ionic tonicity-adjusting
agent, such as sodium chloride, or a mixture of such agents. The
salts may be either added or formed in situ due to a salt formation
process. In a particular embodiment of the disclosure, however, the
non-ionic osmolarity or osmolality adjusting agent is mannitol. The
non-ionic osmolarity or osmolality adjusting agent can be selected
from, for example, the group of carbohydrates. Examples of
carbohydrates that can be used for isotonisation include, but are
not limited to, sugars such as glucose, lactose, sucrose and
trehalose, and sugar alcohols such as mannitol, xylitol, sorbitol,
and isomaltol. In a particular embodiment of the disclosure,
however, the non-ionic osmolarity or osmolality adjusting agent is
not propylene glycol, a cyclodextrin or mannitol.
[0118] The disclosure provides a pharmaceutically acceptable
aerosol for the treatment of chronic cough in a subject having
idiopathic pulmonary fibrosis (IPF), comprising droplets of an
aqueous solution comprising (i) from about 2% to about 6% by weight
of cromolyn sodium and (ii) an osmolarity adjusting agent
comprising (a) between about 0.1% and about 0.5% by weight of
sodium chloride, inclusive of the endpoints, and (b) optionally
salts of ethylenediaminetetraacetic acid (EDTA), wherein said
aerosol has a respirable fraction (.ltoreq.3.3 .mu.m) as measured
by USP <1601> of at least about 30%, and wherein said
treatment of said chronic cough in said subject is achieved via
delivery of a therapeutically effective amount of cromolyn sodium
to the lungs of the subject by said subject orally inhaling said
pharmaceutically acceptable aerosol. In certain embodiments, the
pharmaceutically acceptable aerosol comprises droplets of an
aqueous solution comprising salts of EDTA, wherein the salts are
selected from sodium EDTA. In certain embodiments are the
pharmaceutically aerosols wherein the aqueous solution contains
from about 5 mg to about 80 mg of cromolyn sodium. In certain
embodiments are the pharmaceutically aerosols wherein the aqueous
solution contains from about 36 mg to about 44 mg of cromolyn
sodium. In certain embodiments are the pharmaceutically aerosols
wherein the aqueous solution contains about 5 mg, about 10 mg,
about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 31 mg,
about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg,
about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg,
about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 50 mg,
about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, or
about 80 mg of cromolyn sodium. In certain embodiments, are the
pharmaceutically acceptable aerosols having a respirable fraction
(.ltoreq.5 .mu.m) as measured by USP <1601> of at least about
75%.. In certain embodiments are the pharmaceutically acceptable
aerosols wherein said sodium chloride is at a concentration of
between 0.1% to 0.2% by weight, inclusive of the endpoints.
[0119] The disclosure provides a pharmaceutically acceptable
aerosol for the treatment of chronic cough in a subject having
idiopathic pulmonary fibrosis (IPF), consisting of droplets of an
aqueous solution consisting of (i) from about 2% to about 6% by
weight of cromolyn sodium and (ii) an osmolarity adjusting agent
consisting of (a) between about 0.1% and about 0.5% by weight of
sodium chloride, inclusive of the endpoints, and (b) optionally
salts of ethylenediaminetetraacetic acid (EDTA), wherein said
aerosol has a respirable fraction (.ltoreq.3.3 .mu.m) as measured
by USP <1601> of at least about 30%, and wherein said
treatment of said chronic cough in said subject is achieved via
delivery of a therapeutically effective amount of cromolyn sodium
to the lungs of the subject by said subject orally inhaling said
pharmaceutically acceptable aerosol. In certain embodiments, the
pharmaceutically acceptable aerosol comprises droplets of an
aqueous solution comprising salts of EDTA, wherein the salts are
selected from sodium EDTA. In certain embodiments are the
pharmaceutically aerosols wherein the aqueous solution contains
from about 5 mg to about 80 mg of cromolyn sodium. In certain
embodiments are the pharmaceutically aerosols wherein the aqueous
solution contains from about 36 mg to about 44 mg of cromolyn
sodium. In certain embodiments are the pharmaceutically aerosols
wherein the aqueous solution contains about 5 mg, about 10 mg,
about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 31 mg,
about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg,
about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg,
about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 50 mg,
about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, or
about 80 mg of cromolyn sodium. In certain embodiments, are the
pharmaceutically acceptable aerosols having a respirable fraction
(.ltoreq.5 .mu.m) as measured by USP <1601> of at least about
75%. In certain embodiments are the pharmaceutically acceptable
aerosols wherein said sodium chloride is at a concentration of
between 0.1% to 0.2% by weight, inclusive of the endpoints.
[0120] In certain embodiments are provided methods of treating
chronic cough in a subject having idiopathic pulmonary fibrosis
(IPF), comprising administering a pharmaceutically acceptable
aerosol to said subject by oral inhalation, said pharmaceutically
acceptable aerosol acceptable consisting of droplets of an aqueous
solution consisting of_(i) from about 2% to about 6% by weight of
cromolyn sodium, (ii) between about 0.1% and about 0.5% by weight
of sodium chloride, inclusive of the endpoints, and (iii)
optionally salts of ethylenediaminetetraacetic acid (EDTA). In
certain embodiments are the pharmaceutically acceptable aerosols,
wherein said aerosol has a respirable fraction (.ltoreq.3.3 .mu.m)
as measured by USP <1601> of at least about 30%. In certain
embodiments are the pharmaceutically acceptable aerosols, wherein
said aerosol has a respirable fraction (.ltoreq.5 .mu.m) as
measured by USP <1601> of at least about 75%. In certain
embodiments, the pharmaceutically acceptable aerosol comprises
droplets of an aqueous solution comprising salts of EDTA, wherein
the salts are selected from sodium EDTA. In certain embodiments are
the pharmaceutically aerosols wherein the aqueous solution contains
from about 5 mg to about 80 mg of cromolyn sodium. In certain
embodiments are the pharmaceutically aerosols wherein the aqueous
solution contains from about 36 mg to about 44 mg of cromolyn
sodium. In certain embodiments are the pharmaceutically aerosols
wherein the aqueous solution contains about 5 mg, about 10 mg,
about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 31 mg,
about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg,
about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg,
about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 50 mg,
about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, or
about 80 mg of cromolyn sodium. In certain embodiments, are the
pharmaceutically acceptable aerosols having a respirable fraction
(.ltoreq.5 .mu.m) as measured by USP <1601> of at least about
75%.. In certain embodiments are the pharmaceutically acceptable
aerosols wherein said sodium chloride is at a concentration of
between 0.1% to 0.2% by weight, inclusive of the endpoints.
[0121] In certain embodiments, formulations administered in the
methods disclosed herein produce in a subject AUC.sub.(0-.infin.)
of cromolyn or a pharmaceutically acceptable salt thereof greater
than about 100 ng*hr./mL, greater than about 110 ng*hr./mL, greater
than about 120 ng*hr./mL, greater than about 130 ng*hr./mL, greater
than about 140 ng*hr./mL, greater than about 150 ng*hr./mL, greater
than about 160 ng*hr./mL, greater than about 170 ng*hr./mL, greater
than about 180 ng*hr./mL, greater than about 190 ng*hr./mL, greater
than about 200 ng*hr./mL, greater than about 225 ng*hr./mL, greater
than about 250 ng*hr./mL, greater than about 275 ng*hr./mL, greater
than about 300 ng*hr./mL, greater than about 325 ng*hr./mL, greater
than about 350 ng*hr./mL, greater than about 375 ng*hr./mL, greater
than about 400 ng*hr./mL, greater than about 425 ng*hr./mL, greater
than about 450 ng*hr./mL, greater than about 475 ng*hr./mL, greater
than about 500 ng*hr./mL, greater than about 525 ng*hr./mL, greater
than about 550 ng*hr./mL, greater than about 575 ng*hr./mL, greater
than about 600 ng*hr./mL, greater than about 625 ng*hr./mL, greater
than about 650 ng*hr./mL, greater than about 675 ng*hr./mL, greater
than about 700 ng*hr./mL, greater than about 725 ng*hr./mL, greater
than about 750 ng*hr./mL, greater than about 775 ng*hr./mL, greater
than about 800 ng*hr./mL, greater than about 825 ng*hr./mL, greater
than about 850 ng*hr./mL, greater than about 875 ng*hr./mL, greater
than about 900 ng*hr./mL, greater than about 925 ng*hr./mL, greater
than about 950 ng*hr./mL, greater than about 975 ng*hr./mL, or
greater than about 1000 ng*hr./mL after administration of the
formulation to the subject. In certain embodiments, formulations
administered in the methods disclosed herein produce in a subject
an AUC.sub.(0-.infin.) of cromolyn or a pharmaceutically-acceptable
salt thereof greater than about 100 ng*hr./mL, greater than about
110 ng*hr./mL, greater than about 120 ng*hr./mL, greater than about
130 ng*hr./mL, greater than about 140 ng*hr./mL, greater than about
150 ng*hr./mL, greater than about 160 ng*hr./mL, greater than about
170 ng*hr./mL, greater than about 180 ng*hr./mL, greater than about
190 ng*hr./mL, greater than about 200 ng*hr./mL, greater than about
225 ng*hr./mL, greater than about 250 ng*hr./mL, greater than about
275 ng*hr./mL, greater than about 300 ng*hr./mL, greater than about
325 ng*hr./mL, greater than about 350 ng*hr./mL, greater than about
375 ng*hr./mL, greater than about 400 ng*hr./mL, greater than about
425 ng*hr./mL, greater than about 450 ng*hr./mL, greater than about
475 ng*hr./mL, greater than about 500 ng*hr./mL, greater than about
525 ng*hr./mL, greater than about 550 ng*hr./mL, greater than about
575 ng*hr./mL, greater than about 600 ng*hr./mL, greater than about
625 ng*hr./mL, greater than about 650 ng*hr./mL, greater than about
675 ng*hr./mL, greater than about 700 ng*hr./mL, greater than about
725 ng*hr./mL, greater than about 750 ng*hr./mL, greater than about
775 ng*hr./mL, greater than about 800 ng*hr./mL, greater than about
825 ng*hr./mL, greater than about 850 ng*hr./mL, greater than about
875 ng*hr./mL, greater than about 900 ng*hr./mL, greater than about
925 ng*hr./mL, greater than about 950 ng*hr./mL, greater than about
975 ng*hr./mL, or greater than about 1000 ng*hr./mL after
administration of the formulation to the subject or subject.
[0122] In certain embodiments, formulations administered in the
methods disclosed herein produce in a subject AUC.sub.(0-.infin.)
of cromolyn or a pharmaceutically-acceptable salt thereof of about
100 ng*hr./mL, about 110 ng*hr./mL, about 120 ng*hr./mL, about 130
ng*hr./mL, about 140 ng*hr./mL, about 150 ng*hr./mL, about 160
ng*hr./mL, about 170 ng*hr./mL, about 180 ng*hr./mL, about 190
ng*hr./mL, about 200 ng*hr./mL, about 225 ng*hr./mL, about 250
ng*hr./mL, about 275 ng*hr./mL, about 300 ng*hr./mL, about 325
ng*hr./mL, about 350 ng*hr./mL, about 375 ng*hr./mL, about 400
ng*hr./mL, about 425 ng*hr./mL, about 450 ng*hr./mL, about 475
ng*hr./mL, about 500 ng*hr./mL, about 525 ng*hr./mL, about 550
ng*hr./mL, about 575 ng*hr./mL, about 600 ng*hr./mL, about 625
ng*hr./mL, about 650 ng*hr./mL, about 675 ng*hr./mL, about 700
ng*hr./mL, about 725 ng*hr./mL, about 750 ng*hr./mL, about 775
ng*hr./mL, about 800 ng*hr./mL, about 825 ng*hr./mL, about 850
ng*hr./mL, about 875 ng*hr./mL, about 900 ng*hr./mL, about 925
ng*hr./mL, about 950 ng*hr./mL, about 975 ng*hr./mL, or about 1000
ng*hr./mL after administration of the formulation to the subject.
In certain embodiments, formulations administered in the methods
disclosed herein produce in a subject an AUC.sub.(0-.infin.) of
cromolyn or a pharmaceutically-acceptable salt thereof of about 100
ng*hr./mL, about 110 ng*hr./mL, about 120 ng*hr./mL, about 130
ng*hr./mL, about 140 ng*hr./mL, about 150 ng*hr./mL, about 160
ng*hr./mL, about 170 ng*hr./mL, about 180 ng*hr./mL, about 190
ng*hr./mL, about 200 ng*hr./mL, about 225 ng*hr./mL, about 250
ng*hr./mL, about 275 ng*hr./mL, about 300 ng*hr./mL, about 325
ng*hr./mL, about 350 ng*hr./mL, about 375 ng*hr./mL, about 400
ng*hr./mL, about 425 ng*hr./mL, about 450 ng*hr./mL, about 475
ng*hr./mL, about 500 ng*hr./mL, about 525 ng*hr./mL, about 550
ng*hr./mL, about 575 ng*hr./mL, about 600 ng*hr./mL, about 625
ng*hr./mL, about 650 ng*hr./mL, about 675 ng*hr./mL, about 700
ng*hr./mL, about 725 ng*hr./mL, about 750 ng*hr./mL, about 775
ng*hr./mL, about 800 ng*hr./mL, about 825 ng*hr./mL, about 850
ng*hr./mL, about 875 ng*hr./mL, about 900 ng*hr./mL, about 925
ng*hr./mL, about 950 ng*hr./mL, about 975 ng*hr./mL, or about 1000
ng*hr./mL after administration of the formulation to the subject or
subject.
[0123] In certain embodiments, formulations administered in the
methods disclosed herein produce in a subject an
AUC.sub.(0-.infin.) of cromolyn sodium greater than about 100
ng*hr./mL, greater than about 110 ng*hr./mL, greater than about 120
ng*hr./mL, greater than about 130 ng*hr./mL, greater than about 140
ng*hr./mL, greater than about 150 ng*hr./mL, greater than about 160
ng*hr./mL, greater than about 170 ng*hr./mL, greater than about 180
ng*hr./mL, greater than about 190 ng*hr./mL, greater than about 200
ng*hr./mL, greater than about 225 ng*hr./mL, greater than about 250
ng*hr./mL, greater than about 275 ng*hr./mL, greater than about 300
ng*hr./mL, greater than about 325 ng*hr./mL, greater than about 350
ng*hr./mL, greater than about 375 ng*hr./mL, greater than about 400
ng*hr./mL, greater than about 425 ng*hr./mL, greater than about 450
ng*hr./mL, greater than about 475 ng*hr./mL, greater than about 500
ng*hr./mL, greater than about 525 ng*hr./mL, greater than about 550
ng*hr./mL, greater than about 575 ng*hr./mL, greater than about 600
ng*hr./mL, greater than about 625 ng*hr./mL, greater than about 650
ng*hr./mL, greater than about 675 ng*hr./mL, greater than about 700
ng*hr./mL, greater than about 725 ng*hr./mL, greater than about 750
ng*hr./mL, greater than about 775 ng*hr./mL, greater than about 800
ng*hr./mL, greater than about 825 ng*hr./mL, greater than about 850
ng*hr./mL, greater than about 875 ng*hr./mL, greater than about 900
ng*hr./mL, greater than about 925 ng*hr./mL, greater than about 950
ng*hr./mL, greater than about 975 ng*hr./mL, or greater than about
1000 ng*hr./mL after administration of the formulation to the
subject. In certain embodiments, formulations administered in the
methods disclosed herein produce in a subject an
AUC.sub.(0-.infin.) of cromolyn sodium greater than about 100
ng*hr./mL, greater than about 110 ng*hr./mL, greater than about 120
ng*hr./mL, greater than about 130 ng*hr./mL, greater than about 140
ng*hr./mL, greater than about 150 ng*hr./mL, greater than about 160
ng*hr./mL, greater than about 170 ng*hr./mL, greater than about 180
ng*hr./mL, greater than about 190 ng*hr./mL, greater than about 200
ng*hr./mL, greater than about 225 ng*hr./mL, greater than about 250
ng*hr./mL, greater than about 275 ng*hr./mL, greater than about 300
ng*hr./mL, greater than about 325 ng*hr./mL, greater than about 350
ng*hr./mL, greater than about 375 ng*hr./mL, greater than about 400
ng*hr./mL, greater than about 425 ng*hr./mL, greater than about 450
ng*hr./mL, greater than about 475 ng*hr./mL, greater than about 500
ng*hr./mL, greater than about 525 ng*hr./mL, greater than about 550
ng*hr./mL, greater than about 575 ng*hr./mL, greater than about 600
ng*hr./mL, greater than about 625 ng*hr./mL, greater than about 650
ng*hr./mL, greater than about 675 ng*hr./mL, greater than about 700
ng*hr./mL, greater than about 725 ng*hr./mL, greater than about 750
ng*hr./mL, greater than about 775 ng*hr./mL, greater than about 800
ng*hr./mL, greater than about 825 ng*hr./mL, greater than about 850
ng*hr./mL, greater than about 875 ng*hr./mL, greater than about 900
ng*hr./mL, greater than about 925 ng*hr./mL, greater than about 950
ng*hr./mL, greater than about 975 ng*hr./mL, or greater than about
1000 ng*hr./mL after administration of the formulation to the
subject or subject.
[0124] In certain embodiments, formulations administered in the
methods disclosed herein produce in a subject an
AUC.sub.(0-.infin.) of cromolyn sodium of about 100 ng*hr./mL,
about 110 ng*hr./mL, about 120 ng*hr./mL, about 130 ng*hr./mL,
about 140 ng*hr./mL, about 150 ng*hr./mL, about 160 ng*hr./mL,
about 170 ng*hr./mL, about 180 ng*hr./mL, about 190 ng*hr./mL,
about 200 ng*hr./mL, about 225 ng*hr./mL, about 250 ng*hr./mL,
about 275 ng*hr./mL, about 300 ng*hr./mL, about 325 ng*hr./mL,
about 350 ng*hr./mL, about 375 ng*hr./mL, about 400 ng*hr./mL,
about 425 ng*hr./mL, about 450 ng*hr./mL, about 475 ng*hr./mL,
about 500 ng*hr./mL, about 525 ng*hr./mL, about 550 ng*hr./mL,
about 575 ng*hr./mL, about 600 ng*hr./mL, about 625 ng*hr./mL,
about 650 ng*hr./mL, about 675 ng*hr./mL, about 700 ng*hr./mL,
about 725 ng*hr./mL, about 750 ng*hr./mL, about 775 ng*hr./mL,
about 800 ng*hr./mL, about 825 ng*hr./mL, about 850 ng*hr./mL,
about 875 ng*hr./mL, about 900 ng*hr./mL, about 925 ng*hr./mL,
about 950 ng*hr./mL, about 975 ng*hr./mL, or about 1000 ng*hr./mL
after administration of the formulation to the subject. In certain
embodiments, formulations administered in the methods disclosed
herein produce in a subject an AUC.sub.(0-.infin.) of cromolyn
sodium of about 100 ng*hr./mL, about 110 ng*hr./mL, about 120
ng*hr./mL, about 130 ng*hr./mL, about 140 ng*hr./mL, about 150
ng*hr./mL, about 160 ng*hr./mL, about 170 ng*hr./mL, about 180
ng*hr./mL, about 190 ng*hr./mL, about 200 ng*hr./mL, about 225
ng*hr./mL, about 250 ng*hr./mL, about 275 ng*hr./mL, about 300
ng*hr./mL, about 325 ng*hr./mL, about 350 ng*hr./mL, about 375
ng*hr./mL, about 400 ng*hr./mL, about 425 ng*hr./mL, about 450
ng*hr./mL, about 475 ng*hr./mL, about 500 ng*hr./mL, about 525
ng*hr./mL, about 550 ng*hr./mL, about 575 ng*hr./mL, about 600
ng*hr./mL, about 625 ng*hr./mL, about 650 ng*hr./mL, about 675
ng*hr./mL, about 700 ng*hr./mL, about 725 ng*hr./mL, about 750
ng*hr./mL, about 775 ng*hr./mL, about 800 ng*hr./mL, about 825
ng*hr./mL, about 850 ng*hr./mL, about 875 ng*hr./mL, about 900
ng*hr./mL, about 925 ng*hr./mL, about 950 ng*hr./mL, about 975
ng*hr./mL, or about 1000 ng*hr./mL after administration of the
formulation to the subject.
[0125] In certain embodiments, formulation administered in the
methods disclosed herein produce in a subject a Cmax of cromolyn or
a pharmaceutically-acceptable salt thereof greater than about 40
ng/mL, greater than about 50 ng/mL, greater than about 60 ng/mL,
greater than about 70 ng/mL, greater than about 80 ng/mL, greater
than about 90 ng/mL, greater than about 100 ng/mL, greater than
about 110 ng/mL, greater than about 120 ng/mL, greater than about
130 ng/mL, greater than about 140 ng/mL, greater than about 150
ng/mL, greater than about 160 ng/mL, greater than about 170 ng/mL,
greater than about 180 ng/mL, greater than about 190 ng/mL, greater
than about 200 ng/mL, greater than about 210 ng/mL, greater than
about 220 ng/mL, greater than about 230 ng/mL, greater than about
240 ng/mL, greater than about 250 ng/mL, greater than about 260
ng/mL, greater than about 270 ng/mL, greater than about 280 ng/mL,
greater than about 290 ng/mL, greater than about 300 ng/mL, greater
than about 310 ng/mL, greater than about 320 ng/mL, greater than
about 330 ng/mL, greater than about 340 ng/mL, greater than about
350 ng/mL, greater than about 360 ng/mL, greater than about 370
ng/mL, greater than about 380 ng/mL, greater than about 390 ng/mL,
or greater than about 400 ng/mL after administration of the
formulation to the subject. In certain embodiments, formulations
administered in the methods disclosed herein produce in a subject a
Cm of cromolyn or a pharmaceutically-acceptable salt thereof
greater than about 40 ng/mL, greater than about 50 ng/mL, greater
than about 60 ng/mL, greater than about 70 ng/mL, greater than
about 80 ng/mL, greater than about 90 ng/mL, greater than about 100
ng/mL, greater than about 110 ng/mL, greater than about 120 ng/mL,
greater than about 130 ng/mL, greater than about 140 ng/mL, greater
than about 150 ng/mL, greater than about 160 ng/mL, greater than
about 170 ng/mL, greater than about 180 ng/mL, greater than about
190 ng/mL, greater than about 200 ng/mL, greater than about 210
ng/mL, greater than about 220 ng/mL, greater than about 230 ng/mL,
greater than about 240 ng/mL, greater than about 250 ng/mL, greater
than about 260 ng/mL, greater than about 270 ng/mL, greater than
about 280 ng/mL, greater than about 290 ng/mL, greater than about
300 ng/mL, greater than about 310 ng/mL, greater than about 320
ng/mL, greater than about 330 ng/mL, greater than about 340 ng/mL,
greater than about 350 ng/mL, greater than about 360 ng/mL, greater
than about 370 ng/mL, greater than about 380 ng/mL, greater than
about 390 ng/mL, or greater than about 400 ng/mL after
administration of the formulation to the subject or subject.
[0126] In certain embodiments, formulations administered in the
methods disclosed herein produce in a subject a Cmax of cromolyn or
a pharmaceutically-acceptable salt thereof of about 50 mg/mL, about
60 ng/mL, about 70 ng/mL, about 80 ng/mL, 90 ng/mL, about 100
ng/mL, about 110 ng/mL, about 120 ng/mL, about 130 ng/mL, about 140
ng/mL, about 150 ng/mL, about 160 ng/mL, about 170 ng/mL, about 180
ng/mL, about 190 ng/mL, about 200 ng/mL, about 210 ng/mL, about 220
ng/mL, about 230 ng/mL, about 240 ng/mL, about 250 ng/mL, 260
ng/mL, about 270 ng/mL, about 280 ng/mL, about 290 ng/mL, about 300
ng/mL, about 310 ng/mL, about 320 ng/mL, about 330 ng/mL, about 340
ng/mL, about 350 ng/mL, about 360 ng/mL, about 370 ng/mL, about 380
ng/mL, about 390 ng/mL, or about 400 ng/mL after administration of
the formulation to the subject. In certain embodiments,
formulations administered in the methods disclosed herein produce
in a subject a Cm of cromolyn or a pharmaceutically-acceptable salt
thereof of about 50 mg/mL, about 60 ng/mL, about 70 ng/mL, about 80
ng/mL, 90 ng/mL, about 100 ng/mL, about 110 ng/mL, about 120 ng/mL,
about 130 ng/mL, about 140 ng/mL, about 150 ng/mL, about 160 ng/mL,
about 170 ng/mL, about 180 ng/mL, about 190 ng/mL, about 200 ng/mL,
about 210 ng/mL, about 220 ng/mL, about 230 ng/mL, about 240 ng/mL,
about 250 ng/mL, 260 ng/mL, about 270 ng/mL, about 280 ng/mL, about
290 ng/mL, about 300 ng/mL, about 310 ng/mL, about 320 ng/mL, about
330 ng/mL, about 340 ng/mL, about 350 ng/mL, about 360 ng/mL, about
370 ng/mL, about 380 ng/mL, about 390 ng/mL, or about 400 ng/mL
after administration of the formulation to the subject or
subject.
[0127] In certain embodiments, formulations administered in the
methods disclosed herein produce in a subject a Cmax of cromolyn
sodium greater than about 40 ng/mL, greater than about 50 ng/mL,
greater than about 60 ng/mL, greater than about 70 ng/mL, greater
than about 80 ng/mL, greater than about 90 ng/mL, greater than
about 100 ng/mL, greater than about 110 ng/mL, greater than about
120 ng/mL, greater than about 130 ng/mL, greater than about 140
ng/mL, greater than about 150 ng/mL, greater than about 160 ng/mL,
greater than about 170 ng/mL, greater than about 180 ng/mL, greater
than about 190 ng/mL, greater than about 200 ng/mL, greater than
about 210 ng/mL, greater than about 220 ng/mL, greater than about
230 ng/mL, greater than about 240 ng/mL, greater than about 250
ng/mL, greater than about 260 ng/mL, greater than about 270 ng/mL,
greater than about 280 ng/mL, greater than about 290 ng/mL, greater
than about 300 ng/mL, greater than about 310 ng/mL, greater than
about 320 ng/mL, greater than about 330 ng/mL, greater than about
340 ng/mL, greater than about 350 ng/mL, greater than about 360
ng/mL, greater than about 370 ng/mL, greater than about 380 ng/mL,
greater than about 390 ng/mL, or greater than about 400 ng/mL after
administration of the formulation to the subject. In certain
embodiments, formulations administered in the methods disclosed
herein produce in a subject a Cmax of cromolyn sodium greater than
about 40 ng/mL, greater than about 50 ng/mL, greater than about 60
ng/mL, greater than about 70 ng/mL, greater than about 80 ng/mL,
greater than about 90 ng/mL, greater than about 100 ng/mL, greater
than about 110 ng/mL, greater than about 120 ng/mL, greater than
about 130 ng/mL, greater than about 140 ng/mL, greater than about
150 ng/mL, greater than about 160 ng/mL, greater than about 170
ng/mL, greater than about 180 ng/mL, greater than about 190 ng/mL,
greater than about 200 ng/mL, greater than about 210 ng/mL, greater
than about 220 ng/mL, greater than about 230 ng/mL, greater than
about 240 ng/mL, greater than about 250 ng/mL, greater than about
260 ng/mL, greater than about 270 ng/mL, greater than about 280
ng/mL, greater than about 290 ng/mL, greater than about 300 ng/mL,
greater than about 310 ng/mL, greater than about 320 ng/mL, greater
than about 330 ng/mL, greater than about 340 ng/mL, greater than
about 350 ng/mL, greater than about 360 ng/mL, greater than about
370 ng/mL, greater than about 380 ng/mL, greater than about 390
ng/mL, or greater than about 400 ng/mL after administration of the
formulation to the subject or subject.
[0128] In certain embodiments, formulations administered in the
methods disclosed herein produce in a subject a Cmax of cromolyn
sodium of about 50 mg/mL, about 60 ng/mL, about 70 ng/mL, about 80
ng/mL, 90 ng/mL, about 100 ng/mL, about 110 ng/mL, about 120 ng/mL,
about 130 ng/mL, about 140 ng/mL, about 150 ng/mL, about 160 ng/mL,
about 170 ng/mL, about 180 ng/mL, about 190 ng/mL, about 200 ng/mL,
about 210 ng/mL, about 220 ng/mL, about 230 ng/mL, about 240 ng/mL,
about 250 ng/mL, 260 ng/mL, about 270 ng/mL, about 280 ng/mL, about
290 ng/mL, about 300 ng/mL, about 310 ng/mL, about 320 ng/mL, about
330 ng/mL, about 340 ng/mL, about 350 ng/mL, about 360 ng/mL, about
370 ng/mL, about 380 ng/mL, about 390 ng/mL, or about 400 ng/mL
after administration of the formulation to the subject. In certain
embodiments, formulations administered in the methods disclosed
herein produce in a subject a C.sub.max of cromolyn sodium of about
50 mg/mL, about 60 ng/mL, about 70 ng/mL, about 80 ng/mL, 90 ng/mL,
about 100 ng/mL, about 110 ng/mL, about 120 ng/mL, about 130 ng/mL,
about 140 ng/mL, about 150 ng/mL, about 160 ng/mL, about 170 ng/mL,
about 180 ng/mL, about 190 ng/mL, about 200 ng/mL, about 210 ng/mL,
about 220 ng/mL, about 230 ng/mL, about 240 ng/mL, about 250 ng/mL,
260 ng/mL, about 270 ng/mL, about 280 ng/mL, about 290 ng/mL, about
300 ng/mL, about 310 ng/mL, about 320 ng/mL, about 330 ng/mL, about
340 ng/mL, about 350 ng/mL, about 360 ng/mL, about 370 ng/mL, about
380 ng/mL, about 390 ng/mL, or about 400 ng/mL after administration
of the formulation to the subject or subject.
[0129] Cromolyn or a pharmaceutically acceptable salt thereof may
be administered to a subject in the methods disclosed herein with
an inhalation device, e.g., a nebulizer.
[0130] Cromolyn or a pharmaceutically acceptable salt thereof may
be formulated into any suitable dosage form, including but not
limited to aerosols, aqueous oral dispersions, self-emulsifying
dispersions, liposomal dispersions, pegylated liposomes, liquids,
elixirs, suspensions, aerosols, controlled release formulations,
lyophilized formulations, powders, delayed release formulations,
extended release formulations, multiparticulate formulations or
mixed immediate release formulations. Such formulations may be
manufactured in a conventional manner, such as, by way of example
only, conventional mixing, dissolving, or granulating
processes.
[0131] In certain embodiments, the formulations disclosed herein
may include one or more inactive ingredients or pharmaceutical
excipients that provide suitable properties of the formulation.
Such inactive ingredients may include one or more of the following
classes.
[0132] "Albumin" refers to a family of globular proteins, the most
common of which is serum albumin. Albumins are commonly found in
blood plasma and function to regulate colloidal osmotic pressure of
the blood. Albumin proteins found in the plasma bind some
pharmaceutical compounds to form complexes. Complexation of albumin
with pharmaceutical compounds, e.g., cromolyn or a pharmaceutical
salt thereof, can influence the pharmaceutical compounds' plasma
half-life and/or biological half-life in the body by preventing
metabolism and/or excretion of the complexed compounds. In certain
embodiments, compositions disclosed herein include albumin and
cromolyn or a pharmaceutical salt thereof (e.g. cromolyn
sodium).
[0133] "Antifoaming agents" reduce foaming during processing which
can result in coagulation of aqueous dispersions, bubbles in the
finished film, or generally impair processing. Exemplary
anti-foaming agents include silicon emulsions or sorbitan
sesquoleate
[0134] "Antioxidants" include, for example, butylated
hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium
metabisulfite and tocopherol. In certain embodiments, antioxidants
enhance chemical stability where required.
[0135] "Binders" impart cohesive qualities and include, e.g.,
alginic acid and salts thereof; cellulose derivatives such as
carboxymethylcellulose, methylcellulose (e.g., Methocel.RTM.),
hydroxypropylmethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose (e.g., Klucel.RTM.), ethylcellulose (e.g.,
Ethocel.RTM.), and microcrystalline cellulose (e.g., Avicel.RTM.);
microcrystalline dextrose; amylose; magnesium aluminum silicate;
polysaccharide acids; bentonites; gelatin;
polyvinylpyrrolidone/vinyl acetate copolymer; crosspovidone;
povidone; starch; pregelatinized starch; tragacanth, dextrin, a
sugar, such as sucrose (e.g., Dipac.RTM.), glucose, dextrose,
molasses, mannitol, sorbitol, xylitol (e.g., Xylitab.RTM.), and
lactose; a natural or synthetic gum such as acacia, tragacanth,
ghatti gum, mucilage of isapol husks, polyvinylpyrrolidone (e.g.,
Polyvidone.RTM. CL, Kollidon.RTM. CL, Polyplasdone.RTM. XL-10),
larch arabogalactan, Veegum.RTM., polyethylene glycol, waxes,
sodium alginate, and the like.
[0136] "Carriers" or "carrier materials" include any commonly used
excipients in pharmaceutics and should be selected on the basis of
compatibility with cromolyn or a pharmaceutically acceptable salt
thereof and the release profile properties of the desired dosage
form. Exemplary carrier materials include, e.g., binders,
suspending agents, disintegration agents, filling agents,
surfactants, solubilizers, stabilizers, lubricants, wetting agents,
diluents, and the like. "Pharmaceutically compatible carrier
materials" may include, but are not limited to, acacia, gelatin,
colloidal silicon dioxide, calcium glycerophosphate, calcium
lactate, maltodextrin, glycerine, magnesium silicate,
polyvinylpyrrollidone (PVP), cholesterol, cholesterol esters,
sodium caseinate, soy lecithin, taurocholic acid,
phosphotidylcholine, sodium chloride, tricalcium phosphate,
dipotassium phosphate, cellulose and cellulose conjugates, sugars
sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride,
pregelatinized starch, and the like. See, e.g., Remington: The
Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack
Publishing Company, 1995); Hoover, John E., Remington's
Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975;
Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,
Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage
Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams
& Wilkins 1999).
[0137] "Dispersing agents" and/or "viscosity modulating agents"
include materials that control the diffusion and homogeneity of a
drug through liquid media or a granulation method or blend method.
In certain embodiments, these agents also facilitate the
effectiveness of a coating or eroding matrix. Exemplary diffusion
facilitators/dispersing agents include, e.g., hydrophilic polymers,
electrolytes, Tween.RTM. 60 or 80, PEG, Tyloxapol,
polyvinylpyrrolidone (PVP; commercially known as Plasdone.RTM.),
and the carbohydrate-based dispersing agents such as, for example,
hydroxypropyl celluloses (e.g., HPC, HPC-SL, and HPC-L),
hydroxypropyl methylcelluloses (e.g., HPMC K100, HPMC K4M, HPMC
K15M, and HPMC K100M), carboxymethylcellulose sodium,
methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose phthalate,
hydroxypropylmethylcellulose acetate stearate (HPMCAS),
noncrystalline cellulose, magnesium aluminum silicate,
triethanolamine, polyvinyl alcohol (PVA), vinyl pyrrolidone/vinyl
acetate copolymer (S630), 4-(1,1,3,3-tetramethylbutyl)-phenol
polymer with ethylene oxide and formaldehyde (also known as
tyloxapol), poloxamers (e.g., Pluronics F68.RTM., F88.RTM., and
F108.RTM., which are block copolymers of ethylene oxide and
propylene oxide); and poloxamines (e.g., Tetronic 908.RTM., also
known as Poloxamine 908.RTM., which is a tetrafunctional block
copolymer derived from sequential addition of propylene oxide and
ethylene oxide to ethylenediamine (BASF Corporation, Parsippany,
N.J.)), polyvinylpyrrolidone K12, polyvinylpyrrolidone K17,
polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30,
polyvinylpyrrolidone/vinyl acetate copolymer (S-630), polyethylene
glycol, e.g., the polyethylene glycol can have a molecular weight
of about 300 to about 6000, or about 3350 to about 4000, or about
7000 to about 5400, sodium carboxymethylcellulose, methylcellulose,
polysorbate-80, sodium alginate, gums, such as, e.g., gum
tragacanth and gum acacia, guar gum, xanthans, including xanthan
gum, sugars, cellulosics, such as, e.g., sodium
carboxymethylcellulose, methylcellulose, sodium
carboxymethylcellulose, polysorbate-80, sodium alginate,
polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan
monolaurate, povidone, carbomers, polyvinyl alcohol (PVA),
alginates, chitosans and combinations thereof. Plasticizcers such
as cellulose or triethyl cellulose can also be used as dispersing
agents. Dispersing agents particularly useful in liposomal
dispersions and self-emulsifying dispersions are dimyristoyl
phosphatidylcholine, natural phosphatidyl choline from eggs,
natural phosphatidyl glycerol from eggs, cholesterol and isopropyl
myristate.
[0138] "Diluent" refers to chemical compounds that are used to
dilute the compound of interest (i.e. cromolyn or a
pharmaceutically acceptable salt thereof) prior to delivery.
Diluents can also be used to stabilize compounds because they can
provide a more stable environment. Salts dissolved in buffered
solutions, including, but not limited to, a phosphate buffered
saline solution, are utilized as diluents in the art, and can also
provide pH control or maintenance. In certain embodiments, diluents
increase bulk of the composition to facilitate compression or
create sufficient bulk for homogenous blend for capsule filling.
Such compounds include e.g., lactose, starch, mannitol, sorbitol,
dextrose, microcrystalline cellulose such as Avicel.RTM.; dibasic
calcium phosphate, dicalcium phosphate dihydrate; tricalcium
phosphate, calcium phosphate; anhydrous lactose, spray-dried
lactose; pregelatinized starch, compressible sugar, such as
Di-Pac.RTM. (Amstar); mannitol, hydroxypropylmethylcellulose,
hydroxypropylmethylcellulose acetate stearate, sucrose-based
diluents, confectioner's sugar; monobasic calcium sulfate
monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate,
dextrates; hydrolyzed cereal solids, amylose; powdered cellulose,
calcium carbonate; glycine, kaolin; mannitol, sodium chloride;
inositol, bentonite, and the like.
[0139] "Flavoring agents" and/or "sweeteners" useful in the
formulations described herein, include, e.g., acacia syrup,
acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian
cream, berry, black currant, butterscotch, calcium citrate,
camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble
gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola,
cool cherry, cool citrus, cyclamate, cylamate, dentomint, dextrose,
eucalyptus, eugenol, fructose, fruit punch, ginger,
glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit,
honey, isomalt, lemon, lime, lemon cream, monoammonium
glyrrhizinate (MagnaSweet.RTM.), maltol, mannitol, maple,
marshmallow, menthol, mint cream, mixed berry, neohesperidine DC,
neotame, orange, pear, peach, peppermint, peppermint cream,
Prosweet.RTM. Powder, raspberry, root beer, rum, saccharin,
safrole, sorbitol, spearmint, spearmint cream, strawberry,
strawberry cream, stevia, sucralose, sucrose, sodium saccharin,
saccharin, aspartame, acesulfame potassium, mannitol, talin,
sylitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine,
thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry,
wintergreen, xylitol, or any combination of these flavoring
ingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange,
cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime,
lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and
mixtures thereof.
[0140] "Lubricants" and "glidants" are compounds that prevent,
reduce or inhibit adhesion or friction of materials. Exemplary
lubricants include, e.g., stearic acid, calcium hydroxide, talc,
sodium stearyl fumerate, a hydrocarbon such as mineral oil, or
hydrogenated vegetable oil such as hydrogenated soybean oil
(Sterotex.RTM.), higher fatty acids and their alkali-metal and
alkaline earth metal salts, such as aluminum, calcium, magnesium,
zinc, stearic acid, sodium stearates, glycerol, talc, waxes,
Stearowet.RTM., boric acid, sodium benzoate, sodium acetate, sodium
chloride, leucine, a polyethylene glycol (e.g., PEG-4000) or a
methoxypolyethylene glycol such as Carbowax.TM., sodium oleate,
sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium
or sodium lauryl sulfate, colloidal silica such as Syloid.TM.,
Cab-O-Sil.RTM., a starch such as corn starch, silicone oil, a
surfactant, and the like.
[0141] "Plasticizers" are compounds used to soften the
microencapsulation material or film coatings to make them less
brittle. Suitable plasticizers include, e.g., polyethylene glycols
such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800,
stearic acid, propylene glycol, oleic acid, triethyl cellulose and
triacetin. In certain embodiments, plasticizers can also function
as dispersing agents or wetting agents.
[0142] In certain embodiments, compositions provided herein may
also include one or more preservatives to inhibit microbial
activity. Suitable preservatives include mercury-containing
substances such as merfen and thiomersal; stabilized chlorine
dioxide; octinidine; and quaternary ammonium compounds such as
benzalkonium chloride, cetyltrimethylammonium bromide and
cetylpyridinium chloride.
[0143] "Solubilizers" include compounds such as triacetin,
triethylcitrate, ethyl oleate, ethyl caprylate, sodium lauryl
sulfate, sodium doccusate, vitamin E TPGS, polysorbates (Tweens)
dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone,
polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl
cyclodextrins, ethanol, n-butanol, isopropyl alcohol, cholesterol,
bile salts, polyethylene glycol 200-600, glycofurol, transcutol,
propylene glycol, and dimethyl isosorbide and the like.
[0144] "Stabilizers" include compounds such as any antioxidation
agents, e.g., citric acid, EDTA and pharmaceutically acceptable
salts thereof, buffers, acids, preservatives and the like.
[0145] "Suspending agents" include compounds such as
polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12,
polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or
polyvinylpyrrolidone K30, vinyl pyrrolidone/vinyl acetate copolymer
(S630), polyethylene glycol, e.g., the polyethylene glycol can have
a molecular weight of about 300 to about 6000, or about 3350 to
about 4000, or about 7000 to about 5400, sodium
carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, hydroxymethylcellulose acetate
stearate, polysorbate-80, hydroxyethylcellulose, sodium alginate,
gums, such as, e.g., gum tragacanth and gum acacia, guar gum,
xanthans, including xanthan gum, sugars, cellulosics, such as,
e.g., sodium carboxymethylcellulose, methylcellulose, sodium
carboxymethylcellulose, hydroxypropylmethylcellulose,
hydroxyethylcellulose, polysorbate-80, sodium alginate,
polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan
monolaurate, povidone and the like.
[0146] "Surfactants" include compounds such as sodium lauryl
sulfate, sodium docusate, Tween 60 or 80, triacetin, vitamin E
TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate,
polysorbates, polaxomers, bile salts, glyceryl monostearate,
copolymers of ethylene oxide and propylene oxide, e.g.,
Pluronic.RTM. (BASF), and the like. Some other surfactants include
polyoxyethylene fatty acid glycerides and vegetable oils, e.g.,
polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene
alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol
40. In certain embodiments, surfactants may be included to enhance
physical stability or for other purposes.
[0147] "Viscosity enhancing agents" include, e.g., methyl
cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl
cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl
cellulose acetate stearate, hydroxypropylmethyl cellulose
phthalate, carbomer, polyvinyl alcohol, alginates, acacia,
chitosans, and combinations thereof.
[0148] "Wetting agents" include compounds such as oleic acid,
glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate,
triethanolamine oleate, polyoxyethylene sorbitan monooleate,
polyoxyethylene sorbitan monolaurate, sodium docusate, sodium
oleate, sodium lauryl sulfate, sodium doccusate, triacetin, Tween
80, vitamin E TPGS, ammonium salts and the like.
[0149] It should be appreciated that there is considerable overlap
between classes of inactive ingredients. Thus, the above-listed
ingredients should be taken as merely exemplary, and not limiting,
of the types of inactive ingredients that can be included in
formulations described herein. The amounts of such inactive
ingredients can be readily determined by one skilled in the art,
according to the particular properties desired.
Liquid Oral Formulations
[0150] Liquid formulation dosage forms for oral administration can
be aqueous suspensions selected from the group including, but not
limited to, pharmaceutically acceptable aqueous oral dispersions,
emulsions, solutions, elixirs, gels, and syrups. See, e.g., Singh
et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp.
754-757 (2002). In addition to the particles of cromolyn or a
pharmaceutically-acceptable salt thereof, the liquid dosage forms
may include additives, such as: (a) disintegrating agents; (b)
dispersing agents; (c) wetting agents; (d) at least one
preservative, (e) viscosity enhancing agents, (f) at least one
sweetening agent, and (g) at least one flavoring agent. In certain
embodiments, the aqueous dispersions can further include a
crystalline inhibitor. In certain embodiments, systemically
effective amounts of cromolyn or a pharmaceutically-acceptable salt
thereof are achieved with liquid oral formulations by including
permeation enhancers in the liquid oral formulations.
[0151] Examples of disintegrating agents for use in the aqueous
suspensions and dispersions include, but are not limited to, a
starch, e.g., a natural starch such as corn starch or potato
starch, a pregelatinized starch such as National 1551 or
Amijel.RTM., or sodium starch glycolate such as Promogel.RTM. or
Explotab.RTM.; a cellulose such as a wood product,
methylcrystalline cellulose, e.g., Avicel.RTM., Avicel.RTM. PH101,
Avicel.RTM. PH102, Avicel.RTM. PH105, Elcema.RTM. P100,
Emcocel.RTM., Vivacel.RTM., Ming Tia.RTM., and Solka-Floc.RTM.,
methylcellulose, croscarmellose, or a cross-linked cellulose, such
as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol.RTM.),
cross-linked carboxymethylcellulose, or cross-linked
croscarmellose; a cross-linked starch such as sodium starch
glycolate; a cross-linked polymer such as crospovidone; a
cross-linked polyvinylpyrrolidone; alginate such as alginic acid or
a salt of alginic acid such as sodium alginate; a clay such as
Veegum.RTM. HV (magnesium aluminum silicate); a gum such as agar,
guar, locust bean, Karaya, pectin, or tragacanth; sodium starch
glycolate; bentonite; a natural sponge; a surfactant; a resin such
as a cation-exchange resin; citrus pulp; sodium lauryl sulfate;
sodium lauryl sulfate in combination starch; and the like.
[0152] In certain embodiments, the dispersing agents suitable for
the aqueous suspensions and dispersions described herein include,
for example, hydrophilic polymers, electrolytes, Tween.RTM. 60 or
80, PEG, polyvinylpyrrolidone (PVP; commercially known as
Plasdone.RTM.), and the carbohydrate-based dispersing agents such
as, for example, hydroxypropylcellulose and hydroxypropyl cellulose
ethers (e.g., HPC, HPC-SL, and HPC-L), hydroxypropyl
methylcellulose and hydroxypropyl methylcellulose ethers (e.g. HPMC
K100, HPMC K4M, HPMC K15M, and HPMC K100M), carboxymethylcellulose
sodium, methylcellulose, hydroxyethylcellulose,
hydroxypropylmethyl-cellulose phthalate,
hydroxypropylmethyl-cellulose acetate stearate, noncrystalline
cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl
alcohol (PVA), polyvinylpyrrolidone/vinyl acetate copolymer
(Plasdone.RTM., e.g., S-630), 4-(1,1,3,3-tetramethylbutyl)-phenol
polymer with ethylene oxide and formaldehyde (also known as
tyloxapol), poloxamers (e.g., Pluronics F68.RTM., F88.RTM., and
F108.RTM., which are block copolymers of ethylene oxide and
propylene oxide); and poloxamines (e.g., Tetronic 908.RTM., also
known as Poloxamine 908.RTM., which is a tetrafunctional block
copolymer derived from sequential addition of propylene oxide and
ethylene oxide to ethylenediamine (BASF Corporation, Parsippany,
N.J.)). In other embodiments, the dispersing agent is selected from
a group not comprising one of the following agents: hydrophilic
polymers; electrolytes; Tween.RTM. 60 or 80; PEG;
polyvinylpyrrolidone (PVP); hydroxypropylcellulose and
hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and HPC-L);
hydroxypropyl methylcellulose and hydroxypropyl methylcellulose
ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M, and
Pharmacoat.RTM. USP 2910 (Shin-Etsu)); carboxymethylcellulose
sodium; methylcellulose; hydroxyethylcellulose;
hydroxypropylmethyl-cellulose phthalate;
hydroxypropylmethyl-cellulose acetate stearate; non-crystalline
cellulose; magnesium aluminum silicate; triethanolamine; polyvinyl
alcohol (PVA); 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with
ethylene oxide and formaldehyde; poloxamers (e.g., Pluronics
F68.RTM., F88.RTM., and F108.RTM., which are block copolymers of
ethylene oxide and propylene oxide); or poloxamines (e.g., Tetronic
908.RTM., also known as Poloxamine 908.RTM.).
[0153] Wetting agents suitable for the aqueous suspensions and
dispersions described herein include, but are not limited to, cetyl
alcohol, glycerol monostearate, polyoxyethylene sorbitan fatty acid
esters (e.g., the commercially available Tweens.RTM. such as e.g.,
Tween 20.RTM. and Tween 80.RTM. (ICI Specialty Chemicals)), and
polyethylene glycols (e.g., Carbowaxs 3350.RTM. and 1450.RTM., and
Carbopol 934.RTM. (Union Carbide)), oleic acid, glyceryl
monostearate, sorbitan monooleate, sorbitan monolaurate,
triethanolamine oleate, polyoxyethylene sorbitan monooleate,
polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl
sulfate, sodium docusate, triacetin, vitamin E TPGS, sodium
taurocholate, simethicone, phosphotidylcholine and the like.
[0154] Compositions and formulations of the disclosure may have a
surface tension effective for deposition, penetration or retention
of the composition primarily in the peripheral lung regions,
including the bronchioles and alveoli. In certain embodiments, the
compositions and formulations of the disclosure may have a surface
tension in the range similar to that or water or higher. In certain
embodiments, the compositions and formulations according to the
present disclosure has a surface tension of at least about 30 mN/m,
or at least about 40 mN/m, or at least about 50 mN/m, or at least
about 60 mN/m, or at least about 70 mN/m. In some embodiments, the
compositions and formulations has a surface tension in the range of
about 30 mN/m to about 75 mN/m, or about 50 mN/m to about 75 mN/m,
or about 70 mN/m to about 75 mN/m.
[0155] Compositions and formulations of the disclosure may exclude,
or, may not comprise a surfactant. In certain embodiments,
compositions of the disclosure may not comprise any dispersing
agent, solubilizing agent, or spreading agent. Some examples of
surfactants that are excluded from the present compositions and
formulations include: PEG (polyethylene glycol) 400; Sodium lauryl
sulfate sorbitan laurate, sorbitan palmitate, sorbitan stearate
available under the tradename Span.RTM. (20-40-60 etc.);
polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20)
sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate
available under the tradename Tween (polysorbates, 20-40-60 etc.);
tyloxapol; propylene glycol; and Benzalkoniumrn chloride,
vitamin-TPGS and lecithins, (Exosurf.RTM., GlaxoSmithKline),
surfactant proteins. In certain embodiments, surfactants that are
excluded from the present compositions and formulations include any
compound or agent that lowers the surface tension of a
composition.
Inhalation Therapy
[0156] An "inhalation device," as used herein, refers to any device
that is capable of administering a drug formulation to the
respiratory airways of a subject. Inhalation devices include
conventional inhalation devices such as nebulizers, metered dose
inhalers (MDIs), dry powder inhalers (DPIs), jet nebulizers,
ultrasonic wave nebulizers, heat vaporizers, and soft mist
inhalers. Inhalation devices also include nebulizers. Nebulizers,
metered dose inhalers, and soft mist inhalers deliver
pharmaceuticals by forming an aerosol which includes droplet sizes
that can easily be inhaled. The aerosol can be used by a subject
within the bounds of an inhalation therapy, whereby the cromolyn or
a pharmaceutically-acceptable salt thereof reaches the subject's
respiratory tract upon inhalation. In certain embodiments, the
methods disclosed herein comprise administering to a subject a
nominal dose of cromolyn or a pharmaceutically-acceptable salt
thereof by an inhalation device, such as a nebulizer. In certain
embodiments of the methods disclosed herein, an inhalation device
is not a bronchoscope.
[0157] In certain embodiments of the methods disclosed herein,
administration of a composition comprising cromolyn or a
pharmaceutically acceptable salt thereof, e.g., cromolyn sodium, to
a subject with an inhalation device, e.g., a nebulizer, a dry
powder inhaler, a metered dose inhaler, a thermal aerosol inhaler,
or an electrohydrodynamic-based solution misting inhaler, is
effective for the treatment or prophylaxis of chronic cough due to
IPF because both a systemically effective amount of the cromolyn or
a pharmaceutically acceptable salt thereof and a high deposited
lung dose of the cromolyn or a pharmaceutically acceptable salt
thereof is achieved in the subject. Thus, in certain embodiments of
the methods disclosed herein, administration of a composition
comprising cromolyn or a pharmaceutically acceptable salt thereof,
e.g., cromolyn sodium, to a subject with an inhalation device,
e.g., a nebulizer, a dry powder inhaler, a metered dose inhaler, a
thermal aerosol inhaler, or an electrohydrodynamic-based solution
misting inhaler, is effective for the treatment or prophylaxis of
chronic cough due to IPF that may not be believed to be susceptible
to treatment or prophylaxis with cromolyn or a pharmaceutically
acceptable salt thereof because both a systemically effective
amount of the cromolyn or a pharmaceutically acceptable salt
thereof and a high deposited lung dose of the cromolyn or a
pharmaceutically acceptable salt thereof are achieved in the
subject. Furthermore, in certain embodiments where cromolyn or a
pharmaceutically acceptable salt thereof is administered with an
inhalation device, e.g., a nebulizer, a dry powder inhaler, a
metered dose inhaler, a thermal aerosol inhaler, or an
electrohydrodynamic-based solution misting inhaler, the methods
disclosed herein provide improved efficacy for the treatment or
prophylaxis of chronic cough due to IPF relative to administration
of a systemically effective amount of the cromolyn or a
pharmaceutically acceptable salt thereof by a different route of
administration, e.g., parenterally or orally, because
administration of the cromolyn or a pharmaceutically acceptable
salt thereof with an inhalation device, e.g., a nebulizer, a dry
powder inhaler, a metered dose inhaler, a thermal aerosol inhaler,
or an electrohydrodynamic-based solution misting inhaler, provides
both a systemically effective amount of the cromolyn or a
pharmaceutically acceptable salt thereof and a high deposited lung
dose of the cromolyn or a pharmaceutically acceptable salt thereof
in the subject. In certain embodiments, a systemically effective
amount of cromolyn or a pharmaceutically acceptable salt thereof is
achieved by delivering the cromolyn or a pharmaceutically
acceptable salt thereof in an aerosol generated by a vibrating mesh
nebulizer that produces droplets with a MMD of 3.0-4.0 .mu.m and a
GSD of 1.5-1.8. In certain embodiments of the methods disclosed
herein, an aerosol is administered through a mouthpiece of a
nebulizer using normal tidal breathing.
Characterization of Inhalation Devices
[0158] The efficiency of a particular inhalation device can be
characterized in many different ways, including by pharmacokinetic
properties, lung deposition (deposited lung dose), respirable dose
(RD), delivered dose (DD), respirable fraction (RF), respirable
drug delivery rate (RDDR), volumetric or mass median diameter (VMD
or MMD), mass median aerodynamic diameter (MMAD) in combination
with the geometric standard deviation (GSD), and total output rate
(TOR), among others. The MMAD and GSD can be measured using a
cascade impactor as described in United States Phamacopeia
(USP<1601>). The DD can be measured by using breath
simulation apparatus as described in USP<1601>.
[0159] The RF is derived from measuring the amount of drug
deposited on the cascade impactor plates with a particular cut-off
particle size, and expressing that as a fraction of the total
amount deposited on the cascade impactor plates, the induction port
and the filter. Thus, RF refers to a distribution of particles of
an aerosol indicative of the percentages of the total mass or
volume of the aerosol that are contained in particles of certain
sizes. Such a mass/volume distribution expressed as the resipirable
fraction (RF) is different from a distribution based on the
percentages of the total number of particles in the aerosol that
have certain particle sizes.
[0160] Since it takes fewer large particles to equal the mass or
volume of a large number of small particles, a number distribution
of particles contained in an aerosol can be markedly different from
a mass distribution of the same particles in the same aerosol. As a
simplified numerical example, consider an aerosol containing in
total 9 particles: three 1 .mu.m particles, three 2 .mu.m
particles, and three 3 .mu.m particles, in size (diameter).
Building a number distribution for these particles will generate a
distribution where each particle size accounts for one third of the
total. Yet, building a mass distribution for the same particles
will generate a distribution, where 75% of the total mass/volume of
the aerosol comes from the 3 .mu.m particles, and less than 3%
comes from the 1 .mu.m particles. This is determined as follows:
the volume of a spherical particle of diameter d is
4/3*.pi.*(d/2).sup.3. The volumes of the 1 .mu.m, 2 .mu.m and 3
.mu.m particles would therefore be 0.52.mu..sup.3, 4.2.mu..sup.3,
and 14.13.mu..sup.3. Assuming unit density for all particles, these
numbers would also represent the mass of the particles. Thus, the 3
.mu.m particles would constitute 100*14.13/(0.52+4.2+14.13)=74.96%
of the total mass. Likewise, the 2 .mu.m particles will constitute
22.3% of the total mass and the 1 .mu.m particles will be 2.8% of
the total mass.
[0161] The RD is calculated by multiplying the DD by the RF. The
TOR is measured by the difference in weight of a nebulizer before
and after completion of nebulization divided by the duration of
nebulization. VMD or MMD can be measured with a standard laser
light scattering apparatus such as the Malvern Spraytec.
[0162] Pharmacokinetics is concerned with the uptake, distribution,
metabolism and excretion of a drug substance in a subject. A
pharmacokinetic profile comprises one or more biological
measurements designed to measure the absorption, distribution,
metabolism and excretion of a drug substance in a subject. 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 in a subject 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 AUC.sub.last, AUC.sub.(0-.infin.),
C.sub.max, T.sub.1/2, and T.sub.max. An enhanced pharmacokinetic
profile in a subject can be indicated by increased AUC.sub.last,
AUC.sub.(0-.infin.), C.sub.max, or T.sub.1/2, a decreased
T.sub.max, or an increased T.sub.max. Enhanced levels of cromolyn
or a pharmaceutically-acceptable salt thereof in the blood plasma
of a subject may result in better control of or improved symptoms
of chronic cough due to IPF.
[0163] The deposited lung dose may be expressed as a percentage of
the nominal dose that is deposited in the lung of a subject. For
example, a lung deposition of 30% means 30% of the nominal dose is
deposited in the lung of a subject. Likewise, a lung deposition of
60% means 60% of the nominal dose is deposited in the lung of a
subject, and so forth. Lung deposition (deposited lung dose) can be
determined using methods of scintigraphy or deconvolution.
[0164] Since cromolyn sodium is not metabolized in the body and
approximately 50% of absorbed cromolyn is excreted in urine (Auty
et al, Br. J Dis. Chest Vol. 81, No. 4, 1987, 371-380), and since
its oral bioavailability is very low (.about.1%), the deposited
lung dose for cromolyn during inhalation can also be determined by
measuring the cromolyn sodium content in the urine and multiplying
that number by two.
[0165] RF, DD, RD, and RDDR are calculated parameters based on in
vitro data that provide technical dimensions for the efficiency of
an inhalation device. RF represents the percentage of the delivered
aerosol, or inhaled mass, that penetrates into the gas-exchange
region of the lungs. RF may be measured with a cascade impactor or
laser diffraction apparatus. RF is expressed herein as the
percentage of an aerosol delivered with an inhalation device that
has a particular particle diameter or range of particle diameters.
For example, the term "RF (.ltoreq.3.3 .mu.m)" as used herein
refers to the percentage of an aerosol delivered with an inhalation
device that has a particle diameter less than or equal to 3.3
.mu.m. Similarly, the terms "RF (1-5 .mu.m)" and "RF (.ltoreq.5
.mu.m)" as used herein refer to the percentage of an aerosol
delivered with an inhalation device that has a particle diameter in
the range of 1 .mu.m to 5 .mu.m, or less than 5 .mu.m,
respectively. DD is the portion or percentage of the nominal dose
that is actually emitted from the mouthpiece of the device. The
difference between the nominal dose and the DD is the amount of
drug lost primarily as residues, i.e., the amount of drug remaining
in the inhalation device after administration or lost in aerosol
form during exhalation. RD is an expression of the delivered mass
of drug contained within droplets or particles having a certain
diameter emitted from an inhalation device, such as a DPI, MDI, or
nebulizer, that are small enough to penetrate into the lung of a
subject. The RD is determined by multiplying the DD by the RF. RDDR
is the speed at which a respirable dose of the drug is delivered to
a subject's lungs. RDDR, measured as a function of g/min or mg/min,
is determined by dividing the RD by the amount of time necessary
for inhalation. The amount of time necessary for inhalation is
measured as the amount of time from the first moment of
administration of the emitted droplet or powder from the nebulizer,
DPI, or MDI until the emitted or delivered droplet or powder of a
respirable diameter is delivered to the lung.
[0166] Aerosol particle/droplet size is one factor determining the
deposition of aerosol drugs in the airways. The distribution of
aerosol particle/droplet size can be expressed in terms of one or
more of VMD/MMAD and GSD. GSD is a dimensionless measure of a
droplet size distribution curve relevant for characterizing terms
such as VMD, MMD, and MMAD. In general, the smaller the GSD for a
particular particle size distribution, the narrower the
distribution curve.
Inhalation Devices
[0167] Inhalation devices may be mechanical or electrical, and
include, for example, jet nebulizers, and ultrasonic nebulizers.
Jet nebulizers generally utilize compressors to generate compressed
air, which breaks the liquid medication into small breathable
droplets, which form an aerosolized (atomized) mist. In certain
embodiments, when the subject breathes in, a valve at the top
opens, which then allows air into the apparatus, thereby speeding
up the mist generation; when the subject breathes out, the top
valve closes, thereby slowing down the mist generation while
simultaneously permitting the subject to breathe out through the
opening of a mouthpiece flap. Some nebulizers may provide the
aerosol in a continuous mode (e.g., the eFlow from PARI Pharma
Stamberg), by a breath enhanced mode (e.g., the PARI LC Plus or
Sprint from PARI Stamberg), by breath actuated mode dependent on
the breathing pattern of the subject (e.g., the AeroEclipse from
Trudell, Canada or the I-Neb from Philips Respironics), or
according to given inhalation profile (e.g., the Akita from
Activaero, Gmuenden, Germany).
[0168] Some conventional inhalation devices are disclosed in U.S.
Pat. Nos. 6,513,727, 6,513,519, 6,176,237, 6,085,741, 6,000,394,
5,957,389, 5,740,966, 5,549,102, 5,461,695, 5,458,136, 5,312,046,
5,309,900, 5,280,784, and 4,496,086, each of which is hereby
incorporated by reference in its entirety. Commercial conventional
inhalation devices are available from: PARI (Germany) under the
trade names PARI LC Plus.RTM., LC Star.RTM., and PARI-Jet.RTM.; A
& H Products, Inc. (Tulsa, Okla.) under the trade name
AquaTower.RTM.; Hudson RCI (Temecula, Calif.) under the trade name
AVA-NEB.RTM.; Intersurgical, Inc. (Liverpool, N.Y.) under the trade
name Cirrus.RTM.; Salter Labs (Arvin, Calif.) under the trade name
Salter 8900.RTM.; Respironics (Murrysville, Pa.) under the trade
name Sidestream.RTM.; Bunnell (Salt Lake City, Utah) under the
trade name Whisper Jet.RTM.; Smiths-Medical (Hyth Kent, UK) under
the trade name Downdraft.RTM., and DeVilbiss (Somerset, Pa.) under
the trade name DeVilbiss.RTM.; or Trudell, Canada under the trade
name AeroEclipse.RTM..
[0169] In certain embodiments of the methods disclosed herein,
compositions comprising cromolyn or a pharmaceutically-acceptable
salt thereof are administered with a dry powder inhaler. In certain
embodiments of the methods disclosed herein, compositions
administered with dry powder inhalers comprise one or more of
nanoparticles, spray dried materials, engineered porous particles
with low mass median diameter but a high geometric diameter,
liposomes, and stealth (or PEGylated) liposomes. In certain
embodiments, compositions administered by dry powder inhalers
administered in the methods disclosed herein comprise nanoparticle
clusters that aggregate into micrometer sized particles at neutral
or basic pH but dissociate into nanoparticles at the pH encountered
in the lung. In certain embodiments the nanoparticle clusters
comprise fumaryl diketopiperazine. In certain embodiments,
compositions administered with dry powder inhalers comprise
lactose. In certain embodiments, compositions administered with dry
powder inhalers do not comprise lactose. In certain embodiments,
compositions administered with a dry powder inhaler have a MMAD
between 2 and 4 .mu.m, a GSD between 1.5 and 2.5 .mu.m, and an RF
(.ltoreq.5 .mu.m) between 30% and 80%. In certain embodiments, a
dry powder inhaler used to administer an inhalation formulation in
the methods disclosed herein comprises a pre-metered dose, such as
Plastiape Monodose inhaler, which comprises a capsule pre-filled
with a powder. In certain embodiments, a dry powder inhaler used to
administer an inhalation formulation in the methods disclosed
herein has a device-metered system such as Twisthaler, sold by
Schering Plough, which comprises a reservoir to store a powder and
a twisting top to dispense each dose. Inhalation formulations for
administration with a dry powder inhaler may be prepared by
blending cromolyn or a pharmaceutically acceptable salt thereof,
e.g., cromolyn sodium, with lactose, or spray drying cromolyn or a
pharmaceutically acceptable salt thereof, e.g., cromolyn sodium, or
by pelletizing cromolyn or a pharmaceutically acceptable salt
thereof, e.g., cromolyn sodium, to form free-flowing spherical
agglomerates.
[0170] In certain embodiments of the methods disclosed herein,
compositions comprising cromolyn or a pharmaceutically acceptable
salt thereof are administered with a metered dose inhaler. In
certain embodiments, a composition administered with a metered dose
inhaler in the methods disclosed herein comprises one or more of
nanoparticles, spray dried materials, engineered porous particles
with low mass median diameter but a high geometric diameter,
liposomes, and stealth (or PEGylated) liposomes.
[0171] In certain embodiments of the methods disclosed herein,
compositions comprising cromolyn or a pharmaceutically acceptable
salt thereof are administered with a thermal aerosol inhaler. In
certain embodiments, the aerosol in a thermal aerosol inhaler is
generated by directly heating and vaporizing a thin solid film of
the cromolyn or a pharmaceutically acceptable salt thereof, e.g.,
cromolyn sodium, or by heating and vaporizing a solution of
cromolyn or a pharmaceutically acceptable salt thereof, e.g.,
cromolyn sodium in solvents such as propylene glycol and/or
glycerol and water.
[0172] In certain embodiments of the methods disclosed herein,
compositions comprising cromolyn or a pharmaceutically acceptable
salt thereof are administered with an electrohydrodynamic-based
solution misting inhaler. In certain embodiments, the aerosol in
the electrohydrodynamic-based solution-misting inhaler is generated
by subjecting a solution of cromolyn or a pharmaceutically
acceptable salt thereof, e.g., cromolyn sodium, or a liposome or
pegylated liposome comprising cromolyn or a pharmaceutically
acceptable salt thereof, e.g., cromolyn sodium, to
electrohydrodynamic forces through electrostatic energy.
Nebulizers
[0173] Nebulizers are inhalation devices that comprise a
micro-perforated membrane through which a liquid solution is
converted through electrical or mechanical means into aerosol
droplets suitable for inhalation. Nebulizers can deliver a large
fraction of a loaded dose to a subject. In certain embodiments, the
nebulizer also utilizes one or more actively or passively vibrating
microperforated membranes. In certain embodiments, the nebulizer
contains one or more oscillating membranes. In certain embodiments,
the 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 certain 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
subject inhales the aerosol from the mixing chamber. Still yet, in
certain embodiments, the nebulizer contains a pulsating membrane.
In certain embodiments, the nebulizer is continuously
operating.
[0174] In certain embodiments, the nebulizer contains a vibrating
micro-perforated membrane of tapered nozzles that generates a plume
of droplets without the need for compressed gas. In these
embodiments, a solution in the micro-perforated 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.
[0175] Certain embodiments of nebulizers use passive nozzle
membranes and a separate piezoelectric transducer that stimulates
the membrane. In contrast, some 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.
[0176] Some nebulizers contain a resonant system. In some such
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 certain embodiments, the vibrating membrane
of the nebulizer may be made stainless steel, or of a
nickel-palladium alloy by electroforming.
[0177] In certain embodiments, a nebulizer may be adapted or
adaptable to operate in conjunction with a unit dosage form, such
as an ampule or vial, which contains a single dose of composition
comprising cromolyn or a pharmaceutically-acceptable salt thereof
for the treatment of chronic cough due to IPF. The unit dosage form
comprises a container that contains an inhalation formulation
comprising the cromolyn or a pharmaceutically-acceptable salt
thereof, such as cromolyn sodium. The container is adapted to
cooperate with the nebulizer device in such a way as to permit
administration of the nominal dose of the inhalation formulation to
a subject. In certain embodiments, the nebulizer and the unit
dosage form are configured so that they are useable together, but
not with other devices or dosage forms. In some particular
embodiments, the unit dosage form is configured such that it fits
into a keyhole-like structure in the nebulizer, but will not
operate with other nebulizer devices. In such embodiments, the
nebulizer is configured such that it will accept and properly
operate with the unit dosage form containing the cromolyn or a
pharmaceutically-acceptable salt thereof, but not with other dosage
forms.
[0178] Commercial high efficiency nebulizers are available from:
PARI (Germany) under the trade name eFlow.RTM.; Aerogen, Ltd.
(Ireland) under the trade names AeroNeb.RTM. Go and AeroNeb.RTM.
Pro, AeroNeb.RTM. Solo, and other nebulizers utilizing the OnQ.RTM.
nebulizer technology; Respironics (Murrysville, Calif.) under the
trade names I-Neb.RTM.; Omron (Bannockbum, Ill.) under the trade
name Micro-Air.RTM.; Activaero (Germany) under the trade name
Akita.RTM., and AerovectRx (Atlanta, Ga.) under the trade name
AerovectRx.RTM..
[0179] In certain embodiments, the methods disclosed herein
comprise administration to a subject a nominal dose of cromolyn or
a pharmaceutically-acceptable salt thereof with a nebulizer,
wherein administration of the nominal dose of the cromolyn or a
pharmaceutically-acceptable salt thereof to the subject provides
one or more of the following advantages: (1) an enhanced
pharmacokinetic profile as compared to administration of an oral
solution; (2) an enhanced therapeutic effect as compared to
administration of an oral solution; (3) an enhanced lung deposition
(deposited lung dose) as compared with some inhalation devices used
with other cromolyn sodium compositions evidenced by scintigraphy
or deconvolution, or derived from suitable in vitro indicators such
as enhanced RD, RDDR, RF, and lower GSDs, as compared to
administration with some inhalation devices used with other
cromolyn sodium compositions; (4) reduced administration times,
periods, and/or volumes as compared to administration with some
other formulations and inhalation devices; (5) a reduction in
adverse side effects associated with oral formulations of cromolyn
or a pharmaceutically-acceptable salt thereof, such as
gastrointestinal irritation; and (6) a longer duration of
therapeutic effect as compared to administration of an oral
solution or an inhaled formulations using other formulations of
cromolyn sodium with other inhalation devices.
[0180] In certain embodiments, the DD expressed as the percentage
of the nominal dose of cromolyn or a pharmaceutically-acceptable
salt thereof administered with a nebulizer in the methods disclosed
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%, about 65%, about 70%, about
30% to about 90%, about 40% to about 80%, about 45% to about 75%,
about 50% to about 70%, about 30% to about 75%, about 40% to about
70%, about 45% to about 60%, or about 60% to about 70%.
[0181] TOR is the speed at which the liquid containing cromolyn or
a pharmaceutically-acceptable salt thereof is administered from the
inhalation device. In certain embodiments, administration of the
cromolyn or a pharmaceutically-acceptable salt thereof with the
nebulizer provides a TOR of at least about 2 times, 3 times or 4
times the TOR achievable with a conventional inhalation device,
such as a nebulizer. For example, in certain embodiments the TOR is
at least about at least about 150 mg/min, at least about 200
mg/min, at least about 250 mg/min, at least 300 mg/min, at least
350 mg/min, at least 400 mg/min, at least 500 mg/min, or from 200
to about 700 mg/min.
[0182] In certain embodiments, use of a nebulizer in the methods
disclosed herein provides an aerosol of a solution comprising
cromolyn or a pharmaceutically-acceptable salt thereof, wherein the
aerosol exhibits an RF (.ltoreq.3.3 .mu.m) of 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%, at least about 85%, at
least about 90%, at least about 95%, about 20% to about 95%, about
35% to about 90%, about 40% to about 80%, about 40% to about 90%,
about 40% to about 95%, about 45% to about 90%, about 45% to about
95%, about 50% to about 90%, about 65% to about 90%, about 60% to
about 95%, about 65% to about 95%, about 70% to about 90%, or about
55% to about 90%. In certain embodiments, use of a nebulizer in the
methods disclosed herein provides an aerosol of a solution
comprising cromolyn or a pharmaceutically-acceptable salt thereof,
wherein the aerosol exhibits an RF (.ltoreq.3.3 .mu.m) of cromolyn
sodium of 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%, at least about 85%, at least about 90%, at least about 95%,
about 20% to about 95%, about 35% to about 90%, or about 40% to
about 80%, about 40% to about 90%, about 40% to about 95%, about
45% to about 90%, about 45% to about 95%, about 50% to about 90%,
about 65% to about 90%, about 60% to about 95%, about 65% to about
95%, about 70% to about 90%, about 55% to about 90%, about 40% to
about 50%, about 35% to about 45%, about 35% to about 50%, about
30% to about 50%, about 44%, or about 36%. In certain embodiments,
the solution comprises an osmotic agent comprising sodium chloride.
In certain embodiments, the solution comprises an osmotic agent
consisting of sodium chloride. In certain embodiments, the
osmolality of the solution is between about 100 mOsm/kg and about
175 mOsm/kg, or between about 100 mOsm/kg and about 170 mOsm/kg, or
between about 100 mOsm/kg and about 165 mOsm/kg, or between about
100 mOsm/kg and about 160 mOsm/kg, or between about 100 mOsm/kg and
about 150 mOsm/kg, or between about 110 mOsm/kg and about 150
mOsm/kg, or between about 110 mOsm/kg and about 140 mOsm/kg, or
between about 115 mOsm/kg and about 140 mOsm/kg, or between about
120 mOsm/kg and about 140 mOsm/kg, or between about 120 mOsm/kg and
about 130 mOsm/kg. In certain embodiments, the osmolality of the
solution is about 120 mOsm/kg, about 125 mOsm/kg, about 130
mOsm/kg, about 135 mOsm/kg, about 140 mOsm/kg, about 145 mOsm/kg,
or about 150 mOsm/kg.
[0183] In certain embodiments, the solution of the disclosure may
exclude, or, may not comprise a surfactant. In certain embodiments,
the solution of the disclosure may not comprise any dispersing
agent, solubilizing agent, or spreading agent. Some examples of
surfactants that are excluded from the present compositions and
formulations include: PEG (polyethylene glycol) 400; Sodium lauryl
sulfate sorbitan laurate, sorbitan palmitate, sorbitan stearate
available under the tradename Span.RTM. (20-40-60 etc.);
polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20)
sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate
available under the tradename Tween (polysorbates, 20-40-60 etc.);
tyloxapol; propylene glycol; and Benzalkoniumrn chloride,
vitamin-TPGS and lecithins, (Exosurf.RTM., GlaxoSmithKline),
surfactant proteins. In certain embodiments, surfactants that are
excluded from the present solution include any compound or agent
that lowers the surface tension of a composition.
[0184] In certain embodiments, use of a nebulizer in the methods
disclosed herein provides an aerosol that comprises particles
having a surface tension suitable for deposition, penetration or
retention of the composition primarily in the peripheral lung
regions, including the bronchioles and alveoli. In certain
embodiments, use of a nebulizer in the methods disclosed herein
provides an aerosol of a solution that comprises particles having a
surface tension in the range similar to that or water or higher. In
certain embodiments, use of a nebulizer in the methods disclosed
herein provides an aerosol of a solution that comprises particles
having a surface tension of at least about 30 mN/m, or at least
about 40 mN/m, or at least about 50 mN/m, or at least about 60
mN/m, or at least about 70 mN/m. In some embodiments, use of a
nebulizer in the methods disclosed herein provides an aerosol of a
solution that comprises particles having a surface tension in the
range of about 30 mN/m to about 75 mN/m, or about 50 mN/m to about
75 mN/m, or about 70 mN/m to about 75 mN/m.
[0185] In certain embodiments, use of a nebulizer in the methods
disclosed herein provides an aerosol of a solution comprising
cromolyn or a pharmaceutically-acceptable salt thereof, wherein the
aerosol exhibits an RF (1-5 .mu.m) of cromolyn or a
pharmaceutically-acceptable salt thereof of 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%, at least about 85%, at least
about 90%, at least about 95%, about 20% to about 95%, about 35% to
about 90%, or about 40% to about 80%, about 40% to about 90%, about
40% to about 95%, about 45% to about 90%, about 45% to about 95%,
about 50% to about 90%, about 65% to about 90%, about 60% to about
95%, about 65% to about 95%, about 70% to about 90%, or about 55%
to about 90%. In certain embodiments, use of a nebulizer in the
methods disclosed herein provides an aerosol of a solution
comprising cromolyn or a pharmaceutically-acceptable salt thereof,
wherein the aerosol exhibits an RF (1-5 .mu.m) of cromolyn sodium
of 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%, at
least about 85%, at least about 90%, at least about 95%, about 20%
to about 95%, about 35% to about 90%, or about 40% to about 80%,
about 40% to about 90%, about 40% to about 95%, about 45% to about
90%, about 45% to about 95%, about 50% to about 90%, about 65% to
about 90%, about 60% to about 95%, about 65% to about 95%, about
70% to about 90%, or about 55% to about 90%. In certain
embodiments, the solution comprises an osmotic agent comprising
sodium chloride. In certain embodiments, the solution comprises an
osmotic agent consisting of sodium chloride. In certain
embodiments, the solution comprises an osmotic agent comprising
sodium chloride. In certain embodiments, the solution comprises an
osmotic agent consisting of sodium chloride. In certain
embodiments, the osmolality of the solution is between about 100
mOsm/kg and about 175 mOsm/kg, or between about 100 mOsm/kg and
about 170 mOsm/kg, or between about 100 mOsm/kg and about 165
mOsm/kg, or between about 100 mOsm/kg and about 160 mOsm/kg, or
between about 100 mOsm/kg and about 150 mOsm/kg, or between about
110 mOsm/kg and about 150 mOsm/kg, or between about 110 mOsm/kg and
about 140 mOsm/kg, or between about 115 mOsm/kg and about 140
mOsm/kg, or between about 120 mOsm/kg and about 140 mOsm/kg, or
between about 120 mOsm/kg and about 130 mOsm/kg. In certain
embodiments, the osmolality of the solution is about 120 mOsm/kg,
about 125 mOsm/kg, about 130 mOsm/kg, about 135 mOsm/kg, about 140
mOsm/kg, about 145 mOsm/kg, or about 150 mOsm/kg.
[0186] In certain embodiments, the solution of the disclosure may
exclude, or, may not comprise a surfactant. In certain embodiments,
the solution of the disclosure may not comprise any dispersing
agent, solubilizing agent, or spreading agent. Some examples of
surfactants that are excluded from the present compositions and
formulations include: PEG (polyethylene glycol) 400; Sodium lauryl
sulfate sorbitan laurate, sorbitan palmitate, sorbitan stearate
available under the tradename Span.RTM. (20-40-60 etc.);
polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20)
sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate
available under the tradename Tween (polysorbates, 20-40-60 etc.);
tyloxapol; propylene glycol; and Benzalkoniumrn chloride,
vitamin-TPGS and lecithins, (Exosurf.RTM., GlaxoSmithKline),
surfactant proteins. In certain embodiments, surfactants that are
excluded from the present solution include any compound or agent
that lowers the surface tension of a composition.
[0187] In certain embodiments, use of a nebulizer in the methods
disclosed herein provides an aerosol that comprises particles
having a surface tension suitable for deposition, penetration or
retention of the composition primarily in the peripheral lung
regions, including the bronchioles and alveoli. In certain
embodiments, use of a nebulizer in the methods disclosed herein
provides an aerosol of a solution that comprises particles having a
surface tension in the range similar to that or water or higher. In
certain embodiments, use of a nebulizer in the methods disclosed
herein provides an aerosol of a solution that comprises particles
having a surface tension of at least about 30 mN/m, or at least
about 40 mN/m, or at least about 50 mN/m, or at least about 60
mN/m, or at least about 70 mN/m. In some embodiments, use of a
nebulizer in the methods disclosed herein provides an aerosol of a
solution that comprises particles having a surface tension in the
range of about 30 mN/m to about 75 mN/m, or about 50 mN/m to about
75 mN/m, or about 70 mN/m to about 75 mN/m.
[0188] In certain embodiments, use of a nebulizer in the methods
disclosed herein provides an aerosol of a solution comprising
cromolyn or a pharmaceutically-acceptable salt thereof, wherein the
aerosol exhibits an RF (.ltoreq.5 .mu.m) of an cromolyn or a
pharmaceutically-acceptable salt thereof of 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%, at least about 85%, at least
about 90%, at least about 95%, about 20% to about 95%, about 35% to
about 90%, about 40% to about 80%, about 40% to about 90%, about
40% to about 95%, about 45% to about 90%, about 45% to about 95%,
about 50% to about 90%, about 65% to about 90%, about 60% to about
95%, about 65% to about 95%, about 70% to about 90%, about 55% to
about 90%, about 70% to about 80%, or about 75%. In certain
embodiments, use of a nebulizer in the methods disclosed herein
provides an aerosol of a solution comprising cromolyn or a
pharmaceutically-acceptable salt thereof, wherein the aerosol
exhibits an RF (.ltoreq.5 .mu.m) of cromolyn sodium of 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%, at least about
85%, at least about 90%, at least about 95%, about 20% to about
95%, about 35% to about 90%, about 40% to about 80%, about 40% to
about 90%, about 40% to about 95%, about 45% to about 90%, about
45% to about 95%, about 50% to about 90%, about 65% to about 90%,
about 60% to about 95%, about 65% to about 95%, about 70% to about
90%, about 55% to about 90%, about 70% to about 80%, about 65% to
about 75%, about 65% to about 80%, about 60% to about 80%, about
66%, or about 75%. In certain embodiments, the solution comprises
an osmotic agent comprising sodium chloride. In certain
embodiments, the solution comprises an osmotic agent consisting of
sodium chloride. In certain embodiments, the osmolality of the
solution is between about 100 mOsm/kg and about 175 mOsm/kg, or
between about 100 mOsm/kg and about 170 mOsm/kg, or between about
100 mOsm/kg and about 165 mOsm/kg, or between about 100 mOsm/kg and
about 160 mOsm/kg, or between about 100 mOsm/kg and about 150
mOsm/kg, or between about 110 mOsm/kg and about 150 mOsm/kg, or
between about 110 mOsm/kg and about 140 mOsm/kg, or between about
115 mOsm/kg and about 140 mOsm/kg, or between about 120 mOsm/kg and
about 140 mOsm/kg, or between about 120 mOsm/kg and about 130
mOsm/kg. In certain embodiments, the osmolality of the solution is
about 120 mOsm/kg, about 125 mOsm/kg, about 130 mOsm/kg, about 135
mOsm/kg, about 140 mOsm/kg, about 145 mOsm/kg, or about 150
mOsm/kg.
[0189] In certain embodiments, the solution of the disclosure may
exclude, or, may not comprise a surfactant. In certain embodiments,
the solution of the disclosure may not comprise any dispersing
agent, solubilizing agent, or spreading agent. Some examples of
surfactants that are excluded from the present compositions and
formulations include: PEG (polyethylene glycol) 400; Sodium lauryl
sulfate sorbitan laurate, sorbitan palmitate, sorbitan stearate
available under the tradename Spank (20-40-60 etc.);
polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20)
sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate
available under the tradename Tween (polysorbates, 20-40-60 etc.);
tyloxapol; propylene glycol; and Benzalkoniumrn chloride,
vitamin-TPGS and lecithins, (Exosurf.RTM., GlaxoSmithKline),
surfactant proteins. In certain embodiments, surfactants that are
excluded from the present solution include any compound or agent
that lowers the surface tension of a composition.
[0190] In certain embodiments, the aerosols provided by the present
methods or nebulizer comprise particles having a surface tension
suitable for deposition, penetration or retention of the
composition primarily in the peripheral lung regions, including the
bronchioles and alveoli. In certain embodiments, the aerosols
provided by the present methods or nebulizer comprise particles
having surface tension in the range similar to that or water or
higher. In certain embodiments, the aerosols provided by the
present methods or nebulizer comprise particles having a surface
tension of at least about 30 mN/m, or at least about 40 mN/m, or at
least about 50 mN/m, or at least about 60 mN/m, or at least about
70 mN/m. In some embodiments, the aerosols provided by the present
methods or nebulizer comprise particles having surface tension in
the range of about 30 mN/m to about 75 mN/m, or about 50 mN/m to
about 75 mN/m, or about 70 mN/m to about 75 mN/m.
[0191] The disclosure provides a pharmaceutically acceptable
solution, comprising from about 1% to about 10% by weight of
cromolyn sodium an osmotic agent, wherein the osmotic agent
consists of sodium chloride, wherein an aerosol created from the
pharmaceutically acceptable solution is suitable for inhalation by
a subject having chronic cough due to idiopathic pulmonary
fibrosis. In certain embodiments, the aerosol has a respirable
fraction (.ltoreq.3.3 .mu.m) as measured by USP <1601> of at
least about 30%. In certain embodiments, the aerosol has a
respirable fraction (.ltoreq.3.3 .mu.m) as measured by USP
<1601> of at least about 30% and a respirable fraction
(.ltoreq.5 .mu.m) as measured by USP <1601> of at least about
75%. In certain embodiments, the pharmaceutically acceptable
solution comprises about 1%, or about 2%, or about 3%, or about 4%,
or about 5%, or about 6%, or about 7%, or about 8%, or about 9%, or
about 10% by weight of cromolyn sodium. In certain embodiments, the
osmostic agent comprises an ionic osmotic agent and excludes any
non-ionic osmotic agent. In certain embodiments, the osmotic agent
consists of sodium chloride. In certain embodiments, the osmolality
of the solution is between about 100 mOsm/kg and about 175 mOsm/kg,
or between about 100 mOsm/kg and about 170 mOsm/kg, or between
about 100 mOsm/kg and about 165 mOsm/kg, or between about 100
mOsm/kg and about 160 mOsm/kg, or between about 100 mOsm/kg and
about 150 mOsm/kg, or between about 110 mOsm/kg and about 150
mOsm/kg, or between about 110 mOsm/kg and about 140 mOsm/kg, or
between about 115 mOsm/kg and about 140 mOsm/kg, or between about
120 mOsm/kg and about 140 mOsm/kg, or between about 120 mOsm/kg and
about 130 mOsm/kg. In certain embodiments, the osmolality of the
solution is about 120 mOsm/kg, about 125 mOsm/kg, about 130
mOsm/kg, about 135 mOsm/kg, about 140 mOsm/kg, about 145 mOsm/kg,
or about 150 mOsm/kg.
[0192] In certain embodiments, the pharmaceutically acceptable
solution of the disclosure may exclude, or, may not comprise a
surfactant. In certain embodiments, the pharmaceutically acceptable
solution of the disclosure may not comprise any dispersing agent,
solubilizing agent, or spreading agent. Some examples of
surfactants that are excluded from the present compositions and
formulations include: PEG (polyethylene glycol) 400; Sodium lauryl
sulfate sorbitan laurate, sorbitan palmitate, sorbitan stearate
available under the tradename Span.RTM. (20-40-60 etc.);
polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20)
sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate
available under the tradename Tween (polysorbates, 20-40-60 etc.);
tyloxapol; propylene glycol; and Benzalkonium chloride,
vitamin-TPGS and lecithins, (Exosurf.RTM., GlaxoSmithKline),
surfactant proteins. In certain embodiments, surfactants that are
excluded from the present pharmaceutically acceptable solution
include any compound or agent that lowers the surface tension of a
composition.
[0193] In certain embodiments, the pharmaceutically acceptable
solution has a surface tension suitable for deposition, penetration
or retention of the composition primarily in the peripheral lung
regions, including the bronchioles and alveoli. In certain
embodiments the pharmaceutically acceptable solution has a surface
tension in the range similar to that or water or higher. the
pharmaceutically acceptable solution has a surface tension of at
least about 30 mN/m, or at least about 40 mN/m, or at least about
50 mN/m, or at least about 60 mN/m, or at least about 70 mN/m. the
pharmaceutically acceptable solution has a surface tension in the
range of about 30 mN/m to about 75 mN/m, or about 50 mN/m to about
75 mN/m, or about 70 mN/m to about 75 mN/m.
[0194] The disclosure provides any of the methods or
pharmaceutically acceptable solutions disclosed herein wherein the
pharmaceutically acceptable solution has an osmolality of less than
about 250 mOsm/kg, or less than about 225 mOsm/kg, or less than
about 200 mOsm/kg, or less than about 190 mOsm/kg, or less than
about 180 mOsm/kg, or less than about 175 mOsm/kg, or less than
about 170 mOsm/kg, or less than about 165 mOsm/kg, or less than
about 160 mOsm/kg, or less than about 155 mOsm/kg, or less than
about 150 mOsm/kg, or less than about 145 mOsm/kg, or less than
about 140 mOsm/kg, or less than about 135 mOsm/kg, or less than
about 130 mOsm/kg, or less than about 125 mOsm/kg, or less than
about 120 mOsm/kg, or less than about 115 mOsm/kg, or less than
about 110 mOsm/kg, or less than about 105 mOsm/kg, or less than
about 100 mOsm/kg. In certain embodiments, the pharmaceutically
acceptable solution has an osmolality of between about 70 mOsm/kg
and about 200 mOsm/kg, or between about 70 mOsm/kg and about 190
mOsm/kg, or between about 70 and about 180 mOsm/kg, or between
about 70 mOsm/kg and about 170 mOsm/kg, or between about 70 mOsm/kg
and about 160 mOsm/kg, or between about 70 mOsm/kg and about 150
mOsm/kg, or between about 70 mOsm/kg and about 140 mOsm/kg, or
between about 80 mOsm/kg and about 200 mOsm/kg, or between about 80
mOsm/kg and about 190 mOsm/kg, or between about 90 mOsm/kg and
about 180 mOsm/kg, or between about 90 mOsm/kg and about 175
mOsm/kg, or between about 90 mOsm/kg and about 170 mOsm/kg, or
between about 90 mOsm/kg and about 160 mOsm/kg, or between about
100 mOsm/kg and about 150 mOsm/kg, or between about 110 mOsm/kg and
about 160 mOsm/kg, or between about 100 mOsm/kg and about 160
mOsm/kg, or between about 110 mOsm/kg and about 145 mOsm/kg, or
between about 110 mOsm/kg and about 140 mOsm/kg, or between about
110 mOsm/kg and about 135 mOsm/kg, or between about 120 mOsm/kg and
about 140 mOsm/kg. In certain embodiments, the osmolality of the
pharmaceutically acceptable solution is about 100 mOsm/kg, or about
110 mOsm/kg, or about 115 mOsm/kg, or about 120 mOsm/kg, or about
125 mOsm/kg, or about 130 mOsm/kg, or about 135 mOsm/kg, or about
140 mOsm/kg, or about 145 mOsm/kg, or about 150 mOsm/kg, or about
155 mOsm/kg, or about 160 mOsm/kg, or about 165 mOsm/kg, or about
170 mOsm/kg, or about 175 mOsm/kg, or about 180 mOsm/kg, or about
185 mOsm/kg, or about 190 mOsm/kg, or about 195 mOsm/kg, or about
200 mOsm/kg.
[0195] The disclosure provides any of the methods or
pharmaceutically acceptable solutions disclosed herein wherein the
pharmaceutically acceptable solution may exclude, or, may not
comprise a surfactant. In certain embodiments, the pharmaceutically
acceptable solution of the disclosure may not comprise any
dispersing agent, solubilizing agent, or spreading agent. Some
examples of surfactants that are excluded from the present
compositions and formulations include: PEG (polyethylene glycol)
400; Sodium lauryl sulfate sorbitan laurate, sorbitan palmitate,
sorbitan stearate available under the tradename Span.RTM. (20-40-60
etc.); polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene
(20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan
monostearate available under the tradename Tween (polysorbates,
20-40-60 etc.); tyloxapol; propylene glycol; and Benzalkoniumrn
chloride, vitamin-TPGS and lecithins, (Exosurf.RTM.,
GlaxoSmithKline), surfactant proteins. In certain embodiments,
surfactants that are excluded from the present pharmaceutically
acceptable solution include any compound or agent that lowers the
surface tension of a composition.
[0196] The disclosure provides any of the methods or
pharmaceutically acceptable solutions disclosed herein wherein the
pharmaceutically acceptable solution has a surface tension suitable
for deposition, penetration or retention of the composition
primarily in the peripheral lung regions, including the bronchioles
and alveoli. In certain embodiments, the pharmaceutically
acceptable solution has a surface tension in the range similar to
that or water or higher. the pharmaceutically acceptable solution
has a surface tension of at least about 30 mN/m, or at least about
40 mN/m, or at least about 50 mN/m, or at least about 60 mN/m, or
at least about 70 mN/m. In some embodiments, the pharmaceutically
acceptable solution has a surface tension in the range of about 30
mN/m to about 75 mN/m, or about 50 mN/m to about 75 mN/m, or about
70 mN/m to about 75 mN/m.
[0197] The disclosure provides a pharmaceutically acceptable
solution, comprising from about 2% to about 6% by weight of
cromolyn sodium and an osmolarity adjusting agent consisting of
sodium chloride, wherein an aerosol created from the
pharmaceutically acceptable solution is suitable for inhalation by
a subject in need thereof. In certain embodiments, the aerosol
exhibits an RF (.ltoreq.3.3 .mu.m) as measured by USP <1601>
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%. In certain embodiments, the aerosol
exhibits and RF (.ltoreq.5 .mu.m) as measured by USP <1601>
of at least about 30%, or at least about 35%, or at least about
40%, or at least about 45%, or at least about 50%, or at least
about 55%, or at least about 60%, or at least about 65%, or at
least about 75%, or at least about 80%, or at least about 85%, or
at least about 90%, or at least about 95%.
[0198] In certain embodiments, the pharmaceutically acceptable
solution of the disclosure may exclude, or, may not comprise a
surfactant. In certain embodiments, the pharmaceutically acceptable
solution of the disclosure may not comprise any dispersing agent,
solubilizing agent, or spreading agent. Some examples of
surfactants that are excluded from the present compositions and
formulations include: PEG (polyethylene glycol) 400; Sodium lauryl
sulfate sorbitan laurate, sorbitan palmitate, sorbitan stearate
available under the tradename Span.RTM. (20-40-60 etc.);
polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20)
sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate
available under the tradename Tween (polysorbates, 20-40-60 etc.);
tyloxapol; propylene glycol; and Benzalkonium chloride,
vitamin-TPGS and lecithins, (Exosurf.RTM., GlaxoSmithKline),
surfactant proteins. In certain embodiments, surfactants that are
excluded from the present pharmaceutically acceptable solution
include any compound or agent that lowers the surface tension of a
composition.
[0199] In certain embodiments, the pharmaceutically acceptable
solution has a surface tension suitable for deposition, penetration
or retention of the composition primarily in the peripheral lung
regions, including the bronchioles and alveoli. In certain
embodiments the pharmaceutically acceptable solution has a surface
tension in the range similar to that or water or higher. the
pharmaceutically acceptable solution has a surface tension of at
least about 30 mN/m, or at least about 40 mN/m, or at least about
50 mN/m, or at least about 60 mN/m, or at least about 70 mN/m. the
pharmaceutically acceptable solution has a surface tension in the
range of about 30 mN/m to about 75 mN/m, or about 50 mN/m to about
75 mN/m, or about 70 mN/m to about 75 mN/m.
[0200] The disclosure provides a pharmaceutically acceptable
aerosol, comprising droplets of a solution comprising from about 1%
to about 10% by weight of cromolyn sodium and an osmolarity
adjusting agent consisting of sodium chloride. In certain
embodiments, the aerosol exhibits an RF (.ltoreq.3.3 .mu.m) as
measured by USP <1601> 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%. In certain
embodiments, the aerosol exhibits and RF (.ltoreq.5 .mu.m) as
measured by USP <1601> of at least about 30%, or at least
about 35%, or at least about 40%, or at least about 45%, or at
least about 50%, or at least about 55%, or at least about 60%, or
at least about 65%, or at least about 75%, or at least about 80%,
or at least about 85%, or at least about 90%, or at least about
95%. In certain embodiments, the osmolality of the solution is
between about 100 mOsm/kg and about 175 mOsm/kg, or between about
100 mOsm/kg and about 170 mOsm/kg, or between about 100 mOsm/kg and
about 165 mOsm/kg, or between about 100 mOsm/kg and about 160
mOsm/kg, or between about 100 mOsm/kg and about 150 mOsm/kg, or
between about 110 mOsm/kg and about 150 mOsm/kg, or between about
110 mOsm/kg and about 140 mOsm/kg, or between about 115 mOsm/kg and
about 140 mOsm/kg, or between about 120 mOsm/kg and about 140
mOsm/kg, or between about 120 mOsm/kg and about 130 mOsm/kg. In
certain embodiments, the osmolality of the solution is about 120
mOsm/kg, about 125 mOsm/kg, about 130 mOsm/kg, about 135 mOsm/kg,
about 140 mOsm/kg, about 145 mOsm/kg, or about 150 mOsm/kg.
[0201] In certain embodiments, the pharmaceutically acceptable
solution of the disclosure may exclude, or, may not comprise a
surfactant. In certain embodiments, the pharmaceutically acceptable
solution of the disclosure may not comprise any dispersing agent,
solubilizing agent, or spreading agent. Some examples of
surfactants that are excluded from the present compositions and
formulations include: PEG (polyethylene glycol) 400; Sodium lauryl
sulfate sorbitan laurate, sorbitan palmitate, sorbitan stearate
available under the tradename Span.RTM. (20-40-60 etc.);
polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20)
sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate
available under the tradename Tween (polysorbates, 20-40-60 etc.);
tyloxapol; propylene glycol; and Benzalkoniumrn chloride,
vitamin-TPGS and lecithins, (Exosurf.RTM., GlaxoSmithKline),
surfactant proteins. In certain embodiments, surfactants that are
excluded from the present pharmaceutically acceptable solution
include any compound or agent that lowers the surface tension of a
composition.
[0202] In certain embodiments, droplets of the pharmaceutically
acceptable aerosols have a surface tension suitable for deposition,
penetration or retention of the composition primarily in the
peripheral lung regions, including the bronchioles and alveoli. In
certain embodiments, droplets of the pharmaceutically acceptable
aerosols have a surface tension in the range similar to that or
water or higher. In certain embodiments, droplets of the
pharmaceutically acceptable aerosols have a surface tension of at
least about 30 mN/m, or at least about 40 mN/m, or at least about
50 mN/m, or at least about 60 mN/m, or at least about 70 mN/m. In
some embodiments, In certain embodiments, droplets of the
pharmaceutically acceptable aerosols have a surface tension in the
range of about 30 mN/m to about 75 mN/m, or about 50 mN/m to about
75 mN/m, or about 70 mN/m to about 75 mN/m.
[0203] The disclosure provides a method of administering a
therapeutically effective amount of cromolyn sodium to a subject in
need thereof, comprising administering to the subject a
pharmaceutical composition comprising from about 2% to about 6% by
weight of cromolyn sodium and an osmotic agent consisting of sodium
chloride, wherein the pharmaceutical composition is administered to
the subject by inhalation in the form of an aerosol exhibiting an
RF (.ltoreq.5 .mu.m) as measured by USP <1601> of at least
about 60%. In certain embodiments, the aerosol exhibits an RF
(.ltoreq.3.3 .mu.m) as measured by USP <1601> of at least
about 30%. In certain embodiments, the aerosol exhibits an RF
(.ltoreq.3.3 rpm) as measured by USP <1601> 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%. In certain embodiments, the aerosol exhibits and RF
(.ltoreq.5 .mu.m) as measured by USP <1601> of at least about
30%, or at least about 35%, or at least about 40%, or at least
about 45%, or at least about 50%, or at least about 55%, or at
least about 60%, or at least about 65%, or at least about 75%, or
at least about 80%, or at least about 85%, or at least about 90%,
or at least about 95%. In certain embodiments, the osmolality of
the pharmaceutical composition is between about 100 mOsm/kg and
about 175 mOsm/kg, or between about 100 mOsm/kg and about 170
mOsm/kg, or between about 100 mOsm/kg and about 165 mOsm/kg, or
between about 100 mOsm/kg and about 160 mOsm/kg, or between about
100 mOsm/kg and about 150 mOsm/kg, or between about 110 mOsm/kg and
about 150 mOsm/kg, or between about 110 mOsm/kg and about 140
mOsm/kg, or between about 115 mOsm/kg and about 140 mOsm/kg, or
between about 120 mOsm/kg and about 140 mOsm/kg, or between about
120 mOsm/kg and about 130 mOsm/kg. In certain embodiments, the
osmolality of the pharmaceutical composition is about 120 mOsm/kg,
about 125 mOsm/kg, about 130 mOsm/kg, about 135 mOsm/kg, about 140
mOsm/kg, about 145 mOsm/kg, or about 150 mOsm/kg.
[0204] In certain embodiments, the pharmaceutically acceptable
solution or composition of the disclosure may exclude, or, may not
comprise a surfactant. In certain embodiments, the pharmaceutically
acceptable solution of the disclosure may not comprise any
dispersing agent, solubilizing agent, or spreading agent. Some
examples of surfactants that are excluded from the present
compositions and formulations include: PEG (polyethylene glycol)
400; Sodium lauryl sulfate sorbitan laurate, sorbitan palmitate,
sorbitan stearate available under the tradename Span.RTM. (20-40-60
etc.); polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene
(20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan
monostearate available under the tradename Tween (polysorbates,
20-40-60 etc.); tyloxapol; propylene glycol; and Benzalkoniumrn
chloride, vitamin-TPGS and lecithins, (Exosurf.RTM.,
GlaxoSmithKline), surfactant proteins. In certain embodiments,
surfactants that are excluded from the present pharmaceutically
acceptable solution include any compound or agent that lowers the
surface tension of a composition.
[0205] In certain embodiments, droplets of the pharmaceutically
acceptable aerosols have a surface tension suitable for deposition,
penetration or retention of the composition primarily in the
peripheral lung regions, including the bronchioles and alveoli. In
certain embodiments, droplets of the pharmaceutically acceptable
aerosols have a surface tension in the range similar to that or
water or higher. In certain embodiments, droplets of the
pharmaceutically acceptable aerosols have a surface tension of at
least about 30 mN/m, or at least about 40 mN/m, or at least about
50 mN/m, or at least about 60 mN/m, or at least about 70 mN/m. In
some embodiments, In certain embodiments, droplets of the
pharmaceutically acceptable aerosols have a surface tension in the
range of about 30 mN/m to about 75 mN/m, or about 50 mN/m to about
75 mN/m, or about 70 mN/m to about 75 mN/m.
[0206] The disclosure provides a dosage form comprising: (a) a
pharmaceutical composition comprising from about 2% to about 6% by
weight of cromolyn sodium, and an osmolarity adjusting agent
consisting of sodium chloride; and (b) an inhalation device that
forms an aerosol of the pharmaceutical composition, the aerosol
exhibiting a respirable fraction of the pharmaceutical composition
(.ltoreq.5 .mu.m) as measured by USP <1601> of at least about
60%. In certain embodiments, the aerosol exhibits an RF
(.ltoreq.3.3 .mu.m) as measured by USP <1601> of at least
about 30%. In certain embodiments, the aerosol exhibits an RF
(.ltoreq.3.3 .mu.m) as measured by USP <1601> 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%. In certain embodiments, the aerosol exhibits and
RF (.ltoreq.5 .mu.m) as measured by USP <1601> of at least
about 30%, or at least about 35%, or at least about 40%, or at
least about 45%, or at least about 50%, or at least about 55%, or
at least about 60%, or at least about 65%, or at least about 75%,
or at least about 80%, or at least about 85%, or at least about
90%, or at least about 95%. In certain embodiments, the osmolality
of the pharmaceutical composition is between about 100 mOsm/kg and
about 175 mOsm/kg, or between about 100 mOsm/kg and about 170
mOsm/kg, or between about 100 mOsm/kg and about 165 mOsm/kg, or
between about 100 mOsm/kg and about 160 mOsm/kg, or between about
100 mOsm/kg and about 150 mOsm/kg, or between about 110 mOsm/kg and
about 150 mOsm/kg, or between about 110 mOsm/kg and about 140
mOsm/kg, or between about 115 mOsm/kg and about 140 mOsm/kg, or
between about 120 mOsm/kg and about 140 mOsm/kg, or between about
120 mOsm/kg and about 130 mOsm/kg. In certain embodiments, the
osmolality of the pharmaceutical composition is about 120 mOsm/kg,
about 125 mOsm/kg, about 130 mOsm/kg, about 135 mOsm/kg, about 140
mOsm/kg, about 145 mOsm/kg, or about 150 mOsm/kg.
[0207] In certain embodiments, the pharmaceutically acceptable
dosage form of the disclosure may exclude, or, may not comprise a
surfactant. In certain embodiments, the pharmaceutically acceptable
solution of the disclosure may not comprise any dispersing agent,
solubilizing agent, or spreading agent. Some examples of
surfactants that are excluded from the present compositions and
formulations include: PEG (polyethylene glycol) 400; Sodium lauryl
sulfate sorbitan laurate, sorbitan palmitate, sorbitan stearate
available under the tradename Span.RTM. (20-40-60 etc.);
polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20)
sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate
available under the tradename Tween (polysorbates, 20-40-60 etc.);
tyloxapol; propylene glycol; and Benzalkoniumrn chloride,
vitamin-TPGS and lecithins, (Exosurf.RTM., GlaxoSmithKline),
surfactant proteins. In certain embodiments, surfactants that are
excluded from the present pharmaceutically acceptable solution
include any compound or agent that lowers the surface tension of a
composition.
[0208] In certain embodiments, droplets of the pharmaceutically
acceptable aerosols have a surface tension suitable for deposition,
penetration or retention of the composition primarily in the
peripheral lung regions, including the bronchioles and alveoli. In
certain embodiments, droplets of the pharmaceutically acceptable
aerosols have a surface tension in the range similar to that or
water or higher. In certain embodiments, droplets of the
pharmaceutically acceptable aerosols have a surface tension of at
least about 30 mN/m, or at least about 40 mN/m, or at least about
50 mN/m, or at least about 60 mN/m, or at least about 70 mN/m. In
some embodiments, In certain embodiments, droplets of the
pharmaceutically acceptable aerosols have a surface tension in the
range of about 30 mN/m to about 75 mN/m, or about 50 mN/m to about
75 mN/m, or about 70 mN/m to about 75 mN/m.
[0209] The disclosure provides a dosage form comprising: (a) a
pharmaceutical composition comprising from about 2% to about 6% by
weight of cromolyn sodium, and an osmolarity adjusting agent
consisting of sodium chloride; and (b) a means for producing an
aerosol of the pharmaceutical composition, the aerosol exhibiting a
respirable fraction of the pharmaceutical composition (.ltoreq.5
.mu.m) as measured by USP <1601> of at least about 60%. In
certain embodiments, the aerosol exhibits an RF (.ltoreq.3.3 .mu.m)
as measured by USP <1601> of at least about 30%. In certain
embodiments, the aerosol exhibits an RF (.ltoreq.3.3 .mu.m) as
measured by USP <1601> 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%. In certain
embodiments, the aerosol exhibits and RF (.ltoreq.5 .mu.m) as
measured by USP <1601> of at least about 30%, or at least
about 35%, or at least about 40%, or at least about 45%, or at
least about 50%, or at least about 55%, or at least about 60%, or
at least about 65%, or at least about 75%, or at least about 80%,
or at least about 85%, or at least about 90%, or at least about
95%. In certain embodiments, the osmolality of the pharmaceutical
composition is between about 100 mOsm/kg and about 175 mOsm/kg, or
between about 100 mOsm/kg and about 170 mOsm/kg, or between about
100 mOsm/kg and about 165 mOsm/kg, or between about 100 mOsm/kg and
about 160 mOsm/kg, or between about 100 mOsm/kg and about 150
mOsm/kg, or between about 110 mOsm/kg and about 150 mOsm/kg, or
between about 110 mOsm/kg and about 140 mOsm/kg, or between about
115 mOsm/kg and about 140 mOsm/kg, or between about 120 mOsm/kg and
about 140 mOsm/kg, or between about 120 mOsm/kg and about 130
mOsm/kg. In certain embodiments, the osmolality of the
pharmaceutical composition is about 120 mOsm/kg, about 125 mOsm/kg,
about 130 mOsm/kg, about 135 mOsm/kg, about 140 mOsm/kg, about 145
mOsm/kg, or about 150 mOsm/kg.
[0210] In certain embodiments, the pharmaceutically acceptable
dosage form of the disclosure may exclude, or, may not comprise a
surfactant. In certain embodiments, the pharmaceutically acceptable
solution of the disclosure may not comprise any dispersing agent,
solubilizing agent, or spreading agent. Some examples of
surfactants that are excluded from the present compositions and
formulations include: PEG (polyethylene glycol) 400; Sodium lauryl
sulfate sorbitan laurate, sorbitan palmitate, sorbitan stearate
available under the tradename Span.RTM. (20-40-60 etc.);
polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20)
sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate
available under the tradename Tween (polysorbates, 20-40-60 etc.);
tyloxapol; propylene glycol; and Benzalkonium chloride,
vitamin-TPGS and lecithins, (Exosurf.RTM., GlaxoSmithKline),
surfactant proteins. In certain embodiments, surfactants that are
excluded from the present pharmaceutically acceptable solution
include any compound or agent that lowers the surface tension of a
composition.
[0211] In certain embodiments, droplets of the pharmaceutically
acceptable aerosols have a surface tension suitable for deposition,
penetration or retention of the composition primarily in the
peripheral lung regions, including the bronchioles and alveoli. In
certain embodiments, droplets of the pharmaceutically acceptable
aerosols have a surface tension in the range similar to that or
water or higher. In certain embodiments, droplets of the
pharmaceutically acceptable aerosols have a surface tension of at
least about 30 mN/m, or at least about 40 mN/m, or at least about
50 mN/m, or at least about 60 mN/m, or at least about 70 mN/m. In
some embodiments, In certain embodiments, droplets of the
pharmaceutically acceptable aerosols have a surface tension in the
range of about 30 mN/m to about 75 mN/m, or about 50 mN/m to about
75 mN/m, or about 70 mN/m to about 75 mN/m. In certain embodiments,
use of a nebulizer in the methods disclosed herein provides a RDDR
of at least about 2 times, at least about 3 times or at least about
4 times the RDDR achievable with a conventional inhalation device.
For example, where the cromolyn or a pharmaceutically-acceptable
salt thereof is cromolyn sodium, in certain embodiments the RDDR is
at least about 5 mg/min, at least about 10 mg/min, at least about
15 mg/min, at least about 20 mg/min, at least about 25 mg/min, at
least about 30 mg/min, at least about 35 mg/min, at least about 40
mg/min, at least about 45 mg/min, at least about 50 mg/min, at
least about 55 mg/min, or at least about 60 mg/min.
[0212] In certain embodiments, administration of cromolyn or a
pharmaceutically-acceptable salt thereof with a nebulizer in the
methods disclosed herein provides a GSD of emitted droplet size
distribution of about 1.1 to about 2.1, about 1.2 to about 2.0,
about 1.3 to about 1.9, less than about 2, at least about 1.4 to
about 1.8, at least about 1.5 to about 1.7, about 1.4, about 1.5,
about 1.6, or about 1.7. In certain embodiments, administration of
cromolyn or a pharmaceutically-acceptable salt thereof with a
nebulizer in the methods disclosed herein provides a MMAD of
droplet size of about 1 .mu.m to about 5 m, about 2 to about 4 m,
about 3 to about 4 m, about 3.5 to about 4.5 m, or about 3.5 .mu.m.
In some particular embodiments, administration of cromolyn or a
pharmaceutically-acceptable salt thereof in the methods disclosed
herein provides droplets having a particular combination of MMAD
and GSD, for example: an MMAD of less than about 5 .mu.m and a GSD
of about 1.1 to about 2.1; an MMAD of less than about 4.5 .mu.m and
a GSD of about 1.1 to about 2.1; an MMAD of about 1 .mu.m to about
5 .mu.m and a GSD of about 1.1 to about 2.1; an MMAD of about 1.5
to about 4.5 .mu.m and a GSD of about 1.1 to about 2.1; an MMAD of
less than about 5 .mu.m and a GSD of about 1.1 to about 2.0; an
MMAD of less than about 4.5 .mu.m and a GSD of about 1.1 to about
2.0; an MMAD of about 1 .mu.m to about 5 .mu.m and a GSD of about
1.1 to about 2.0; an MMAD of about 1.5 to about 4.5 .mu.m and a GSD
of about 1.1 to about 2.0; an MMAD of less than about 5 .mu.m and a
GSD of about 1.1 to about 1.9; an MMAD of less than about 4.5 .mu.m
and a GSD of about 1.1 to about 1.9; an MMAD of about 1 .mu.m to
about 5 .mu.m and a GSD of about 1.1 to about 1.9; an MMAD of about
1.5 to about 4.5 .mu.m and a GSD of about 1.1 to about 1.9; an MMAD
of less than about 5 .mu.m and a GSD of about 1.1 to about 1.8; an
MMAD of less than about 4.5 .mu.m and a GSD of about 1.1 to about
1.8; an MMAD of about 1 .mu.m to about 5 .mu.m and a GSD of about
1.1 to about 1.8; an MMAD of about 1.5 to about 4.5 .mu.m and a GSD
of about 1.1 to about 1.8; an MMAD of about 3.5 .mu.m or less and a
GSD of about 1.7; an MMAD of about 4.1 .mu.m or less and a GSD of
about 1.7; an MMAD of about 3.5 .mu.m and a GSD of about 1.7; or an
MMAD of about 4.1 .mu.m and a GSD of about 1.7.
[0213] In certain embodiments, the median particle size of cromolyn
or a pharmaceutically-acceptable salt thereof aerosol administered
with a nebulizer is between about 1 .mu.m and about 6 .mu.m,
between about 2 .mu.m and about 5 .mu.m, between about 3 .mu.m and
about 5 m, between about 3 .mu.m and about 4 m, about 1 m, about 2
.mu.m, about 3 m, about 4 .mu.m, about 5 .mu.m, or about 6 .mu.m.
In certain embodiments, the median particle size of cromolyn sodium
aerosol administered with a nebulizer is between about 1 .mu.m and
about 6 m, between about 2 .mu.m and about 5 m, between about 3
.mu.m and about 5 m, between about 3 .mu.m and about 4 m, about 1
m, about 2 .mu.m, about 3 m, about 4 m, about 5 m, or about 6
.mu.m.
Inhalation Formulations
[0214] In certain embodiments disclosed herein are provided
formulations comprising from about 2% to about 10% by weight
cromolyn sodium and an osmotic agent consisting of sodium chloride,
wherein the formulation is stable when stored at 25.degree. C. for
at least 4 weeks, or at least 6 weeks, or at least 8 weeks, or at
least 10 weeks, or at least 12 weeks, or at least 6 months, or at
least 8 months, or at least 10 months, or at least 12 months, or at
least 14 months, or at least 16 months, or at least 18 months, or
at least 20 months, or at least 24 months. In certain embodiments,
the formulations remain clear solutions when stored at 25.degree.
C. for these same time periods. In certain embodiments, the
formulations exhibit less than 1% by weight total impurities when
stored at 25.degree. C. for these same time periods. In certain
embodiments, the formulation comprises about 4% by weight of
cromolyn sodium. In certain embodiments, the formulation comprises
about 6% by weight of cromolyn sodium. In certain embodiments, the
osmolality of the formulation is between about 100 mOsm/kg and
about 175 mOsm/kg, or between about 100 mOsm/kg and about 170
mOsm/kg, or between about 100 mOsm/kg and about 165 mOsm/kg, or
between about 100 mOsm/kg and about 160 mOsm/kg, or between about
100 mOsm/kg and about 150 mOsm/kg, or between about 110 mOsm/kg and
about 150 mOsm/kg, or between about 110 mOsm/kg and about 140
mOsm/kg, or between about 115 mOsm/kg and about 140 mOsm/kg, or
between about 120 mOsm/kg and about 140 mOsm/kg, or between about
120 mOsm/kg and about 130 mOsm/kg. In certain embodiments, the
osmolality of the formulation is about 120 mOsm/kg, about 125
mOsm/kg, about 130 mOsm/kg, about 135 mOsm/kg, about 140 mOsm/kg,
about 145 mOsm/kg, or about 150 mOsm/kg.
[0215] In certain embodimentsdisclosed herein are provided
formulations comprising from about 2% to about 10% by weight
cromolyn sodium and an osmotic agent consisting of sodium chloride,
wherein the formulation is stable when stored at 40.degree. C. for
at least 4 weeks, or at least 6 weeks, or at least 8 weeks, or at
least 10 weeks, or at least 12 weeks, or at least 6 months, or at
least 8 months, or at least 10 months, or at least 12 months, or at
least 14 months, or at least 16 months, or at least 18 months, or
at least 20 months, or at least 24 months. In certain embodiments,
the formulations remain clear solutions when stored at 40.degree.
C. for these same time periods. In certain embodiments, the
formulations exhibit less than 1% by weight total impurities when
stored at 40.degree. C. for these same time periods. In certain
embodiments, the formulation comprises about 4% by weight of
cromolyn sodium. In certain embodiments, the formulation comprises
about 6% by weight of cromolyn sodium In certain embodiments, the
osmolality of the formulation is between about 100 mOsm/kg and
about 175 mOsm/kg, or between about 100 mOsm/kg and about 170
mOsm/kg, or between about 100 mOsm/kg and about 165 mOsm/kg, or
between about 100 mOsm/kg and about 160 mOsm/kg, or between about
100 mOsm/kg and about 150 mOsm/kg, or between about 110 mOsm/kg and
about 150 mOsm/kg, or between about 110 mOsm/kg and about 140
mOsm/kg, or between about 115 mOsm/kg and about 140 mOsm/kg, or
between about 120 mOsm/kg and about 140 mOsm/kg, or between about
120 mOsm/kg and about 130 mOsm/kg. In certain embodiments, the
osmolality of the formulation is about 120 mOsm/kg, about 125
mOsm/kg, about 130 mOsm/kg, about 135 mOsm/kg, about 140 mOsm/kg,
about 145 mOsm/kg, or about 150 mOsm/kg.
[0216] In certain embodiments of the methods disclosed herein,
inhalation formulations are administered by an inhalation device,
e.g., a nebulizer, to provide a systemically effective amount of
cromolyn or a pharmaceutically-acceptable salt thereof for the
treatment of chronic cough due to IPF. In certain embodiments, the
methods disclosed herein comprise administering a nominal dose of
cromolyn or a pharmaceutically-acceptable salt thereof in an
aqueous inhalation solution to the subject with an inhalation
device, e.g., a nebulizer.
[0217] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject an AUC.sub.(0-.infin.) of
cromolyn or a pharmaceutically-acceptable salt thereof greater than
about 100 ng*hr/mL, greater than about 110 ng*hr/mL, greater than
about 120 ng*hr/mL, greater than about 130 ng*hr/mL, greater than
about 140 ng*hr/mL, greater than about 150 ng*hr/mL, greater than
about 160 ng*hr/mL, greater than about 170 ng*hr/mL, greater than
about 180 ng*hr/mL, greater than about 190 ng*hr/mL, greater than
about 200 ng*hr/mL, greater than about 225 ng*hr/mL, greater than
about 250 ng*hr/mL, greater than about 275 ng*hr/mL, greater than
about 300 ng*hr/mL, greater than about 325 ng*hr/mL, greater than
about 350 ng*hr/mL, greater than about 375 ng*hr/mL, greater than
about 400 ng*hr/mL, greater than about 425 ng*hr/mL, greater than
about 450 ng*hr/mL, greater than about 475 ng*hr/mL, greater than
about 500 ng*hr/mL, greater than about 525 ng*hr/mL, greater than
about 550 ng*hr/mL, greater than about 575 ng*hr/mL, greater than
about 600 ng*hr/mL, greater than about 625 ng*hr/mL, greater than
about 650 ng*hr/mL, greater than about 675 ng*hr/mL, greater than
about 700 ng*hr/mL, greater than about 725 ng*hr/mL, greater than
about 750 ng*hr/mL, greater than about 775 ng*hr/mL, greater than
about 800 ng*hr/mL, greater than about 825 ng*hr/mL, greater than
about 850 ng*hr/mL, greater than about 875 ng*hr/mL, greater than
about 900 ng*hr/mL, greater than about 925 ng*hr/mL, greater than
about 950 ng*hr/mL, greater than about 975 ng*hr/mL, or greater
than about 1000 ng*hr/mL after administration of the formulation to
the subject. In certain embodiments of the methods disclosed
herein, an inhalation formulation administered with an inhalation
device, e.g., a nebulizer, produces in a subject an
AUC.sub.(0-.infin.) of cromolyn or a pharmaceutically-acceptable
salt thereof greater than about 100 ng*hr/mL, greater than about
110 ng*hr/mL, greater than about 120 ng*hr/mL, greater than about
130 ng*hr/mL, greater than about 140 ng*hr/mL, greater than about
150 ng*hr/mL, greater than about 160 ng*hr/mL, greater than about
170 ng*hr/mL, greater than about 180 ng*hr/mL, greater than about
190 ng*hr/mL, greater than about 200 ng*hr/mL, greater than about
225 ng*hr/mL, greater than about 250 ng*hr/mL, greater than about
275 ng*hr/mL, greater than about 300 ng*hr/mL, greater than about
325 ng*hr/mL, greater than about 350 ng*hr/mL, greater than about
375 ng*hr/mL, greater than about 400 ng*hr/mL, greater than about
425 ng*hr/mL, greater than about 450 ng*hr/mL, greater than about
475 ng*hr/mL, greater than about 500 ng*hr/mL, greater than about
525 ng*hr/mL, greater than about 550 ng*hr/mL, greater than about
575 ng*hr/mL, greater than about 600 ng*hr/mL, greater than about
625 ng*hr/mL, greater than about 650 ng*hr/mL, greater than about
675 ng*hr/mL, greater than about 700 ng*hr/mL, greater than about
725 ng*hr/mL, greater than about 750 ng*hr/mL, greater than about
775 ng*hr/mL, greater than about 800 ng*hr/mL, greater than about
825 ng*hr/mL, greater than about 850 ng*hr/mL, greater than about
875 ng*hr/mL, greater than about 900 ng*hr/mL, greater than about
925 ng*hr/mL, greater than about 950 ng*hr/mL, greater than about
975 ng*hr/mL, or greater than about 1000 ng*hr/mL after
administration of the formulation to the subject.
[0218] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject an AUC.sub.(0-.infin.) of
cromolyn or a pharmaceutically-acceptable salt thereof of about 100
ng*hr/mL, about 110 ng*hr/mL, about 120 ng*hr/mL, about 130
ng*hr/mL, about 140 ng*hr/mL, about 150 ng*hr/mL, about 160
ng*hr/mL, about 170 ng*hr/mL, about 180 ng*hr/mL, about 190
ng*hr/mL, about 200 ng*hr/mL, about 225 ng*hr/mL, about 250
ng*hr/mL, ng*hr/mL, about 275 ng*hr/mL, about 300 ng*hr/mL, about
325 ng*hr/mL, about 350 ng*hr/mL, about 375 ng*hr/mL, about 400
ng*hr/mL, about 425 ng*hr/mL, about 450 ng*hr/mL, about 475
ng*hr/mL, about 500 ng*hr/mL, about 525 ng*hr/mL, about 550
ng*hr/mL, about 575 ng*hr/mL, about 600 ng*hr/mL, about 625
ng*hr/mL, about 650 ng*hr/mL, about 675 ng*hr/mL, about 700
ng*hr/mL, about 725 ng*hr/mL, about 750 ng*hr/mL, about 775
ng*hr/mL, about 800 ng*hr/mL, about 825 ng*hr/mL, about 850
ng*hr/mL, about 875 ng*hr/mL, about 900 ng*hr/mL, about 925
ng*hr/mL, about 950 ng*hr/mL, about 975 ng*hr/mL, or about 1000
ng*hr/mL after administration of the formulation to the subject. In
certain embodiments of the methods disclosed herein, an inhalation
formulation administered with an inhalation device, e.g., a
nebulizer, produces in a subject an AUC.sub.(0-.infin.) of cromolyn
or a pharmaceutically-acceptable salt thereof of about 100
ng*hr/mL, about 110 ng*hr/mL, about 120 ng*hr/mL, about 130
ng*hr/mL, about 140 ng*hr/mL, about 150 ng*hr/mL, about 160
ng*hr/mL, about 170 ng*hr/mL, about 180 ng*hr/mL, about 190
ng*hr/mL, about 200 ng*hr/mL, about 225 ng*hr/mL, about 250
ng*hr/mL, ng*hr/mL, about 275 ng*hr/mL, about 300 ng*hr/mL, about
325 ng*hr/mL, about 350 ng*hr/mL, about 375 ng*hr/mL, about 400
ng*hr/mL, about 425 ng*hr/mL, about 450 ng*hr/mL, about 475
ng*hr/mL, about 500 ng*hr/mL, about 525 ng*hr/mL, about 550
ng*hr/mL, about 575 ng*hr/mL, about 600 ng*hr/mL, about 625
ng*hr/mL, about 650 ng*hr/mL, about 675 ng*hr/mL, about 700
ng*hr/mL, about 725 ng*hr/mL, about 750 ng*hr/mL, about 775
ng*hr/mL, about 800 ng*hr/mL, about 825 ng*hr/mL, about 850
ng*hr/mL, about 875 ng*hr/mL, about 900 ng*hr/mL, about 925
ng*hr/mL, about 950 ng*hr/mL, about 975 ng*hr/mL, or about 1000
ng*hr/mL after administration of the formulation to the subject or
subject.
[0219] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject an AUC.sub.(0-.infin.) of
cromolyn sodium greater than about 100 ng*hr/mL, greater than about
110 ng*hr/mL, greater than about 120 ng*hr/mL, greater than about
130 ng*hr/mL, greater than about 140 ng*hr/mL, greater than about
150 ng*hr/mL, greater than about 160 ng*hr/mL, greater than about
170 ng*hr/mL, greater than about 180 ng*hr/mL, greater than about
190 ng*hr/mL, greater than about 200 ng*hr/mL, greater than about
225 ng*hr/mL, greater than about 250 ng*hr/mL, greater than about
275 ng*hr/mL, greater than about 300 ng*hr/mL, greater than about
325 ng*hr/mL, greater than about 350 ng*hr/mL, greater than about
375 ng*hr/mL, greater than about 400 ng*hr/mL, greater than about
425 ng*hr/mL, greater than about 450 ng*hr/mL, greater than about
475 ng*hr/mL, greater than about 500 ng*hr/mL, greater than about
525 ng*hr/mL, greater than about 550 ng*hr/mL, greater than about
575 ng*hr/mL, greater than about 600 ng*hr/mL, greater than about
625 ng*hr/mL, greater than about 650 ng*hr/mL, greater than about
675 ng*hr/mL, greater than about 700 ng*hr/mL, greater than about
725 ng*hr/mL, greater than about 750 ng*hr/mL, greater than about
775 ng*hr/mL, greater than about 800 ng*hr/mL, greater than about
825 ng*hr/mL, greater than about 850 ng*hr/mL, greater than about
875 ng*hr/mL, greater than about 900 ng*hr/mL, greater than about
925 ng*hr/mL, greater than about 950 ng*hr/mL, greater than about
975 ng*hr/mL, or greater than about 1000 ng*hr/mL after
administration of the formulation to the subject. In certain
embodiments of the methods disclosed herein, an inhalation
formulation administered with an inhalation device, e.g., a
nebulizer, produces in a subject an AUC.sub.(0-.infin.) of cromolyn
sodium greater than about 100 ng*hr/mL, greater than about 110
ng*hr/mL, greater than about 120 ng*hr/mL, greater than about 130
ng*hr/mL, greater than about 140 ng*hr/mL, greater than about 150
ng*hr/mL, greater than about 160 ng*hr/mL, greater than about 170
ng*hr/mL, greater than about 180 ng*hr/mL, greater than about 190
ng*hr/mL, greater than about 200 ng*hr/mL, greater than about 225
ng*hr/mL, greater than about 250 ng*hr/mL, greater than about 275
ng*hr/mL, greater than about 300 ng*hr/mL, greater than about 325
ng*hr/mL, greater than about 350 ng*hr/mL, greater than about 375
ng*hr/mL, greater than about 400 ng*hr/mL, greater than about 425
ng*hr/mL, greater than about 450 ng*hr/mL, greater than about 475
ng*hr/mL, greater than about 500 ng*hr/mL, greater than about 525
ng*hr/mL, greater than about 550 ng*hr/mL, greater than about 575
ng*hr/mL, greater than about 600 ng*hr/mL, greater than about 625
ng*hr/mL, greater than about 650 ng*hr/mL, greater than about 675
ng*hr/mL, greater than about 700 ng*hr/mL, greater than about 725
ng*hr/mL, greater than about 750 ng*hr/mL, greater than about 775
ng*hr/mL, greater than about 800 ng*hr/mL, greater than about 825
ng*hr/mL, greater than about 850 ng*hr/mL, greater than about 875
ng*hr/mL, greater than about 900 ng*hr/mL, greater than about 925
ng*hr/mL, greater than about 950 ng*hr/mL, greater than about 975
ng*hr/mL, or greater than about 1000 ng*hr/mL after administration
of the formulation to the subject or subject.
[0220] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject an AUC.sub.(0-.infin.) of
cromolyn sodium of about 100 ng*hr/mL, about 110 ng*hr/mL, about
120 ng*hr/mL, about 130 ng*hr/mL, about 140 ng*hr/mL, about 150
ng*hr/mL, about 160 ng*hr/mL, about 170 ng*hr/mL, about 180
ng*hr/mL, about 190 ng*hr/mL, about 200 ng*hr/mL, about 225
ng*hr/mL, about 250 ng*hr/mL, ng*hr/mL, about 275 ng*hr/mL, about
300 ng*hr/mL, about 325 ng*hr/mL, about 350 ng*hr/mL, about 375
ng*hr/mL, about 400 ng*hr/mL, about 425 ng*hr/mL, about 450
ng*hr/mL, about 475 ng*hr/mL, about 500 ng*hr/mL, about 525
ng*hr/mL, about 550 ng*hr/mL, about 575 ng*hr/mL, about 600
ng*hr/mL, about 625 ng*hr/mL, about 650 ng*hr/mL, about 675
ng*hr/mL, about 700 ng*hr/mL, about 725 ng*hr/mL, about 750
ng*hr/mL, about 775 ng*hr/mL, about 800 ng*hr/mL, about 825
ng*hr/mL, about 850 ng*hr/mL, about 875 ng*hr/mL, about 900
ng*hr/mL, about 925 ng*hr/mL, about 950 ng*hr/mL, about 975
ng*hr/mL, or about 1000 ng*hr/mL after administration of the
formulation to the subject. In certain embodiments of the methods
disclosed herein, an inhalation formulation administered with an
inhalation device, e.g., a nebulizer, produces in a subject an
AUC.sub.(0-.infin.) of cromolyn sodium of about 100 ng*hr/mL, about
110 ng*hr/mL, about 120 ng*hr/mL, about 130 ng*hr/mL, about 140
ng*hr/mL, about 150 ng*hr/mL, about 160 ng*hr/mL, about 170
ng*hr/mL, about 180 ng*hr/mL, about 190 ng*hr/mL, about 200
ng*hr/mL, about 225 ng*hr/mL, about 250 ng*hr/mL, ng*hr/mL, about
275 ng*hr/mL, about 300 ng*hr/mL, about 325 ng*hr/mL, about 350
ng*hr/mL, about 375 ng*hr/mL, about 400 ng*hr/mL, about 425
ng*hr/mL, about 450 ng*hr/mL, about 475 ng*hr/mL, about 500
ng*hr/mL, about 525 ng*hr/mL, about 550 ng*hr/mL, about 575
ng*hr/mL, about 600 ng*hr/mL, about 625 ng*hr/mL, about 650
ng*hr/mL, about 675 ng*hr/mL, about 700 ng*hr/mL, about 725
ng*hr/mL, about 750 ng*hr/mL, about 775 ng*hr/mL, about 800
ng*hr/mL, about 825 ng*hr/mL, about 850 ng*hr/mL, about 875
ng*hr/mL, about 900 ng*hr/mL, about 925 ng*hr/mL, about 950
ng*hr/mL, about 975 ng*hr/mL, or about 1000 ng*hr/mL after
administration of the formulation to the subject or subject.
[0221] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject a Cmax of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 40
ng/mL, greater than about 50 ng/mL, greater than about 60 ng/mL,
greater than about 70 ng/mL, greater than about 80 ng/mL, greater
than about 90 ng/mL, greater than about 100 ng/mL, greater than
about 110 ng/mL, greater than about 120 ng/mL, greater than about
130 ng/mL, greater than about 140 ng/mL, greater than about 150
ng/mL, greater than about 160 ng/mL, greater than about 170 ng/mL,
greater than about 180 ng/mL, greater than about 190 ng/mL, greater
than about 200 ng/mL, greater than about 210 ng/mL, greater than
about 220 ng/mL, greater than about 230 ng/mL, greater than about
240 ng/mL, greater than about 250 ng/mL, greater than about 260
ng/mL, greater than about 270 ng/mL, greater than about 280 ng/mL,
greater than about 290 ng/mL, greater than about 300 ng/mL, greater
than about 310 ng/mL, greater than about 320 ng/mL, greater than
about 330 ng/mL, greater than about 340 ng/mL, greater than about
350 ng/mL, greater than about 360 ng/mL, greater than about 370
ng/mL, greater than about 380 ng/mL, greater than about 390 ng/mL,
or greater than about 400 ng/mL after administration of the
formulation to the subject. In certain embodiments of the methods
disclosed herein, an inhalation formulation administered with an
inhalation device, e.g., a nebulizer, produces in a subject a Cmax
of cromolyn or a pharmaceutically-acceptable salt thereof greater
than about 40 ng/mL, greater than about 50 ng/mL, greater than
about 60 ng/mL, greater than about 70 ng/mL, greater than about 80
ng/mL, greater than about 90 ng/mL, greater than about 100 ng/mL,
greater than about 110 ng/mL, greater than about 120 ng/mL, greater
than about 130 ng/mL, greater than about 140 ng/mL, greater than
about 150 ng/mL, greater than about 160 ng/mL, greater than about
170 ng/mL, greater than about 180 ng/mL, greater than about 190
ng/mL, greater than about 200 ng/mL, greater than about 210 ng/mL,
greater than about 220 ng/mL, greater than about 230 ng/mL, greater
than about 240 ng/mL, greater than about 250 ng/mL, greater than
about 260 ng/mL, greater than about 270 ng/mL, greater than about
280 ng/mL, greater than about 290 ng/mL, greater than about 300
ng/mL, greater than about 310 ng/mL, greater than about 320 ng/mL,
greater than about 330 ng/mL, greater than about 340 ng/mL, greater
than about 350 ng/mL, greater than about 360 ng/mL, greater than
about 370 ng/mL, greater than about 380 ng/mL, greater than about
390 ng/mL, or greater than about 400 ng/mL after administration of
the formulation to the subject or subject.
[0222] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject a Cmax of cromolyn or a
pharmaceutically-acceptable salt thereof of about 50 mg/mL, about
60 ng/mL, about 70 ng/mL, about 80 ng/mL, about 90 ng/mL, about 100
ng/mL, about 110 ng/mL, about 120 ng/mL, about 130 ng/mL, about 140
ng/mL, about 150 ng/mL, about 160 ng/mL, about 170 ng/mL, about 180
ng/mL, about 190 ng/mL, about 200 ng/mL, about 210 ng/mL, about 220
ng/mL, about 230 ng/mL, about 240 ng/mL, about 250 ng/mL, about 260
ng/mL, about 270 ng/mL, about 280 ng/mL, about 290 ng/mL, about 300
ng/mL, about 310 ng/mL, about 320 ng/mL, about 330 ng/mL, about 340
ng/mL, about 350 ng/mL, about 360 ng/mL, about 370 ng/mL, about 380
ng/mL, about 390 ng/mL, or about 400 ng/mL after administration of
the formulation to the subject. In certain embodiments of the
methods disclosed herein, an inhalation formulation administered
with an inhalation device, e.g., a nebulizer, produces in a subject
a Cmax of cromolyn or a pharmaceutically-acceptable salt thereof of
about 50 mg/mL, about 60 ng/mL, about 70 ng/mL, about 80 ng/mL,
about 90 ng/mL, about 100 ng/mL, about 110 ng/mL, about 120 ng/mL,
about 130 ng/mL, about 140 ng/mL, about 150 ng/mL, about 160 ng/mL,
about 170 ng/mL, about 180 ng/mL, about 190 ng/mL, about 200 ng/mL,
about 210 ng/mL, about 220 ng/mL, about 230 ng/mL, about 240 ng/mL,
about 250 ng/mL, about 260 ng/mL, about 270 ng/mL, about 280 ng/mL,
about 290 ng/mL, about 300 ng/mL, about 310 ng/mL, about 320 ng/mL,
about 330 ng/mL, about 340 ng/mL, about 350 ng/mL, about 360 ng/mL,
about 370 ng/mL, about 380 ng/mL, about 390 ng/mL, or about 400
ng/mL after administration of the formulation to the subject or
subject.
[0223] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject a Cmax of cromolyn sodium
greater than about 40 ng/mL, greater than about 50 ng/mL, greater
than about 60 ng/mL, greater than about 70 ng/mL, greater than
about 80 ng/mL, greater than about 90 ng/mL, greater than about 100
ng/mL, greater than about 110 ng/mL, greater than about 120 ng/mL,
greater than about 130 ng/mL, greater than about 140 ng/mL, greater
than about 150 ng/mL, greater than about 160 ng/mL, greater than
about 170 ng/mL, greater than about 180 ng/mL, greater than about
190 ng/mL, greater than about 200 ng/mL, greater than about 210
ng/mL, greater than about 220 ng/mL, greater than about 230 ng/mL,
greater than about 240 ng/mL, greater than about 250 ng/mL, greater
than about 260 ng/mL, greater than about 270 ng/mL, greater than
about 280 ng/mL, greater than about 290 ng/mL, greater than about
300 ng/mL, greater than about 310 ng/mL, greater than about 320
ng/mL, greater than about 330 ng/mL, greater than about 340 ng/mL,
greater than about 350 ng/mL, greater than about 360 ng/mL, greater
than about 370 ng/mL, greater than about 380 ng/mL, greater than
about 390 ng/mL, or greater than about 400 ng/mL after
administration of the formulation to the subject. In certain
embodiments of the methods disclosed herein, an inhalation
formulation administered with an inhalation device, e.g., a
nebulizer, produces in a subject a Cmax of cromolyn sodium greater
than about 40 ng/mL, greater than about 50 ng/mL, greater than
about 60 ng/mL, greater than about 70 ng/mL, greater than about 80
ng/mL, greater than about 90 ng/mL, greater than about 100 ng/mL,
greater than about 110 ng/mL, greater than about 120 ng/mL, greater
than about 130 ng/mL, greater than about 140 ng/mL, greater than
about 150 ng/mL, greater than about 160 ng/mL, greater than about
170 ng/mL, greater than about 180 ng/mL, greater than about 190
ng/mL, greater than about 200 ng/mL, greater than about 210 ng/mL,
greater than about 220 ng/mL, greater than about 230 ng/mL, greater
than about 240 ng/mL, greater than about 250 ng/mL, greater than
about 260 ng/mL, greater than about 270 ng/mL, greater than about
280 ng/mL, greater than about 290 ng/mL, greater than about 300
ng/mL, greater than about 310 ng/mL, greater than about 320 ng/mL,
greater than about 330 ng/mL, greater than about 340 ng/mL, greater
than about 350 ng/mL, greater than about 360 ng/mL, greater than
about 370 ng/mL, greater than about 380 ng/mL, greater than about
390 ng/mL, or greater than about 400 ng/mL after administration of
the formulation to the subject or subject.
[0224] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject a Cmax of cromolyn sodium
of about 50 mg/mL, about 60 ng/mL, about 70 ng/mL, about 80 ng/mL,
about 90 ng/mL, about 100 ng/mL, about 110 ng/mL, about 120 ng/mL,
about 130 ng/mL, about 140 ng/mL, about 150 ng/mL, about 160 ng/mL,
about 170 ng/mL, about 180 ng/mL, about 190 ng/mL, about 200 ng/mL,
about 210 ng/mL, about 220 ng/mL, about 230 ng/mL, about 240 ng/mL,
about 250 ng/mL, about 260 ng/mL, about 270 ng/mL, about 280 ng/mL,
about 290 ng/mL, about 300 ng/mL, about 310 ng/mL, about 320 ng/mL,
about 330 ng/mL, about 340 ng/mL, about 350 ng/mL, about 360 ng/mL,
about 370 ng/mL, about 380 ng/mL, about 390 ng/mL, or about 400
ng/mL after administration of the formulation to the subject. In
certain embodiments of the methods disclosed herein, an inhalation
formulation administered with an inhalation device, e.g., a
nebulizer, produces in a subject a Cmax of cromolyn sodium of about
50 mg/mL, about 60 ng/mL, about 70 ng/mL, about 80 ng/mL, about 90
ng/mL, about 100 ng/mL, about 110 ng/mL, about 120 ng/mL, about 130
ng/mL, about 140 ng/mL, about 150 ng/mL, about 160 ng/mL, about 170
ng/mL, about 180 ng/mL, about 190 ng/mL, about 200 ng/mL, about 210
ng/mL, about 220 ng/mL, about 230 ng/mL, about 240 ng/mL, about 250
ng/mL, about 260 ng/mL, about 270 ng/mL, about 280 ng/mL, about 290
ng/mL, about 300 ng/mL, about 310 ng/mL, about 320 ng/mL, about 330
ng/mL, about 340 ng/mL, about 350 ng/mL, about 360 ng/mL, about 370
ng/mL, about 380 ng/mL, about 390 ng/mL, or about 400 ng/mL after
administration of the formulation to the subject.
[0225] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject an AUC.sub.(0-.infin.) of
cromolyn or a pharmaceutically-acceptable salt thereof greater than
about 120 ng*hr/mL and/or an average Cmax of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 55
ng/mL. In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject an AUC.sub.(0-.infin.) of
cromolyn or a pharmaceutically-acceptable salt thereof greater than
about 120 ng*hr/mL and/or a Cmax of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 55
ng/mL.
[0226] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject an e.g., a nebulizer,
produces in a subject an AUC.sub.(0-.infin.) of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 200
ng*hr/mL and an average Cmax of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 80
ng/mL. In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject an AUC.sub.(0-.infin.) of
cromolyn or a pharmaceutically-acceptable salt thereof greater than
about 200 ng*hr/mL and a Cmax of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 80
ng/mL.
[0227] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject an AUC.sub.(0-.infin.) of
cromolyn or a pharmaceutically-acceptable salt thereof greater than
about 330 ng*hr/mL and an average Cmax of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 150
ng/mL. In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject an AUC.sub.(0-.infin.) of
cromolyn or a pharmaceutically-acceptable salt thereof greater than
about 330 ng*hr/mL and a Cmax of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 150
ng/mL.
[0228] In certain embodiments, of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject an AUC.sub.(0-.infin.) of
cromolyn or a pharmaceutically-acceptable salt thereof greater than
about 525 ng*hr/mL and an average Cmax of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 230
ng/mL. In certain embodiments, of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject an AUC.sub.(0-.infin.) of
cromolyn or a pharmaceutically-acceptable salt thereof greater than
about 525 ng*hr/mL and a Cmax of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 230
ng/mL.
[0229] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject an AUC.sub.(0-.infin.) of
cromolyn sodium greater than about 120 ng*hr/mL and/or an average
Cmax of cromolyn sodium greater than about 55 ng/mL. In certain
embodiments of the methods disclosed herein, an inhalation
formulation administered with an inhalation device, e.g., a
nebulizer, produces in a subject an AUC.sub.(0-.infin.) of cromolyn
sodium greater than about 120 ng*hr/mL and/or a Cmax of cromolyn
sodium greater than about 55 ng/mL.
[0230] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject an AUC.sub.(0-.infin.) of
cromolyn sodium greater than about 120 ng*hr/mL and an average Cmax
of cromolyn sodium greater than about 55 ng/mL. In certain
embodiments of the methods disclosed herein, an inhalation
formulation administered with an inhalation device, e.g., a
nebulizer, produces in a subject an AUC.sub.(0-.infin.) of cromolyn
sodium greater than about 120 ng*hr/mL and a Cmax of cromolyn
sodium greater than about 55 ng/mL.
[0231] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject an AUC.sub.(0-.infin.) of
cromolyn sodium greater than about 200 ng*hr/mL and an average Cmax
of cromolyn sodium greater than about 80 ng/mL. In certain
embodiments of the methods disclosed herein, an inhalation
formulation administered with an inhalation device, e.g., a
nebulizer, produces in a subject an AUC.sub.(0-.infin.) of cromolyn
sodium greater than about 200 ng*hr/mL and a Cmax of cromolyn
sodium greater than about 80 ng/mL.
[0232] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject an AUC.sub.(0-.infin.) of
cromolyn sodium greater than about 330 ng*hr/mL and an average Cmax
of cromolyn sodium greater than about 150 ng/mL. In certain
embodiments of the methods disclosed herein, an inhalation
formulation administered with an inhalation device, e.g., a
nebulizer, produces in a subject an AUC.sub.(0-.infin.) of cromolyn
sodium greater than about 330 ng*hr/mL and a Cmax of cromolyn
sodium greater than about 150 ng/mL.
[0233] In certain embodiments, of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject an AUC.sub.(0-.infin.) of
cromolyn sodium greater than about 525 ng*hr/mL and an average Cmax
of cromolyn sodium greater than about 230 ng/mL. In certain
embodiments, of the methods disclosed herein, an inhalation
formulation administered with an inhalation device, e.g., a
nebulizer, produces in a subject an AUC.sub.(0-.infin.) of cromolyn
sodium greater than about 525 ng*hr/mL and a Cmax of cromolyn
sodium greater than about 230 ng/mL.
[0234] In certain embodiments of the methods disclosed herein, the
administration of a formulation comprising about 40 mg of cromolyn
sodium, or a pharmaceutically acceptable salt thereof, to a subject
by means of an inhalation device affords a Cmax or average Cmax of
cromolyn sodium in the subject of from about from 30 ng/mL to about
120 ng/mL, or from about 40 ng/mL to about 120 ng/mL, or from about
40 ng/mL to about 110 ng/mL. In certain embodiments, the
administration of a formulation comprising about 40 mg of cromolyn
sodium, or a pharmaceutically acceptable salt thereof, to a subject
by means of an inhalation device affords an AUC.sub.(0-.infin.) of
cromolyn sodium in the subject of between about 100 ng*hr/mL and
about 350 ng*hr/mL, or between about 100 ng*hr/mL and about 325
ng*hr/mL, or between about 115 ng*hr/mL and about 325 ng*hr/mL, or
between about 120 ng*hr/mL and about 320 ng*hr/mL, or between about
125 ng*hr/mL and about 300 ng*hr/mL. In certain embodiments, the
formulation comprises between 1% and 10% by weight cromolyn sodium,
or between about 4% by weight and 6% by weight cromolyn sodium. In
certain embodiments, the formulation comprises 4% by weight
cromolyn sodium. In certain embodiments, the formulation comprises
6% by weight cromolyn sodium. In certain embodiments, use of a
nebulizer to administer the formulation provides an aerosol of the
formulation comprising cromolyn or a pharmaceutically-acceptable
salt thereof, wherein the aerosol exhibits an RF (.ltoreq.5 .mu.m)
of an cromolyn or a pharmaceutically-acceptable salt thereof of 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%, at least
about 85%, at least about 90%, at least about 95%, about 20% to
about 95%, about 35% to about 90%, or about 40% to about 80%, about
40% to about 90%, about 40% to about 95%, about 45% to about 90%,
about 45% to about 95%, about 50% to about 90%, about 65% to about
90%, about 60% to about 95%, about 65% to about 95%, about 70% to
about 90%, about 55% to about 90%, about 70% to about 80%, or about
75%. In certain embodiments, use of a nebulizer in the methods
disclosed herein provides an aerosol of a solution comprising
cromolyn or a pharmaceutically-acceptable salt thereof, wherein the
aerosol exhibits an RF (.ltoreq.5 .mu.m) of cromolyn sodium of 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%, at least
about 85%, at least about 90%, at least about 95%, about 20% to
about 95%, about 35% to about 90%, or about 40% to about 80%, about
40% to about 90%, about 40% to about 95%, about 45% to about 90%,
about 45% to about 95%, about 50% to about 90%, about 65% to about
90%, about 60% to about 95%, about 65% to about 95%, about 70% to
about 90%, about 55% to about 90%, about 70% to about 80%, about
65% to about 75%, about 65% to about 80%, about 60% to about 80%,
about 66%, or about 75%. In certain embodiments, the formulation
comprises an osmotic agent comprising sodium chloride. In certain
embodiments, the formulation comprises an osmotic agent consisting
of sodium chloride. In certain embodiments, the osmolality of the
formulation is between about 100 mOsm/kg and about 175 mOsm/kg, or
between about 100 mOsm/kg and about 170 mOsm/kg, or between about
100 mOsm/kg and about 165 mOsm/kg, or between about 100 mOsm/kg and
about 160 mOsm/kg, or between about 100 mOsm/kg and about 150
mOsm/kg, or between about 110 mOsm/kg and about 150 mOsm/kg, or
between about 110 mOsm/kg and about 140 mOsm/kg, or between about
115 mOsm/kg and about 140 mOsm/kg, or between about 120 mOsm/kg and
about 140 mOsm/kg, or between about 120 mOsm/kg and about 130
mOsm/kg. In certain embodiments, the osmolality of the formulation
is about 120 mOsm/kg, about 125 mOsm/kg, about 130 mOsm/kg, about
135 mOsm/kg, about 140 mOsm/kg, about 145 mOsm/kg, or about 150
mOsm/kg.
[0235] In certain embodiments of the methods disclosed herein, the
administration of a formulation comprising about 60 mg of cromolyn
sodium, or a pharmaceutically acceptable salt thereof, to a subject
by means of an inhalation device affords a Cmax or average Cmax of
cromolyn sodium in the subject of from about from 50 ng/mL to about
175 ng/mL, or from about 60 ng/mL to about 175 ng/mL, or from about
60 ng/mL to about 170 ng/mL, or from about 60 ng/mL to about 165
ng/mL, or from about 70 ng/mL to about 165 ng/mL. In certain
embodiments, the administration of a formulation comprising about
60 mg of cromolyn sodium, or a pharmaceutically acceptable salt
thereof, to a subject by means of an inhalation device affords an
AUC.sub.(0-.infin.) of cromolyn sodium in the subject of between
about 200 ng*hr/mL and about 600 ng*hr/mL, or between about 200
ng*hr/mL and about 575 ng*hr/mL, or between about 200 ng*hr/mL and
about 550 ng*hr/mL, or between about 200 ng*hr/mL and about 525
ng*hr/mL, or between about 210 ng*hr/mL and about 525 ng*hr/mL, or
between about 215 ng*hr/mL and about 515 ng*hr/mL, or between about
175 ng*hr/mL and about 500 ng*hr/mL, or between about 195 ng*hr/mL
and about 515 ng*hr/mL, or between about 200 ng*hr/mL and about 500
ng*hr/mL. In certain embodiments, the formulation comprises between
1% and 10% by weight cromolyn sodium, or between about 4% by weight
and 6% by weight cromolyn sodium. In certain embodiments, the
formulation comprises 4% by weight cromolyn sodium. In certain
embodiments, the formulation comprises 6% by weight cromolyn
sodium. In certain embodiments, use of a nebulizer to administer
the formulation provides an aerosol of the formulation comprising
cromolyn or a pharmaceutically-acceptable salt thereof, wherein the
aerosol exhibits an RF (.ltoreq.5 .mu.m) of an cromolyn or a
pharmaceutically-acceptable salt thereof of 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%, at least about 85%, at least
about 90%, at least about 95%, about 20% to about 95%, about 35% to
about 90%, or about 40% to about 80%, about 40% to about 90%, about
40% to about 95%, about 45% to about 90%, about 45% to about 95%,
about 50% to about 90%, about 65% to about 90%, about 60% to about
95%, about 65% to about 95%, about 70% to about 90%, about 55% to
about 90%, about 70% to about 80%, or about 75%. In certain
embodiments, use of a nebulizer in the methods disclosed herein
provides an aerosol of a solution comprising cromolyn or a
pharmaceutically-acceptable salt thereof, wherein the aerosol
exhibits an RF (.ltoreq.5 .mu.m) of cromolyn sodium of 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%, at least about
85%, at least about 90%, at least about 95%, about 20% to about
95%, about 35% to about 90%, or about 40% to about 80%, about 40%
to about 90%, about 40% to about 95%, about 45% to about 90%, about
45% to about 95%, about 50% to about 90%, about 65% to about 90%,
about 60% to about 95%, about 65% to about 95%, about 70% to about
90%, about 55% to about 90%, about 70% to about 80%, about 65% to
about 75%, about 65% to about 80%, about 60% to about 80%, about
66%, or about 75%. In certain embodiments, the formulation
comprises an osmotic agent comprising sodium chloride. In certain
embodiments, the formulation comprises an osmotic agent consisting
of sodium chloride. In certain embodiments, the osmolality of the
formulation is between about 100 mOsm/kg and about 175 mOsm/kg, or
between about 100 mOsm/kg and about 170 mOsm/kg, or between about
100 mOsm/kg and about 165 mOsm/kg, or between about 100 mOsm/kg and
about 160 mOsm/kg, or between about 100 mOsm/kg and about 150
mOsm/kg, or between about 110 mOsm/kg and about 150 mOsm/kg, or
between about 110 mOsm/kg and about 140 mOsm/kg, or between about
115 mOsm/kg and about 140 mOsm/kg, or between about 120 mOsm/kg and
about 140 mOsm/kg, or between about 120 mOsm/kg and about 130
mOsm/kg. In certain embodiments, the osmolality of the formulation
is about 120 mOsm/kg, about 125 mOsm/kg, about 130 mOsm/kg, about
135 mOsm/kg, about 140 mOsm/kg, about 145 mOsm/kg, or about 150
mOsm/kg.
[0236] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject an AUC.sub.(0-.infin.) of
cromolyn sodium of about 330 ng*hr/mL and an average Cmax of
cromolyn sodium of about 150 ng/mL when a nominal dose of 40 mg of
cromolyn sodium is administered with the inhalation device. In
certain embodiments of the methods disclosed herein, an inhalation
formulation administered with an inhalation device, e.g., a
nebulizer, produces in a subject an AUC.sub.(0-.infin.) of cromolyn
sodium of about 330 ng*hr/mL and a Cmax of cromolyn sodium of about
150 ng/mL when a nominal dose of 40 mg of cromolyn sodium is
administered with the inhalation device.
[0237] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject an AUC.sub.(0-.infin.) of
cromolyn sodium of about 525 ng*hr/mL and an average Cmax of
cromolyn sodium of about 230 ng/mL when a nominal dose of 80 mg of
cromolyn sodium is administered with the inhalation device. In
certain embodiments of the methods disclosed herein, an inhalation
formulation administered with an inhalation device, e.g., a
nebulizer, produces in a subject an AUC.sub.(0-.infin.) of cromolyn
sodium of about 525 ng*hr/mL and a Cmax of cromolyn sodium of about
230 ng/mL when a nominal dose of 80 mg of cromolyn sodium is
administered with the inhalation device.
[0238] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject an AUC.sub.(0-.infin.) of
cromolyn sodium of about 180 ng*hr/mL to about 220 ng*hr/mL and an
average Cmax of cromolyn sodium of about 70 ng/mL to about 90 ng/mL
when a nominal dose of 40 mg of cromolyn sodium is administered
with the inhalation device. In certain embodiments of the methods
disclosed herein, an inhalation formulation administered with an
inhalation device, e.g., a nebulizer, produces in a subject an
AUC.sub.(0-.infin.) of cromolyn sodium of about 180 ng*hr/mL to
about 220 ng*hr/mL and a Cmax of cromolyn sodium of about 70 ng/mL
to about 90 ng/mL when a nominal dose of 40 mg of cromolyn sodium
is administered with the inhalation device.
[0239] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject an AUC.sub.(0-.infin.) of
cromolyn sodium of about 300 ng*hr/mL to about 360 ng*hr/mL and an
average Cmax of cromolyn sodium of about 135 ng/mL to about 165
ng/mL when a nominal dose of 40 mg of cromolyn sodium is
administered with the inhalation device. In certain embodiments of
the methods disclosed herein, an inhalation formulation
administered with an inhalation device, e.g., a nebulizer, produces
in a subject an AUC.sub.(0-.infin.) of cromolyn sodium of about 300
ng*hr/mL to about 360 ng*hr/mL and a Cmax of cromolyn sodium of
about 135 ng/mL to about 165 ng/mL when a nominal dose of 40 mg of
cromolyn sodium is administered with the inhalation device.
[0240] In certain embodiments, of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject an AUC.sub.(0-.infin.) of
cromolyn sodium of about 475 ng*hr/mL to about 575 ng*hr/mL and an
average Cmax of cromolyn sodium of about 200 ng/mL to about 260
ng/mL when a nominal dose of 80 mg of cromolyn sodium is
administered with the inhalation device. In certain embodiments, of
the methods disclosed herein, an inhalation formulation
administered with an inhalation device, e.g., a nebulizer, produces
in a subject an AUC.sub.(0-.infin.) of cromolyn sodium of about 475
ng*hr/mL to about 575 ng*hr/mL and a Cmax of cromolyn sodium of
about 200 ng/mL to about 260 ng/mL when a nominal dose of 80 mg of
cromolyn sodium is administered with the inhalation device.
[0241] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a lung deposition (deposited lung dose)
comprising cromolyn or pharmaceutically acceptable salt thereof of
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%, about 20% to about 40%, about 25% to about 35%, about 25% to
about 30%, about 25% to about 75%, about 30% to about 50%, about
35% to about 90%, about 40% to about 80%, about 40% to about 60%,
about 50% to about 60%, about 50% to about 70%, or about 60% to
about 75% based on the nominal dose of the cromolyn or a
pharmaceutically-acceptable salt thereof. In certain embodiments of
the methods disclosed herein, an inhalation formulation
administered with an inhalation device, e.g., a nebulizer, provides
cromolyn sodium deposition (deposited lung dose) of 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%, about 20% to
about 40%, about 25% to about 35%, about 25% to about 30%, about
25% to about 75%, about 30% to about 50%, about 35% to about 90%,
about 40% to about 80%, about 40% to about 60%, about 50% to about
60%, about 50% to about 70%, or about 60% to about 75% based on the
nominal dose of the cromolyn sodium.
[0242] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a lung deposition (deposited lung dose)
comprising cromolyn or a pharmaceutically-acceptable salt thereof
of 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%, or about
100% based on the nominal dose of the cromolyn or a
pharmaceutically-acceptable salt thereof. In certain embodiments of
the methods disclosed herein, an inhalation formulation
administered with an inhalation device, e.g., a nebulizer, provides
cromolyn sodium lung deposition (deposited lung dose) of 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%, or about 100% based on
the nominal dose of the cromolyn sodium.
[0243] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a lung deposition (deposited lung dose)
comprising cromolyn or a pharmaceutically-acceptable salt thereof
of greater than about 0.5 mg, greater than about 1 mg, greater than
about 1.5 mg, greater than about 2 mg, greater than about 2.5 mg,
greater than about 3 mg, greater than about 3.5 mg, greater than
about 4 mg, greater than about 5 mg, greater than about 6 mg,
greater than about 7 mg, greater than about 8 mg, greater than
about 9 mg, greater than about 10 mg, greater than about 11 mg,
greater than about 12 mg, greater than about 13 mg, greater than
about 14 mg, or greater than about 15 mg. In certain embodiments of
the methods disclosed herein, an inhalation formulation
administered with an inhalation device, e.g., a nebulizer, provides
a lung deposition (deposited lung dose) comprising cromolyn or a
pharmaceutically-acceptable salt thereof of about 0.5 mg, about 1.0
mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about
3.5 mg, about 4.0 mg, about 5.0 mg, about 6.0 mg, about 7.0 mg,
about 8.0 mg, about 9.0 mg, about 10 mg, about 11 mg, about 12 mg,
about 13 mg, about 14 mg, or about 15 mg.
[0244] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides cromolyn sodium lung deposition
(deposited lung dose) of greater than about 0.5 mg, greater than
about 1 mg, greater than about 1.5 mg, greater than about 2 mg,
greater than about 2.5 mg, greater than about 3 mg, greater than
about 3.5 mg, greater than about 4 mg, greater than about 5 mg,
greater than about 6 mg, greater than about 7 mg, greater than
about 8 mg, greater than about 9 mg, greater than about 10 mg,
greater than about 11 mg, greater than about 12 mg, greater than
about 13 mg, greater than about 14 mg, or greater than about 15 mg.
In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides cromolyn sodium lung deposition
(deposited lung dose) of about 0.5 mg, about 1.0 mg, about 1.5 mg,
about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0
mg, about 5.0 mg, about 6.0 mg, about 7.0 mg, about 8.0 mg, about
9.0 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about
14 mg, or about 15 mg.
[0245] In certain embodiments of the methods disclosed herein, an
inhalation formulation containing cromolyn or a
pharmaceutically-acceptable salt thereof is administered with an
inhalation device, e.g., a nebulizer, at an administration of less
than about 1 mg/dose, about 1 mg/dose to about 100 mg/dose, about 5
mg/dose to about 80 mg/dose, about 20 mg/dose to about 60 mg/dose,
about 30 mg/dose to about 50 mg/dose, or greater than 100 mg/dose.
In certain embodiments of the methods disclosed herein, an
inhalation formulation containing cromolyn sodium is administered
with an inhalation device, e.g., a nebulizer, at an administration
of less than about 1 mg/dose, about 1 mg/dose to about 100 mg/dose,
about 5 mg/dose to about 80 mg/dose, about 20 mg/dose to about 60
mg/dose, about 30 mg/dose to about 50 mg/dose, or greater than 100
mg/dose. In certain embodiments of the methods disclosed herein,
cromolyn or a pharmaceutically-acceptable salt thereof is
administered in an inhalation formulation with an inhalation
device, e.g., a nebulizer, in about 1 mg, about 5 mg, about 10 mg,
about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg,
about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg,
about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg,
about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg,
about 115 mg, about 120 mg, about 125 mg, about 130 mg doses, about
135 mg, about 140 mg, about 145 mg, about 150 mg, about 200 mg,
about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450
mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about
700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg,
about 950 mg, or about 1000 mg doses. In certain embodiments of the
methods disclosed herein, cromolyn sodium is administered in an
inhalation formulation with an inhalation device, e.g., a
nebulizer, in about 1 mg, about 5 mg, about 10 mg, about 15 mg,
about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg,
about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg,
about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg,
about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115
mg, about 120 mg, about 125 mg, about 130 mg doses, about 135 mg,
about 140 mg, about 145 mg, about 150 mg, about 200 mg, about 250
mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about
500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg,
about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950
mg, or about 1000 mg doses.
[0246] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer provides a bioavailability of cromolyn or a
pharmaceutically-acceptable salt thereof of greater than about 5%,
greater than about 6%, greater than about 7%, greater than about
8%, greater than about 9%, greater than about 10%, greater than
about 11%, greater than about 12%, greater than about 13%, greater
than about 14%, greater than about 15%, greater than about 16%,
greater than about 17%, greater than about 18%, greater than about
19%, greater than about 20%, greater than about 25%, greater than
about 30%, greater than about 35%, greater than about 40%, greater
than about 45%, greater than about 50%, greater than about 55%, or
greater than about 60% of the nominal dose. In certain embodiments,
an inhalation formulation administered with an inhalation device,
e.g., a nebulizer, in the methods disclosed herein provides a
bioavailability of cromolyn or a pharmaceutically-acceptable salt
thereof of about 5%, about 6%, about 7%, about 8%, about 9%, about
10%, about 11%, about 12%, about 13%, about 14%, about 15%, about
16%, about 17%, about 18%, about 19%, about 20%, about 25%, about
30%, about 35%, about 40%, about 45%, about 50%, about 55%, or
about 60% of the nominal dose.
[0247] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer provides a bioavailability of cromolyn sodium of
greater than about 5%, greater than about 6%, greater than about
7%, greater than about 8%, greater than about 9%, greater than
about 10%, greater than about 11%, greater than about 12%, greater
than about 13%, greater than about 14%, greater than about 15%,
greater than about 16%, greater than about 17%, greater than about
18%, greater than about 19%, greater than about 20%, greater than
about 25%, greater than about 30%, greater than about 35%, greater
than about 40%, greater than about 45% or greater than about 50% of
the nominal dose. In certain embodiments, an aqueous inhalation
formulation administered with an inhalation device, e.g., a
nebulizer, in the methods disclosed herein provides a
bioavailability of cromolyn sodium of about 5%, about 6%, about 7%,
about 8%, about 9%, about 10%, about 11%, about 12%, about 13%,
about 14%, about 15%, about 16%, about 17%, about 18%, about 19%,
about 20%, about 25%, about 30%, about 35%, about 40%, about 45%,
or about 50% of the nominal dose.
[0248] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 5% and
produces in a subject an AUC.sub.(0-.infin.) of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 120
ng*hr/mL and/or an average Cmax of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 55
ng/mL. In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 5% and
produces in a subject an AUC.sub.(0-.infin.) of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 120
ng*hr/mL and/or a Cmax of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 55
ng/mL. In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 5% and
produces in a subject an AUC.sub.(0-.infin.) of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 120
ng*hr/mL and an average Cmax of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 55
ng/mL. In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 5% and
produces in a subject an AUC.sub.(0-.infin.) of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 120
ng*hr/mL and a Cmax of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 55
ng/mL. In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 5% and
produces in a subject an AUC.sub.(0-.infin.) of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 200
ng*hr/mL and an average Cmax of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 80
ng/mL. In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 5% and
produces in a subject an AUC.sub.(0-.infin.) of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 200
ng*hr/mL and a Cmax of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 80
ng/mL. In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 5% and
produces in a subject an AUC.sub.(0-.infin.) of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 330
ng*hr/mL and an average Cmax of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 150
ng/mL. In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 5% and
produces in a subject an AUC.sub.(0-.infin.) of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 330
ng*hr/mL and a Cmax of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 150
ng/mL. In certain embodiments, of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 5% and
produces in a subject an AUC.sub.(0-.infin.) of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 525
ng*hr/mL and an average Cmax of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 230
ng/mL. In certain embodiments, of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 5% and
produces in a subject an AUC.sub.(0-.infin.) of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 525
ng*hr/mL and a Cmax of the cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 230
ng/mL.
[0249] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn sodium
greater than about 5% and produces in a subject an
AUC.sub.(0-.infin.) of cromolyn sodium greater than about 120
ng*hr/mL and/or an average Cmax of cromolyn sodium greater than
about 55 ng/mL. In certain embodiments of the methods disclosed
herein, an inhalation formulation administered with an inhalation
device, e.g., a nebulizer, provides a bioavailability of cromolyn
sodium greater than about 5% and produces in a subject an
AUC.sub.(0-.infin.) of cromolyn sodium greater than about 120
ng*hr/mL and/or a Cmax of cromolyn sodium greater than about 55
ng/mL. In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn sodium
greater than about 5% and produces in a subject an
AUC.sub.(0-.infin.) of cromolyn sodium greater than about 120
ng*hr/mL and an average Cmax of cromolyn sodium greater than about
55 ng/mL. In certain embodiments of the methods disclosed herein,
an inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn sodium
greater than about 5% and produces in a subject an
AUC.sub.(0-.infin.) of cromolyn sodium greater than about 120
ng*hr/mL and a Cmax of cromolyn sodium greater than about 55 ng/mL.
In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn sodium
greater than about 5% and produces in a subject an
AUC.sub.(0-.infin.) of cromolyn sodium greater than about 200
ng*hr/mL and an average Cmax of cromolyn sodium greater than about
80 ng/mL. In certain embodiments of the methods disclosed herein,
an inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn sodium
greater than about 5% and produces in a subject an
AUC.sub.(0-.infin.) of cromolyn sodium greater than about 200
ng*hr/mL and a Cmax of cromolyn sodium greater than about 80 ng/mL.
In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn sodium
greater than about 5% and produces in a subject an
AUC.sub.(0-.infin.) of cromolyn sodium greater than about 330
ng*hr/mL and an average Cmax of cromolyn sodium greater than about
150 ng/mL. In certain embodiments of the methods disclosed herein,
an inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn sodium
greater than about 5% and produces in a subject an
AUC.sub.(0-.infin.) of cromolyn sodium greater than about 330
ng*hr/mL and a Cmax of cromolyn sodium greater than about 150
ng/mL. In certain embodiments, of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn sodium
greater than about 5% and produces in a subject an
AUC.sub.(0-.infin.) of cromolyn sodium greater than about 525
ng*hr/mL and an average Cmax of cromolyn sodium greater than about
230 ng/mL. In certain embodiments, of the methods disclosed herein,
an inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn sodium
greater than about 5% and produces in a subject an
AUC.sub.(0-.infin.) of cromolyn sodium greater than about 525
ng*hr/mL and a Cmax of cromolyn sodium greater than about 230
ng/mL.
[0250] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 5% and
produces in a subject an AUC.sub.(0-.infin.) of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 120
ng*hr/mL. In certain embodiments of the methods disclosed herein,
an inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 5% and
produces in a subject an AUC.sub.(0-.infin.) of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 120
ng*hr/mL. In certain embodiments of the methods disclosed herein,
an inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 5% and
produces in a subject an AUC.sub.(0-.infin.) of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 200
ng*hr/mL. In certain embodiments of the methods disclosed herein,
an inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 5% and
produces in a subject an AUC.sub.(0-.infin.) of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 200
ng*hr/mL. In certain embodiments of the methods disclosed herein,
an inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 5% and
produces in a subject an AUC.sub.(0-.infin.) of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 330
ng*hr/mL. In certain embodiments of the methods disclosed herein,
an inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 5% and
produces in a subject an AUC.sub.(0-.infin.) of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 330
ng*hr/mL. In certain embodiments of the methods disclosed herein,
an inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 5% and
produces in a subject an AUC.sub.(0-.infin.) of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 525
ng*hr/mL. In certain embodiments of the methods disclosed herein,
an inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 5% and
produces in a subject an AUC.sub.(0-.infin.) of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 525
ng*hr/mL.
[0251] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn sodium
greater than about 5% and produces in a subject an
AUC.sub.(0-.infin.) of cromolyn sodium greater than about 120
ng*hr/mL. In certain embodiments of the methods disclosed herein,
an inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn sodium
greater than about 5% and produces in a subject an
AUC.sub.(0-.infin.) of cromolyn sodium greater than about 120
ng*hr/mL. In certain embodiments of the methods disclosed herein,
an inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn sodium
greater than about 5% and produces in a subject an
AUC.sub.(0-.infin.) of cromolyn sodium greater than about 200
ng*hr/mL. In certain embodiments of the methods disclosed herein,
an inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn sodium
greater than about 5% and produces in a subject an
AUC.sub.(0-.infin.) of cromolyn sodium greater than about 200
ng*hr/mL. In certain embodiments of the methods disclosed herein,
an inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn sodium
greater than about 5% and produces in a subject an
AUC.sub.(0-.infin.) of cromolyn sodium greater than about 330
ng*hr/mL. In certain embodiments of the methods disclosed herein,
an inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn sodium
greater than about 5% and produces in a subject an
AUC.sub.(0-.infin.) of cromolyn sodium greater than about 330
ng*hr/mL. In certain embodiments, of the methods disclosed herein,
an inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn sodium
greater than about 5% and produces in a subject an
AUC.sub.(0-.infin.) of cromolyn sodium greater than about 525
ng*hr/mL. In certain embodiments, of the methods disclosed herein,
an inhalation formulation administered with an inhalation device,
e.g., a nebulizer, provides a bioavailability of cromolyn sodium
greater than about 5% and produces in a subject an
AUC.sub.(0-.infin.) of cromolyn sodium greater than about 525
ng*hr/mL.
[0252] In certain embodiments of the methods disclosed herein, an
inhalation formulation comprising 40 mg cromolyn sodium
administered with an inhalation device, e.g., a nebulizer, provides
a bioavailability of cromolyn sodium greater than about 5% and
produces in a subject an AUC.sub.(0-.infin.) of cromolyn sodium
greater than about 200 ng*hr/mL. In certain embodiments of the
methods disclosed herein, an inhalation formulation comprising 40
mg cromolyn sodium administered with an inhalation device, e.g., a
nebulizer, provides a bioavailability of cromolyn sodium greater
than about 5% and produces in a subject an AUC.sub.(0-.infin.) of
cromolyn sodium greater than about 200 ng*hr/mL. In certain
embodiments of the methods disclosed herein, an inhalation
formulation comprising 40 mg cromolyn sodium administered with an
inhalation device, e.g., a nebulizer, provides a bioavailability of
cromolyn sodium greater than about 5% and produces in a subject an
AUC.sub.(0-.infin.) of cromolyn sodium greater than about 330
ng*hr/mL. In certain embodiments of the methods disclosed herein,
an inhalation formulation comprising 40 mg cromolyn sodium
administered with an inhalation device, e.g., a nebulizer, provides
a bioavailability of cromolyn sodium greater than about 5% and
produces in a subject an AUC.sub.(0-.infin.) of cromolyn sodium
greater than about 330 ng*hr/mL. In certain embodiments, of the
methods disclosed herein, an inhalation formulation comprising 80
mg cromolyn sodium administered with an inhalation device, e.g., a
nebulizer, provides a bioavailability of cromolyn sodium greater
than about 5% and produces in a subject an AUC.sub.(0-.infin.) of
cromolyn sodium greater than about 525 ng*hr/mL. In certain
embodiments, of the methods disclosed herein, an inhalation
formulation comprising 80 mg cromolyn sodium administered with an
inhalation device, e.g., a nebulizer, provides a bioavailability of
cromolyn sodium greater than about 5% and produces in a subject an
AUC.sub.(0-.infin.) of cromolyn sodium greater than about 525
ng*hr/mL.
[0253] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, has an RF (.ltoreq.3.3 am) of at least about 30%
and produces in a subject an AUC.sub.(0-.infin.) of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 120
ng*hr/mL. In certain embodiments of the methods disclosed herein,
an inhalation formulation administered with an inhalation device,
e.g., a nebulizer, has an RF (.ltoreq.3.3 am) of at least about 30%
and produces in a subject an AUC.sub.(0-.infin.) of cromolyn or a
pharmaceutically-acceptable salt thereof greater than about 120
ng*hr/mL. In certain embodiments of the methods disclosed herein,
an inhalation formulation administered with an inhalation device,
e.g., a nebulizer, has an RF (.ltoreq.3.3 .mu.m) of at least about
30% and produces in a subject an AUC.sub.(0-.infin.) of cromolyn or
a pharmaceutically-acceptable salt thereof greater than about 200
ng*hr/mL. In certain embodiments of the methods disclosed herein,
an inhalation formulation administered with an inhalation device,
e.g., a nebulizer, has an RF (.ltoreq.3.3 .mu.m) of at least about
30% and produces in a subject an AUC.sub.(0-.infin.) of cromolyn or
a pharmaceutically-acceptable salt thereof greater than about 200
ng*hr/mL. In certain embodiments of the methods disclosed herein,
an inhalation formulation administered with an inhalation device,
e.g., a nebulizer, has an RF (.ltoreq.3.3 .mu.m) of at least about
40% and produces in a subject an AUC.sub.(0-.infin.) of cromolyn or
a pharmaceutically-acceptable salt thereof greater than about 330
ng*hr/mL. In certain embodiments of the methods disclosed herein,
an inhalation formulation administered with an inhalation device,
e.g., a nebulizer, has an RF (.ltoreq.3.3 .mu.m) of at least about
40% and produces in a subject an AUC.sub.(0-.infin.) of cromolyn or
a pharmaceutically-acceptable salt thereof greater than about 330
ng*hr/mL. In certain embodiments, of the methods disclosed herein,
an inhalation formulation administered with an inhalation device,
e.g., a nebulizer, has an RF (.ltoreq.3.3 .mu.m) of at least about
40% and produces in a subject an AUC.sub.(0-.infin.) of cromolyn or
a pharmaceutically-acceptable salt thereof greater than about 525
ng*hr/mL. In certain embodiments of the methods disclosed herein,
an inhalation formulation administered with an inhalation device,
e.g., a nebulizer, has an RF (.ltoreq.3.3 .mu.m) of at least about
40% and produces in a subject an AUC.sub.(0-.infin.) of cromolyn or
a pharmaceutically-acceptable salt thereof greater than about 525
ng*hr/mL.
[0254] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, has an RF (.ltoreq.3.3 .mu.m) of at least about
30% and produces in a subject an AUC.sub.(0-.infin.) of cromolyn
sodium greater than about 120 ng*hr/mL. In certain embodiments of
the methods disclosed herein, an inhalation formulation
administered with an inhalation device, e.g., a nebulizer, has an
RF (.ltoreq.3.3 .mu.m) of at least about 30% and produces in a
subject an AUC.sub.(0-.infin.) of cromolyn sodium greater than
about 120 ng*hr/mL. In certain embodiments of the methods disclosed
herein, an inhalation formulation administered with an inhalation
device, e.g., a nebulizer, has an RF (.ltoreq.3.3 .mu.m) of at
least about 30% and produces in a subject an AUC.sub.(0-.infin.) of
cromolyn sodium greater than about 200 ng*hr/mL. In certain
embodiments of the methods disclosed herein, an inhalation
formulation administered with an inhalation device, e.g., a
nebulizer, has an RF (.ltoreq.3.3 .mu.m) of at least about 30% and
produces in a subject an AUC.sub.(0-.infin.) of cromolyn sodium
greater than about 200 ng*hr/mL. In certain embodiments of the
methods disclosed herein, an inhalation formulation administered
with an inhalation device, e.g., a nebulizer, has an RF
(.ltoreq.3.3 .mu.m) of at least about 40% and produces in a subject
an AUC.sub.(0-.infin.) of cromolyn sodium greater than about 330
ng*hr/mL. In certain embodiments of the methods disclosed herein,
an inhalation formulation administered with an inhalation device,
e.g., a nebulizer, has an RF (.ltoreq.3.3 .mu.m) of at least about
40% and produces in a subject an AUC.sub.(0-.infin.) of cromolyn
sodium greater than about 330 ng*hr/mL. In certain embodiments, of
the methods disclosed herein, an inhalation formulation
administered with an inhalation device, e.g., a nebulizer, has an
RF (.ltoreq.3.3 .mu.m) of at least about 40% and produces in a
subject an AUC.sub.(0-.infin.) of cromolyn sodium greater than
about 525 ng*hr/mL. In certain embodiments, of the methods
disclosed herein, an inhalation formulation administered with an
inhalation device, e.g., a nebulizer, has an RF (.ltoreq.3.3 .mu.m)
of at least about 40% and produces in a subject an
AUC.sub.(0-.infin.) of cromolyn sodium greater than about 525
ng*hr/mL.
[0255] In certain embodiments of the methods disclosed herein, an
inhalation formulation comprising 40 mg cromolyn sodium
administered with an inhalation device, e.g., a nebulizer, has an
RF (.ltoreq.3.3 .mu.m) of at least about 30% and produces in a
subject an AUC.sub.(0-.infin.) of cromolyn sodium greater than
about 200 ng*hr/mL. In certain embodiments of the methods disclosed
herein, an inhalation formulation comprising 40 mg cromolyn sodium
administered with an inhalation device, e.g., a nebulizer, has an
RF (.ltoreq.3.3 .mu.m) of at least about 30% and produces in a
subject an AUC.sub.(0-.infin.) of cromolyn sodium greater than
about 200 ng*hr/mL. In certain embodiments of the methods disclosed
herein, an inhalation formulation comprising 40 mg cromolyn sodium
administered with an inhalation device, e.g., a nebulizer, has an
RF (.ltoreq.3.3 .mu.m) of at least about 40% and produces in a
subject an AUC.sub.(0-.infin.) of cromolyn sodium greater than
about 330 ng*hr/mL. In certain embodiments of the methods disclosed
herein, an inhalation formulation comprising 40 mg cromolyn sodium
administered with an inhalation device, e.g., a nebulizer, has an
RF (.ltoreq.3.3 .mu.m) of at least about 40% and produces in a
subject an AUC.sub.(0-.infin.) of cromolyn sodium greater than
about 330 ng*hr/mL. In certain embodiments of the methods disclosed
herein, an inhalation formulation comprising 80 mg cromolyn sodium
administered with an inhalation device, e.g., a nebulizer, has an
RF (.ltoreq.3.3 .mu.m) of at least about 40% and produces in a
subject an AUC.sub.(0-.infin.) of cromolyn sodium greater than
about 525 ng*hr/mL. In certain embodiments of the methods disclosed
herein, an inhalation formulation comprising 80 mg cromolyn sodium
administered with an inhalation device, e.g., a nebulizer, has an
RF (.ltoreq.3.3 .mu.m) of at least about 40% and produces in a
subject an AUC.sub.(0-.infin.) of cromolyn sodium greater than
about 525 ng*hr/mL.
[0256] In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject an AUC.sub.(0-.infin.) of
cromolyn sodium of about 8.5 ng*hr/mL per mg of cromolyn sodium,
and an average Cmax of cromolyn sodium of about 3.9 ng/mL per mg of
cromolyn sodium when a nominal dose of 40 mg cromolyn sodium is
administered to the subject with an inhalation device. In certain
embodiments of the methods disclosed herein, an inhalation
formulation administered with an inhalation device, e.g., a
nebulizer, produces in a subject an AUC.sub.(0-.infin.) of cromolyn
sodium of about 8.5 ng*hr/mL per mg of cromolyn sodium, and an
average Cmax of cromolyn sodium of about 1.9 ng/mL per mg of
cromolyn sodium when a nominal dose of 40 mg cromolyn sodium is
administered to the subject with an inhalation device. In certain
embodiments of the methods disclosed herein, an inhalation
formulation administered with an inhalation device, e.g., a
nebulizer, produces in a subject an AUC.sub.(0-.infin.) of cromolyn
sodium of about 9 ng*hr/mL and a Cmax of cromolyn sodium of about
2.6 ng/mL per mg of cromolyn sodium when a nominal dose of 60 mg of
cromolyn sodium administered to the subject with the inhalation
device. In certain embodiments of the methods disclosed herein, an
inhalation formulation administered with an inhalation device,
e.g., a nebulizer, produces in a subject an AUC.sub.(0-.infin.) of
cromolyn sodium of about 6.6 ng*hr/mL and an average Cmax of
cromolyn sodium of about 2.95 ng/mL per mg of cromolyn sodium when
a nominal dose of 80 mg of cromolyn sodium is administered to the
subject with the inhalation device.
[0257] In certain embodiments of the methods disclosed herein, an
inhalation formulation containing cromolyn or a
pharmaceutically-acceptable salt thereof such as cromolyn sodium is
administered with an inhalation device, e.g., a nebulizer, at a
fill volume of less than about 0.25 mL, less than about 0.5 mL, at
least about 0.5 mL to about 1.5 mL, at least about 0.5 mL to about
1.8 mL, at least about 1.5 mL, or at least about 2.0 mL. In certain
embodiments, an inhalation formulation is administered with an
inhalation device, e.g., a nebulizer, at a fill volume about 0.1 mL
to about 5.0 mL, about 0.25 mL to about 2.0 mL, about 0.5 mL to
about 1.8 mL, about 0.5 mL to about 2 mL, about 0.5 mL to about 1.5
mL, about 0.5 mL to about 1.0 mL, about 0.5 mL or less, about 1 mL
or less, about 1.5 mL or less, about 2.0 mL or less, about 2.5 mL
or less, about 3.0 mL or less, about 3.5 mL or less, about 4.0 mL
or less, about 4.5 mL or less, or about 5.0 mL or less. In certain
embodiments, an inhalation formulation is administered with an
inhalation device, e.g., a nebulizer, at a fill volume of about 0.5
mL, about 1.0 mL, about 1.5 mL, about 1.8 mL, about 2.0 mL, about
2.5 mL, about 3.0 mL, about 3.5 mL, about 4.0 mL, about 4.5 mL, or
about 5.0 mL. In certain embodiments, an inhalation formulation is
administered with an inhalation device, e.g., a nebulizer, which
provides for a residual volume of cromolyn or a
pharmaceutically-acceptable salt thereof after administration of
the cromolyn or a pharmaceutically-acceptable salt thereof of less
than about 10%, less than about 5%, or less than about 3% of the
nominal dose. In certain embodiments of the methods disclosed
herein, an inhalation formulation containing cromolyn or a
pharmaceutically-acceptable salt thereof is administered with an
inhalation device, e.g., a nebulizer, wherein the concentration of
the cromolyn or a pharmaceutically-acceptable salt thereof is
greater than about 1% by weight, greater than about 2% by weight,
greater than about 3% by weight, greater than about 4% by weight,
greater than about 5% by weight, greater than about 6% by weight,
greater than about 7% by weight, greater than about 8% by weight,
greater than about 9% by weight, or greater than about 10% by
weight. In certain embodiments of the methods disclosed herein, an
inhalation formulation containing cromolyn or a
pharmaceutically-acceptable salt thereof is administered with an
inhalation device, e.g., a nebulizer, wherein the concentration of
the cromolyn or a pharmaceutically-acceptable salt thereof is from
about 1% by weight to about 10% by weight, from about 2% by weight
to about 8% by weight, from about 2% by weight to about 6% by
weight, or from about 3% by weight to about 5% by weight. In
certain embodiments of the methods disclosed herein, an inhalation
formulation containing cromolyn or a pharmaceutically-acceptable
salt thereof is administered with an inhalation device, e.g., a
nebulizer, wherein the concentration of the cromolyn or a
pharmaceutically-acceptable salt thereof is about 1% by weight,
about 2% by weight, about 3% by weight, about 4% by weight, about
5% by weight, about 6% by weight, about 7% by weight, about 8% by
weight, about 9% by weight, or about 10% by weight.
[0258] In certain embodiments of the methods disclosed herein, an
inhalation formulation containing cromolyn sodium is administered
with an inhalation device, e.g., a nebulizer, wherein the
concentration of the cromolyn sodium is greater than about 1% by
weight, greater than about 2% by weight, greater than about 3% by
weight, greater than about 4% by weight, greater than about 5% by
weight, greater than about 6% by weight, greater than about 7% by
weight, greater than about 8% by weight, greater than about 9% by
weight, or greater than about 10% by weight. In certain embodiments
of the methods disclosed herein, an inhalation formulation
containing cromolyn sodium is administered with an inhalation
device, e.g., a nebulizer, wherein the concentration of the
cromolyn sodium is from about 1% by weight to about 10% by weight,
from about 2% by weight to about 8% by weight, from about 2% by
weight to about 6% by weight, or from about 3% by weight to about
5% by weight. In certain embodiments of the methods disclosed
herein, an inhalation formulation containing cromolyn sodium is
administered with an inhalation device, e.g., a nebulizer, wherein
the concentration of the cromolyn sodium is about 1% by weight,
about 2% by weight, about 3% by weight, about 4% by weight, about
5% by weight, about 6% by weight, about 7% by weight, about 8% by
weight, about 9% by weight, or about 10% by weight.
[0259] In certain embodiments, an inhalation formulation containing
cromolyn or a pharmaceutically-acceptable salt thereof is
administered with an inhalation device, e.g., a nebulizer, in about
0.25 to about 10 minutes, about 0.50 to about 8 minutes, less than
about 8 minutes, less than about 7 minutes, less than about 6
minutes, less than about 5 minutes, less than about 4 minutes, less
than about 3 minutes, less than about 2 minutes, less than about
1.8 minutes, less than about 1.5 minutes, or less than 1 minute. In
certain embodiments, the inhalation formulation is administered in
about 3 minutes or less. In certain embodiments, the inhalation
formulation is administered in about 1 minute, about 2 minutes,
about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes,
about 7 minutes, about 8 minutes, about 9 minutes, or about 10
minutes.
[0260] In certain embodiments of the methods disclosed herein,
administration of cromolyn or a pharmaceutically-acceptable salt
thereof with a nebulizer provides at least about a 1.5-fold, at
least about a 1.8-fold, at least about a two-fold, at least about a
three-fold, at least about a four-fold, or at least about a
five-fold increase in one or more of AUC.sub.last,
AUC.sub.(0-.infin.), or Cmx as compared to the same or lower
nominal dose of the cromolyn or a pharmaceutically-acceptable salt
thereof administered with a conventional inhalation device or an
oral formulation, e.g., a liquid oral formulation, tablet, or
capsule.
[0261] In certain embodiments of the methods disclosed herein,
inhalation formulations administered with a nebulizer are
substantially free of a preservative, such as benzyl alcohol. In
certain embodiments of the methods disclosed herein, inhalation
formulations administered with a nebulizer further comprise at
least one excipient. In certain embodiments, the excipient is
selected from the group consisting of stabilizers and antioxidants
(such as citric acid, ascorbic acid, ethylenediamine tetra acetic
acid (EDTA), sodium metabisulfite, or a salt of any thereof), an
osmolarity adjusting agent (such as sodium chloride, mannitol, or
sorbitol), a surfactant (such as polysorbate 80, vitamin E,
tocopherol polyethylene glycol, and Tyloxapol), or a pH buffer.
[0262] In certain embodiments of the methods disclosed herein,
inhalation formulations administered with an inhalation device,
e.g., a nebulizer, are hypotonic. In certain embodiments of the
methods disclosed herein, inhalation formulations administered with
an inhalation device, e.g., a nebulizer, are sub-isotonic. In
certain embodiments of the methods disclosed herein, inhalation
formulations administered with an inhalation device, e.g., a
nebulizer, have an osmolality greater than about 70 mOsm/kg. In
certain embodiments of the methods disclosed herein, inhalation
formulations administered with an inhalation device, e.g.,
nebulizer, have an osmolality of at least about 100 mOsm/kg. In
certain embodiments of the methods disclosed herein, inhalation
formulations administered with an inhalation device, e.g.,
nebulizer, have an osmolality of at least about 150 mOsm/kg.
[0263] Combination Therapies
[0264] In certain embodiments of the methods disclosed herein, the
formulations comprising from about 2% to about 10% by weight of
cromolyn sodium and an osmotic agent consisting of sodium chloride,
are administered to a subject in need thereof in combination with
an additional agent used to treat IPF. In certain embodiments, the
additional agent is selected from pirfenidone, an inhibitor of
platelet-derived growth factor receptor (PDGFR) a, platelet-derived
growth factor receptor (PDGFR) J3, an inhibitor of fibroblast
growth factor receptor (FGFR) 1-3, an inhibitor of vascular
endothelial growth factor receptor (VEGFR) 1-3, and an inhibitor of
Fms-like tyrosine kinase-3 (FLT3). In certain embodiments, the
additional agent is pirfenadone or nintedanib esylate. In certain
embodiments, the additional agent is pifenadone. In certain
embodiments, the additional agent is nintedanib esylate.
[0265] In certain embodiments are disclosed methods of treating
chronic cough in a subject having IPF, comprising administering to
the subject a combination of (a) a formulation comprising from
about 2% to about 10% by weight of cromolyn sodium and an osmotic
agent consisting of sodium chloride, and (b) an additional agent.
In certain embodiments, the additional agent is selected from
pirfenidone, an inhibitor of platelet-derived growth factor
receptor (PDGFR) u, platelet-derived growth factor receptor (PDGFR)
J3, an inhibitor of fibroblast growth factor receptor (FGFR) 1-3,
an inhibitor of vascular endothelial growth factor receptor (VEGFR)
1-3, and an inhibitor of Fms-like tyrosine kinase-3 (FLT3). In
certain embodiments, the additional agent is pirfenadone or
nintedanib esylate. In certain embodiments, the additional agent is
pifenadone. In certain embodiments, the additional agent is
nintedanib esylate.
[0266] In certain embodiments of the methods disclosed herein, one
or more different formulations of cromolyn or a
pharmaceutically-acceptable salt thereof are co-administered by
different routes of administration to provide systemically
effective amounts of the cromolyn or a pharmaceutically-acceptable
salt thereof. For example, in certain embodiments, a composition
comprising cromolyn or a pharmaceutically-acceptable salt thereof,
e.g., cromolyn sodium, is administered with a dry powder inhaler
and a different composition comprising cromolyn or a
pharmaceutically-acceptable salt thereof, e.g., cromolyn sodium, is
co-administered in a liquid oral formulation to treat chronic cough
due to IPF. In certain embodiments, a composition comprising
cromolyn or a pharmaceutically-acceptable salt thereof, e.g.,
cromolyn sodium, is administered with a metered dose inhaler and a
different composition comprising cromolyn or a
pharmaceutically-acceptable salt thereof, e.g., cromolyn sodium, is
co-administered in a liquid oral formulation to treat chronic cough
due to IPF. In certain embodiments, a composition comprising
cromolyn or a pharmaceutically-acceptable salt thereof, e.g.,
cromolyn sodium, is administered with a dry powder inhaler and a
different composition comprising cromolyn or a
pharmaceutically-acceptable salt thereof, e.g., cromolyn sodium, is
co-administered with a metered dose inhaler to treat chronic cough
due to IPF. In certain embodiments, a composition comprising
cromolyn or a pharmaceutically-acceptable salt thereof, e.g.,
cromolyn sodium, is administered with a dry powder inhaler and a
different composition comprising cromolyn or a
pharmaceutically-acceptable salt thereof, e.g., cromolyn sodium, is
co-administered with a metered dose inhaler to treat chronic cough
due to IPF. In certain embodiments, a composition comprising
cromolyn or a pharmaceutically-acceptable salt thereof, e.g.,
cromolyn sodium, is administered with a nebulizer and a different
composition comprising cromolyn or a pharmaceutically-acceptable
salt thereof, e.g., cromolyn sodium, is co-administered in a liquid
oral formulation to treat chronic cough due to IPF. In certain
embodiments, a composition comprising cromolyn or a
pharmaceutically-acceptable salt thereof, e.g., cromolyn sodium, is
administered with a jet nebulizer and a different composition
comprising cromolyn or a pharmaceutically-acceptable salt thereof,
e.g., cromolyn sodium, is co-administered in a liquid oral
formulation to treat chronic cough due to IPF.
Definition of Terms
[0267] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
skill in the art to which the inventions described herein belong.
All publications, patents, and patent applications mentioned in
this specification are hereby incorporated by reference to the same
extent as if each individual publication, patent, or patent
application was specifically and individually indicated to be
incorporated by reference.
[0268] 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 in a range spanning a
cited value, e.g., plus or minus up to 10% of a cited value, are
also effective and safe.
[0269] As used herein, the terms "comprising," "including," "such
as," and "for example" (or "e.g.") are used in their open,
non-limiting sense.
[0270] As used herein, the phrase "consisting essentially of" is a
transitional phrase used in a claim to indicate that the following
list of ingredients, parts or process steps must be present in the
claimed composition, machine or process, but that the claim is open
to unlisted ingredients, parts or process steps that do not
materially affect the basic and novel properties of the
invention.
[0271] "Nominal dose," as used herein, refers to the loaded dose,
which is the amount of active pharmaceutical ingredient (API) in an
inhalation device prior to administration to the subject. The
volume of solution containing the nominal dose is referred to as
the "fill volume."
[0272] "AUC.sub.last" as used herein refers to the area under the
curve from time zero to time of last measurable concentration of
active pharmaceutical ingredient (API).
[0273] "AUC.sub.lastHEN" as used herein refers to the area under a
blood plasma concentration curve up to the last time point for the
nominal dose of active pharmaceutical ingredient (API) administered
with a nebulizer.
[0274] "AUC.sub.lastConv" as used herein refers to the area under a
blood plasma concentration curve up to the last time point for a
nominal dose of active pharmaceutical ingredient (API) administered
with a conventional inhalation device.
[0275] "AUC.sub.(0-.infin.)" as used herein refers to the total
area under a blood plasma concentration curve for an active
pharmaceutical ingredient (API).
[0276] "AUC.sub.(0-.infin.)HEN" as used herein refers to the total
area under a blood plasma concentration curve for a nominal dose of
active pharmaceutical ingredient (API) administered with a
nebulizer.
[0277] "AUC.sub.(0-.infin.)CONV" as used herein refers to the total
area under a blood plasma concentration curve for a nominal dose of
active pharmaceutical ingredient (API) administered with a
conventional inhalation device.
[0278] AUC.sub.(0-.infin.) can be determined by methods known to
those of skill in the art. For example, the AUC.sub.(0-.infin.) of
an API can be determined by collecting blood samples from a subject
at various time points after administration of an API to the
subject, separating plasma from the blood samples, extracting the
API from the separated plasma samples, e.g., by solid-phase
extraction, quantifying the amount of the API extracted from each
sample of separated plasma, e.g., by liquid chromatography-tandem
mass spectrometry (LC-MS/MS), plotting the concentration of API in
each sample versus the time of collection after administration, and
calculating the area under the curve.
[0279] "Substantially the same nominal dose" as used herein means
that a first nominal dose of an active pharmaceutical ingredient
(API) contains approximately the same number of millimoles of the
cromolyn or a pharmaceutically-acceptable salt thereof as a second
nominal dose of the cromolyn or a pharmaceutically-acceptable salt
thereof.
[0280] "Bioavailability" as used herein refers to the amount of
unchanged API that reaches the systemic circulation, expressed as a
percentage of the dosage of the API that is administered to a
subject. By definition, the bioavailability of an intravenous
solution containing the active pharmaceutical ingredient (API) is
100%. The bioavailability of an API can be determined by methods
known to those of skill in the art. For example, the
bioavailability of an API can be determined by collecting urine
samples from a subject at various time points following
administration of the API to the subject, extracting the API from
the urine samples, e.g., by solid-phase extraction, quantifying the
amount of the API in each urine sample, adjusting the amount of API
collected from the urine by a factor based on the amount of API
reaching systemic circulation that is excreted in the urine, and
calculating the percentage of the API administered to the subject
that reaches the systemic circulation of the subject. In a specific
embodiment, the bioavailability of cromolyn sodium can be
determined as described in Walker et al., 24 J. Pharm. Pharmacol.
525-31 (1972). In the case of cromolyn sodium, the amount of the
compound isolated from the urine is multiplied by two to calculate
the total amount reaching systemic circulation after administration
because the compound is known to be excreted unmetabolized in equal
parts in the urine and feces, i.e., approximately 50% of the amount
of cromolyn sodium that reaches systemic circulation is excreted in
the urine and approximately 50% of the amount of cromolyn sodium
that reaches systemic circulation is excreted in the feces.
[0281] "Enhanced lung deposition" as used herein refers to an
increase in drug deposition (deposited lung dose) arising out of,
for example, improved efficiency of drug delivery.
[0282] "Deposited dose" or "deposited lung dose" is the amount of
cromolyn or a pharmaceutically-acceptable salt thereof deposited in
the lung. The deposited dose or deposited lung dose may be
expressed in absolute terms, for example in mg or .mu.g of API
deposited in the lungs. The deposited lung dose may also be
expressed in relative terms, for example calculating the amount of
API deposited as a percentage of the nominal dose.
[0283] "C.sub.max" as used herein refers to the maximum plasma
concentration for an active pharmaceutical ingredient (API).
[0284] "C.sub.maxHEN" as used herein refers to the maximum blood
plasma concentration for a nominal dose of the active
pharmaceutical ingredient (API) administered with a nebulizer.
[0285] "C.sub.maxCONV" as used herein refers to the maximum blood
plasma concentration for a nominal dose of the active
pharmaceutical ingredient (API) administered with a conventional
inhalation device.
[0286] C.sub.max can be determined by methods known to those of
skill in the art. For example, the C.sub.max of an API can be
determined by collecting blood samples from a subject at various
time points after administration of an API to the subject,
separating plasma from the blood samples, extracting the API from
the separated plasma samples, e.g., by solid-phase extraction,
quantifying the amount of the API extracted from each sample of
separated plasma, e.g., by LC-MS/MS, plotting the concentration of
API in each sample versus the time of collection after
administration, and identifying the peak concentration of the API
on the curve.
[0287] "Enhanced pharmacokinetic profile" means an improvement in
some pharmacokinetic parameter. Pharmacokinetic parameters that may
be improved include AUC (0-4 or 0-6 or 0-8 h), AUC.sub.last,
AUC.sub.(0-.infin.), T.sub.max, T.sub.1/2, and C.sub.max. In
certain 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 by one route of administration, such as an
inhalation device (e.g., a nebulizer) with the same pharmacokinetic
parameter obtained with the same nominal dose of active
pharmaceutical ingredient (API) administered by a different route
of administration, such as a different type of inhalation device or
an oral formulation (e.g., oral tablet, oral capsule, or oral
solution).
[0288] "Blood plasma concentration" refers to the concentration of
an active pharmaceutical ingredient (API) in the plasma component
of blood of a subject or subject population.
[0289] "Subject" or "subject" refers to the animal (especially
mammal) or human being treated.
[0290] A "subject group" or "subject group" has a sufficient number
of subjects or subjects to provide a statistically significant
average measurement of the relevant pharmacokinetic parameter. All
members of the "subject group" or "subject group" have
pharmacokinetic parameters for the cromolyn or a
pharmaceutically-acceptable salts thereof that fall within
statistically normal ranges (i.e., there are no outliers), and no
member is included on the basis of non-standard or unusual
measurements.
[0291] "Nebulizer," as used herein, refers to a device that turns
medications, compositions, formulations, suspensions, and mixtures,
etc. into a fine aerosol mist for delivery to the lungs.
[0292] "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 via the pulmonary capillary beds of the alveoli
into the systemic circulation.
[0293] "T.sub.max" as used herein refers to the amount of time
necessary for an active pharmaceutical ingredient (API) to attain
maximum blood plasma concentration.
[0294] "T.sub.maxHEN" as used herein refers to the amount of time
necessary for a nominal dose of an active pharmaceutical ingredient
(API) to attain maximum blood plasma concentration after
administration with a nebulizer.
[0295] "T.sub.maxCONV" as used herein refers to the amount of time
necessary for a nominal dose of an active pharmaceutical ingredient
(API) to attain maximum blood plasma concentration after
administration with a conventional inhalation device.
[0296] The term "treat" and its grammatical variants (e.g., "to
treat," "treating," and "treatment") refer to administration of an
active pharmaceutical ingredient to a subject with the purpose of
ameliorating or reducing the incidence of one or more symptoms of a
condition or disease state in the subject. Such symptoms may be
chronic or acute; and such amelioration may be partial or complete.
In the present context, treatment entails administering cromolyn or
a pharmaceutically-acceptable salt thereof to a subject via any
route of administration disclosed herein.
[0297] As used herein, the term "high concentration" refers to a
concentration greater than 1% by weight. For example, in a specific
embodiment, a "high concentration" formulation of cromolyn sodium
comprises cromolyn sodium at a concentration of greater than 1% by
weight.
[0298] As used herein, the term "hypotonic" refers to a formulation
that has a tonicity less than 295 mOsm/kg.
[0299] The term "prophylaxis" refers to administration of an active
pharmaceutical ingredient to a subject with the purpose of reducing
the occurrence or recurrence of one or more acute symptoms
associated with a disease state or a condition in the subject. In
the present context, prophylaxis entails administering cromolyn or
a pharmaceutically-acceptable salt thereof to a subject via any
route of administration disclosed herein. Thus, prophylaxis
includes reduction in the occurrence or recurrence rate of chronic
cough due to IPF. However, prophylaxis is not intended to include
complete prevention of onset of a disease state or a condition in a
subject who has not previously been identified as suffering from
chronic cough due to IPF.
[0300] As used herein, a "systemically effective amount" is an
amount of cromolyn or a pharmaceutically-acceptable salt thereof in
the body of a subject as a whole that is effective for the
treatment or prophylaxis of chronic cough due to IPF. A
"systemically effective amount" may be expressed, for example, as
the mass of cromolyn or a pharmaceutically-acceptable salt thereof,
or concentration of cromolyn or a pharmaceutically-acceptable salt
thereof, in a subject's plasma. A "systemically effective amount"
may differ depending on the formulation of cromolyn or a
pharmaceutically-acceptable salt thereof.
[0301] As used herein, a "locally effective amount" is an amount of
cromolyn or a pharmaceutically-acceptable salt thereof in a
particular region of the body of a subject that is effective for
the treatment or prophylaxis of chronic cough due to IPF. A
"locally effective amount" may be expressed, for example, as the
mass of cromolyn or a pharmaceutically-acceptable salt thereof, or
concentration of cromolyn or a pharmaceutically-acceptable salt
thereof, in a subject's tissue. A "locally effective amount" may
differ depending on the formulation of cromolyn or a
pharmaceutically-acceptable salt thereof.
[0302] As used herein, a difference is "significant" if a person
skilled in the art would recognize that the difference is probably
real. In certain embodiments, significance may be determined
statistically, in which case two measured parameters may be
referred to as statistically significant. In certain embodiments,
statistical significance may be quantified in terms of a stated
confidence interval (CI), e.g., greater than 90%, greater than 95%,
greater than 98%, etc. In certain embodiments, statistical
significance may be quantified in terms of a p value, e.g., less
than 0.5, less than 0.1, less than 0.05, etc. The person skilled in
the art will recognize these expressions of significance and will
know how to apply them appropriately to the specific parameters
that are being compared.
EXAMPLES
Example 1: Safety and Tolerability of Inhaled PA101 in IPF Subjects
with Chronic Cough
[0303] As shown in Table 1, PA101 contains 4% (by weight) cromolyn
as the active substance, 0.2% sodium chloride as an osmotic agent,
0.02% EDTA as a chelating agent, 1.25% mannitol as a non-ionic
osmotic agent, and purified water q.s. PA101 has an osmolality of
200 mOsm/kg. Placebo A contained 0.4% sodium chloride as an osmotic
agent, 0.02% EDTA as a chelating agent, 1.25% mannitol as a
non-ionic osmotic agent, and purified water q.s., but no cromolyn
sodium. The osmolality of Placebo A was adjusted to about 200
mOsm/kg. Placebo B contained 0.6% sodium chloride as an osmotic
agent, 0.02% EDTA as a chelating agent, and purified water q.s.,
but no cromolyn sodium or mannitol. The osmolality of Placebo B was
adjusted to about 200 mOsm/kg.
[0304] A primary objective of the study was to assess the safety
and tolerability of inhaled PA101 (including the excipient mannitol
in the formulation) in IPF subjects with refractory chronic cough.
A secondary objective of the study was to assess the efficacy
potential of inhaled PA101 after 3 days dosing.
[0305] The study design was as follows: Phase 1b, randomized,
double-blind, single-center, 3-period crossover study in 6 IPF
subjects (40-79 years of age) with refractory chronic cough. Each
study treatment administered three times daily (TID) for 3 days and
one dose the next day (total of 10 doses). 72-hours continuous
monitoring for cough count.
[0306] The treatments given were one of the following: 1) 40 mg
PA101, 2) Placebo-A (A=without cromolyn sodium, but included
mannitol), and 3) Placebo-B (B=without mannitol and without
cromolyn sodium). All treatments administered as oral inhalation
using eFlow nebulizer.
[0307] Following administration of the treatment and two placebos
to the subjects, any adverse events were recorded. Table 2 provides
a summary of adverse events, divided by severity, type, and
treatment.
TABLE-US-00003 TABLE 2 Adverse Events PA101 Placebo A Placebo B 40
mg (n = 6) (n = 6) (n = 6) Subjects with at 2 (33.3%) 3 (50%) 5
(83.3%) least one AE Related AEs 1 (16.7%) 2 (33.30%) 5 (83.3%) Not
related AEs 1 (16.7%) 2 (33.30%) 3 (50%) Mild AEs 2 (33.30%) 3
(50%) 5 (83.3%) Moderate AEs 0 0 1 (16.7%) Severe AEs 0 0 0 Cough 1
(16.7%) 0 4 (66.7%) Throat Irritation 1 (16.7%) 0 3 (50%)
Oropharyngeal pain 0 0 1 (16.7%) Rhinorrhoea 0 0 1 (16.7%)
Dizziness 1 (16.7%) 2 (33.30%) 2 (33.30%) Headache 0 1 (16.7%) 2
(33.30%) Chills 0 0 1 (16.7%) Malaise 0 1 (16.7%) 0 Flushing 1
(16.7%) 0 1 (16.7%) Defectation urgency 0 0 1 (16.7%) Nausea 1
(16.7%) 1 (16.7%) 0 Nasopharyngitis 1 (16.7%) 0 0
[0308] Following administration of the treatment and two placebos
to the subjects, the number of daytime coughs was recorded for each
subject. FIG. 1 provides a summary of the average number of coughs
at three daytime time points for each subject. FIG. 2 provides a
summary of the total number of coughs at three daytime time points
for each subject.
[0309] Whereas the number of coughs provided in FIGS. 1 and 2 are
based upon subjective subject reports, the following cough counts
are based upon an objective measure. To obtain an objective count
of the subjects' coughs, the study used the Leicester Cough Monitor
(LCM), a validated 24-h automated cough frequency monitor. The LCM
requires the subject to wear a microphone adhered to the subject's
chest and attached to a monitor (carried with shoulder strap) that
is present on the subject 24 hours each day to record all
coughs.
[0310] Table 3 provides the LCM count of the average cough per hour
for each subject in each treatment condition as well as a breakout
of the data across 24 hours, daytime hours, and nighttime hours.
SD=Standard Deviation.
TABLE-US-00004 TABLE 3 LCM Cough Count Placebo A Placebo B PA101
Mean SD Mean SD Mean SD 24 hr Day 1 25 13 30 18 35 23 Cough/hr Day
2 33 31 32 15 34 21 Day 3 34 28 32 18 32 22 .DELTA.D 3 vs. D 1 8.3
16.7 2.0 5.4 -3.3 11.6 Daytime Day 1 38 20 45 26 53 36 Cough/hr Day
2 48 25 48 22 51 30 Day 3 47 26 46 27 45 30 .DELTA.D 3 vs. D 1 8.6
22.8 1.0 7.3 -8.5 16.2 Nighttime Day 1 4 1 7 6 4 2 Cough/hr Day 2 4
2 5 4 5 2 Day 3 4 4 3 2 6 5 .DELTA.D 3 vs. D 1 0.3 4.5 -4.2 6.6 2.0
3.8
[0311] The study includes two additional subjective measures: Cough
Severity and Urge-to-Cough, both provided quantitatively as a
measure on a visual analogue scale (VAS). When using the visual
analogue scale (VAS), for example, to measure cough severity, the
subject is asked to mark on a 100 mm scale between `no cough` and
`the worst cough severity`. When using the visual analogue scale
(VAS), for example, to measure urge-to-cough, the subject is asked
to mark on a 100 mm scale between `no urge` and `the worst
urge-to-cough`.
[0312] Table 4 provides the mean, standard deviation (SD) and
median scores on the VAS for each parameter by treatment at either
day 1 or day 4 of the study.
TABLE-US-00005 TABLE 4 Parameter (unit) Treatment Visit Mean SD
Median Cough Severity Placebo A Day 1 61.7 18.4 62.0 (mm) Day 4
64.0 13.5 58.0 Placebo B Day 1 68.2 11.5 66.5 Day 4 67.3 15.0 72.0
40 mg PA101 Day 1 68.5 10.3 70.5 Day 4 67.0 20.6 72.0 Urge-to-Cough
Placebo A Day 1 62.5 16.5 62.0 (mm) Day 4 58.0 19.2 52.0 Placebo B
Day 1 69.2 12.1 72.5 Day 4 70.0 14.3 72.5 40 mg PA101 Day 1 70.7
11.4 72.5 Day 4 67.5 20.1 70.0
[0313] To assess pulmonary function of each of the subjects
following treatment with PA101 or with one of the two placebo
formulations, the subjects were evaluated using a forced vital
capacity (FVC) test. The Forced Expiratory Volume in One Second
(FEV1), the amount of air that is forcefully exhaled in the first
second of the FVC test, was measured for each subject either on Day
1 or Day 3 of treatment. FIG. 3 summarizes the results for each
treatment group.
[0314] The data from this study indicated that treatment with 40 mg
PA101 including mannitol as the excipient in the formulation was
overall safe and well tolerated following administration three
times daily for 3 days in IPF subjects with refractory chronic
cough. No difference in tolerability was observed between PA101
formulated with mannitol, placebo with mannitol, and placebo
without mannitol. The majority of the adverse events were of mild
intensity and did not require treatment. Most commonly reported
adverse events were cough, throat irritation, dizziness, and
headache. There were no clinically significant changes in cough
count, severity of cough and urge to cough between the treatment
groups following 3 days of treatment.
Example 2: Phase I Pharmacokinetics, Relative Bioavailability, and
Safety Study of PA101 in Healthy Subjects (PK-01)
[0315] The primary objective of the study is to determine the
systemic availability and pharmacokinetic (PK) profile of single
doses of a representative inhaled cromolyn sodium formulation
(PA-101) delivered via a nebulizer (eFlow.RTM., PARI) using two
different aerosol membranes (30L and 40L) in comparison with
marketed formulations of cromolyn sodium (oral solution and an
inhalation aerosol) in healthy subjects.
[0316] The secondary objective of the study is to assess the safety
and tolerability of PA-101 in comparison with marketed formulations
of cromolyn sodium (oral solution and an inhalation aerosol).
[0317] This was a Phase 1, randomized, open-label, single-centre,
dose-ranging, cross-over study conducted in a total of 12 healthy
adult subjects of 18-45 years of age.
[0318] Study Treatments, Dose and Mode of Administration:
1. 40 mg PA-101 (4% DSCG, 40 mg/1 mL), oral inhalation via eFlow
30L. 2. 80 mg PA-101 (4% DSCG, 80 mg/2 mL), oral inhalation via
eFlow 30L. 3. 40 mg PA-101 (4% DSCG, 40 mg/1 mL), oral inhalation
via eFlow 40L. 4. 20 mg cromolyn sodium inhalation aerosol (1%
DSCG, 20 mg/2 mL) (commercially available product), oral inhalation
via LC Plus. 5. 200 mg oral sodium cromoglycate solution
(commercially available product), oral administration.
[0319] All study subjects received each study treatment in the
morning (at 8:00 am, +/-30 minutes) as a single dose treatment.
Prior to each dosing day, subjects were admitted to the clinic in
the morning for baseline (pre-dose) assessments. Subjects were
required to remain in the clinic for 12 h after study drug
administration on each dosing day. Treatment Visits were separated
by a washout period of 2 to 5 days.
[0320] The main delivery device for administering PA-101 was the
open system eFlow nebulizer using the 30L aerosol head, which
generates aerosol particles with a median size of about 3.0 .mu.m.
The duration of the study was one day.
[0321] Criteria for Evaluation:
[0322] Pharmacokinetic Measurements:
[0323] The PK parameters evaluated for plasma cromolyn sodium
(DSCG) were maximum concentration (C.sub.max), time to maximum
concentration (T.sub.max), terminal elimination half-life
(T.sub.1/2), area under the plasma concentration-time curve from
time=0 to time of last measurable drug concentration (AUC.sub.0-t),
and area under the plasma concentration-time curve from time=0 to
infinity (AUC.sub.0-.infin.). Urine DSCG levels were measured for
total DSCG excretion in the urine, and the bioavailability of the
DSCG was calculated from the measured levels.
[0324] Safety measurements: Adverse events including
gastrointestinal disturbance (e.g., abdominal pain, nausea,
vomiting), changes in vital signs, 12-lead ECG and clinical
laboratory tests (hematology, chemistry and urinalysis).
[0325] Statistical Measurements:
[0326] Pharmacokinetic parameters and plasma concentrations are
listed and summarized. The summary statistics are presented as the
geometric mean, arithmetic mean, arithmetic standard deviation
(SD), min, median, max and n. The geometric statistics are not
presented for Tmax. Analysis of variance (ANOVA) including terms
for subject and treatment are used to calculate point estimates,
and confidence intervals (CI) for treatment differences with
respect to PK parameters (90% CI) are calculated.
[0327] The incidence of AEs was compared between treatment groups:
Summary tables and individual subject listings are provided for all
safety measurements and the results are presented by treatment
group. Descriptive statistics are used to summarize data where
appropriate.
[0328] Results:
[0329] The pharmacokinetic parameters measured in the single dose
study are shown in the following table:
TABLE-US-00006 TABLE 5 Inhalation Ratio (PA-101 Ratio (PA-101 Oral
aerosol, PA-101 PA-101 PA-101 (30L; 40 mg))/ (30L; 40 mg))/ PK
solution, 20 mg (40L), (30L), (30L), (oral solution, (inhalation
parameter 200 mg (Intal) 40 mg 40 mg 80 mg 200 mg)) aerosol, 20
mg)) C.sub.max (ng/mL) 5.2 (.+-.3.1) 17.8 (.+-.10.4) 88.6
(.+-.45.5) 156 (.+-.104) 236 (.+-.124) x30 x8.8 T.sub.max (h) 3.2
(.+-.2.1) 0.6 (.+-.0.1) 0.6 (.+-.0.1) 0.7 (.+-.0.1) 0.7 (.+-.0.1)
AUC.sub.0-t 29.4 (.+-.10.4) 39.1 (.+-.15.1) 206 (.+-.94.3) 329
(.+-.144) 514 (.+-.186) x11 x8.4 (h*ng/mL) AUC.sub.(0-.infin.) 33.3
(.+-.11.7) 40.6 (.+-.15.6) 212 (.+-.96.0) 338 (.+-.146) 526
(.+-.198) (h*ng/mL) T.sub.1/2 (h) 4.3 (.+-.1.3) 2.5 (.+-.0.8) 2.5
(.+-.0.7) 2.2 (.+-.0.6) 2.1 (.+-.0.5) Bioavailability 0.6 6.5 16.3
25.0 22.7 x42 x3.8 (%)
Values shown in parentheses are (+SD).
[0330] Modeling of lung deposition with an aerosol from the 30L and
40L devices using the Finlay model (Finlay, W H, and A R Martin,
"Recent advances in predictive understanding respiratory tract
deposition", Journal of Aerosol Medicine, Vol 21:189-205 (2008))
indicated that the lung deposition with the two devices should be
very similar. However, the AUC value obtained with 40 mg dose using
the 30L device (338 ng*hr/mL) was surprisingly high compared to the
value (212 ng*hr/mL) from the 40L device. Cromolyn sodium is not
metabolized in the body and is excreted intact via bile and urine.
Cromolyn sodium deposited in the lung during inhalation will appear
in the plasma, and the AUC would therefore be a surrogate for
cromolyn sodium deposited in the lung. Any cromolyn sodium
swallowed during inhalation will contribute negligibly to the AUC
since the oral bioavailability of cromolyn is only about 1%
(Richards et al, J Pharmacol Exp Ther, Vol. 241, No. 3: 1028-1032
(1987)). The AUC data therefore indicate that at the same dose (40
mg), the lung deposition with the 30L device was surprisingly
higher than that with the 40L device.
[0331] The numbers of adverse events observed in the single dose
study are shown in the following table:
TABLE-US-00007 TABLE 6 PA-101 PA-101 PA-101 Inhalation Oral (40L),
(30 L), (30 L), aerosol, solution, Adverse Event Placebo 40 mg 40
mg 80 mg 20 mg 200 mg Cough 1 1 0 1 1 0 Oropharyngeal pain 0 0 0 0
1 1 Rhinorrhoea 1 0 0 0 0 0 Dizziness 0 0 2 0 0 0 Headache 0 0 0 1
0 1 Dysgeusia 0 0 0 0 0 1 Somnolence 0 0 0 1 0 0 Catheter-site
Reaction 0 0 1 0 0 1 Nasopharygitis 0 0 0 0 1 0 Sinusitis 0 0 0 1 0
0 Abdominal Discomfort 0 0 0 0 0 1 Increased Appetite 0 1 0 0 0
0
[0332] Table 7 provides a summary of adverse events observed
following treatment with PA101 formulations versus placebo or other
available cromolyn formulations.
TABLE-US-00008 TABLE 7 Part 1 20 mg 200 mg Placebo 40 mg PA 80 mg
PA 40 mg PA Intal Nalcrom (30 L) (30 L) (30 L) (40L) (LC Plus)
(oral) (N = 12) (N = 12) (N = 12) (N = 12) (N = 12) (N = 12) n (%)
n (%) n (%) n (%) n (%) n (%) Any AE 2 (16.7) 3 (25.0) 4 (33.3) 2
(16.7) 3 (25.0) 2 (16.7) Any SAE 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0
(0.0) 0 (0.0) Probably related AE 0 (0.0) 0 (0.0) 0 (0.0) 1 (8.3) 0
(0.0) 1 (8.3) Possibly related AE 0 (0.0) 2 (16.7) 2 (16.7) 0 (0.0)
0 (0.0) 0 (0.0) Unlikely related AE 1 (8.3) 0 (0.0) 2 (16.7) 1
(8.3) 2 (16.7) 1 (8.3) Not related AE 1 (8.3) 1 (8.3) 0 (0.0) 0
(0.0) 1 (8.3) 1 (8.3) Related AE 0 (0.0) 2 (16.7) 2 (16.7) 1 (8.3)
0 (0.0) 1 (8.3) Not related AE 2 (16.7) 1 (8.3) 2 (16.7) 1 (8.3) 3
(25.0) 2 (16.7) Discontinued due to AE 0 (0.0) 0 (0.0) 0 (0.0) 0
(0.0) 0 (0.0) 0 (0.0)
Example 3: Phase II Pharmacokinetics, Relative Bioavailability, and
Tolerability Study of Three Different PA101 Formulations in Healthy
Subjects (PK-02)
[0333] As shown in Table 1, PA101 contains 4% (by weight) cromolyn
as the active substance, 0.2% Sodium Chloride as an osmotic agent,
0.02% EDTA as a chelating agent, 1.25% mannitol as a non-ionic
osmotic agent, and purified water q.s. PA101 has an osmolality of
200 mOsm/kg. PA101-B contains 4% or 6% (by weight) cromolyn as the
active substance, 0.2% sodium chloride as an osmotic agent, 0.02%
EDTA as a chelating agent, and purified water q.s. PA101-B (40 mg)
has an osmolality of 125 mOsm/kg. PA101-B (60 mg) has an osmolality
of 135 mOsm/kg.
[0334] A primary objective of the study was to evaluate the
pharmacokinetics, relative bioavailability, and tolerability three
different PA101 formulations in healthy subjects.
[0335] The study was designed as a randomized, double-blind, 4
period cross-over study using 12 healthy volunteers, between 18 and
45 years old.
[0336] The treatments given were one of the following: 1) 40 mg
PA101 (with mannitol), 2) 40 mg PA101B (no mannitol), 3) 60 mg
PA101B (no mannitol), and 4) Placebo TID (no mannitol). All
treatments administered three times per day (TID) as a single day
treatment. Each study treatment separated by a washout period of
minimum 24 hrs. All formulations were administered with a Pari
eFlow 30L device. The placebo contained 0.2% sodium chloride as an
osmotic agent, 0.02% EDTA as a chelating agent, and purified water
q.s. The osmolality of the placebo was about 65 mOsm/kg.
[0337] Study demographics: 13 total subjects, 5 male and 8 female,
having a mean age of 28 years old (total range of 21-40 years
old).
[0338] Disposition: 13 subjects were randomized. 12 subjects
completed the study whereas one subject discontinued during the
treatment period 1 (subject was receiving placebo) due to an
adverse event (a cough that started 1 minute post-dosing and lasted
three minutes).
[0339] Table 8 provides a summary of the adverse events observed
during this study.
TABLE-US-00009 TABLE 8 PA101 PA101-B (40) PA101-B (60) Placebo (N =
12) (N = 12) (N = 12) (N = 13) n (%) n (%) n (%) n (%) Any AE 5
(41.7) 7 (58.3) 5 (41.7) 7 (53.8) Any SAE 0 (0.0) 0 (0.0) 0 (0.0) 0
(0.0) Probably related AE 0 (0.0) 2 (16.7) 1 (8.3) 4 (30.8)
Possibly related AE 0 (0.0) 0 (0.0) 1 (8.3) 1 (7.7) Unlikely
related AE 1 (8.3) 1 (8.3) 2 (16.7) 1 (7.7) Not related AE 5 (41.7)
6 (50.0) 1 (8.3) 2 (15.4) Related AE* 0 (0.0) 2 (16.7) 2 (16.7) 4
(30.8) Not related AE* 5 (41.7) 6 (50.0) 3 (25.0) 3 (23.1)
Discontinued due to AE 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.7) Concomitant
medication given 2 (16.7) 2 (16.7) 0 (0.0) 0 (0.0) AE of mild
intensity 5 (41.7) 7 (58.3) 5 (41.7) 7 (53.8) AE of moderate
intensity 2 (16.7) 2 (16.7) 0 (0.0) 2 (15.4) AE of severe intensity
0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
[0340] Tables 9a and 9b provide an accounting of all adverse events
observed during this study.
TABLE-US-00010 TABLE 9a PA101 PA101-B (40) PA101-B (60) Placebo (N
= 12) (N = 12) (N = 12) (N = 13) System Organ Class Preferred term
n (%) n (%) n (%) n (%) Number of subject with at least one TEAE 5
(41.7) 7 (58.3) 5 (41.7) 7 (53.8) GENERAL DISORDERS AND 4 (33.3) 2
(16.7) 2 (16.7) 2 (15.4) ADMINISTRATION SITE CONDITIONS APPLICATION
SITE REACTION 1 (8.3) 1 (8.3) 1 (8.3) 0 (0.0) FEELING HOT 0 (0.0) 0
(0.0) 1 (8.3) 0 (0.0) ASTHENIA 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.7)
CATHETER SITE PAIN 1 (8.3) 0 (0.0) 0 (0.0) 1 (7.7) CATHETER SITE
RELATED REACTION (16.7) 1 (8.3) 0 (0.0) 0 (0.0) FATIGUE 0 (0.0) 0
(0.0) 0 (0.0) 1 (7.7) GASTROINTESTINAL DISORDERS 0 (0.0) 1 (8.3) 0
(0.0) 2 (15.4) ABDOMINAL PAIN UPPER 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.7)
DRY MOUTH 0 (0.0) 1 (8.3) 0 (0.0) 0 (0.0) NAUSEA 0 (0.0) 0 (0.0) 0
(0.0) 1 (7.7) INVESTIGATIONS 0 (0.0) 1 (8.3) 0 (0.0) 0 (0.0) SPUTUM
ABNORMAL 0 (0.0) 1 (8.3) 0 (0.0) 0 (0.0) MUSCULOSKELETAL AND 1
(8.3) 0 (0.0) 0 (0.0) 0 (0.0) CONNECTIVE TISSUE DISORDERS BACK PAIN
1 (8.3) 0 (0.0) 0 (0.0) 0 (0.0)
TABLE-US-00011 TABLE 9b PA101 PA101-B (40) PA101-B (60) Placebo (N
= 12) (N = 12) (N = 12) (N = 13) System Organ Class Preferred term
n (%) n (%) n (%) n (%) NERVOUS SYSTEM DISORDERS 1 (8.3) 4 (33.3) 3
(25.0) 1 (7.7) DIZZINESS 1 (8.3) 3 (25.0) 2 (16.7) 1 (7.7) HEADACHE
1 (8.3) 2 (16.7) 2 (16.7) 0 (0.0) RESPIRATORY, THORACIC AND 0 (0.0)
3 (25.0) 3 (25.0) 4 (30.8) MEDIASTINAL DISORDERS COUGH 0 (0.0) 0
(0.0) 2 (16.7) 4 (30.8) THROAT IRRITATION 0 (0.0) 1 (8.3) 1 (8.3) 2
(15.4) NASAL CONGESTION 0 (0.0) 1 (8.3) 0 (0.0) 0 (0.0)
OROPHARYNGEAL PAIN 0 (0.0) 1 (8.3) 0 0 (0.0) SKIN AND SUBCUTANEOUS
(8.3) 0 (0.0) 0 (0.0) 1 (7.7) TISSUE DISORDERS PETECHIAE 1 (8.3) 0
(0.0) 0 (0.0) 0 (0.0) SKIN REACTION 0 (0.0) 0 (0.0) 0 1 (7.7)
VASCULAR DISORDERS 1 (8.3) 0 (0.0) 0 (0.0) 0 (0.0) THROMBOPHLEBITIS
1 (8.3) 0 (0.0) 0 (0.0) 0 (0.0)
[0341] Table 10 provides a summary of adverse events observed
during this study related to administration of PA101 or
PA101-B.
TABLE-US-00012 TABLE 10 PA101 PA101-B (40) PA101-B (60) Placebo (N
= 12) (N = 12) (N = 12) (N = 13) System Organ Class Preferred term
n (%) n (%) n (%) n (%) Number of subject with at least one TEAE 0
(0.0) 2 (16.7) 2 (16.7) 4 (30.8) RESPIRATORY, THORACIC AND 0 (0.0)
1 (8.3) 2 (16.7) 4 (30.8) MEDIASTINAL DISORDERS COUGH 0 (0.0) 0
(0.0) 1 (8.3) 4 (30.8) THROAT IRRITATION 0 (0.0) 1 (8.3) 1 (8.3) 2
(15.4) NERVOUS SYSTEM DISORDERS 0 (0.0) 0 (0.0) 1 (8.3) 0 (0.0)
DIZZINESS 0 (0.0) 0 (0.0) 1 (8.3) 0 (0.0) GASTROINTESTINAL
DISORDERS 0 (0.0) 1 (8.3) 0 (0.0) 1 (7.7) DRY MOUTH 0 (0.0) 1 (8.3)
0 (0.0) 0 (0.0) NAUSEA 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.7)
[0342] Table 11 provides a summary of moderate adverse events
observed during this study.
TABLE-US-00013 TABLE 11 PA101 PA101-B (40) PA101-B (60) Placebo (N
= 12) (N = 12) (N = 12) (N = 13) System Organ Class Preferred term
n (%) n (%) n (%) n (%) Number of subject with at least one TEAE 2
(16.7) 2 (16.7) 0 (0.0) 2 (15.4) GENERAL DISORDERS AND 0 (0.0) 1
(8.3) 0 (0.0) 1 (7.7) ADMINISTRATION SITE CONDITIONS APPLICATION
SITE REACTION 0 (0.0) 1 (8.3) 0 (0.0) 0 (0.0) CATHETER SITE PAIN 0
(0.0) 0 (0.0) 0 (0.0) 1 (7.7) NERVOUS SYSTEM DISORDERS 1 (8.3) 2
(16.7) 0 (0.0) 0 (0.0) HEADACHE 1 (8.3) 2 (16.7) 0 (0.0) 0 (0.0)
RESPIRATORY, THORACIC AND 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.7)
MEDIASTINAL DISORDERS COUGH 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.7)
VASCULAR DISORDERS 1 (8.3) 0 (0.0) 0 (0.0) 0 (0.0) THROMBOPHLEBITIS
1 (8.3) 0 (0.0) 0 (0.0) 0 (0.0)
[0343] Pharmacokinetic Results:
[0344] Table 12 provides the mean and standard deviation (SD) for
each pharmacokinetic parameter measured for each PA101 formulation
studied. As used herein, "K.sub.e1"=is the elimination rate
constant that describes the rate at which the cromolyn of PA101 or
PA101-B formulations is removed from the subject's system. This
measure is equivalent to the fraction of cromolyn that is removed
per unit of time (T.sup.-1, or in this case 1/hours (h)).
TABLE-US-00014 TABLE 12 40 mg PA101 40 mg PA101-B 60 mg PA101-B
Parameter Mean SD Mean SD Mean SD 1.sup.st Dose C.sub.max, ng/mL
76.8 31.0 75.6 29.1 119 41.0 T.sub.max, h.sup.a 0.56 (0.31-2.04)
0.56 (0.31-2.04) 0.56 (0.13-2.04) AUC.sub.0-6, h ng/mL 229.sup.b
96.6.sup.b 216.sup.b 79.7.sup.b 358.sup.b 136.sup.b 2.sup.nd Dose
C.sub.max, ng/mL 84.7 34.7 82.3 32.1 148 60.3 T.sub.max, h.sup.a
0.56 (0.23-2.04) 0.56 (0.13-2.06) 0.56 (0.23-1.04) AUC.sub.0-6, h
ng/mL 266.sup.b 123.sup.b 258.sup.b 101.sup.b 420 175 3.sup.rd Dose
C.sub.max, ng/mL 92.1 30.1 92.9 35.1 157 58.2 T.sub.max, h.sup.a
0.56 (0.23-0.81) 0.56 (0.23-2.04) 0.56 (0.13-0.56) AUC.sub.0-t, h
ng/mL 330 142 330 140 529 257 AUC.sub.0-inf, h ng/mL 342 147 340
145 542 262 k.sub.el, 1/h 0.281 0.0282 0.294 0.0229 0.306 0.0385
t.sub.1/2, h 2.49 0.237 2.37 0.184 2.30 0.265
[0345] The pharmacokinetic parameters of the PA101 treatments of
the Phase I study (described in Example 2--PK-01) and the Phase II
study (described in this Example-PK-02) are compared in Table 13
below. Note that subjects in one of the PK-01, 40 mg group was
administered the formulation comprising cromolyn sodium using a
Pari eFlow 40L device, while the formulations were administered to
all other subjects in the study using a Pari eFlow 30L device. In
the PK-01 study there were three subjects whose plasma values were
very high compared to the average, and these outlier values skewed
the Cmax and AUC results in the PK-01 study. If the data are
analyzed by excluding these outliers, the Cmax and AUC results of
the PK-01 and PK-02 studies are comparable. This was supported by
the finding that the urine cromolyn levels were similar in the two
studies.
TABLE-US-00015 TABLE 13 PK-01 PK-01 PK-01 PK-02 PK-02 PK-02 PA101
PA101 PA101 PA101 PA101B PA101B Intal Nalcrom 40 mg 40 mg 80 mg 40
mg 40 mg 60 mg 20 mg 200 mg (40L) (30L) (30L) (30L) (30L) (30L)
C.sub.max 17.8 (10.4) 5.2 (3.1) 88.6 (45.5) 156 (104) 236 (104)
76.8 (31.0) 75.6 (29.1) 119 (41.0) (ng/mL) T.sub.max (h) 0.6 (0.1)
3.2 (2.1) 0.6 (0.1) 0.7 (0.1) 0.7 (0.1) 0.6 (0.3) 0.6 (0.3) 0.6
(0.1) AUC.sub.0-t 39.1 (15.1) 29.4 (10.4) 206 (94.3) 329 (144) 514
(186) 229 (97) 216 (80) 358 (136) (h ng/mL) AUC.sub.0-.infin. 40.6
(15.6) 33.3 (11.7) 212 (96.0) 338 (146) 526 (198) (h ng/mL)
T.sub.1/2(h) 2.5 (0.8) 4.3 (1.3) 2.5 (0.7) 2.2 (0.6) 2.1 (0.5)
[0346] PA101 formulations from the Phase I and Phase II studies are
safe and well-tolerated. The most common adverse events, reported
in at least 2 subjects, include cough, throat irritation,
dizziness, headache and catheter-site reaction. Treatment-related
adverse events include cough, throat irritation, dizziness, dry
mouth and nausea. Both the frequency and severity of adverse events
are comparable between active and placebo treatments, which was
unexpected given that the PA101-B formulations (without mannitol)
exhibited osmolalities that were significantly different than
formulations comprising mannitol. Accordingly, the majority of
adverse events have a mild intensity and transient duration. Thus,
the PA101-B formulations (at both 40 mg and 60 mg dosages) are
well-tolerated with an adverse event (AE) profile similar to
PA101.
[0347] PA101-B formulations (at both 40 mg and 60 mg dosages) have
a comparable pharmacokinetic profile to PA101.
Example 4: Phase II Safety and Efficacy Study of Cromolyn
Formulations in Subjects with Chronic Cough Due to Idiopathic
Pulmonary Fibrosis (IPF)
[0348] This is a randomized, double-blind, placebo-controlled,
2-period crossover, 2-cohort, multi-center, Phase 2 study in 48
subjects with chronic cough: 24 subjects exhibiting chronic cough
associated with idiopathic pulmonary fibrosis (IPF, Cohort 1) and
24 subjects with chronic idiopathic cough not associated with IPF
(CIC, Cohort 2) (see Example 5).
[0349] The study consists of two treatment periods of 14 days each
separated by a Washout Period of 14 days (+2 days) between Period 1
and Period 2. A Screening Visit will be conducted within 14 days
before the Baseline Visit of Period 1. The two periods are
identical except that in Period 2, subjects are crossed over to the
alternate treatment from that received in Period 1, according to a
1:1 randomization scheme. At the Screening Visit subjects with a
daytime cough severity score >40 mm using a linear 100 mm visual
analogue scale are placed on 24-hour objective cough count
monitoring using the LCM cough monitor. Subjects with an average
daytime cough count of at least 15 coughs per hour using LCM at the
Screening Visit are eligible for randomization. During each period,
subjects self-administer study drug (i.e., 40 mg PA101 or Placebo
PA101 via eFlow) three times daily (i.e., 8:00 am.+-.1 hour, 2:00
pm.+-.1 hour, and 8:00 pm.+-.1 hour) for 14 consecutive days of
each period (e.g., Days 1-14). Subjects attend a Pre-study Visit
(Visit 1, Day -1) at the clinic in the morning prior to the
Baseline/Treatment Visit (Visit 2, Day 1) and a cough count device
(LCM) is dispensed for measurement of baseline 24-hour cough count.
Subjects return to the clinic next day in the morning (Visit 2, Day
1) to return the devices, assessment of quality of life measures,
and to receive the first dose of the study treatment. Additional
treatment visits during the Treatment Period occur on Day 7.+-.1
day (Visit 3) and Day 15.+-.1 day (Visit 5). Subjects visit the
clinic on Day 7.+-.1 day (Visit 3) and Day 14.+-.1 day (Visit 4) in
the morning and the LCM device is dispensed for measurement of
24-hour cough count. Study assessments include assessment of
quality of life (LCQ and K-BILD), cough severity (VAS), pulmonary
function tests (forced expiratory volume in one second [FEV1],
forced vital capacity [FVC], and FEV1/FVC ratio), fraction of
exhaled nitric oxide (FeNO), and safety assessments (AEs, vital
signs, and ECG) on Days 1, 7 and 15 of each treatment period.
[0350] Pulmonary function tests and K-BILD assessment are only be
performed in the IPF cohort.
[0351] A safety follow-up call is placed within 7.+-.2 days
following the last study treatment. Clinical safety laboratory
samples are collected at the start and end of the treatment of each
treatment period (Screening Visit and Visit 5 during the Treatment
Period 1, and at Visit 2 and Visit 5 during the Treatment Period
2). All post-dose study procedures are conducted from time 0. Time
0 is defined as the start of the first study drug administration
(i.e., when the nebulizer has been turned on) of each period.
[0352] In the IPF cohort, subjects are allowed to use antifibrotic
therapy i.e., pirfenidone, nintedanib, and N-acetylcysteine) during
the course of the study provided that the dose is stabilized at
least 3 months prior to the Screening visit and throughout the
study period. Subjects are not allowed to use the following drugs
(i.e., prednisone, narcotic antitussives, baclofen, gabapentin,
inhaled corticosteroids, benzonatate, dextromethorphan,
carbetapentane, and H1 antihistamines, leukotriene modifiers, and
cromolyn sodium) for at least 2 weeks prior to the Screening Visit
and throughout the study. Drugs containing bronchodilators
(including beta-2 agonists and anticholinergics) are not allowed
for at least 1 week prior to the Baseline Visit and during the
study.
[0353] As shown in Table 1, PA101 contains 4% (by weight) cromolyn
as the active substance, 0.2% Sodium Chloride as an osmotic agent,
0.02% EDTA as a chelating agent, 1.25% mannitol as a non-ionic
osmotic agent, and purified water q.s. PA101 has an osmolality of
200 mOsm/kg.
[0354] A primary objective of the study was to assess the
effectiveness of inhaled PA101 delivered via a Pari eFlow 30L
nebulizer for treating chronic cough due to IPF.
[0355] The study design is provided graphically in FIG. 4.
[0356] Inclusion Criteria: 1) male or female subjects age 40
through 79 years, inclusive of the endpoints, 2) diagnosis of
Idiopathic Pulmonary Fibrosis (IPF) with the consensus of the
multidisciplinary team based on the presence of definitive or
possible usual interstitial pneumonia (UIP) pattern on
high-resolution computed tomography (HRCT) and after excluding
alternative diagnoses, including lung diseases associated with
environmental and occupational exposure, with connective tissue
diseases and with drugs, 3) chronic cough present for at least 8
weeks and not responsive to current therapies, 4) daytime cough
severity score on visual analogue scale >40 mm at the Screening
Visit, 5) daytime average cough count of at least 15 coughs per
hour using objective cough count monitor at the Screening Visit, 6)
transfer capacity for carbon monoxide corrected for hemoglobin
(TLCOc) >25% predicted value within 12 months of the Screening
Visit and Forced Vital Capacity (FVC) >50% predicted value
within 1 month of the Screening Visit, and 7) willingness and
ability to provide written informed consent.
[0357] Exclusion Criteria: 1) current or recent history of
clinically significant medical condition, laboratory abnormality,
or illness that could put the subject at risk or compromise the
quality of the study data as determined by the investigator, 2)
significant coronary artery disease (i.e., myocardial infarction
within 6 months or unstable angina within 1 month of the Screening
Visit), 3) an upper or lower respiratory tract infection within 4
weeks of the Screening Visit, 4) acute exacerbation of IPF within 3
months of the Screening Visit, 5) long-term daily oxygen therapy
(>10 hours/day), 6) presence of pulmonary arterial hypertension
with limitation of activity, 7) history of malignancy of any organ
system, treated or untreated within the past 5 years, with the
exception of localized basal cell carcinoma or cervix carcinoma in
situ, 8) current or recent history (previous 12 months) of
excessive use or abuse of alcohol, 9) current or recent history
(previous 12 months) of abusing legal drugs or use of illegal drugs
or substances, 10) participation in any other investigational drug
study within 4 weeks prior to the Screening Visit, 11) use of the
following drugs within 2 weeks of the Screening Visit: Prednisone,
narcotic antitussives, baclofen, gabapentin, inhaled
corticosteroids, benzonatate, dextromethorphan, carbetapentane, H1
antihistamines, leukotriene modifiers, and cromolyn sodium, 12)
females who are pregnant or breastfeeding, or if of child-bearing
potential unwilling to practice acceptable means of birth control
or abstinence during the study (e.g., abstinence, combination
barrier and spermicide, or hormonal), and 13) history of
hypersensitivity or intolerance to cromolyn sodium.
[0358] Table 14 provides the demographics of the study
participants.
TABLE-US-00016 TABLE 14 Number (N) 24 Age 67 .+-. 6 (56-79 years)
Sex 15 Male/9 Female Race 2 Asian/22 White Body Mass Index (BMI)
29.1 .+-. 3.8 Time since IPF diagnosis 4.1 .+-. 3.3 (1-13 years)
Time since Cough diagnosis 5.6 .+-. 4.2 (1-16 years) Forced Vital
Capacity (FVC) - Mean (L) 2.54 .+-. 0.96 Forced Vital Capacity
(FVC) - Predicted (%) 73 .+-. 15 FEV1/FVC (%) 83 .+-. 9 FEV1 =
Volume that has been exhaled at the end of the first second of
forced expiration
[0359] Safety Results:
[0360] Table 15 below summarizes the treatment emergent adverse
events (AEs) reported for at least two subjects having chronic
cough due to IPF.
TABLE-US-00017 TABLE 15 Adverse Events (AEs) PA101 (n = 23) Placebo
(n = 23) Subjects with at least one 14 (61%) 14 (61%) Adverse Event
(AE) Severe AEs 0 0 AEs leading to withdrawal 1 (4.3%) 1 (4.3%)
Related AEs 11 (48%) 9 (39%) Unrelated AEs 3 (13%) 5 (22%) Mild AEs
11 (48%) 9 (39%) Moderate AEs 3 (13%) 5 (22%) Severe AEs 0 0
Respiratory System Cough 3 (13%) 4 (17.4%) Dyspnoea 1 (4.3%) 2
(8.7%) Exertional dyspnoea 0 1 (4.3%) Dysphonia 0 1 (4.3%)
Hyperventilation 0 1 (4.3%) Idiopathic pulmonary fibrosis 0 1
(4.3%) Oropharyngeal pain 1 (4.3%) 0 Increased sputum 0 1 (4.3%)
Wheezing 1 (4.3%) 0 Other Systems Headache 3 (13%) 2 (8.7%)
Dizziness 1 (4.3%) 2 (8.7%) Diarrhea 2 (8.7%) 1 (4.3%) Defecation
urgency 2 (8.7%) 0 Dry mouth 2 (8.7%) 0 Fatigue 1 (4.3%) 2 (8.7%)
Flushing 2 (8.7%) 0
[0361] There were two participants who withdrew from the study. One
participant who received the placebo treatment experienced
increased shortness of breath & cough (mild, possibly related)
starting on Day 1, lasting 13 days, at which time the symptoms
resolved. The other participant received the PA101 treatment and
contracted the common cold (moderate, unlikely to be related to the
treatment), starting on day 5 and lasting 17 days, at which time
the symptoms resolved.
[0362] Efficacy Results:
[0363] Cough count was measured by Leicester Cough Monitor (LCM).
FIG. 5 provides a summary of the daytime average cough/hour in
subjects with chronic cough due to IPF receiving either PA101 or a
placebo at baseline, Day 7, and Day 14 of the study. When the
change from baseline is analyzed (see FIG. 6), a statistically
significant difference emerges at Days 7 and 14 for the
PA101-treated subjects. To demonstrate the clinical relevance of
this result, this statistically significant difference can be
expressed as both a placebo-adjusted (PBO-adjusted) reduction in
cough frequency (see FIG. 7) and a least squares (LS) means ratio
with a 95% confidence interval (CI) (see FIGS. 7 and 8). Taken
together, the data indicate that treatment with PA101 provides a
reduction in cough that is not only statistically significant but
also clinically meaningful.
[0364] Table 16 summarizes the data shown graphically in FIGS. 7
and 8.
TABLE-US-00018 TABLE 16 Treatment PA101 Placebo (N = 23) (N = 23)
Day 7 Number of subjects included in 23 (100) 21 (91.3) analysis
(n) (%) Adjusted Least squares 0.78 1.08 treatment mean estimate
mean 95% CI 0.64, 0.96 0.87, 1.33 (LSMean) Treatment Ratio of means
0.73 Comparison p-value 0.0329 95% CI 0.54, 0.97 Day 14/ Number of
subjects included in 23 (100) 21 (91.3) ET analysis (n) (%)
Adjusted Least squares 0.70 1.05 treatment mean estimate mean 95%
CI 0.55, 0.90 0.81, 1.36 (LSMean) Treatment Ratio of means 0.67
Comparison p-value 0.0241 95% CI 0.48, 0.94
[0365] Table 17 summarizes the data shown graphically in FIGS. 7
and 8.
TABLE-US-00019 TABLE 17 PA101 (n = 23) Placebo (n = 21) Mean .+-.
SD Mean .+-. SD Baseline 54.7 .+-. 54.5 50.9 .+-. 36.5 Day 7 38.1
.+-. 24.7 56.5 .+-. 42.3 Change from Baseline -16.4 .+-. 50.5
(-30%) 5.5 .+-. 28.1 (11%) LS Mean Ratio (95% CI) 0.73 (0.54, 0.97)
p = 0.03 Day 14 38.8 .+-. 29.0 51.9 .+-. 39.9 Change from Baseline
-16.2 .+-. 44.9 (-29%) 1.3 .+-. 17.1 (2%) LS Mean Ratio (95% CI)
0.67 (0.48-0.94) p = 0.02
[0366] FIG. 12 provides a summary of the nighttime average
cough/hour in subjects with chronic cough due to IPF receiving
either PA101 or a placebo at baseline, Day 7, and Day 14 of the
study. Similar to the analysis performed for daytime cough, FIG. 13
provides the change from baseline for nighttime cough at Days 7 and
14 for the PA101-treated subjects.
[0367] Table 18 summarizes the data shown graphically in FIGS. 12
and 13.
TABLE-US-00020 TABLE 18 Treatment PA101 Placebo (N = 23) (N = 23)
Day 7 Number of subjects included in 21 (91.3) 20 (87.0) analysis
(n) (%) Adjusted Least squares 0.70 1.31 treatment mean estimate
mean 95% CI 0.43, 1.15 0.79, 2.18 (LSMean) Treatment Ratio of means
0.53 Comparison p-value 0.0122 95% CI 0.33, 0.85 Day 14/ Number of
subjects included in 23 (100.0) 20 (87.0) ET analysis (n) (%)
Adjusted Least squares 0.60 0.93 treatment mean estimate mean 95%
CI 0.33, 1.10 0.48, 1.81 (LSMean) Treatment Ratio of means 0.64
Comparison p-value 0.3022 95% CI 0.26, 1.57
[0368] To demonstrate clinical relevance of the change in 24-hour
average cough/hour in PA101-treated subjects, this difference can
be expressed as both a placebo-adjusted (PBO-adjusted) reduction in
cough frequency (see FIGS. 15 and 17) and a least squares (LS)
means ration with a 95% confidence interval (CI) (see FIGS. 16 and
17). Taken together, the data indicate that treatment with PA101
provides a reduction in 24-hour average cough/hour that is
clinically meaningful.
[0369] Table 19 summarizes the data shown graphically in FIGS.
15-17.
TABLE-US-00021 TABLE 19 Treatment PA101 Placebo (N = 23) (N = 23)
Day 7 Number of subjects included in 23 (100.0) 21 (91.3) analysis
(n) (%) Adjusted Least squares 0.75 1.05 treatment mean estimate
mean 95% CI 0.62, 0.91 0.86, 1.29 (LSMean) Treatment Ratio of means
0.71 Comparison p-value 0.0163 95% CI 0.54, 0.94 Day 14/ Number of
subjects included in 23 (100.0) 21 (91.3) ET analysis (n) (%)
Adjusted Least squares 0.71 1.04 treatment mean estimate mean 95%
CI 0.56, 0.90 0.81, 1.34 (LSMean) Treatment Ratio of means 0.68
Comparison p-value 0.0245 95% CI 0.49, 0.95
[0370] FIG. 18 synthesizes the data from daytime, nighttime and
24-hour cough/hour analyses to generate a 24-hour cough profile for
subjects in this study with chronic cough due to IPF who receive
either placebo or PA101. For each treatment group, the average
cough/hour rates over a 24-hour window are drawn contrasting
baseline rates to those rates demonstrated following 14 days of
administration of either the placebo or PA101. The PA101-treated
group shows a statistically-significant and clinically relevant
reduction in cough/hour rates by Day 14, particularly from the
hours of 8 am to 11 pm.
[0371] In addition to the objective cough/hour data captured using
the LCM, subjective data was collected from study subjects. A
quality of life score was measured by the Leicester Cough
Questionnaire (LCQ) and King's Brief Interstitial Lung Disease
Questionnaire (K-BILD).
[0372] Table 20 summarizes the data collected using the Leicester
Cough Questionnaire to assess Quality of Life changes from baseline
to Days 7 and 14. Quality of Life was a secondary endpoint of this
Phase II study. LCQ: worst score=3, best score=21; MID:
>1.3.
TABLE-US-00022 TABLE 20 PA101 (n = 23) Placebo (n = 21) Mean .+-.
SD Mean .+-. SD Baseline 13.6 .+-. 3.6 13.7 .+-. 3.5 Day 7 14.4
.+-. 3.2 14.0 .+-. 3.3 Change from Baseline 0.7 0.3 Day 14 14.8
.+-. 3.3 13.4 .+-. 3.7 Change from Baseline 1.1 0 LS Mean
Difference 1.1 p = 0.09
[0373] Table 21 summarizes the change from baseline in the
Leicester Cough Questionnaire measuring Quality of Life.
TABLE-US-00023 TABLE 21 Treatment PA101 Placebo (N = 23) (N = 23)
Day 7 Number of subjects included in 23 (100.0) 22 (95.7) analysis
(n) (%) Adjusted Least squares 0.66 0.33 treatment mean estimate
mean 95% CI -0.06, 1.38 -0.41, 1.07 (LSMean) Treatment Ratio of
means 0.33 Comparison p-value 0.5057 95% CI -0.70, 1.37 Day 14/
Number of subjects included in 23 (100.0) 23 (100.0) ET analysis
(n) (%) Adjusted Least squares 1.04 -0.03 treatment mean estimate
mean 95% CI 0.16, 1.93 -0.92, 0.85 (LSMean) Treatment Ratio of
means 1.08 Comparison p-value 0.0905 95% CI -0.18, 2.33
[0374] Table 22 summarizes the cough specific Quality of Life in
Responders. Responders are defined herein as those subjects with
chronic cough due to IPF who experience a greater than 30%
reduction in the average daytime cough following treatment with a
composition of the disclosure, or in this study, PA101.
TABLE-US-00024 TABLE 22 PA101 (n = 8) Placebo (n = 4) Mean .+-. SD
Mean .+-. SD Baseline 14.5 .+-. 4.0 14.2 .+-. 2.9 Day 7 15.6 .+-.
3.2 13.6 .+-. 3.1 Change from Baseline 1.1 -0.6 Day 14 16.8 .+-.
2.8 14.4 .+-. 3.3 Change from Baseline 2.3 0.2
[0375] Table 23 summarizes the data collected using the King's
Brief Interstitial Lung Disease Questionnaire (K-BILD) to assess
Quality of Life changes from baseline to day 14. Disease-specific
quality of life was a secondary efficacy endpoint of this Phase II
study. LCQ: worst score=15, best score=100.
TABLE-US-00025 TABLE 23 PA101 (n = 23) Placebo (n = 23) Mean .+-.
SD Mean .+-. SD MID Baseline - Total Score 55.4 .+-. 9.2 57.0 .+-.
11.7 Psychological 55.5 .+-. 13.0 57.7 .+-. 13.3 Breathlessness
& Activities 44.1 .+-. 15.2 45.0 .+-. 20.9 Chest 61.8 .+-. 19.9
63.5 .+-. 21.7 Day 14 - Total Score 56.7 .+-. 9.1 55.1 .+-. 10.0
Psychological 57.9 .+-. 13.4 55.0 .+-. 13.7 Breathlessness &
Activities 44.3 .+-. 18.7 44.5 .+-. 17.9 Chest 69.3 .+-. 14.3 60.8
.+-. 19.3 Change from Baseline 1.3 .+-. 4.1 -1.9 .+-. 7.5 (Mean
.+-. SD) Psychological 2.4 .+-. 6.3 -2.7 .+-. 10.2 Breathlessness
& Activities 0.2 .+-. 10.1 -0.5 .+-. 11.0 Chest 7.4 .+-. 9.9
-2.7 .+-. 18.2 LS Mean Difference (95% CI) Total 2.2 (-0.8, 5.2) (p
= 0.11) 5 Psychological 3.9 (0.4, 7.4) (p = 0.03)* 6 Breathlessness
& Activities 0.5 (-7.2, 8.2) (p = 0.88) 7 Chest 8.7 (1.4, 16.0)
(p = 0.03)* 11
[0376] Table 24 summarizes the change from baseline in K-BILD
psychological domain measuring Quality of Life using a mixed score
model in subjects with chronic cough due to IPF treated with either
placebo or PA101.
TABLE-US-00026 TABLE 24 Treatment PA101 Placebo (N = 23) (N = 23)
Day 7 Number of subjects included in 23 (100.0) 22 (95.7) analysis
(n) (%) Adjusted Least squares 2.36 -0.94 treatment mean estimate
mean 95% CI -0.63, 5.35 -3.99, 2.11 (LSMean) Treatment Ratio of
means 3.30 Comparison p-value 0.0783 95% CI -0.41, 7.00 Day 14/
Number of subjects included in 23 (100.0) 23 (100.0) ET analysis
(n) (%) Adjusted Least squares 1.34 -2.55 treatment mean estimate
mean 95% CI -2.46, 5.14 -6.37, 1.26 (LSMean) Treatment Ratio of
means 3.89 Comparison p-value 0.0322 95% CI 0.37, 7.40
[0377] Table 25 summarizes the change from baseline in K-BILD
breathlessness and activities domain measuring Quality of Life
using a mixed score model in subjects with chronic cough due to IPF
treated with either placebo or PA101.
TABLE-US-00027 TABLE 25 Treatment PA101 Placebo (N = 23) (N = 23)
Day 7 Number of subjects included in 23 (100.0) 22 (95.7) analysis
(n) (%) Adjusted Least squares -1.02 2.01 treatment mean estimate
mean 95% CI -4.74, 2.70 -1.79, 5.80 (LSMean) Treatment Ratio of
means -3.02 Comparison p-value 0.1627 95% CI -7.43, 1.38 Day 14/
Number of subjects included in 23 (100.0) 23 (100.0) ET analysis
(n) (%) Adjusted Least squares 0.08 -0.41 treatment mean estimate
mean 95% CI -4.39, 4.55 -4.88, 4.07 (LSMean) Treatment Ratio of
means 0.49 Comparison p-value 0.8794 95% CI -7.24, 8.21
[0378] Table 26 summarizes the change from baseline in K-BILD chest
symptoms domain measuring Quality of Life using a mixed score model
in subjects with chronic cough due to IPF treated with either
placebo or PA101.
TABLE-US-00028 TABLE 26 Treatment PA101 Placebo (N = 23) (N = 23)
Day 7 Number of subjects included in 23 (100.0) 22 (95.7) analysis
(n) (%) Adjusted Least squares 3.47 2.58 treatment mean estimate
mean 95% CI -1.36, 8.31 -2.33, 7.50 (LSMean) Treatment Ratio of
means 0.89 Comparison p-value 0.7129 95% CI -4.19, 5.98 Day 14/
Number of subjects included in 23 (100.0) 23 (100.0) ET analysis
(n) (%) Adjusted Least squares 6.26 -2.42 treatment mean estimate
mean 95% CI 0.77, 11.75 -7.92, 3.08 (LSMean) Treatment Ratio of
means 8.68 Comparison p-value 0.0270 95% CI 1.38, 15.99
[0379] Table 27 summarizes the change from baseline in K-BILD total
score measuring Quality of Life using a mixed score model in
subjects with chronic cough due to IPF treated with either placebo
or PA101.
TABLE-US-00029 TABLE 27 Treatment PA101 Placebo (N = 23) (N = 23)
Day 7 Number of subjects included 23 (100.0) 22 (95.7) in analysis
(n) (%) Adjusted Least squares 0.37 0.06 treatment mean estimate
mean 95% CI -1.61, 2.35 -1.96, 2.08 (LSMean) Treatment Ratio of
means 0.31 Comparison p-value 0.7655 95% CI -1.85, 2.46 Day 14/
Number of subjects included 23 (100.0) 23 (100.0) ET in analysis
(n) (%) Adjusted Least squares 0.49 -1.73 treatment mean estimate
mean 95% CI -2.22, 3.20 -4.44, 0.99 (LSMean) Treatment Ratio of
means 2.22 Comparison p-value 0.1189 95% CI -0.76, 5.19
[0380] Table 28 summarizes the data from measuring cough severity
by VAS in subjects with chronic cough due to IPF treated with
either placebo or PA101. Cough severity was measured by Visual
Analog Scale (VAS). When using the visual analogue scale (VAS), for
example, to measure cough severity, the subject is asked to mark on
a 100 mm scale between `no cough` and `the worst cough severity`.
VAS: worse score=100, best score=0
TABLE-US-00030 TABLE 28 PA101 (n = 23) Placebo (n = 21) Mean .+-.
SD Mean .+-. SD Baseline 54.8 .+-. 20.6 55.3 .+-. 23.8 Day 7 52.5
.+-. 20.7 51.2 .+-. 26.5 Change from Baseline -2.3 -3.4 Day 14 44.3
.+-. 26.7 53.3 .+-. 26.6 Change from Baseline -10.3 -1.8 LS Mean
Difference -8.5 p = 0.14
[0381] Table 29 summarizes the change from baseline in cough
severity by VAS in subjects with chronic cough due to IPF treated
with either placebo or PA101.
TABLE-US-00031 TABLE 29 Treatment PA101 Placebo (N = 23) (N = 23)
Day 7 Number of subjects 23 (100.0) 22 (95.7) included in analysis
(n) (%) Adjusted Least squares -2.27 -3.38 treatment mean estimate
mean 95% CI -8.15, 3.61 -9.38, 2.63 (LSMean) Treatment Ratio of
means 1.11 Comparison p-value 0.7914 95% CI -7.30, 9.51 Day 14/
Number of subjects 23 (100.0) 23 (100.0) ET included in analysis
(n) (%) Adjusted Least squares -10.31 -1.84 treatment mean estimate
mean 95% CI -18.22, -2.41 -9.74, 6.06 (LSMean) Treatment Ratio of
means -8.48 Comparison p-value 0.1331 95% CI -19.65, 2.70
[0382] Table 30 summarizes the data from measuring cough severity
by VAS in Responders.
TABLE-US-00032 TABLE 30 PA101 (n = 8) Placebo (n = 4) Mean .+-. SD
Mean .+-. SD Baseline 57.3 .+-. 17.2 69.0 .+-. 17.2 Day 7 45.3 .+-.
14.5 64.0 .+-. 20.6 Change from Baseline -12 -5 Day 14 26.6 .+-.
14.2 56.3 .+-. 12.8 Change from Baseline -31 -13
[0383] The LCQ and VAS scores in Responders were compared (see FIG.
19). The data indicate a significant difference in VAS scores in
Responders treated with PA101 between baseline and day 14. This
subjective measure of cough severity corroborates the objective
measure of cough frequency measured by using a cough monitor. Both
methods demonstrate a clinically relevant reduction in symptoms of
chronic cough due to IPF following 14 days of treatment with
PA101.
[0384] This phase II study confirmed that PA101 has a very good
safety profile. Moreover, the data from this study demonstrate a
statistically significant 30% reduction in the objective cough
count vs. placebo. The data indicate positive trends in
cough-specific quality of life (QoL) measurements (LCQ) and
subject-reported cough severity (VAS). The data also demonstrate a
minimal placebo effect, which is clinically relevant for future
trials in IPF-chronic cough.
Example 5: Phase II Safety and Efficacy Study of Cromolyn
Formulations in Subjects with Chronic Idiopathic Cough
[0385] This is a randomized, double-blind, placebo-controlled,
2-period crossover, 2-cohort, multi-center, Phase 2 study in 48
subjects with chronic cough: 24 subjects with idiopathic pulmonary
fibrosis (IPF, Cohort 1) (see Example 4) and 24 subjects with
chronic idiopathic cough (CIC, Cohort 2).
[0386] The study consists of two treatment periods of 14 days each
separated by a Washout Period of 14 days (+2 days) between Period 1
and Period 2. A Screening Visit will be conducted within 14 days
before the Baseline Visit of Period 1. The two periods are
identical except that in Period 2, subjects were crossed over to
the alternate treatment from that received in Period 1, according
to a 1:1 randomization scheme. At the Screening Visit subjects with
a daytime cough severity score >40 mm using a linear 100 mm
visual analogue scale are placed on 24-hour objective cough count
monitoring using the LCM cough monitor. Subjects with an average
daytime cough count of at least 15 coughs per hour using LCM at the
Screening Visit are eligible for randomization. During each period,
subjects self-administer study drug (i.e., 40 mg PA101 or Placebo
PA101 via a Pari eFlow 30L device) three times daily (i.e., 8:00
am.+-.1 hour, 2:00 pm.+-.1 hour, and 8:00 pm.+-.1 hour) for 14
consecutive days of each period (e.g., Days 1-14). Subjects attend
a Pre-study Visit (Visit 1, Day -1) at the clinic in the morning
prior to the Baseline/Treatment Visit (Visit 2, Day 1) and a cough
count device (LCM) is dispensed for measurement of baseline 24-hour
cough count. Subjects return to the clinic next day in the morning
(Visit 2, Day 1) to return the devices, assessment of quality of
life measures, and to receive the first dose of the study
treatment. Additional treatment visits during the Treatment Period
occur on Day 7.+-.1 day (Visit 3) and Day 15.+-.1 day (Visit 5).
Subjects visit the clinic on Day 7.+-.1 day (Visit 3) and Day
14.+-.1 day (Visit 4) in the morning and the LCM device is
dispensed for measurement of 24-hour cough count. Study assessments
include assessment of quality of life (LCQ and K-BILD), cough
severity (VAS), pulmonary function tests (forced expiratory volume
in one second [FEV1], forced vital capacity [FVC], and FEV1/FVC
ratio), fraction of exhaled nitric oxide (FeNO), and safety
assessments (AEs, vital signs, and ECG) on Days 1, 7 and 15 of each
treatment period.
[0387] A safety follow-up call is placed within 7.+-.2 days
following the last study treatment. Clinical safety laboratory
samples are collected at the start and end of the treatment of each
treatment period (Screening Visit and Visit 5 during the Treatment
Period 1, and at Visit 2 and Visit 5 during the Treatment Period
2). All post-dose study procedures are conducted from time 0. Time
0 is defined as the start of the first study drug administration
(i.e., when the nebulizer has been turned on) of each period.
[0388] Subjects are not allowed to use the following drugs (i.e.,
prednisone, narcotic antitussives, baclofen, gabapentin, inhaled
corticosteroids, benzonatate, dextromethorphan, carbetapentane, and
H1 antihistamines, leukotriene modifiers, and cromolyn sodium) for
at least 2 weeks prior to the Screening Visit and throughout the
study. Drugs containing bronchodilators (including beta-2 agonists
and anticholinergics) are not allowed for at least 1 week prior to
the Baseline Visit and during the study.
[0389] As shown in Table 1, PA101 contains 4% (by weight) cromolyn
as the active substance, 0.2% Sodium Chloride as an osmotic agent,
0.02% EDTA as a chelating agent, 1.25% mannitol as a non-ionic
osmotic agent, and purified water q.s. PA101 has an osmolality of
200 mOsm/kg.
[0390] A primary objective of the study was to assess the
effectiveness of inhaled PA101 delivered via an eFlow nebulizer for
treating chronic idiopathic cough.
[0391] The study design is provided graphically in FIG. 20.
[0392] The inclusion criteria of the chronic idiopathic cough (CIC)
cohort are: 1) male or female subjects age 18 through 75 years,
inclusive of the endpoints, 2) chronic cough that has been present
for at least 8 weeks, 3) diagnosis of chronic idiopathic cough
(CIC) that is unresponsive to targeted treatment for identified
underlying triggers (i.e., post-nasal drip, asthmatic/non-asthmatic
eosinophilic bronchitis, and gastro-esophageal reflux disease), 4)
cough score on visual analogue scale of .gtoreq.40 mm at the
Screening Visit, 5) daytime average cough count of at least 15
coughs per hour using objective cough count monitor at the
Screening Visit, and 6) willingness and ability to provide written
informed consent.
[0393] The exclusion criteria of the chronic idiopathic cough (CIC)
cohort are: 1) current or recent history of clinically significant
medical condition, laboratory abnormality, or illness that could
put the subject at risk or compromise the quality of the study data
as determined by the investigator, 2) an upper or lower respiratory
tract infection within 4 weeks of the Screening Visit, 3) history
of malignancy of any organ system, treated or untreated within the
past 5 years, with the exception of localized basal cell carcinoma
or cervix carcinoma in situ, 4) current or recent history (previous
12 months) of excessive use or abuse of alcohol, 5) current or
recent history (previous 12 months) of abusing legal drugs or use
of illegal drugs or substances, 5) participation in any other
investigational drug study within 4 weeks prior to the Screening
Visit, 6) use of the following drugs within 2 weeks of the
Screening Visit: Prednisone, narcotic antitussives, baclofen,
gabapentin, inhaled corticosteroids, benzonatate, dextromethorphan,
carbetapentane, H1 antihistamines, leukotriene modifiers, and
cromolyn sodium, 7) females who are pregnant or breastfeeding, or
if of child-bearing potential unwilling to practice acceptable
means of birth control or abstinence during the study (e.g.,
abstinence, combination barrier and spermicide, or hormonal), and
8) history of hypersensitivity or intolerance to cromolyn
sodium.
[0394] Table 31 summarizes the CIC cohort demographics.
TABLE-US-00033 TABLE 31 Number of subjects (N) 27 Age 62 .+-. 11
(23-73 years) Sex 6 Male/21 Female Race 2 African American/25 White
BMI 27.7 .+-. 5.7 Time since Diagnosis 9.9 .+-. 9.8 (2-43
years)
[0395] Safety Results:
[0396] As shown in Example 4, this study demonstrates that the use
of PA101 is safe as the number of adverse events observed in
subjects receiving PA101 and subjects receiving the placebo is not
statistically significantly different.
[0397] Table 32 summarizes the Treatment Emergent Adverse Events
(AEs) observed in at least two subjects of the CIC cohort.
TABLE-US-00034 TABLE 32 Adverse Events (AEs) PA101 (n = 25) Placebo
(n = 27) Subjects with at least one Adverse 10 (40%) 13 (48.1%)
Event (AE) Severe AEs 0 0 AEs leading to withdrawal 2 (7.4%) 2
(7.4%) Related AEs 6 (24%) 6 (22.2%) Unrelated AEs 4 (16%) 7
(25.9%) Mild AEs 6 (24%) 11 (40.7%) Moderate AEs 4 (16%) 2 (7.4%)
Severe AEs 0 0 Respiratory System Cough 3 (12%) 3 (11.1%)
Oropharyngeal pain 2 (8%) 3 (11.1%) Dyspnoea 1 (4%) 1 (4%)
Pharyngeal hypoasthesia 2 (8%) 0 Throat clearing 0 1 (4%) Increased
bronchial secretion 0 1 (4%) Nasal congestion 1 (4%) 0 Other
Systems Tremor 2 (8%) 0 Dry Mouth 3 (12%) 0
[0398] Two subjects receiving the placebo withdrew from the study,
one subject experiencing sore throat and headache post-dose (Period
1--Day 3) and the other subject experiencing dizziness (Period
1--Day 7).
[0399] Two subjects receiving PA101 withdrew from the study, one
subject experiencing angioedema (thought to be a possible allergic
reaction to IP) (Period 2--Day 6) and the other subject
experiencing increased cough and shortness of breath (Period 2--Day
7).
[0400] Efficacy Results:
[0401] In sharp contrast to the results of the IPF cohort provided
in Example 4, this study demonstrates that PA101 is not effective
for the treatment of chronic idiopathic cough. Subjects with CIC
who received PA101 did not present a statistically significant or
clinically relevant improvement compared to the subjects with CIC
who received the placebo.
[0402] Cough count was measured by Leicester Cough Monitor (LCM).
Table 33 provides a summary of the daytime average cough/hour in
subjects with CIC.
TABLE-US-00035 TABLE 33 PA101 (n = 25) Placebo (n = 26) Mean .+-.
SD Mean .+-. SD Baseline 48 .+-. 79 44 .+-. 35 Day 7 41 .+-. 38 34
.+-. 29 Change from Baseline -8 .+-. 53 (-15%) -11 .+-. 20 (-23%)
Day 14 36 .+-. 39 36 .+-. 38 Change from Baseline -12 .+-. 72
(-25%) -8 .+-. 21 -18%) LS Mean Difference 1.27 (0.798-2.06) p =
0.32
[0403] Table 34 provides a summary of the change from baseline in
log transformed daytime average cough/hour in subjects with CIC.
This data is provided graphically in FIG. 23.
TABLE-US-00036 TABLE 34 Treatment PA101 Placebo (N = 22) (N = 22)
Day 7 Number of subjects included in 22 (100.0) 21 (95.5) analysis
(n) (%) Adjusted Least squares 0.98 0.73 treatment mean estimate
mean 95% CI 0.76, 1.25 0.57, 0.93 (LSMean) Treatment Ratio of means
1.35 Comparison p-value 0.0382 95% CI 1.02, 1.78 Day 14/ Number of
subjects included in 22 (100.0) 21 (95.5) ET analysis (n) (%)
Adjusted Least squares 0.87 0.68 treatment mean estimate mean 95%
CI 0.58, 1.30 0.45, 1.02 (LSMean) Treatment Ratio of means 1.28
Comparison p-value 0.3370 95% CI 0.76, 2.18
[0404] The individual average daytime cough/hour rates for the CIC
cohort are provided in FIG. 21 at baseline and Day 14. FIG. 22
depicts the change from baseline log transformed daytime average
cough/hour for the CIC cohort. The number of subjects responsive to
treatment with PA101 versus placebo for CIC is shown in FIG.
24.
[0405] The 24-hour average cough/hour rates for the CIC cohort are
provided in FIG. 22 at baseline, Day7 and Day 14. FIG. 25 depicts
the change from baseline log transformed daytime average cough/hour
for the CIC cohort.
[0406] Table 35 provides a summary of the change from baseline in
log transformed 24-hour average cough/hour in subjects with
CIC.
TABLE-US-00037 TABLE 35 Treatment PA101 Placebo (N = 25) (N = 27)
Day 7 Number of subjects included in 23 (92.0) 24 (88.9) analysis
(n) (%) Adjusted Least squares 0.93 0.72 treatment mean estimate
mean 95% CI 0.73, 1.18 0.57, 0.90 (LSMean) Treatment Ratio of means
1.30 Comparison p-value 0.0690 95% CI 0.98, 1.73 Day 14/ Number of
subjects included in 23 (92.0) 24 (88.9) ET analysis (n) (%)
Adjusted Least squares 0.86 0.66 treatment mean estimate mean 95%
CI 0.60, 1.25 0.46, 0.94 (LSMean) Treatment Ratio of means 1.30
Comparison p-value 0.2553 95% CI 0.81, 2.09
[0407] In addition to the objective cough/hour data captured using
the LCM, subjective data was collected from study subjects. A
quality of life score was measured by the Leicester Cough
Questionnaire (LCQ). Table 36 summarizes the data collected using
the Leicester Cough Questionnaire to assess Quality of Life changes
from baseline to Days 7 and 14. Quality of Life was a secondary
endpoint of this Phase II study. LCQ: worst score=3, best score=21;
MID: >1.3.
TABLE-US-00038 TABLE 36 PA101 (n = 25) Placebo (n = 27) Mean .+-.
SD Mean .+-. SD Baseline 10.9 .+-. 3.4 11.1 .+-. 3.1 Day 7 12.5
.+-. 3.9 12.3 .+-. 3.9 Change from Baseline 1.4 1.2 Day 14 12.6
.+-. 4.5 12.0 .+-. 4.1 Change from Baseline 1.6 1.0 LS Mean
Difference 0.50 (-0.80, 1.80) p = 0.42
[0408] Table 37 summarizes the changes from baseline from the
Leicester Cough Questionnaire for the CIC cohort.
TABLE-US-00039 TABLE 37 Treatment PA101 Placebo (N = 25) (N = 27)
Day 7 Number of subjects included 23 (92.0) 25 (92.6) in analysis
(n) (%) Adjusted Least squares 1.27 1.21 treatment mean estimate
mean 95% CI 0.23, 2.32 0.22, 2.20 (LSMean) Treatment Ratio of means
0.06 Comparison p-value 0.9280 95% CI -1.41, 1.54 Day 14/ Number of
subjects included 25 (100.0) 27 (100.0) ET in analysis (n) (%)
Adjusted Least squares 1.51 1.01 treatment mean estimate mean 95%
CI 0.37, 2.65 -0.09, 2.10 (LSMean) Treatment Ratio of means 0.50
Comparison p-value 0.4232 95% CI -0.80, 1.80
[0409] The study includes an additional subjective measure: Cough
Severity, provided quantitatively as a measure on a visual analogue
scale (VAS). When using the visual analogue scale (VAS), for
example, to measure cough severity, the subject is asked to mark on
a 100 mm scale between `no cough` and `the worst cough severity`.
Table 38 provides the mean, standard deviation (SD) and median
scores on the VAS for each parameter by treatment at either day 7
or day 14 of the study for the CIC cohort.
TABLE-US-00040 TABLE 38 PA101 (n = 25) Placebo (n = 27) Mean .+-.
SD Mean .+-. SD Baseline 65 .+-. 21 71 .+-. 12 Day 7 60 .+-. 22 63
.+-. 20 Change from Baseline -5.3 -8.1 Day 14 58 .+-. 23 61 .+-. 24
Change from Baseline -7.7 -10.0 LS Mean Difference -0.40 (-9.37,
8.58) p = 0.93
[0410] Table 39 summarizes the changes from baseline for Cough
Severity as measured by the VAS score for the CIC cohort.
TABLE-US-00041 TABLE 39 Treatment PA101 Placebo (N = 25) (N = 27)
Day 7 Number of subjects included 23 (92.0) 25 (92.6) in analysis
(n) (%) Adjusted Least squares -5.81 -7.47 treatment mean estimate
mean 95% CI -13.08, 1.46 -14.39, -0.55 (LSMean) Treatment Ratio of
means 1.66 Comparison p-value 0.6914 95% CI -6.86, 10.18 Day 14/
Number of subjects included 25 (100.0) 27 (100.0) ET in analysis
(n) (%) Adjusted Least squares -9.20 -8.80 treatment mean estimate
mean 95% CI -17.73, -0.66 -17.06, -0.54 (LSMean) Treatment Ratio of
means -0.40 Comparison p-value 0.9277 95% CI -9.37, 8.58
[0411] Tables 40a and 40b summarize the treatment period effect
using daytime average count for the CIC cohort.
TABLE-US-00042 TABLE 40a Treatment Period 1 Baseline D 7 D 14 PA101
(n = 13) 65.2 48.6 35.0 Change from baseline -46% Placebo (n = 12)
52.8 41.1 48.3 Change from baseline -8%
TABLE-US-00043 TABLE 40b Treatment Period 2 Baseline D 7 D 14 PA101
(n = 13) 29 32 43 Change from baseline 47% Placebo (n = 12) 37 27
25 Change from baseline -34%
[0412] Taken together, PA101 has a very good safety profile for the
treatment of CIC.
[0413] The efficacy results for the use of PA101 in the CIC cohort
do not indicate a statistically significant difference between
treatment groups using objective measures of count cough rate.
Those subjects who received PA101 for CIC and those subject who
receive the placebo for CIC present similar results 7 and 14 days
after treatment begins. There are no favorable trends in
cough-specific Quality of Life measurements (LCQ) or
subject-reported cough severity using the VAS scale.
[0414] The results do not support the use of PA101 for the
treatment of CIC.
Example 6: Cromolyn Sodium Formulations for Treatment of Chronic
Cough Due to IPF Versus Chronic Idiopathic Cough (CIC)
[0415] The data from Example 4 demonstrate that the compositions of
the disclosure, of which PA101 is an exemplary formulation, are
safe and efficacious for the treatment of chronic cough due to IPF.
In contrast, the data from Example 5 demonstrate that the
compositions of the disclosure, of which PA101 is an exemplary
formulation, are safe but are not efficacious for the treatment of
chronic idiopathic cough (CIC). To further demonstrate this
unexpected clinical result, FIGS. 26-29 compare the results of the
daytime and 24-hour average cough/hour data between subjects with
chronic cough due to IPF (Example 4) versus subjects with chronic
idiopathic cough (CIC) (Example 5). The pharmacokinetic parameters
in subjects administered PA101 (with mannitol) and PA101-B (without
mannitol) are expected to be similar in subjects with chronic cough
associated with IPF.
Example 7: Stability of Cromolyn Sodium Formulations
[0416] The compositions and formulations of the disclosure are both
physically and chemically stable.
[0417] As shown by the physical appearance, Table 41 demonstrates
that each formulation remains clear, and, therefore, free of any
precipitate, from manufacture through the 24 month time point (i.e.
for at least 24 months) when the formulations are stored at
25.degree. C. As shown by the physical appearance, Table 42
demonstrates that each formulation remains clear, and, therefore,
free of any precipitate, from manufacture through the 24 month time
point (i.e. for at least 24 months) when the formulations are
stored at 40.degree. C.
[0418] As shown by the chemical measures of pH and osmolality,
Table 41 demonstrates that each formulation maintains consistent
appearance, pH, osmolality assay and related substances from
manufacture through the 24 month time point (i.e. for at least 24
months) when the formulations are stored at 25.degree. C. As shown
by the chemical measures of pH and osmolality, Table 42
demonstrates that each formulation maintains consistent appearance,
pH, osmolality, assay and related substances from manufacture
through the 6 month time point (i.e. for at least 6 months) when
the formulations are stored at 40.degree. C.
TABLE-US-00044 TABLE 41 Stability data at 25.degree. C. Stability
Duration T0 3 months 6 months 9 months 12 months 18 months 24
months Appearance PA101, 20 mg/mL Clear Clear Clear Clear Clear
PA101, 40 mg/mL Clear Clear Clear Clear Clear Clear PA101B, 10
mg/mL Clear Clear Clear Clear Clear Clear PA101B, 20 mg/mL Clear
Clear Clear Clear Clear Clear PA101B, 40 mg/mL Clear Clear Clear
Clear Clear Clear Clear PA101B, 60 mg/mL Clear Clear Clear Clear
Clear Clear KM104, 60 mg/mL Clear Clear Clear Clear Clear pH PA101,
20 mg/mL 5.3 5.6 5.5 5.8 5.8 PA101, 40 mg/mL 5.4 5.7 5.5 5.9 5.7
5.8 PA101B, 10 mg/mL 5.5 6.1 5.9 5.7 5.4 6.2 PA101B, 20 mg/mL 5.7
6.2 5.7 5.8 5.4 6 PA101B, 40 mg/mL 5.5 6 6 5.8 5.9 6.32 5.94
PA101B, 60 mg/mL 5.2 5.3 5.4 5.5 5.6 5.6 KM104, 60 mg/mL 5.6 5.6
5.8 5.9 5.8 Osmolality PA101, 20 mg/mL 195 192 194 196 195
(mOsm/kg) PA101, 40 mg/mL 204 202 203 206 205 204 PA101B, 10 mg/mL
106 108 105 106 105 110 PA101B, 20 mg/mL 117 114 117 117 116 124
PA101B, 40 mg/mL 126 126 127 126 128 125 126 PA101B, 60 mg/mL 138
138 138 142 N/A 144 KM104, 60 mg/mL 294 288 291 289 291 Assay
PA101, 20 mg/mL 101.8 103.6 102.6 102.6 104.6 (% Label PA101, 40
mg/mL 102.4 102.6 101.8 96.9 100.6 104.3 claim) PA101B, 10 mg/mL
98.9 102.2 102.2 100.8 101.2 96.7 PA101B, 20 mg/mL 98.1 101.7 98.7
100.2 99.1 96.6 PA101B, 40 mg/mL 97.3 99.2 101.1 103.7 100.7 98.9
101.6 PA101B, 60 mg/mL 98.7 100.8 100.7 101.8 99.9 102.2 KM104, 60
mg/mL 100 100.4 98.7 101.1 100.8 Related PA101, 20 mg/mL 0.11 0.11
0.11 0.11 <LOD substance PA101, 40 mg/mL 0.11 0.11 0.11 0.11
<LOD <LOD (% total) PA101B, 10 mg/mL 0.11 <LOD N/A <LOD
<LOD <LOD PA101B, 20 mg/mL 0.11 <LOD <LOD <LOD
<LOD <LOD PA101B, 40 mg/mL 0.11 0.11 <LOD <LOD <LOD
<LOD <LOD PA101B, 60 mg/mL 0.1 0.1 0.1 0.1 0.1 0.1 KM104, 60
mg/mL 0.1 0.1 0.1 0.2 <LOD
TABLE-US-00045 TABLE 42 Stability at 40.degree. C. Stability
Duration T0 1 month 2 months 3 months 6 months Appearance PA101, 20
mg/mL Clear Clear Clear PA101, 40 mg/mL Clear Clear Clear PA101B,
10 mg/mL Clear Clear Clear Clear Clear PA101B, 20 mg/mL Clear Clear
Clear Clear Clear PA101B, 40 mg/mL Clear Clear Clear Clear Clear
KM104, 60 mg/mL Clear Clear Clear Clear* pH PA101, 20 mg/mL 5.3 5.6
5.8 5.6 PA101, 40 mg/mL 5.4 5.6 5.8 5.7 PA101B, 10 mg/mL 5.5 5.9
6.4 6.1 5.6 PA101B, 20 mg/mL 5.7 5.9 5.8 6.3 5.9 PA101B, 40 mg/mL
5.5 6.0 5.9 5.8 5.9 KM104, 60 mg/mL 5.6 5.5 5.6 5.7* Osmolality
PA101, 20 mg/mL 195 206 193 192 mOsm/kg PA101, 40 mg/mL 204 206 203
205 PA101B, 10 mg/mL 106 108 107 109 105 PA101B, 20 mg/mL 117 117
117 118 117 PA101B, 40 mg/mL 126 127 128 126 128 KM104, 60 mg/mL
294 293 288 292* Assay PA101, 20 mg/mL 101.8 102.9 102.9 102.7 (%
Label PA101, 40 mg/mL 102.4 102.9 102.5 101.4 claim) PA101B, 10
mg/mL 98.9 98.9 98.9 100.3 103.6 PA101B, 20 mg/mL 98.1 98.5 98.8
100.2 98.1 PA101B, 40 mg/mL 97.3 98.0 98.9 99.2 101.8 KM104, 60
mg/mL 100 100.1 99.8 99.5 Related PA101, 20 mg/mL 0.11 0.11 0.11
0.11 substance PA101, 40 mg/mL 0.11 0.11 0.11 0.11 (% total)
PA101B, 10 mg/mL 0.11 0.11 <LOD <LOD <LOD PA101B, 20 mg/mL
0.11 0.11 <LOD <LOD <LOD PA101B, 40 mg/mL 0.11 0.1 0.11
0.11 <LOD KM104, 60 mg/mL 0.11 <LOD 0.11 0.11* *KM104 data
are at 13 months duration
INCORPORATION BY REFERENCE
[0419] Every document cited herein, including any cross referenced
or related patent or application is hereby incorporated herein by
reference in its entirety unless expressly excluded or otherwise
limited. The citation of any document is not an admission that it
is prior art with respect to any invention disclosed or claimed
herein or that it alone, or in any combination with any other
reference or references, teaches, suggests or discloses any such
invention. Further, to the extent that any meaning or definition of
a term in this document conflicts with any meaning or definition of
the same term in a document incorporated by reference, the meaning
or definition assigned to that term in this document shall
govern.
Other Embodiments
[0420] While particular embodiments of the disclosure have been
illustrated and described, various other changes and modifications
can be made without departing from the spirit and scope of the
disclosure. The scope of the appended claims includes all such
changes and modifications that are within the scope of this
disclosure.
* * * * *