U.S. patent application number 15/493554 was filed with the patent office on 2017-12-07 for methods of treating lung infection with caspofungin.
The applicant listed for this patent is TRILOGY THERAPEUTICS, INC.. Invention is credited to David M. RYCKMAN, Iching G. YU.
Application Number | 20170348378 15/493554 |
Document ID | / |
Family ID | 58100696 |
Filed Date | 2017-12-07 |
United States Patent
Application |
20170348378 |
Kind Code |
A1 |
RYCKMAN; David M. ; et
al. |
December 7, 2017 |
METHODS OF TREATING LUNG INFECTION WITH CASPOFUNGIN
Abstract
Methods for the treatment and/or prevention of a fungal
infection in the pulmonary system of a subject in need thereof with
caspofungin or a derivative thereof are disclosed herein.
Inventors: |
RYCKMAN; David M.; (San
Diego, CA) ; YU; Iching G.; (San Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
TRILOGY THERAPEUTICS, INC. |
San Diego |
CA |
US |
|
|
Family ID: |
58100696 |
Appl. No.: |
15/493554 |
Filed: |
April 21, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15241645 |
Aug 19, 2016 |
9675659 |
|
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15493554 |
|
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62208396 |
Aug 21, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 38/08 20130101;
A61K 9/0075 20130101; A61P 31/06 20180101; A61P 11/00 20180101;
A61K 9/0078 20130101 |
International
Class: |
A61K 38/08 20060101
A61K038/08; A61K 9/00 20060101 A61K009/00 |
Claims
1-29. (canceled)
30. A kit comprising: a composition suitable for administration via
inhalation, wherein the composition comprises caspofungin, or a
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof, and wherein the composition is an aqueous solution
essentially free of mannitol; and an inhalation device; wherein the
composition is administered as droplets or particles having a mass
median aerodynamic diameter (MMAD) from about 0.5 .mu.m to about 10
.mu.m.
31. The kit of claim 30, wherein the composition is essentially
free of sugar alcohol.
32. The kit of claim 30, wherein the composition is essentially
free of sugar alcohol or sugar.
33. The kit of claim 30, wherein the pharmaceutically acceptable
salt of caspofungin is an acetate salt.
34. The kit of claim 30, wherein the administration of the
composition provides a lung tissue concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof that is from about 1-fold to about 100-fold greater
than intravenous administration at the same delivery dose.
35. The kit of claim 34, wherein the lung tissue concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof is greater than intravenous
administration at the same delivery dose for about 0.5 hour to
about 168 hours.
36. The kit of claim 30, wherein the administration of the
composition provides a lung tissue concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof that is from about 1-fold to about 50-fold greater
than intravenous administration at the same delivery dose.
37. The kit of claim 36, wherein the lung tissue concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof is greater than intravenous
administration at the same delivery dose for about 0.5 hour to
about 168 hours.
38. The kit of claim 30, wherein the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
1000-fold greater than a concentration of capsofungin or the
polymorph, the pharmaceutically acceptable salt, hydrate, or
solvate thereof in the liver, kidney, spleen, pancreas or
plasma.
39. The kit of claim 38, wherein the concentration of caspofungin
or the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung is greater than a concentration of
capsofungin or the polymorph, the pharmaceutically acceptable salt,
hydrate, or solvate thereof in the liver, kidney, spleen, pancreas
or plasma for about 0.5 hour to about 168 hours.
40. The kit of claim 30, wherein the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
150-fold greater than a concentration of capsofungin or the
polymorph, the pharmaceutically acceptable salt, hydrate, or
solvate thereof in the liver, kidney, spleen, pancreas or
plasma.
41. The kit of claim 40, wherein the concentration of caspofungin
or the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung is greater than the concentration of
capsofungin or the polymorph, the pharmaceutically acceptable salt,
hydrate, or solvate thereof in the liver, kidney, spleen, pancreas
or plasma for about 0.5 hour to about 168 hours.
42. The kit of claim 30, wherein the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is above the minimum inhibitory
concentration (MIC) or the minimum effective concentration (MEC)
for about 3 hours after administration.
43. The kit of claim 30, wherein the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is above the minimum inhibitory
concentration (MIC) or the minimum effective concentration (MEC)
for about 12 hours after administration.
44. The kit of claim 30, wherein the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is above the minimum inhibitory
concentration (MIC) or the minimum effective concentration (MEC)
for about 24 hours after administration.
45. The kit of claim 30, wherein the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is above the minimum inhibitory
concentration (MIC) or the minimum effective concentration (MEC)
for about 48 hours after administration.
46. The kit of claim 42, wherein the minimum inhibitory
concentration (MIC) is from about 0.001 .mu.g/mL to about 128
.mu.g/mL.
47. The kit of claim 42, wherein the minimum inhibitory
concentration (MIC) is from about 0.001 .mu.g/mL to about 32
.mu.g/mL.
48. The kit of claim 42, wherein the minimum effective
concentration (MEC) is from about 0.001 .mu.g/mL to about 128
.mu.g/mL.
49. The kit of claim 42, wherein the minimum inhibitory
concentration (MEC) is from about 0.001 .mu.g/mL to about 32
.mu.g/mL.
50. The kit of claim 30, wherein the inhalation device is selected
from a jet nebulizer, ultrasonic wave nebulizer, high efficiency
nebulizer, heat vaporizer, soft mist inhaler, thermal aerosol
inhaler, and electrohydrodynamic-based solution misting
inhaler.
51. The kit of claim 30, wherein the composition is administered as
droplets or particles having a mass median aerodynamic diameter
(MMAD) from about 1 .mu.m to about 5 .mu.m.
52. The kit of claim 30, wherein the half-life of the caspofungin,
or a polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung is about 1 hour to about 50 hours.
53. The kit of claim 30, wherein the half-life of the caspofungin,
or a polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung is about 20 hours to about 50
hours.
54. The kit of claim 30, wherein the composition is stable from at
about -20.degree. C. to about 25.degree. C.
55. The kit of claim 30, wherein the composition is stable for at
least about 6 months.
56. The kit of claim 30, wherein the composition has a pH from
about 4.0 to about 7.5.
57. The kit of claim 30, wherein the kit is for treating a fungal
infection caused by Candida sp., and/or by Aspergillus sp., and/or
by Pneumocystis jirovecii.
Description
CROSS REFERENCE
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/241,645, filed Aug. 19, 2016, which claims
the benefit of U.S. Provisional Application No. 62/208,396, filed
Aug. 21, 2015, each of which are hereby incorporated by reference
in their entirety.
BACKGROUND
[0002] A pulmonary infection caused by Aspergillus species is a
serious invasive infection that usually occurs in people with
compromised immune systems due to cancer, AIDS, leukemia, an organ
transplant, chemotherapy, or other conditions or medications that
lower the number or function of normal white blood cells or weaken
the immune system. The usual course of treatment requires the
intravenous or oral use of antifungal agents.
SUMMARY OF THE DISCLOSURE
[0003] Provided herein is a method of preventing or treating a
fungal infection in the pulmonary system of a subject in need
thereof comprising administering to the subject an inhalation
composition comprising caspofungin, or a polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof,
wherein the inhalation composition is essentially free of
mannitol.
[0004] In some embodiments, the inhalation composition is
essentially free of sugar alcohol. In some embodiments, the
inhalation composition is essentially free of sugar alcohol or
sugar. In some embodiments, the pharmaceutically acceptable salt of
caspofungin is the acetate.
[0005] In some embodiments, the administration of the inhalation
composition provides a lung tissue concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof that is from about 1-fold to about 100-fold greater
than the concentration in the lung via intravenous administration
at the same delivery dose. In some embodiments, the administration
of the inhalation composition provides a lung tissue concentration
of caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof that is from about 1-fold to about
50-fold greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the inhalation composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is about 1-fold
greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the inhalation composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is about 10-fold
greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the inhalation composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is about 20-fold
greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the inhalation composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is about 30-fold
greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the inhalation composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is about 40-fold
greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the inhalation composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is about 50-fold
greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the inhalation composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is about 60-fold
greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the inhalation composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is about 70-fold
greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the inhalation composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is about 80-fold
greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the inhalation composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is about 90-fold
greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the inhalation composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is about 100-fold
greater than the concentration in the lung via intravenous
administration at the same delivery dose.
[0006] In some embodiments, the lung tissue concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof is greater than the concentration in
the lung via intravenous administration at the same delivery dose
for about 0.5 hour to about 168 hours.
[0007] In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
1000-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the inhalation composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 150-fold greater than the concentration in the
liver, kidney, spleen, pancreas or plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 1-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the inhalation composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is about 2-fold
greater than the concentration in the liver, kidney, spleen,
pancreas or plasma. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung that is about 3-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is about 4-fold greater than the concentration in the
liver, kidney, spleen, pancreas or plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 5-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the inhalation composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is about 10-fold
greater than the concentration in the liver, kidney, spleen,
pancreas or plasma. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung that is about 15-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is about 20-fold greater than the concentration in
liver, kidney, spleen, pancreas or plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 50-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the inhalation composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is about 70-fold
greater than the concentration in the liver, kidney, spleen,
pancreas or plasma. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung that is about 100-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is about 500-fold greater than the concentration in
the liver, kidney, spleen, pancreas or plasma. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 1000-fold greater than the concentration in the liver,
kidney, spleen, pancreas or plasma.
[0008] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the liver,
kidney, spleen, pancreas or plasma for about 0.5 hour to about 168
hours.
[0009] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is above the minimum inhibitory concentration
(MIC) or the minimum effective concentration (MEC) for about 3
hours after administration. In some embodiments, the concentration
of caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is above the minimum
inhibitory concentration (MIC) or the minimum effective
concentration (MEC) for about 6 hours after administration. In some
embodiments, the concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung is above the minimum inhibitory concentration (MIC) or the
minimum effective concentration (MEC) for about 12 hours after
administration. In some embodiments, the concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is above the minimum
inhibitory concentration (MIC) or the minimum effective
concentration (MEC) for about 24 hours after administration. In
some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is above the minimum inhibitory concentration
(MIC) or the minimum effective concentration (MEC) for about 48
hours after administration. In some embodiments, the concentration
of caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is above the minimum
inhibitory concentration (MIC) or the minimum effective
concentration (MEC) for about 72 hours after administration. In
some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is above the minimum inhibitory concentration
(MIC) or the minimum effective concentration (MEC) for about 96
hours after administration. In some embodiments, the concentration
of caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is above the minimum
inhibitory concentration (MIC) or the minimum effective
concentration (MEC) for about 120 hours after administration. In
some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is above the minimum inhibitory concentration
(MIC) or the minimum effective concentration (MEC) for about 168
hours after administration. In some embodiments, the concentration
of caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is above the minimum
inhibitory concentration (MIC) or the minimum effective
concentration (MEC) for about 336 hours after administration.
[0010] In some embodiments, the minimum inhibitory concentration
(MIC) is from about 0.001 .mu.g/mL to about 128 .mu.g/mL. In some
embodiments, the minimum inhibitory concentration (MIC) is from
about 0.001 .mu.g/mL to about 32 .mu.g/mL. In some embodiments, the
minimum inhibitory concentration (MIC) is from about 0.001 .mu.g/mL
to about 16 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is from about 0.125 .mu.g/mL to about 128
.mu.g/mL. In some embodiments, the minimum inhibitory concentration
(MIC) is from about 0.125 .mu.g/mL to about 32 .mu.g/mL. In some
embodiments, the minimum inhibitory concentration (MIC) is from
about 0.25 .mu.g/mL to about 16 .mu.g/mL. In some embodiments, the
minimum inhibitory concentration (MIC) is from about 0.25 .mu.g/mL
to about 32 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is from about 16 .mu.g/mL to about 128
.mu.g/mL. In some embodiments, the minimum inhibitory concentration
(MIC) is about 0.001 .mu.g/mL. In some embodiments, the minimum
inhibitory concentration (MIC) is about 0.005 .mu.g/mL. In some
embodiments, the minimum inhibitory concentration (MIC) is about
0.010 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is about 0.015 .mu.g/mL. In some embodiments,
the minimum inhibitory concentration (MIC) is about 0.020 .mu.g/mL.
In some embodiments, the minimum inhibitory concentration (MIC) is
about 0.030 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is about 0.040 .mu.g/mL. In some embodiments,
the minimum inhibitory concentration (MIC) is about 0.050 .mu.g/mL.
In some embodiments, the minimum inhibitory concentration (MIC) is
about 0.060 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is about 0.100 .mu.g/mL. In some embodiments,
the minimum inhibitory concentration (MIC) is about 0.125 .mu.g/mL.
In some embodiments, the minimum inhibitory concentration (MIC) is
about 0.25 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is about 0.30 .mu.g/mL. In some embodiments,
the minimum inhibitory concentration (MIC) is about 0.50 .mu.g/mL.
In some embodiments, the minimum inhibitory concentration (MIC) is
about 0.75 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is about 1.00 .mu.g/mL. In some embodiments,
the minimum inhibitory concentration (MIC) is about 2.00 .mu.g/mL.
In some embodiments, the minimum inhibitory concentration (MIC) is
about 4.00 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is about 8.00 .mu.g/mL. In some embodiments,
the minimum inhibitory concentration (MIC) is about 16.00 .mu.g/mL.
In some embodiments, the minimum inhibitory concentration (MIC) is
about 32.00 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is about 128.00 .mu.g/mL.
[0011] In some embodiments, the minimum effective concentration
(MEC) is from about 0.001 .mu.g/mL to about 128 .mu.g/mL. In some
embodiments, the minimum effective concentration (MEC) is from
about 0.001 .mu.g/mL to about 32 .mu.g/mL. In some embodiments, the
minimum effective concentration (MEC) is from about 0.001 .mu.g/mL
to about 16 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is from about 0.001 .mu.g/mL to about 0.6
.mu.g/mL. In some embodiments, the minimum effective concentration
(MEC) is from about 0.008 .mu.g/mL to about 0.6 .mu.g/mL. In some
embodiments, the minimum effective concentration (MEC) is about
0.001 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 0.005 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 0.010 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 0.015 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 0.020 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 0.030 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 0.040 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 0.050 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 0.060 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 0.100 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 0.125 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 0.250 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 0.300 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 0.500 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 0.75 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 1.00 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 2.00 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 4.00 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 8.00 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 16.00 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 32.00 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 128.00 .mu.g/mL.
[0012] In some embodiments, the inhalation composition is
administered with an inhalation device selected from a jet
nebulizer, ultrasonic wave nebulizer, high efficiency nebulizer,
heat vaporizer, soft mist inhaler, thermal aerosol inhaler, or
electrohydrodynamic-based solution misting inhaler. In some
embodiments, the inhalation device is a jet nebulizer. In some
embodiments, the inhalation device is an ultrasonic wave
nebulizer.
[0013] In some embodiments, the inhalation composition is
administered by the inhalation device as droplets or particles
having a mass median aerodynamic diameter (MMAD) from about 1 .mu.m
to about 10 .mu.m. In some embodiments, the inhalation composition
is administered by the inhalation device as droplets or particles
having a mass median aerodynamic diameter (MMAD) from about 1 .mu.m
to about 5 .mu.m. In some embodiments, the inhalation composition
is administered by the inhalation device as droplets or particles
having a mass median aerodynamic diameter (MMAD) from about 2 .mu.m
to about 3 .mu.m. In some embodiments, the half-life of the
caspofungin, or a polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is about 1 hour to about 50
hours. In some embodiments, the half-life of the caspofungin, or a
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is about 20 hours to about 50 hours.
[0014] In some embodiments, the inhalation composition is stable
from at about -20.degree. C. to about 25.degree. C. In some
embodiments, the inhalation composition is stable from at about
5.degree. C. to about 25.degree. C. In some embodiments, the
inhalation composition is stable at about 25.degree. C. In some
embodiments, the inhalation composition is stable for at least
about 6 months to about 2 years. In some embodiments, the
inhalation composition has a pH from about 4.0 to about 7.5. In
some embodiments, the inhalation composition has a pH from about
4.0 to about 8.5. In some embodiments, the inhalation composition
has a pH from about 5.0 to about 8.5. In some embodiments, the
inhalation composition has a pH from about 6.0 to about 7.5. In
some embodiments, the inhalation composition has a pH from about
7.0 to about 7.5.
[0015] In some embodiments, the method is for treating a fungal
infection caused by Candida sp., and/or by Aspergillus sp., and/or
by Pneumocystis jirovecii. In some embodiments, the method is for
treating a fungal infection caused by Candida albicans, Candida
tropicalis, Candida krusei, or Candida glabrata. In some
embodiments, the method is for treating a fungal infection caused
by Aspergillus fumigatus, Aspergillus flavus, or Aspergillus niger.
In some embodiments, the method is for preventing a fungal
infection caused by Candida sp., and/or by Aspergillus sp., and/or
by Pneumocystis jirovecii. In some embodiments, the method is for
preventing a fungal infection caused by Candida albicans, Candida
tropicalis, Candida krusei, or Candida glabrata. In some
embodiments, the method is for preventing a fungal infection caused
by Aspergillus fumigatus, Aspergillus flavus, or Aspergillus
niger.
[0016] In some embodiments, the subject is immunocompromised. In
some embodiments, the subject is a transplant recipient or a
subject undergoing cancer chemotherapy. In some embodiments, the
subject is a recipient of a hematopoietic stem-cell transplant,
bone marrow transplant, lung transplant, liver transplant, heart
transplant, kidney transplant, pancreas transplant or a combination
thereof.
[0017] Also provided here is a kit comprising: a composition
suitable for administration via inhalation, wherein the composition
comprises caspofungin, or a polymorph, pharmaceutically acceptable
salt, hydrate, or solvate thereof, and wherein the composition is
essentially free of mannitol; and an inhalation device. In some
embodiments, the administration of the composition provides a lung
tissue concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof that
is from about 1-fold to about 100-fold greater than the
concentration in the lung via intravenous administration at the
same delivery dose. In some embodiments, the administration of the
inhalation composition provides a lung tissue concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof that is from about 1-fold to about
50-fold greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is about 1-fold
greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is about 10-fold
greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is about 20-fold
greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is about 30-fold
greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is about 40-fold
greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is about 50-fold
greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is about 60-fold
greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is about 70-fold
greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is about 80-fold
greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is about 90-fold
greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is about 100-fold
greater than the concentration in the lung via intravenous
administration at the same delivery dose.
[0018] In some embodiments, the lung tissue concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof is greater than the concentration in
the lung via intravenous administration at the same delivery dose
for about 0.5 hour to about 168 hours.
[0019] In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 1000-fold
greater than the concentration in the liver, kidney, spleen,
pancreas or plasma. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung that is from about 1-fold greater to
about 150-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is about 1-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 2-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is about 3-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 4-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is about 5-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 10-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is about 15-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 20-fold greater than the concentration in liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is about 50-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 70-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is about 100-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 500-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the inhalation composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is about 1000-fold
greater than the concentration in the liver, kidney, spleen,
pancreas or plasma
[0020] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the liver,
kidney, spleen, pancreas or plasma for about 0.5 hour to about 168
hours.
[0021] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is above the minimum inhibitory concentration
(MIC) or the minimum effective concentration (MEC) for about 3
hours after administration. In some embodiments, the concentration
of caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is above the minimum
inhibitory concentration (MIC) or the minimum effective
concentration (MEC) for about 6 hours after administration. In some
embodiments, the concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung is above the minimum inhibitory concentration (MIC) or the
minimum effective concentration (MEC) for about 12 hours after
administration. In some embodiments, the concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is above the minimum
inhibitory concentration (MIC) or the minimum effective
concentration (MEC) for about 24 hours after administration. In
some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is above the minimum inhibitory concentration
(MIC) or the minimum effective concentration (MEC) for about 48
hours after administration. In some embodiments, the concentration
of caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is above the minimum
inhibitory concentration (MIC) or the minimum effective
concentration (MEC) for about 72 hours after administration. In
some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is above the minimum inhibitory concentration
(MIC) or the minimum effective concentration (MEC) for about 96
hours after administration. In some embodiments, the concentration
of caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is above the minimum
inhibitory concentration (MIC) or the minimum effective
concentration (MEC) for about 120 hours after administration. In
some embodiments the concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung is above the minimum inhibitory concentration (MIC) or the
minimum effective concentration (MEC) for about 168 hours after
administration. In some embodiments, the concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is above the minimum
inhibitory concentration (MIC) or the minimum effective
concentration (MEC) for about 336 hours after administration.
[0022] In some embodiments, the minimum inhibitory concentration
(MIC) is from about 0.001 .mu.g/mL to about 128 .mu.g/mL. In some
embodiments, the minimum inhibitory concentration (MIC) is from
about 0.001 .mu.g/mL to about 32 .mu.g/mL. In some embodiments, the
minimum inhibitory concentration (MIC) is from about 0.001 .mu.g/mL
to about 16 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is from about 0.125 .mu.g/mL to about 128
.mu.g/mL. In some embodiments, the minimum inhibitory concentration
(MIC) is from about 0.125 .mu.g/mL to about 32 .mu.g/mL. In some
embodiments, the minimum inhibitory concentration (MIC) is from
about 0.25 .mu.g/mL to about 16 .mu.g/mL. In some embodiments, the
minimum inhibitory concentration (MIC) is from about 0.25 .mu.g/mL
to about 32 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is from about 16 .mu.g/mL to about 128
.mu.g/mL. In some embodiments, the minimum inhibitory concentration
(MIC) is about 0.001 .mu.g/mL. In some embodiments, the minimum
inhibitory concentration (MIC) is about 0.005 .mu.g/mL. In some
embodiments, the minimum inhibitory concentration (MIC) is about
0.010 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is about 0.015 .mu.g/mL. In some embodiments,
the minimum inhibitory concentration (MIC) is about 0.020 .mu.g/mL.
In some embodiments, the minimum inhibitory concentration (MIC) is
about 0.030 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is about 0.040 .mu.g/mL. In some embodiments,
the minimum inhibitory concentration (MIC) is about 0.050 .mu.g/mL.
In some embodiments, the minimum inhibitory concentration (MIC) is
about 0.060 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is about 0.100 .mu.g/mL. In some embodiments,
the minimum inhibitory concentration (MIC) is about 0.125 .mu.g/mL.
In some embodiments, the minimum inhibitory concentration (MIC) is
about 0.25 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is about 0.30 .mu.g/mL. In some embodiments,
the minimum inhibitory concentration (MIC) is about 0.50 .mu.g/mL.
In some embodiments, the minimum inhibitory concentration (MIC) is
about 0.75 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is about 1.00 .mu.g/mL. In some embodiments,
the minimum inhibitory concentration (MIC) is about 2.00 .mu.g/mL.
In some embodiments, the minimum inhibitory concentration (MIC) is
about 4.00 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is about 8.00 .mu.g/mL. In some embodiments,
the minimum inhibitory concentration (MIC) is about 16.00 .mu.g/mL.
In some embodiments, the minimum inhibitory concentration (MIC) is
about 32.00 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is about 128.00 .mu.g/mL.
[0023] In some embodiments, the minimum effective concentration
(MEC) is from about 0.001 .mu.g/mL to about 128 .mu.g/mL. In some
embodiments, the minimum effective concentration (MEC) is from
about 0.001 .mu.g/mL to about 32 .mu.g/mL. In some embodiments, the
minimum effective concentration (MEC) is from about 0.001 .mu.g/mL
to about 16 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is from about 0.001 .mu.g/mL to about 0.6
.mu.g/mL. In some embodiments, the minimum effective concentration
(MEC) is from about 0.008 .mu.g/mL to about 0.6 .mu.g/mL. In some
embodiments, the minimum effective concentration (MEC) is about
0.001 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 0.005 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 0.010 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 0.015 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 0.020 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 0.030 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 0.040 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 0.050 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 0.060 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 0.100 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 0.125 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 0.250 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 0.300 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 0.500 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 0.75 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 1.00 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 2.00 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 4.00 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 8.00 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 16.00 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 32.00 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 128.00 .mu.g/mL.
[0024] In some embodiments, the inhalation device selected from a
jet nebulizer, ultrasonic wave nebulizer, high efficiency
nebulizer, heat vaporizer, soft mist inhaler, thermal aerosol
inhaler, or electrohydrodynamic-based solution misting inhaler. In
some embodiments, the inhalation device is a jet nebulizer. In some
embodiments, the inhalation device is an ultrasonic wave
nebulizer.
[0025] In some embodiments, the composition is capable of being
administered by the inhalation device as droplets or particles
having a mass median aerodynamic diameter (MMAD) of about 1 .mu.m
to about 10 .mu.m. In some embodiments, the composition is capable
of being administered by the inhalation device as droplets or
particles having a mass median aerodynamic diameter (MMAD) of about
1 .mu.m to about 5 .mu.m. In some embodiments, the composition is
capable of being administered by the inhalation device as droplets
or particles having a mass median aerodynamic diameter (MMAD) of
about 2 .mu.m to about 3 .mu.m. In some embodiments, the half-life
of the caspofungin, or a polymorph, pharmaceutically acceptable
salt, hydrate, or solvate thereof in the lung is about 1 hour to
about 50 hours. In some embodiments, the half-life of the
caspofungin, or a polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is about 20 hours to about
50 hours.
[0026] In some embodiments, the inhalation composition is stable
from at about -20.degree. C. to about 25.degree. C. In some
embodiments, the composition is stable from at about 5.degree. C.
to about 25.degree. C. In some embodiments, the composition is
stable at about 25.degree. C. In some embodiments, the composition
is stable for at least about 6 months to about 2 years. In some
embodiments, the composition has a pH from about 4.0 to about 7.5.
In some embodiments, the composition has a pH from about 4.0 to
about 8.5. In some embodiments, the composition has a pH from about
5.0 to about 8.5. In some embodiments, the composition has a pH
from about 6.0 to about 7.5. In some embodiments, the composition
has a pH from about 7.0 to about 7.5.
[0027] In some embodiments, the kit is used for preventing or
treating a fungal infection in the pulmonary system of a subject.
In some embodiments, the kit is used for preventing a fungal
infection in the pulmonary system of a subject. In some
embodiments, the kit is used for treating a fungal infection in the
pulmonary system of a subject.
INCORPORATION BY REFERENCE
[0028] All publications, patents, and patent applications mentioned
in this specification are herein 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.
BRIEF DESCRIPTION OF THE DRAWINGS
[0029] The novel features of the disclosure are set forth with
particularity in the appended claims. A better understanding of the
features and advantages of the present disclosure will be obtained
by reference to the following detailed description that sets forth
illustrative embodiments, in which the principles of the disclosure
are utilized, and the accompanying drawings of which:
[0030] FIG. 1 shows the pharmacokinetics of caspofungin in rat
plasma when delivered intravenously (dashed line) or via inhalation
(solid line) at 2 mg/kg.
[0031] FIG. 2 shows the pharmacokinetics of caspofungin in rat
plasma when delivered intravenously (dashed line) or via inhalation
(solid line) at 2 mg/kg.
[0032] FIG. 3 shows the pharmacokinetics of caspofungin in rat lung
tissue when delivered intravenously (dashed line) or via inhalation
(solid line) at 2 mg/kg.
[0033] FIG. 4 shows the pharmacokinetics of caspofungin in rat
kidney tissue when delivered intravenously (dashed line) or via
inhalation (solid line) at 2 mg/kg.
[0034] FIG. 5 shows the pharmacokinetics of caspofungin in rat
liver tissue when delivered intravenously (dashed line) or via
inhalation (solid line) at 2 mg/kg.
[0035] FIG. 6 shows the relative weekly exposure per tissue,
Inhaled vs IV, from a single 2 mg/kg dose--a ratio of the 7 day AUC
for the inhaled route of delivery compared to the 7 day AUC for
intravenous administration.
DETAILED DESCRIPTION OF THE DISCLOSURE
[0036] While preferred embodiments of the present disclosure have
been shown and described herein, it will be obvious to those
skilled in the art that such embodiments are provided by way of
example only. Numerous variations, changes, and substitutions will
now occur to those skilled in the art without departing from the
present disclosure. It should be understood that various
alternatives to the embodiments of the present disclosure described
herein may be employed. It is intended that the following claims
define the scope of the present disclosure and that methods and
structures within the scope of these claims and their equivalents
be covered thereby.
[0037] 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 present disclosure 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.
[0038] The section headings used herein are for organizational
purposes only and are not to be construed as limiting the subject
matter described. All documents, or portions of documents, cited in
the application including, without limitation, patents, patent
applications, articles, books, manuals, and treatises are hereby
expressly incorporated by reference in their entirety for any
purpose.
[0039] Pulmonary fungal infections are serious infections that
usually occur in patients with compromised immune systems and lead
to significant mortality and morbidity in such patients. The
standard course of treatment requires the administration of
antifungal agents intravenously or orally; however, such systemic
delivery is associated with numerous side effects, ranging from
phlebitis at the infusion site and chills to renal toxicity. The
aerosolized delivery of antifungal agents is an attractive
alternative for the prevention and treatment of pulmonary fungal
lung infections because it allows for the concentrated delivery of
the anti-fungal agent directly to the site of infection with
minimal systemic exposure, thus limiting the potential side effects
usually associated with intravenous delivery.
[0040] The antifungal agent caspofungin is an attractive candidate
for aerosolized antifungal therapy. Caspofungin, a macrocyclic
lipopeptide, is a member of a class of antifungal agents known as
echinocandins, which inhibit the synthesis of glucan in the fungal
cell wall through the noncompetitive inhibition of 1,343 glucan
synthesis. Caspofungin has significant activity against fungal
infections caused by the Candida species, Aspergillus species and
Pneumocystis carinii pneumonia. Furthermore, caspofungin is
relatively less toxic than other antifungal agents that are
commonly employed for anti-fungal treatment, such as amphotericin
B. Despite these advantages, there are no commercially available
aerosol formulations of caspofungin for the prevention and/or
treatment of antifungal infections.
[0041] The commercial formulation of caspofungin is a lyophilized,
diacetate salt containing sucrose, mannitol, glacial acetic acid
and sodium hydroxide and is reconstituted for intravenous use. Sold
by Merck & Company, Inc under the trade name Cancidas.RTM.,
caspofungin is the first member of the echinocandins to receive US
Food and Drug Administration and has been approved for the
treatment of invasive aspergillosis in patients who are refractory
to or intolerant of other therapies; the empirical therapy for
presumed fungal infections in febrile, neutropenic patients; the
treatment of candidemia; intra-abdominal abscesses, peritonitis and
pleural space infections caused by candida infections, and the
treatment of esophageal candidiasis.
[0042] One challenge in administering caspofungin is that
caspofungin is unstable and prone to degradation, especially at
room temperature (-25.degree. C.). As such, caspofungin is stored
under low temperatures (e.g. 2-8.degree. C.) and is used shortly
after reconstitution. There have been various efforts at developing
caspofungin formulations with improved stability. The development
of the acetate salt of caspofungin, which led to the formulation of
Cancidas.RTM., was an improvement over earlier formulations that
used the tartrate salt (U.S. Pat. No. 5,952,300). Another example
include a formulation that eliminated the acetic acid and sodium
hydroxide present in Cancidas.RTM. as pH modifiers, wherein the
lyophilized and reconstituted formulations demonstrated improved
stabilities at 25.degree. C. when compared to the conventional
formulations of caspofungin (U.S. Patent Publication 2009/0170753).
In another example, a non-reducible sugar, such as trehalose, was
used to replace the sucrose and mannitol present in the
Cancidas.RTM. to provide formulations that have improved storage
stability (US Patent Publication 2010/0137197).
[0043] Described herein are methods of treating and/or preventing
fungal infections in the pulmonary system in a subject in need
thereof comprising administering to the subject a composition
caspofungin, or a polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof. In some embodiments, the composition
is essentially free of mannitol. In some embodiments, the
composition is essentially free of sugar alcohol. In some
embodiments, the composition is essentially free of sugar alcohol
or sugar. In some embodiments, the composition further comprises an
anti-forming agent. The methods described herein allow for the
localized and concentrated delivery the caspofungin, or a
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof directly to the site of infection, the pulmonary tissues,
while minimizing the systemic exposure of caspofungin, or a
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof to other organs.
Echinocandin Tissue Distribution
[0044] There are three echinocandins approved for antifungal
therapy: caspofungin, micafungin and anidulafungin. All of these
compounds are active against a similar range of fungi and are
structurally very similar as they are chemically close analogs.
Despite their structural similarities it is recognized herein that
their distribution and disposition in animals and humans are
markedly different and not predictable. For instance, in rat
studies, anidulafungin rapidly distributes into tissues to achieve
peak concentrations within 30 min and maintains levels above MICs
for common pathogens over 72 hours. Furthermore anidulafungin
exposure is 9-12 fold higher in tissues susceptible to fungal
infection, such as the liver, lung, spleen, kidney, than in plasma
(Damle et al., Pharmacokinetics and Tissue Distribution of
Anidulafungin in Rats, Antimicrob. Agents Chemo., 2008, 52, 7, p
2673-2676). In contrast, in rat studies, micafungin distributes
moderately into the liver, kidney, and lungs, and the tissue
concentrations decrease in parallel with micafungin in plasma.
Micafungin exposures in the liver, kidney, and lung are 1.6, 3.4,
and 2.9 fold higher than that for plasma (Niwa et al., Tissue
Distribution after Intravenous Dosing of Micafungin, an Antifungal
Drug, to Rats. Bio Pharm Bull, 2004, 27, 7, p 1154-1156). It is
clear from these studies that tissue/plasma ratios and, thus, the
overall tissue penetration for micafungin is considerably less than
that observed with anidulafungin.
[0045] Caspofungin's tissue distribution has also been examined in
non-human species using radiolabeled compound caspofungin (Hadju et
al., Preliminary Animal Pharmacokinetics of the Parenteral
Antifungal Agent MK-0991 (L-743,872), Antimicrob. Agents Chemo.,
1997, 41, 11, p 2339-2344; Stone et. al, Disposition of
Caspofungin: Role of Distribution in Determining Pharmacokinetics
in Plasma, Antimicrob. Agents Chemo., 2004, 48, 3, p 815-823; and
Sandhu et al., Disposition of Caspofungin, a Novel Antifungal
Agent, in Mice, Rats, Rabbits, and Monkeys, Antimicrob. Agents
Chemo., 2004, 48, 4, p 1272-1280). However, the use of radiolabeled
material enables the detection of both parent compound and labeled
metabolites, but not the ability to distinguish between them. As
such, the reported quantitation of caspofungin may be all
caspofungin, all metabolites or an unknown mix of the two with the
final case being the most likely scenario. Caspofungin levels in
plasma (but not other tissues) were also analyzed for parent
compound by Sandhu in 2004. The most complete analysis of
caspofungin tissue distribution was published by Stone in 2004 also
using radiolabeled material. Comparing Stone's reported radioactive
plasma distribution with Sandhu's analysis of the parent compound
in plasma it is clear that the parent compound could be 17%, 24% or
even 49% of the reported radiolabeled amount. From these studies,
it is clear that the tissue distribution of caspofungin has not
been determined and is not predictable from comparisons with other
echinocandins.
[0046] Disclosed herein are tissue distribution studies of
caspofungin via intravenous and inhalation administration. The lung
retention and tissue distribution characteristics of caspofungin,
let alone any approved echinocandin, upon inhaled delivery has not
been reported.
Definition of Terms
[0047] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as is commonly understood by one
of skill in the art to which the claimed subject matter belongs. In
the event that there is a plurality of definitions for terms
herein, those in this section prevail.
[0048] It is to be understood that the foregoing general
description and the following detailed description are exemplary
and explanatory only and are not restrictive of any subject matter
claimed. In this application, the use of the singular includes the
plural unless specifically stated otherwise. It must be noted that,
as used in the specification and the appended claims, the singular
forms "a", "an" and "the" include plural referents unless the
context clearly dictates otherwise. It should also be noted that
use of "or" means "and/or" unless stated otherwise. Furthermore,
use of the term "including" as well as other forms, such as
"include", "includes", and "included" is not limiting.
[0049] As used herein, the term "about" is used synonymously with
the term "approximately." Illustratively, the use of the term
"about" with regard to a certain therapeutically effective
pharmaceutical dose indicates that values slightly outside the
cited values, e.g., plus or minus 0.1% to 10%, are also effective
and safe.
[0050] 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 present
disclosure.
[0051] The term "prophylaxis" refers to administration of an active
pharmaceutical ingredient to a patient 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 patient. In
the present context, prophylaxis entails administering caspofungin
or the pharmaceutically acceptable salt thereof to a patient via
any route of administration disclosed herein. Thus, prophylaxis
includes reduction in the occurrence or recurrence rate of a
disorder. However, prophylaxis is not intended to include complete
prevention of onset of a disease state or a condition in a patient
who has not previously been identified as suffering from the
disease or the condition.
[0052] As used herein, a difference is "significant" if a person
skilled in the art would recognize that the difference is probably
real. In some embodiments, significance may be determined
statistically, in which case two measured parameters may be
referred to as statistically significant. In some 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 some 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.
[0053] The term "patient", "subject" or "individual" are used
interchangeably. As used herein, they refer to individuals
suffering from a disorder, and the like, encompasses mammals and
non-mammals. None of the terms require that the individual be under
the care and/or supervision of a medical professional. Mammals are
any member of the Mammalian class, including but not limited to
humans, non-human primates such as chimpanzees, and other apes and
monkey species; farm animals such as cattle, horses, sheep, goats,
swine; domestic animals such as rabbits, dogs, and cats; laboratory
animals including rodents, such as rats, mice and guinea pigs, and
the like. Examples of non-mammals include, but are not limited to,
birds, fish and the like. In some embodiments of the methods and
compositions provided herein, the individual is a mammal. In
preferred embodiments, the individual is a human.
[0054] The terms "treat," "treating" or "treatment," and other
grammatical equivalents as used herein, include alleviating,
abating or ameliorating a disease or condition or one or more
symptoms thereof, preventing additional symptoms, ameliorating or
preventing the underlying metabolic causes of symptoms, inhibiting
the disease or condition, e.g., arresting the development of the
disease or condition, relieving the disease or condition, causing
regression of the disease or condition, relieving a condition
caused by the disease or condition, or stopping the symptoms of the
disease or condition, and are intended to include prophylaxis. The
terms further include achieving a therapeutic benefit and/or a
prophylactic benefit. By therapeutic benefit is meant eradication
or amelioration of the underlying disorder being treated. Also, a
therapeutic benefit is achieved with the eradication or
amelioration of one or more of the physiological symptoms
associated with the underlying disorder such that an improvement is
observed in the individual, notwithstanding that the individual is
still be afflicted with the underlying disorder. For prophylactic
benefit, the compositions are administered to an individual at risk
of developing a particular disease, or to an individual reporting
one or more of the physiological symptoms of a disease, even though
a diagnosis of this disease has not been made.
[0055] The terms "administer," "administering", "administration,"
and the like, as used herein, refer to the methods that may be used
to enable delivery of compounds or compositions to the desired site
of biological action. These methods include, but are not limited to
inhalation routes, oral routes, intraduodenal routes, parenteral
injection (including intravenous, subcutaneous, intraperitoneal,
intramuscular, intravascular or infusion), topical and rectal
administration. Those of skill in the art are familiar with
administration techniques that can be employed with the compounds
and methods described herein. In preferred embodiments, the
compounds and compositions described herein are administered via
inhalation.
[0056] The terms "effective amount", "therapeutically effective
amount" or "pharmaceutically effective amount" as used herein,
refer to a sufficient amount of at least one agent or compound
being administered which will relieve to some extent one or more of
the symptoms of the disease or condition being treated. The result
can be reduction and/or alleviation of the signs, symptoms, or
causes of a disease, or any other desired alteration of a
biological system. For example, an "effective amount" for
therapeutic uses is the amount of the composition comprising a
compound as disclosed herein required to provide a clinically
significant decrease in a disease. An appropriate "effective"
amount may differ from one individual to another. An appropriate
"effective" amount in any individual case may be determined using
techniques, such as a dose escalation study.
[0057] The term "acceptable" as used herein, with respect to a
formulation, composition or ingredient, means having no persistent
detrimental effect on the general health of the individual being
treated.
[0058] The term "minimum inhibitory concentration" or MIC as used
herein, refers to the lowest concentration of an antifungal agent
that will inhibit the visible growth of a microorganism after
overnight incubation.
[0059] The term "minimum effective concentration" or MEC as used
herein, refers to the lowest concentration of an antifungal agent
that causes abnormal hyphal growth, which is characterized by short
abundant branchings.
[0060] The term "pharmaceutically acceptable" as used herein,
refers to a material, such as a carrier or diluent, which does not
abrogate the biological activity or properties of the compounds
described herein, and is relatively nontoxic, i.e., the material
may be administered to an individual without causing undesirable
biological effects or interacting in a deleterious manner with any
of the components of the composition in which it is contained.
[0061] The term "pharmaceutically acceptable salt" as used herein,
refers to salts that retain the biological effectiveness of the
free acids and bases of the specified compound and that are not
biologically or otherwise undesirable. Compounds described herein
may possess acidic or basic groups and therefore may react with any
of a number of inorganic or organic bases, and inorganic and
organic acids, to form a pharmaceutically acceptable salt. These
salts can be prepared in situ during the final isolation and
purification of the compounds of the present disclosure, or by
separately reacting a purified compound in its free base form with
a suitable organic or inorganic acid, and isolating the salt thus
formed.
Methods of Treatment
[0062] Described herein is a method of preventing or treating a
fungal infection in the pulmonary system of a subject in need
thereof comprising administering to the subject a composition
comprising caspofungin, or a polymorph, pharmaceutically acceptable
salt, hydrate, or solvate thereof, wherein the composition is
essentially free of mannitol. Also described herein is a method of
preventing or treating a fungal infection in the pulmonary system
of a subject in need thereof comprising administering to the
subject a composition comprising caspofungin, or a polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof, and
an anti-foaming agent. Further described herein is a method of
preventing or treating a fungal infection in the pulmonary system
of a subject in need thereof comprising administering to the
subject a composition comprising caspofungin, or a polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof, and
an anti-foaming agent, and wherein the composition is essentially
free of mannitol.
Caspofungin
[0063] As used herein, caspofungin (CAS 162808-62-0) refers to the
compound of the following structure:
##STR00001##
Pharmaceutically Acceptable Salts
[0064] The term "pharmaceutically acceptable salt" refers to a form
of a therapeutically active agent that consists of a cationic form
of the therapeutically active agent in combination with a suitable
anion, or in alternative embodiments, an anionic form of the
therapeutically active agent in combination with a suitable cation.
Handbook of Pharmaceutical Salts: Properties, Selection and Use.
International Union of Pure and Applied Chemistry, Wiley-VCH 2002.
S. M. Berge, L. D. Bighley, D. C. Monkhouse, J. Pharm. Sci. 1977,
66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of
Pharmaceutical Salts: Properties, Selection and Use,
Weinheim/Zurich:Wiley-VCH/VHCA, 2002.
[0065] In some embodiments, the compounds described herein exist as
their pharmaceutically acceptable salts. In some embodiments, the
methods disclosed herein include methods of treating diseases by
administering such pharmaceutically acceptable salts. In some
embodiments, the methods disclosed herein include methods of
treating diseases by administering such pharmaceutically acceptable
salts as pharmaceutical compositions.
[0066] In some embodiments, the compounds described herein possess
acidic or basic groups and therefore react with any of a number of
inorganic or organic bases, and inorganic and organic acids, to
form a pharmaceutically acceptable salt. In some embodiments, these
salts are prepared in situ during the final isolation and
purification of the compounds of the present disclosure, or by
separately reacting a purified compound in its free form with a
suitable acid or base, and isolating the salt thus formed.
[0067] Examples of pharmaceutically acceptable salts include those
salts prepared by reaction of the compounds described herein with a
mineral, organic acid or inorganic base, such salts including,
acetate, acrylate, adipate, alginate, aspartate, benzoate,
benzenesulfonate, bisulfate, bisulfite, bromide, butyrate,
butyn-1,4-dioate, camphorate, camphorsulfonate, caproate,
caprylate, chlorobenzoate, chloride, citrate,
cyclopentanepropionate, decanoate, digluconate,
dihydrogenphosphate, dinitrobenzoate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptanoate,
glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate,
hexyne-1,6-dioate, hydroxybenzoate, .gamma.-hydroxybutyrate,
hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,
iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate,
mandelate. metaphosphate, methanesulfonate, methoxybenzoate,
methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate,
2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate,
persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,
propionate, pyrosulfate, pyrophosphate, propiolate, phthalate,
phenylacetate, phenylbutyrate, propanesulfonate, salicylate,
succinate, sulfate, sulfite, succinate, suberate, sebacate,
sulfonate, tartrate, thiocyanate, tosylate undeconate and
xylenesulfonate.
[0068] Further, in some embodiments, the compounds described herein
are prepared as pharmaceutically acceptable salts formed by
reacting the free base form of the compound with a pharmaceutically
acceptable inorganic or organic acid, including, but not limited
to, inorganic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid,
and the like; and organic acids such as acetic acid, propionic
acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid,
pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid,
maleic acid, fumaric acid, Q-toluenesulfonic acid, tartaric acid,
trifluoroacetic acid, citric acid, benzoic acid,
3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,
arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid,
1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,
benzenesulfonic acid, 2-naphthalenesulfonic acid,
4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic
acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid),
3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic
acid, lauryl sulfuric acid, gluconic acid, glutamic acid,
hydroxynaphthoic acid, salicylic acid, stearic acid and muconic
acid. In some embodiments, other acids, such as oxalic, while not
in themselves pharmaceutically acceptable, are employed in the
preparation of salts useful as intermediates in obtaining the
compounds of the present disclosure and their pharmaceutically
acceptable acid addition salts.
[0069] Representative organic amines useful for the formation of
base addition salts include ethylamine, diethylamine,
ethylenediamine, ethanolamine, diethanolamine, piperazine and the
like. It should be understood that the compounds described herein
also include the quaternization of any basic nitrogen-containing
groups they contain. In some embodiments, water or oil-soluble or
dispersible products are obtained by such quaternization. The
compounds described herein can be prepared as pharmaceutically
acceptable salts formed when an acidic proton present in the parent
compound either is replaced by a metal ion, for example an alkali
metal ion, an alkaline earth ion, or an aluminum ion; or
coordinates with an organic base. Base addition salts can also be
prepared by reacting the free acid form of the compounds described
herein with a pharmaceutically acceptable inorganic or organic
base, including, but not limited to organic bases such as
ethanolamine, diethanolamine, triethanolamine, tromethamine,
N-methylglucamine, and the like and inorganic bases such as
aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium
carbonate, sodium hydroxide, and the like. In addition, the salt
forms of the disclosed compounds can be prepared using salts of the
starting materials or intermediates.
[0070] Pharmaceutically acceptable salts of caspofungin include but
are not limited to those derived with cations, such as sodium,
potassium, aluminum, calcium, lithium, magnesium, and zinc; acids,
such as hydrochloric, hydrobromic, phosphoric, sulfuric, maleic,
citric, tartaric, succinic, oxalic, malic, glutamic, lactic,
propionic and pamoic acids; bases, such as ammonia,
ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine,
choline, N,N'-dibenzylethylenediamine, chloroprocaine,
diethanolamine, procaine, N-benzylphenethylamine, diethylamine,
piperazine, tris(hydroxymethyl)aminomethane, and
tetramethyl-ammonium hydroxide. Pharmaceutically acceptable salts
of caspofungin include the mono-, di-, and tri-acid forms. Also
included are pharmaceutically acceptable salts disclosed in U.S.
Pat. No. 5,378,804, U.S. Pat. No. 5,936,062, and US 2009/0170753,
which are incorporated in reference for their disclosure of such
compounds.
[0071] In some embodiments, the pharmaceutically acceptable salt of
caspofungin is acetate, acrylate, adipate, alginate, aspartate,
benzoate, benzenesulfonate, bisulfate, bisulfite, bromide,
butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate,
caprylate, chlorobenzoate, chloride, citrate,
cyclopentanepropionate, decanoate, digluconate,
dihydrogenphosphate, dinitrobenzoate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptanoate,
glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate,
hexyne-1,6-dioate, hydroxybenzoate, .gamma.-hydroxybutyrate,
hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,
iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate,
mandelate. metaphosphate, methanesulfonate, methoxybenzoate,
methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate,
2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate,
persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,
propionate, pyrosulfate, pyrophosphate, propiolate, phthalate,
phenylacetate, phenylbutyrate, propanesulfonate, salicylate,
succinate, sulfate, sulfite, succinate, suberate, sebacate,
sulfonate, tartrate, thiocyanate, tosylate undeconate or
xylenesulfonate.
[0072] Other examples of suitable pharmaceutically acceptable salts
of caspofungin include but are not limited to acetates, citrates,
tartrates, propionates, succinates, oxalates, malates, maleates,
lactates, glutamates, and pamoates. In some embodiments, the
pharmaceutically acceptable salt of caspofungin is the acetate. In
some embodiments, the pharmaceutically acceptable salt of
caspofungin is the propionate. In some embodiments, the
pharmaceutically acceptable salt of caspofungin is the lactate.
Solvates and Hydrates
[0073] In some embodiments, the compounds described herein exist as
solvates. The present disclosure provides for methods of treating
diseases by administering such solvates. The present disclosure
further provides for methods of treating diseases by administering
such solvates as pharmaceutical compositions.
[0074] Solvates contain either stoichiometric or non-stoichiometric
amounts of a solvent, and, in some embodiments, are formed during
the process of crystallization with pharmaceutically acceptable
solvents such as water, ethanol, and the like. Hydrates are formed
when the solvent is water, or alcoholates are formed when the
solvent is alcohol. Solvates of the compounds described herein can
be conveniently prepared or formed during the processes described
herein. By way of example only, hydrates of the compounds described
herein can be conveniently prepared by recrystallization from an
aqueous/organic solvent mixture, using organic solvents including,
but not limited to, dioxane, tetrahydrofuran or methanol. In
addition, the compounds provided herein can exist in unsolvated as
well as solvated forms. In general, the solvated forms are
considered equivalent to the unsolvated forms for the purposes of
the compounds and methods provided herein.
Polymorphs
[0075] In some embodiments, the compounds described herein exist as
polymorphs. The present disclosure provides for methods of treating
diseases by administering such polymorphs. The present disclosure
further provides for methods of treating diseases by administering
such polymorphs as pharmaceutical compositions.
[0076] Thus, the compounds described herein include all their
crystalline forms, known as polymorphs. Polymorphs include the
different crystal packing arrangements of the same elemental
composition of a compound. In certain instances, polymorphs have
different X-ray diffraction patterns, infrared spectra, melting
points, density, hardness, crystal shape, optical and electrical
properties, stability, and solubility. In certain instances,
various factors such as the recrystallization solvent, rate of
crystallization, and storage temperature cause a single crystal
form to dominate.
[0077] In some embodiments, compounds described herein include
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, caspofungin is isotopically labeled
caspofungin, or a polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof.
Mannitol-Free Caspofungin
[0078] It is recognized herein that the aerosolization of the
intravenous formulation of caspofungin would not be ideal for
inhalation therapy as the mannitol, which is present Cancidas.RTM.
as a bulking agent that is effective for forming a lyophilized
cake, induces cough when inhaled and as well as sugar promotes
fungal growth. In some embodiments, the inhalation composition
disclosed herein is essentially free of mannitol. In some
embodiments, the inhalation composition disclosed herein is
essentially free of sugar alcohol. In some embodiments, the
inhalation composition disclosed herein is essentially free of
sugar alcohol or sugar. Examples of relevant sugar alcohols include
but are not limited to glycerol, erythritol, threitol, arabitol,
xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol,
inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol,
maltotetraitol, and polyglycitol. In some embodiments, the sugar
alcohol is glycerol, erythritol, arabitol, xylitol, mannitol, and
sorbitol. Examples of relevant sugars include but are not limited
to lactose, sucrose, trehalose, dextrose, dextran, and ficoll. In
some embodiments, the sugar is sucrose.
Anti-Forming Agents
[0079] It is recognized herein that the aerosolization of the
intravenous formulation of caspofungin would not be ideal for
inhalation therapy as the intravenous formulation of caspofungin
foams when nebulized. Such foaming is undesired as it can have an
effect on the aerosolization process. In some embodiments, the
inhalation compositions described herein comprise an antiforming
agent. Antifoaming agents as used herein reduce foaming during
processing, which results in coagulation of aqueous
dispersions.
[0080] In some embodiments the anti-foaming agent is selected from
a phospholipid, a fatty acid or derivative thereof, a
silicone-based compound, polyethylene glycol copolymer,
polypropylene glycol copolymer, and an alkyl polyacrylate. In some
embodiments the anti-foaming agent is a phospholipid. Exemplary
phospholipids include but are not limited to phosphoglycerides and
phosphosphingolipids. Suitable phospholipids also include natural,
such as those derived from animal and plant sources, and synthetic
phospholipids. Natural phospholipids include, but are not limited
to, plasmalogen, cardiolipin, dipalmitoylphosphatidylcholine,
glycerophospholipid, glycerophosphoric acid, lecithin,
lysophosphatidic acid, phosphatidylcholine,
phosphatidylethanolamine, phosphatidylserine, platelet-activating
factor, sphingomyelin, and sphingosyl phosphatide.
[0081] In some embodiments, the anti-foaming agent is a fatty acid
or derivative thereof. Fatty acids are saturated or unsaturated.
Saturated fatty acids include, but are not limited to, lauric acid,
myristic acid, palmitic acid, stearic acid, arachidic acid.
Unsaturated fatty acids include, but are not limited to,
palmitoleic acid, oleic acid, linoleic acid, linolenic acid,
arachidonic acid. Suitable fatty acid derivatives include but are
not limited to fatty alcohols and fatty esters.
[0082] In some embodiments, the anti-foaming agent is a
silicone-based compound. Silcone-based compounds include but are
not limited to siloxane-based compounds, such as
polydimethylsiloxane; simethicone compounds. In some embodiments,
the anti-foaming agent is a polyethylene glycol copolymer or a
polypropylene glycol copolymer. In some embodiments, the
anti-forming agent is an alkyl polyacrylate.
Inhalation Devices
[0083] An "inhalation device," as used herein, refers to any device
that is capable of administering a drug formulation to the
respiratory airways of a patient. Inhalation devices include
conventional inhalation devices, such as jet nebulizers, ultrasonic
wave nebulizers, high efficiency nebuilizers, heat vaporizers, soft
mist inhalers, thermal aerosol inhaler, or
electrohydrodynamic-based solution misting inhaler. Nebulizers
deliver pharmaceuticals by forming an aerosol which includes
droplet sizes that can easily be inhaled. The aerosol can be used
by a patient within the bounds of an inhalation therapy, whereby
the caspofungin reaches the patient's respiratory tract upon
inhalation.
[0084] Conventional 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 some embodiments, when the patient breathes in, a valve at
the top opens, which then allows air into the apparatus, thereby
speeding up the mist generation; when the patient breathes out, the
top valve closes, thereby slowing down the mist generation while
simultaneously permitting the patient 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
Starnberg), by a breath enhanced mode (e.g., the PARI LC Plus or
Sprint from PARI Starnberg), by breath actuated mode dependent on
the breathing pattern of the patient (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).
[0085] 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 include but are not limited to: 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..
[0086] High efficiency 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. High efficiency
nebulizers can deliver a large fraction of a loaded dose to a
patient. Commercial high efficiency nebulizers include but are not
limited to: 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 (Bannockburn, 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..
[0087] In some embodiments, the inhalation device selected from a
jet nebulizer, ultrasonic wave nebulizer, high efficiency
nebulizer, heat vaporizer, soft mist inhaler, thermal aerosol
inhaler, or electrohydrodynamic-based solution misting inhaler. In
some embodiments, the inhalation device is a jet nebulizer. In some
embodiments, the inhalation device is an ultrasonic wave nebulizer.
In some embodiments, the inhalation device is a high efficiency
nebulizer. In some embodiments, the inhalation device is a heat
vaporizer. In some embodiments, the inhalation device is a soft
mist inhaler. In some embodiments, the inhalation device is a
thermal aerosol inhaler. In some embodiments, the inhalation device
is an electrohydrodynamic-based solution misting inhaler.
[0088] In some embodiments the caspofungin, or a polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof is
administered with an inhalation device, e.g., jet nebulizers,
ultrasonic wave nebulizers, high efficiency nebulizers, heat
vaporizers, soft mist inhalers, thermal aerosol inhaler, or
electrohydrodynamic-based solution misting inhaler, the methods
disclosed herein provide improved efficacy for the treatment or
prophylaxis of a fungal infection in the pulmonary system of a
subject relative to administration of caspofungin, or a polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof by a
different route of administration, e.g., intravenously, because
administration of the caspofungin, or a polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof with an inhalation
device, e.g., jet nebulizers, ultrasonic wave nebulizers, high
efficiency nebulizers, heat vaporizers, soft mist inhalers, thermal
aerosol inhaler, or electrohydrodynamic-based solution misting
inhaler, allows for the attainment of high concentration of
caspofungin, or a polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the pulmonary system. In further
embodiments, administration of caspofungin, or a polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof via
an inhalation device minimizes systemic toxicities.
Inhalation Therapy
[0089] In some embodiments, the administration of the inhalation
composition provides a lung tissue concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof that is from about 1-fold to about 100-fold greater
than the concentration in the lung via intravenous administration
at the same delivery dose. In some embodiments, the administration
of the inhalation composition provides a lung tissue concentration
of caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof that is from about 1-fold to about
90-fold greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the inhalation composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is from about
1-fold to about 80-fold greater than the concentration in the lung
via intravenous administration at the same delivery dose. In some
embodiments, the administration of the inhalation composition
provides a lung tissue concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof that is from about 1-fold to about 70-fold greater than the
concentration in the lung via intravenous administration at the
same delivery dose. In some embodiments, the administration of the
inhalation composition provides a lung tissue concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof that is from about 1-fold to about
60-fold greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the inhalation composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is from about
1-fold to about 50-fold greater than the concentration in the lung
via intravenous administration at the same delivery dose. In some
embodiments, the administration of the inhalation composition
provides a lung tissue concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof that is from about 1-fold to about 40-fold greater than the
concentration in the lung via intravenous administration at the
same delivery dose. In some embodiments, the administration of the
inhalation composition provides a lung tissue concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof that is from about 1-fold to about
30-fold greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the inhalation composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is from about
1-fold to about 20-fold greater than the concentration in the lung
via intravenous administration at the same delivery dose. In some
embodiments, the administration of the inhalation composition
provides a lung tissue concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof that is from about 1-fold to about 10-fold greater than the
concentration in the lung via intravenous administration at the
same delivery dose. In some embodiments, the administration of the
inhalation composition provides a lung tissue concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof that is from about 1-fold to about
5-fold greater than the concentration in the lung via intravenous
administration at the same delivery dose.
[0090] In some embodiments, the administration of the inhalation
composition provides a lung tissue concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof that is about 1-fold greater than the concentration
in the lung via intravenous administration at the same delivery
dose. In some embodiments, the administration of the inhalation
composition provides a lung tissue concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof that is about 5-fold greater than the concentration
in the lung via intravenous administration at the same delivery
dose. In some embodiments, the administration of the inhalation
composition provides a lung tissue concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof that is about 10-fold greater than the
concentration in the lung via intravenous administration at the
same delivery dose. In some embodiments, the administration of the
inhalation composition provides a lung tissue concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof that is about 20-fold greater than the
concentration in the lung via intravenous administration at the
same delivery dose. In some embodiments, the administration of the
inhalation composition provides a lung tissue concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof that is about 30-fold greater than the
concentration in the lung via intravenous administration at the
same delivery dose. In some embodiments, the administration of the
inhalation composition provides a lung tissue concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof that is about 40-fold greater than the
concentration in the lung via intravenous administration at the
same delivery dose. In some embodiments, the administration of the
inhalation composition provides a lung tissue concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof that is about 50-fold greater than the
concentration in the lung via intravenous administration at the
same delivery dose. In some embodiments, the administration of the
inhalation composition provides a lung tissue concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof that is about 60-fold greater than the
concentration in the lung via intravenous administration at the
same delivery dose. In some embodiments, the administration of the
inhalation composition provides a lung tissue concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof that is about 70-fold greater than the
concentration in the lung via intravenous administration at the
same delivery dose. In some embodiments, the administration of the
inhalation composition provides a lung tissue concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof that is about 80-fold greater than the
concentration in the lung via intravenous administration at the
same delivery dose. In some embodiments, the administration of the
inhalation composition provides a lung tissue concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof that is about 90-fold greater than the
concentration in the lung via intravenous administration at the
same delivery dose. In some embodiments, the administration of the
inhalation composition provides a lung tissue concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof that is about 100-fold greater than the
concentration in the lung via intravenous administration at the
same delivery dose.
[0091] In some embodiments, the lung tissue concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof is greater than the concentration in
the lung via intravenous administration at the same delivery dose
for about 0.5 hour to about 336 hours, about 0.5 hour to about 168
hours, about 0.5 hour to about 144 hours, about 0.5 hour to about
120 hours, about 0.5 hour to about 96 hours, about 0.5 hour to
about 72 hours, about 0.5 hour to about 60 hours, about 0.5 hour to
about 48 hours, about 0.5 to about 36 hours, about 0.5 to about 24
hours, about 0.5 hour to about 12 hours, about 0.5 hour to about 6
hours, about 0.5 hour to about 3 hours, or about 0.5 hour to about
2 hours. In some embodiments, the lung tissue concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof is greater than the concentration in
the lung via intravenous administration at the same delivery dose
for about 1 hour to about 336 hours, about 1 hour to about 168
hours, about 1 hour to about 144 hours, about 1 hour to about 120
hours, about 1 hour to about 96 hours, about 1 hour to about 72
hours, about 1 hour to about 60 hours, about 1 hour to about 48
hours, about 1 hour to about 36 hours, about 1 hour to about 24
hours, about 1 hour to about 12 hours, about 1 hour to about 6
hours, for about 1 hour to about 3 hours, or about 1 hour to about
2 hours. In some embodiments, the lung tissue concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof is greater than the concentration in
the lung via intravenous administration at the same delivery dose
for 3 hours to about 336 hours, about 3 hours to about 168 hours,
about 3 hours to about 144 hours, about 3 hours to about 120 hours,
about 3 hours to about 96 hours, about 3 hours to about 72 hours,
about 3 hours to about 60 hours, about 3 hours to about 48 hours,
about 3 hours to about 36 hours, about 3 hours to about 24 hours,
about 3 hours to about 12 hours, or about 3 hours to about 6 hours.
In some embodiments, the lung tissue concentration of caspofungin
or the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof is greater than the concentration in the lung via
intravenous administration at the same delivery dose for 6 hours to
about 336 hours, about 6 hours to about 168 hours, about 6 hours to
about 144 hours, about 6 hours to about 120 hours, about 6 hours to
about 96 hours, about 6 hours to about 72 hours, about 6 hours to
about 60 hours, about 6 hours to about 48 hours, about 6 hours to
about 36 hours, about 6 hours to about 24 hours, or about 6 hours
to about 12 hours.
[0092] In some embodiments, the lung tissue concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof is greater than the concentration in
the lung via intravenous administration at the same delivery dose
for about 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6
hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 18
hours, 24 hours, 32 hours, 48 hours, 72 hours, 96 hours, 120 hours,
144 hours, 168 hours, 240 hours, or 336 hours.
[0093] In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
1000-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the inhalation composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 500-fold greater than the concentration in the
liver, kidney, spleen, pancreas or plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 200-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 150-fold
greater than the concentration in the liver, kidney, spleen,
pancreas or plasma. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung that is from about 1-fold greater to
about 120-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the inhalation composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 110-fold greater than the concentration in the
liver, kidney, spleen, pancreas or plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 100-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 90-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
80-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the inhalation composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 70-fold greater than the concentration in the
liver, kidney, spleen, pancreas or plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 60-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 50-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
40-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the inhalation composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 30-fold greater than the concentration in the
liver, kidney, spleen, pancreas or plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 20-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 10-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
5-fold greater than the concentration in the liver, kidney, spleen,
pancreas or plasma.
[0094] In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is about 1-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is about 2-fold greater than the concentration in the
liver, kidney, spleen, pancreas or plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 3-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the inhalation composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is about 4-fold
greater than the concentration in the liver, kidney, spleen,
pancreas or plasma. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung that is about 5-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is about 10-fold greater than the concentration in
the liver, kidney, spleen, pancreas or plasma. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 15-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the inhalation composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is about 20-fold
greater than the concentration in the liver, kidney, spleen,
pancreas or plasma. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung that is about 30-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is about 40-fold greater than the concentration in
the liver, kidney, spleen, pancreas or plasma. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 50-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the inhalation composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is about 60-fold
greater than the concentration in the liver, kidney, spleen,
pancreas or plasma. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung that is about 70-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is about 80-fold greater than the concentration in
the liver, kidney, spleen, pancreas or plasma. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 90-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the inhalation composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is about 100-fold
greater than the concentration in the liver, kidney, spleen,
pancreas or plasma. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung that is about 110-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is about 120-fold greater than the concentration in
the liver, kidney, spleen, pancreas or plasma. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 130-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the inhalation composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is about 140-fold
greater than the concentration in the liver, kidney, spleen,
pancreas or plasma. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung that is about 150-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is about 200-fold greater than the concentration in
the liver, kidney, spleen, pancreas or plasma. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 300-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the inhalation composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is about 400-fold
greater than the concentration in the liver, kidney, spleen,
pancreas or plasma. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung that is about 500-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is about 600-fold greater than the concentration in
the liver, kidney, spleen, pancreas or plasma. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 700-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the inhalation composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is about 800-fold
greater than the concentration in the liver, kidney, spleen,
pancreas or plasma. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung that is about 900-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is about 1000-fold greater than the concentration in
the liver, kidney, spleen, pancreas or plasma.
[0095] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the liver,
kidney, spleen, pancreas, or plasma for about 0.5 hour to about 336
hours, about 0.5 hour to about 168 hours, about 0.5 hour to about
144 hours, about 0.5 hour to about 120 hours, about 0.5 hour to
about 96 hours, about 0.5 hour to about 72 hours, about 0.5 hour to
about 60 hours, about 0.5 hour to about 48 hours, about 0.5 to
about 36 hours, about 0.5 to about 24 hours, about 0.5 hour to
about 12 hours, about 0.5 hour to about 6 hours, about 0.5 hour to
about 3 hours, or about 0.5 hour to about 2 hours. In some
embodiments, the concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung is greater than the concentration in the liver, kidney,
spleen, pancreas, or plasma for about 1 hour to about 336 hours,
about 1 hour to about 168 hours, about 1 hour to about 144 hours,
about 1 hour to about 120 hours, about 1 hour to about 96 hours,
about 1 hour to about 72 hours, about 1 hour to about 60 hours,
about 1 hour to about 48 hours, about 1 hour to about 36 hours,
about 1 hour to about 24 hours, about 1 hour to about 12 hours,
about 1 hour to about 6 hours, for about 1 hour to about 3 hours,
or about 1 hour to about 2 hours. In some embodiments, the
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung is greater
than the concentration in the liver, kidney, spleen, pancreas, or
plasma for about 3 hours to about 336 hours, about 3 hours to about
168 hours, about 3 hours to about 144 hours, about 3 hours to about
120 hours, about 3 hours to about 96 hours, about 3 hours to about
72 hours, about 3 hours to about 60 hours, about 3 hours to about
48 hours, about 3 hours to about 36 hours, about 3 hours to about
24 hours, about 3 hours to about 12 hours, or about 3 hours to
about 6 hours. In some embodiments, the concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is greater than the
concentration in the liver, kidney, spleen, pancreas, or plasma for
6 hours to about 336 hours, about 6 hours to about 168 hours, about
6 hours to about 144 hours, about 6 hours to about 120 hours, about
6 hours to about 96 hours, about 6 hours to about 72 hours, about 6
hours to about 60 hours, about 6 hours to about 48 hours, about 6
hours to about 36 hours, about 6 hours to about 24 hours, or about
6 hours to about 12 hours.
[0096] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the liver,
kidney, spleen, pancreas, or plasma for about 0.5 hour, 1 hour, 2
hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9
hours, 10 hours, 11 hours, 12 hours, 18 hours, 24 hours, 32 hours,
48 hours, 72 hours, 96 hours, 120 hours, 144 hours, 168 hours, 240
hours, or 336 hours.
[0097] In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
1000-fold greater than the concentration in the liver. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 500-fold
greater than the concentration in the liver. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 200-fold greater than the
concentration in the liver. In some embodiments, the administration
of the inhalation composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 150-fold greater than the concentration in the
liver. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
120-fold greater than the concentration in the liver. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 110-fold
greater than the concentration in the liver. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 100-fold greater than the
concentration in the liver. In some embodiments, the administration
of the inhalation composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 90-fold greater than the concentration in the
liver. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
80-fold greater than the concentration in the liver. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 70-fold greater
than the concentration in the liver. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 60-fold greater than the
concentration in the liver. In some embodiments, the administration
of the inhalation composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 50-fold greater than the concentration in the
liver. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
40-fold greater than the concentration in the liver. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 30-fold greater
than the concentration in the liver. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 20-fold greater than the
concentration in the liver. In some embodiments, the administration
of the inhalation composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 10-fold greater than the concentration in the
liver. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
5-fold greater than the concentration in the liver.
[0098] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the liver
for about 0.5 hour to about 336 hours, about 0.5 hour to about 168
hours, about 0.5 hour to about 144 hours, about 0.5 hour to about
120 hours, about 0.5 hour to about 96 hours, about 0.5 hour to
about 72 hours, about 0.5 hour to about 60 hours, about 0.5 hour to
about 48 hours, about 0.5 to about 36 hours, about 0.5 to about 24
hours, about 0.5 hour to about 12 hours, about 0.5 hour to about 6
hours, about 0.5 hour to about 3 hours, or about 0.5 hour to about
2 hours. In some embodiments, the concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung is greater than the concentration in
the liver for about 1 hour to about 336 hours, about 1 hour to
about 168 hours, about 1 hour to about 144 hours, about 1 hour to
about 120 hours, about 1 hour to about 96 hours, about 1 hour to
about 72 hours, about 1 hour to about 60 hours, about 1 hour to
about 48 hours, about 1 hour to about 36 hours, about 1 hour to
about 24 hours, about 1 hour to about 12 hours, about 1 hour to
about 6 hours, for about 1 hour to about 3 hours, or about 1 hour
to about 2 hours. In some embodiments, the concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is greater than the
concentration in the liver for about 3 hours to about 336 hours,
about 3 hours to about 168 hours, about 3 hours to about 144 hours,
about 3 hours to about 120 hours, about 3 hours to about 96 hours,
about 3 hours to about 72 hours, about 3 hours to about 60 hours,
about 3 hours to about 48 hours, about 3 hours to about 36 hours,
about 3 hours to about 24 hours, about 3 hours to about 12 hours,
or about 3 hours to about 6 hours. In some embodiments, the
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung is greater
than the concentration in the liver for about 6 hours to about 336
hours, about 6 hours to about 168 hours, about 6 hours to about 144
hours, about 6 hours to about 120 hours, about 6 hours to about 96
hours, about 6 hours to about 72 hours, about 6 hours to about 60
hours, about 6 hours to about 48 hours, about 6 hours to about 36
hours, about 6 hours to about 24 hours, or about 6 hours to about
12 hours.
[0099] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the liver
for about 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6
hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 18
hours, 24 hours, 32 hours, 48 hours, 72 hours, 96 hours, 120 hours,
144 hours, 168 hours, 240 hours, or 336 hours.
[0100] In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
1000-fold greater than the concentration in the kidney. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 500-fold
greater than the concentration in the kidney. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 200-fold greater than the
concentration in the kidney. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 150-fold greater than the
concentration in the kidney. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 120-fold greater than the
concentration in the kidney. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 110-fold greater than the
concentration in the kidney. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 100-fold greater than the
concentration in the kidney. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 90-fold greater than the
concentration in the kidney. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 80-fold greater than the
concentration in the kidney. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 70-fold greater than the
concentration in the kidney. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 60-fold greater than the
concentration in the kidney. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 50-fold greater than the
concentration in the kidney. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 40-fold greater than the
concentration in the kidney. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 30-fold greater than the
concentration in the kidney. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 20-fold greater than the
concentration in the kidney. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 10-fold greater than the
concentration in the kidney. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 5-fold greater than the
concentration in the kidney.
[0101] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the kidney
for about 0.5 hour to about 336 hours, about 0.5 hour to about 168
hours, about 0.5 hour to about 144 hours, about 0.5 hour to about
120 hours, about 0.5 hour to about 96 hours, about 0.5 hour to
about 72 hours, about 0.5 hour to about 60 hours, about 0.5 hour to
about 48 hours, about 0.5 to about 36 hours, about 0.5 to about 24
hours, about 0.5 hour to about 12 hours, about 0.5 hour to about 6
hours, about 0.5 hour to about 3 hours, or about 0.5 hour to about
2 hours. In some embodiments, the concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung is greater than the concentration in
the kidney for about 1 hour to about 336 hours, about 1 hour to
about 168 hours, about 1 hour to about 144 hours, about 1 hour to
about 120 hours, about 1 hour to about 96 hours, about 1 hour to
about 72 hours, about 1 hour to about 60 hours, about 1 hour to
about 48 hours, about 1 hour to about 36 hours, about 1 hour to
about 24 hours, about 1 hour to about 12 hours, about 1 hour to
about 6 hours, for about 1 hour to about 3 hours, or about 1 hour
to about 2 hours. In some embodiments, the concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is greater than the
concentration in the kidney for about 3 hours to about 336 hours,
about 3 hours to about 168 hours, about 3 hours to about 144 hours,
about 3 hours to about 120 hours, about 3 hours to about 96 hours,
about 3 hours to about 72 hours, about 3 hours to about 60 hours,
about 3 hours to about 48 hours, about 3 hours to about 36 hours,
about 3 hours to about 24 hours, about 3 hours to about 12 hours,
or about 3 hours to about 6 hours. In some embodiments, the
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung is greater
than the concentration in the kidney for about 6 hours to about 336
hours, about 6 hours to about 168 hours, about 6 hours to about 144
hours, about 6 hours to about 120 hours, about 6 hours to about 96
hours, about 6 hours to about 72 hours, about 6 hours to about 60
hours, about 6 hours to about 48 hours, about 6 hours to about 36
hours, about 6 hours to about 24 hours, or about 6 hours to about
12 hours.
[0102] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the kidney
for about 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6
hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 18
hours, 24 hours, 32 hours, 48 hours, 72 hours, 96 hours, 120 hours,
144 hours, 168 hours, 240 hours, or 336 hours.
[0103] In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
1000-fold greater than the concentration in the spleen. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 500-fold
greater than the concentration in the spleen. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 200-fold greater than the
concentration in the spleen. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 150-fold greater than the
concentration in the spleen. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 120-fold greater than the
concentration in the spleen. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 110-fold greater than the
concentration in the spleen. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 100-fold greater than the
concentration in the spleen. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 90-fold greater than the
concentration in the spleen. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 80-fold greater than the
concentration in the spleen. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 70-fold greater than the
concentration in the spleen. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 60-fold greater than the
concentration in the spleen. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 50-fold greater than the
concentration in the spleen. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 40-fold greater than the
concentration in the spleen. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 30-fold greater than the
concentration in the spleen. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 20-fold greater than the
concentration in the spleen. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 10-fold greater than the
concentration in the spleen. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 5-fold greater than the
concentration in the spleen.
[0104] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the spleen
for about 0.5 hour to about 336 hours, about 0.5 hour to about 168
hours, about 0.5 hour to about 144 hours, about 0.5 hour to about
120 hours, about 0.5 hour to about 96 hours, about 0.5 hour to
about 72 hours, about 0.5 hour to about 60 hours, about 0.5 hour to
about 48 hours, about 0.5 to about 36 hours, about 0.5 to about 24
hours, about 0.5 hour to about 12 hours, about 0.5 hour to about 6
hours, about 0.5 hour to about 3 hours, or about 0.5 hour to about
2 hours. In some embodiments, the concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung is greater than the concentration in
the spleen for about 1 hour to about 336 hours, about 1 hour to
about 168 hours, about 1 hour to about 144 hours, about 1 hour to
about 120 hours, about 1 hour to about 96 hours, about 1 hour to
about 72 hours, about 1 hour to about 60 hours, about 1 hour to
about 48 hours, about 1 hour to about 36 hours, about 1 hour to
about 24 hours, about 1 hour to about 12 hours, about 1 hour to
about 6 hours, for about 1 hour to about 3 hours, or about 1 hour
to about 2 hours. In some embodiments, the concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is greater than the
concentration in the spleen for about 3 hours to about 336 hours,
about 3 hours to about 168 hours, about 3 hours to about 144 hours,
about 3 hours to about 120 hours, about 3 hours to about 96 hours,
about 3 hours to about 72 hours, about 3 hours to about 60 hours,
about 3 hours to about 48 hours, about 3 hours to about 36 hours,
about 3 hours to about 24 hours, about 3 hours to about 12 hours,
or about 3 hours to about 6 hours. In some embodiments, the
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung is greater
than the concentration in the spleen for about 6 hours to about 336
hours, about 6 hours to about 168 hours, about 6 hours to about 144
hours, about 6 hours to about 120 hours, about 6 hours to about 96
hours, about 6 hours to about 72 hours, about 6 hours to about 60
hours, about 6 hours to about 48 hours, about 6 hours to about 36
hours, about 6 hours to about 24 hours, or about 6 hours to about
12 hours.
[0105] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the spleen
for about 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6
hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 18
hours, 24 hours, 32 hours, 48 hours, 72 hours, 96 hours, 120 hours,
144 hours, 168 hours, 240 hours, or 336 hours.
[0106] In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
1000-fold greater than the concentration in the pancreas. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 500-fold
greater than the concentration in the pancreas. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 200-fold
greater than the concentration in the pancreas. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 150-fold
greater than the concentration in the pancreas. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 120-fold
greater than the concentration in the pancreas. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 110-fold
greater than the concentration in the pancreas. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 100-fold
greater than the concentration in the pancreas. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 90-fold greater
than the concentration in the pancreas. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 80-fold greater than the
concentration in the pancreas. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 70-fold greater than the
concentration in the pancreas. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 60-fold greater than the
concentration in the pancreas. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 50-fold greater than the
concentration in the pancreas. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 40-fold greater than the
concentration in the pancreas. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 30-fold greater than the
concentration in the pancreas. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 20-fold greater than the
concentration in the pancreas. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 10-fold greater than the
concentration in the pancreas. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 5-fold greater than the
concentration in the pancreas.
[0107] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the
pancreas for about 0.5 hour to about 336 hours, about 0.5 hour to
about 168 hours, about 0.5 hour to about 144 hours, about 0.5 hour
to about 120 hours, about 0.5 hour to about 96 hours, about 0.5
hour to about 72 hours, about 0.5 hour to about 60 hours, about 0.5
hour to about 48 hours, about 0.5 to about 36 hours, about 0.5 to
about 24 hours, about 0.5 hour to about 12 hours, about 0.5 hour to
about 6 hours, about 0.5 hour to about 3 hours, or about 0.5 hour
to about 2 hours. In some embodiments, the concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is greater than the
concentration in the pancreas for about 1 hour to about 336 hours,
about 1 hour to about 168 hours, about 1 hour to about 144 hours,
about 1 hour to about 120 hours, about 1 hour to about 96 hours,
about 1 hour to about 72 hours, about 1 hour to about 60 hours,
about 1 hour to about 48 hours, about 1 hour to about 36 hours,
about 1 hour to about 24 hours, about 1 hour to about 12 hours,
about 1 hour to about 6 hours, for about 1 hour to about 3 hours,
or about 1 hour to about 2 hours. In some embodiments, the
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung is greater
than the concentration in the pancreas for about 3 hours to about
336 hours, about 3 hours to about 168 hours, about 3 hours to about
144 hours, about 3 hours to about 120 hours, about 3 hours to about
96 hours, about 3 hours to about 72 hours, about 3 hours to about
60 hours, about 3 hours to about 48 hours, about 3 hours to about
36 hours, about 3 hours to about 24 hours, about 3 hours to about
12 hours, or about 3 hours to about 6 hours. In some embodiments,
the concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung is greater
than the concentration in the pancreas for about 6 hours to about
336 hours, about 6 hours to about 168 hours, about 6 hours to about
144 hours, about 6 hours to about 120 hours, about 6 hours to about
96 hours, about 6 hours to about 72 hours, about 6 hours to about
60 hours, about 6 hours to about 48 hours, about 6 hours to about
36 hours, about 6 hours to about 24 hours, or about 6 hours to
about 12 hours.
[0108] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the
pancreas for about 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 5
hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12
hours, 18 hours, 24 hours, 32 hours, 48 hours, 72 hours, 96 hours,
120 hours, 144 hours, 168 hours, 240 hours, or 336 hours.
[0109] In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
1000-fold greater than the concentration in plasma. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 500-fold
greater than the concentration in plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 200-fold greater than the
concentration in plasma. In some embodiments, the administration of
the inhalation composition provides a concentration of caspofungin
or the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung that is from about 1-fold greater to
about 150-fold greater than the concentration in plasma. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 120-fold
greater than the concentration in plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 110-fold greater than the
concentration in plasma. In some embodiments, the administration of
the inhalation composition provides a concentration of caspofungin
or the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung that is from about 1-fold greater to
about 100-fold greater than the concentration in plasma. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 90-fold greater
than the concentration in plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 80-fold greater than the
concentration in plasma. In some embodiments, the administration of
the inhalation composition provides a concentration of caspofungin
or the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung that is from about 1-fold greater to
about 70-fold greater than the concentration in plasma. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 60-fold greater
than the concentration in plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 50-fold greater than the
concentration in plasma. In some embodiments, the administration of
the inhalation composition provides a concentration of caspofungin
or the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung that is from about 1-fold greater to
about 40-fold greater than the concentration in plasma. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 30-fold greater
than the concentration in plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 20-fold greater than the
concentration in plasma. In some embodiments, the administration of
the inhalation composition provides a concentration of caspofungin
or the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung that is from about 1-fold greater to
about 10-fold greater than the concentration in plasma. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 5-fold greater
than the concentration in plasma.
[0110] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the plasma
for about 0.5 hour to about 336 hours, about 0.5 hour to about 168
hours, about 0.5 hour to about 144 hours, about 0.5 hour to about
120 hours, about 0.5 hour to about 96 hours, about 0.5 hour to
about 72 hours, about 0.5 hour to about 60 hours, about 0.5 hour to
about 48 hours, about 0.5 to about 36 hours, about 0.5 to about 24
hours, about 0.5 hour to about 12 hours, about 0.5 hour to about 6
hours, about 0.5 hour to about 3 hours, or about 0.5 hour to about
2 hours.
[0111] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in plasma for
about 1 hour to about 336 hours, about 1 hour to about 168 hours,
about 1 hour to about 144 hours, about 1 hour to about 120 hours,
about 1 hour to about 96 hours, about 1 hour to about 72 hours,
about 1 hour to about 60 hours, about 1 hour to about 48 hours,
about 1 hour to about 36 hours, about 1 hour to about 24 hours,
about 1 hour to about 12 hours, about 1 hour to about 6 hours, for
about 1 hour to about 3 hours, or about 1 hour to about 2 hours. In
some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the plasma
for about 3 hours to about 336 hours, about 3 hours to about 168
hours, about 3 hours to about 144 hours, about 3 hours to about 120
hours, about 3 hours to about 96 hours, about 3 hours to about 72
hours, about 3 hours to about 60 hours, about 3 hours to about 48
hours, about 3 hours to about 36 hours, about 3 hours to about 24
hours, about 3 hours to about 12 hours, or about 3 hours to about 6
hours. In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the plasma
for about 6 hours to about 336 hours, about 6 hours to about 168
hours, about 6 hours to about 144 hours, about 6 hours to about 120
hours, about 6 hours to about 96 hours, about 6 hours to about 72
hours, about 6 hours to about 60 hours, about 6 hours to about 48
hours, about 6 hours to about 36 hours, about 6 hours to about 24
hours, or about 6 hours to about 12 hours.
[0112] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the plasma
for about 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6
hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 18
hours, 24 hours, 32 hours, 48 hours, 72 hours, 96 hours, 120 hours,
144 hours, 168 hours, 240 hours, or 336 hours.
[0113] In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 1000-fold greater than the concentration in the
liver, kidney, spleen, pancreas or plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is from about 5-fold greater to about 500-fold
greater than the concentration in the liver, kidney, spleen,
pancreas or plasma. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is from about
5-fold greater to about 200-fold greater than the concentration in
the liver, kidney, spleen, pancreas or plasma. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is from about 5-fold greater to about 150-fold
greater than the concentration in the liver, kidney, spleen,
pancreas or plasma. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is from about
5-fold greater to about 100-fold greater than the concentration in
the liver, kidney, spleen, pancreas or plasma. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is from about 5-fold greater to about 50-fold
greater than the concentration in the liver, kidney, spleen,
pancreas or plasma. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is from about
5-fold greater to about 20-fold greater than the concentration in
the liver, kidney, spleen, pancreas or plasma. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is from about 5-fold greater to about 10-fold
greater than the concentration in the liver, kidney, spleen,
pancreas or plasma.
[0114] In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 5-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 10-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 20-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 30-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 40-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 50-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 60-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 70-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 80-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 90-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 100-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 150-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 200-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 300-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 400-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 500-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 600-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 700-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 800-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 900-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 1000-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma.
[0115] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages is greater than the
concentration in the liver, kidney, spleen, pancreas, or plasma for
about 0.5 hour to about 336 hours, about 0.5 hour to about 168
hours, about 0.5 hour to about 144 hours, about 0.5 hour to about
120 hours, about 0.5 hour to about 96 hours, about 0.5 hour to
about 72 hours, about 0.5 hour to about 60 hours, about 0.5 hour to
about 48 hours, about 0.5 to about 36 hours, about 0.5 to about 24
hours, about 0.5 hour to about 12 hours, about 0.5 hour to about 6
hours, about 0.5 hour to about 3 hours, or about 0.5 hour to about
2 hours. In some embodiments, the concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages is greater than the
concentration in the liver, kidney, spleen, pancreas, or plasma for
1 hour to about 336 hours, about 1 hour to about 168 hours, about 1
hour to about 144 hours, about 1 hour to about 120 hours, about 1
hour to about 96 hours, about 1 hour to about 72 hours, about 1
hour to about 60 hours, about 1 hour to about 48 hours, about 1
hour to about 36 hours, about 1 hour to about 24 hours, about 1
hour to about 12 hours, about 1 hour to about 6 hours, for about 1
hour to about 3 hours, or about 1 hour to about 2 hours. In some
embodiments, the concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages is greater than the concentration in the
liver, kidney, spleen, pancreas, or plasma for about 3 hours to
about 336 hours, about 3 hours to about 168 hours, about 3 hours to
about 144 hours, about 3 hours to about 120 hours, about 3 hours to
about 96 hours, about 3 hours to about 72 hours, about 3 hours to
about 60 hours, about 3 hours to about 48 hours, about 3 hours to
about 36 hours, about 3 hours to about 24 hours, about 3 hours to
about 12 hours, or about 3 hours to about 6 hours. In some
embodiments, the concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages is greater than the concentration in the
liver, kidney, spleen, pancreas, or plasma for 6 hours to about 336
hours, about 6 hours to about 168 hours, about 6 hours to about 144
hours, about 6 hours to about 120 hours, about 6 hours to about 96
hours, about 6 hours to about 72 hours, about 6 hours to about 60
hours, about 6 hours to about 48 hours, about 6 hours to about 36
hours, about 6 hours to about 24 hours, or about 6 hours to about
12 hours.
[0116] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages is greater than the
concentration in the liver, kidney, spleen, pancreas, or plasma for
about 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6
hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 18
hours, 24 hours, 32 hours, 48 hours, 72 hours, 96 hours, 120 hours,
144 hours, 168 hours, 240 hours, or 336 hours.
[0117] In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 1000-fold greater than the concentration in the
liver. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 500-fold greater than the concentration in the
liver. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 100-fold greater than the concentration in the
liver. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 50-fold greater than the concentration in the
liver. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 20-fold greater than the concentration in the
liver. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 10-fold greater than the concentration in the
liver.
[0118] In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 5-fold greater
than the concentration in the liver. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 10-fold greater than the concentration in
the liver. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 20-fold
greater than the concentration in the liver. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 30-fold greater than the concentration in
the liver. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 40-fold
greater than the concentration in the liver. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 50-fold greater than the concentration in
the liver. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 60-fold
greater than the concentration in the liver. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 70-fold greater than the concentration in
the liver. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 80-fold
greater than the concentration in the liver. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 90-fold greater than the concentration in
the liver. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 100-fold
greater than the concentration in the liver. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 200-fold greater than the concentration
in the liver. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 300-fold
greater than the concentration in the liver. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 400-fold greater than the concentration
in the liver. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 500-fold
greater than the concentration in the liver. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 600-fold greater than the concentration
in the liver. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 700-fold
greater than the concentration in the liver. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 800-fold greater than the concentration
in the liver. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 900-fold
greater than the concentration in the liver. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 1000-fold greater than the concentration
in the liver.
[0119] In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 1000-fold greater than the concentration in the
kidney. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 500-fold greater than the concentration in the
kidney. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 100-fold greater than the concentration in the
kidney. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 50-fold greater than the concentration in the
kidney. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 20-fold greater than the concentration in the
kidney. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 10-fold greater than the concentration in the
kidney.
[0120] In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 5-fold greater
than the concentration in the kidney. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 10-fold greater than the concentration in
the kidney. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 20-fold
greater than the concentration in the kidney. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 30-fold greater than the concentration in
the kidney. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 40-fold
greater than the concentration in the kidney. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 50-fold greater than the concentration in
the kidney. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 60-fold
greater than the concentration in the kidney. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 70-fold greater than the concentration in
the kidney. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 80-fold
greater than the concentration in the kidney. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 90-fold greater than the concentration in
the kidney. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 100-fold
greater than the concentration in the kidney. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 200-fold greater than the concentration
in the kidney. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 300-fold
greater than the concentration in the kidney. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 400-fold greater than the concentration
in the kidney. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 500-fold
greater than the concentration in the kidney. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 600-fold greater than the concentration
in the kidney. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 700-fold
greater than the concentration in the kidney. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 800-fold greater than the concentration
in the kidney. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 900-fold
greater than the concentration in the kidney. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 1000-fold greater than the concentration
in the kidney.
[0121] In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 1000-fold greater than the concentration in the
spleen. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 500-fold greater than the concentration in the
spleen. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 100-fold greater than the concentration in the
spleen. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 50-fold greater than the concentration in the
spleen. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 20-fold greater than the concentration in the
spleen. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 10-fold greater than the concentration in the
spleen.
[0122] In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 5-fold greater
than the concentration in the spleen. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 10-fold greater than the concentration in
the spleen. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 20-fold
greater than the concentration in the spleen. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 30-fold greater than the concentration in
the spleen. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 40-fold
greater than the concentration in the spleen. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 50-fold greater than the concentration in
the spleen. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 60-fold
greater than the concentration in the spleen. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 70-fold greater than the concentration in
the spleen. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 80-fold
greater than the concentration in the spleen. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 90-fold greater than the concentration in
the spleen. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 100-fold
greater than the concentration in the spleen. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 200-fold greater than the concentration
in the spleen. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 300-fold
greater than the concentration in the spleen. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 400-fold greater than the concentration
in the spleen. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 500-fold
greater than the concentration in the spleen. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 600-fold greater than the concentration
in the spleen. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 700-fold
greater than the concentration in the spleen. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 800-fold greater than the concentration
in the spleen. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 900-fold
greater than the concentration in the spleen. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 1000-fold greater than the concentration
in the spleen.
[0123] In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 1000-fold greater than the concentration in the
pancreas. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 500-fold greater than the concentration in the
pancreas. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 100-fold greater than the concentration in the
pancreas. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 50-fold greater than the concentration in the
pancreas. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 20-fold greater than the concentration in the
pancreas. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 10-fold greater than the concentration in the
pancreas.
[0124] In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 5-fold greater
than the concentration in the pancreas. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 10-fold greater than the concentration in
the pancreas. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 20-fold
greater than the concentration in the pancreas. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages that is about 30-fold greater than the
concentration in the pancreas. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 40-fold greater than the concentration in
the pancreas. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 50-fold
greater than the concentration in the pancreas. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages that is about 60-fold greater than the
concentration in the pancreas. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 70-fold greater than the concentration in
the pancreas. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 80-fold
greater than the concentration in the pancreas. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages that is about 90-fold greater than the
concentration in the pancreas. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 100-fold greater than the concentration
in the pancreas. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 200-fold
greater than the concentration in the pancreas. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages that is about 300-fold greater than the
concentration in the pancreas. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 400-fold greater than the concentration
in the pancreas. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 500-fold
greater than the concentration in the pancreas. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages that is about 600-fold greater than the
concentration in the pancreas. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 700-fold greater than the concentration
in the pancreas. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 800-fold
greater than the concentration in the pancreas. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages that is about 900-fold greater than the
concentration in the pancreas. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 1000-fold greater than the concentration
in the pancreas.
[0125] In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 1000-fold greater than the concentration in
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 500-fold greater than the concentration in plasma.
In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 100-fold greater than the concentration in plasma.
In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 50-fold greater than the concentration in plasma.
In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 20-fold greater than the concentration in plasma.
In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 10-fold greater than the concentration in
plasma.
[0126] In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 5-fold greater
than the concentration in plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 10-fold greater than the concentration in
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 20-fold greater
than the concentration in plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 30-fold greater than the concentration in
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 40-fold greater
than the concentration in plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 50-fold greater than the concentration in
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 60-fold greater
than the concentration in plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 70-fold greater than the concentration in
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 80-fold greater
than the concentration in plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 90-fold greater than the concentration in
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 100-fold greater
than the concentration in plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 200-fold greater than the concentration
in plasma. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 300-fold
greater than the concentration in plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 400-fold greater than the concentration
in plasma. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 500-fold
greater than the concentration in plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 600-fold greater than the concentration
in plasma. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 700-fold
greater than the concentration in plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 800-fold greater than the concentration
in plasma. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 900-fold
greater than the concentration in plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 1000-fold greater than the concentration
in plasma.
[0127] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages is above the minimum inhibitory
concentration (MIC) or the minimum effective concentration (MEC)
for about 1 hour to about 336 hours after administration. In some
embodiments, the concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages is above the minimum inhibitory
concentration (MIC) or the minimum effective concentration (MEC)
for about 3 hours to about 336 hours after administration. In some
embodiments, the concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages is above the minimum inhibitory
concentration (MIC) or the minimum effective concentration (MEC)
for about 1 hour after administration. In some embodiments, the
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages is above the minimum inhibitory concentration (MIC) or
the minimum effective concentration (MEC) for about 3 hours after
administration. In some embodiments, the concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages is above
the minimum inhibitory concentration (MIC) or the minimum effective
concentration (MEC) for about 6 hours after administration. In some
embodiments, the concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages is above the minimum inhibitory
concentration (MIC) or the minimum effective concentration (MEC)
for about 12 hours after administration. In some embodiments, the
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages is above the minimum inhibitory concentration (MIC) or
the minimum effective concentration (MEC) for about 24 hours after
administration. In some embodiments, the concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages is above
the minimum inhibitory concentration (MIC) or the minimum effective
concentration (MEC) for about 48 hours after administration. In
some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages is above the minimum inhibitory
concentration (MIC) or the minimum effective concentration (MEC)
for about 72 hours after administration. In some embodiments, the
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages is above the minimum inhibitory concentration (MIC) or
the minimum effective concentration (MEC) for about 96 hours after
administration. In some embodiments, the concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages is above
the minimum inhibitory concentration (MIC) or the minimum effective
concentration (MEC) for about 120 hours after administration. In
some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages is above the minimum inhibitory
concentration (MIC) or the minimum effective concentration (MEC)
for about 168 hours after administration. In some embodiments, the
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages is above the minimum inhibitory concentration (MIC) or
the minimum effective concentration (MEC) for about 336 hours after
administration.
[0128] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is above the minimum inhibitory concentration
(MIC) or the minimum effective concentration (MEC) for about 1 hour
to about 336 hours after administration. In some embodiments, the
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung is above
the minimum inhibitory concentration (MIC) or the minimum effective
concentration (MEC) for about 3 hours to about 336 hours after
administration. In some embodiments, the concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is above the minimum
inhibitory concentration (MIC) or the minimum effective
concentration (MEC) for about 1 hour after administration. In some
embodiments, the concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung is above the minimum inhibitory concentration (MIC) or the
minimum effective concentration (MEC) for about 2 hours after
administration. In some embodiments, the concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is above the minimum
inhibitory concentration (MIC) or the minimum effective
concentration (MEC) for about 3 hours after administration. In some
embodiments, the concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung is above the minimum inhibitory concentration (MIC) or the
minimum effective concentration (MEC) for about 6 hours after
administration. In some embodiments, the concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is above the minimum
inhibitory concentration (MIC) or the minimum effective
concentration (MEC) for about 12 hours after administration. In
some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is above the minimum inhibitory concentration
(MIC) or the minimum effective concentration (MEC) for about 24
hours after administration. In some embodiments, the concentration
of caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is above the minimum
inhibitory concentration (MIC) or the minimum effective
concentration (MEC) for about 48 hours after administration. In
some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is above the minimum inhibitory concentration
(MIC) or the minimum effective concentration (MEC) for about 72
hours after administration. In some embodiments, the concentration
of caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is above the minimum
inhibitory concentration (MIC) or the minimum effective
concentration (MEC) for about 96 hours after administration. In
some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is above the minimum inhibitory concentration
(MIC) or the minimum effective concentration (MEC) for about 120
hours after administration. In some embodiments, the concentration
of caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is above the minimum
inhibitory concentration (MIC) or the minimum effective
concentration (MEC) for about 168 hours after administration. In
some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is above the minimum inhibitory concentration
(MIC) or the minimum effective concentration (MEC) for about 336
hours after administration.
[0129] In some embodiments, the minimum inhibitory concentration
(MIC) is from about 0.001 .mu.g/mL to about 500 .mu.g/mL. In some
embodiments, the minimum inhibitory concentration (MIC) is from
about 0.001 .mu.g/mL to about 300 .mu.g/mL. In some embodiments,
the minimum inhibitory concentration (MIC) is from about 0.001
.mu.g/mL to about 128 .mu.g/mL. In some embodiments, the minimum
inhibitory concentration (MIC) is from about 0.001 .mu.g/mL to
about 32 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is from about 0.001 .mu.g/mL to about 16
.mu.g/mL.
[0130] In some embodiments, the minimum inhibitory concentration
(MIC) is from about 0.125 .mu.g/mL to about 500 .mu.g/mL. In some
embodiments, the minimum inhibitory concentration (MIC) is from
about 0.125 .mu.g/mL to about 300 .mu.g/mL. In some embodiments,
the minimum inhibitory concentration (MIC) is from about 0.125
.mu.g/mL to about 128 .mu.g/mL. In some embodiments, the minimum
inhibitory concentration (MIC) is from about 0.125 .mu.g/mL to
about 32 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is from about 0.125 .mu.g/mL to about 16
.mu.g/mL. In some embodiments, the minimum inhibitory concentration
(MIC) is from about 0.25 .mu.g/mL to about 16 .mu.g/mL. In some
embodiments, the minimum inhibitory concentration (MIC) is from
about 0.25 .mu.g/mL to about 32 .mu.g/mL. In some embodiments, the
minimum inhibitory concentration (MIC) is from about 0.25 .mu.g/mL
to about 128 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is from about 16 .mu.g/mL to about 128
.mu.g/mL.
[0131] In some embodiments, the minimum inhibitory concentration
(MIC) is about 0.001 .mu.g/mL. In some embodiments, the minimum
inhibitory concentration (MIC) is about 0.005 .mu.g/mL. In some
embodiments, the minimum inhibitory concentration (MIC) is about
0.010 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is about 0.015 .mu.g/mL. In some embodiments,
the minimum inhibitory concentration (MIC) is about 0.020 .mu.g/mL.
In some embodiments, the minimum inhibitory concentration (MIC) is
about 0.030 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is about 0.040 .mu.g/mL. In some embodiments,
the minimum inhibitory concentration (MIC) is about 0.050 .mu.g/mL.
In some embodiments, the minimum inhibitory concentration (MIC) is
about 0.060 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is about 0.070 .mu.g/mL. In some embodiments,
the minimum inhibitory concentration (MIC) is about 0.080 .mu.g/mL.
In some embodiments, the minimum inhibitory concentration (MIC) is
about 0.090 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is about 0.100 .mu.g/mL. In some embodiments,
the minimum inhibitory concentration (MIC) is about 0.125 .mu.g/mL.
In some embodiments, the minimum inhibitory concentration (MIC) is
about 0.20 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is about 0.25 .mu.g/mL. In some embodiments,
the minimum inhibitory concentration (MIC) is about 0.30 .mu.g/mL.
In some embodiments, the minimum inhibitory concentration (MIC) is
about 0.50 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is about 0.75 .mu.g/mL. In some embodiments,
the minimum inhibitory concentration (MIC) is about 1.00 .mu.g/mL.
In some embodiments, the minimum inhibitory concentration (MIC) is
about 1.50 .mu.g/mL. In some embodiments, wherein the minimum
inhibitory concentration (MIC) is about 2.00 .mu.g/mL. In some
embodiments, wherein the minimum inhibitory concentration (MIC) is
about 2.50 .mu.g/mL. In some embodiments, wherein the minimum
inhibitory concentration (MIC) is about 3.00 .mu.g/mL. In some
embodiments, the minimum inhibitory concentration (MIC) is about
4.00 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is about 8.00 .mu.g/mL. In some embodiments,
the minimum inhibitory concentration (MIC) is about 10.00 .mu.g/mL.
In some embodiments, the minimum inhibitory concentration (MIC) is
about 16.00 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is about 20.00 .mu.g/mL. In some embodiments,
the minimum inhibitory concentration (MIC) is about 30.00 .mu.g/mL.
In some embodiments, the minimum inhibitory concentration (MIC) is
about 32.00 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is about 40.00 .mu.g/mL. In some embodiments,
the minimum inhibitory concentration (MIC) is about 60.00 .mu.g/mL.
In some embodiments, the minimum inhibitory concentration (MIC) is
about 80.00 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is about 100.00 .mu.g/mL. In some embodiments,
the minimum inhibitory concentration (MIC) is about 120.00
.mu.g/mL. In some embodiments, the minimum inhibitory concentration
(MIC) is about 128.00 .mu.g/mL. In some embodiments, the minimum
inhibitory concentration (MIC) is about 150.00 .mu.g/mL. In some
embodiments, the minimum inhibitory concentration (MIC) is about
200.00 .mu.g/mL. In some embodiments, the minimum inhibitory
concentration (MIC) is about 300.00 .mu.g/mL. In some embodiments,
the minimum inhibitory concentration (MIC) is about 400.00
.mu.g/mL. In some embodiments, the minimum inhibitory concentration
(MIC) is about 500.00 .mu.g/mL.
[0132] In some embodiments, the minimum effective concentration
(MEC) is from about 0.001 .mu.g/mL to about 500 .mu.g/mL. In some
embodiments, the minimum effective concentration (MEC) is from
about 0.001 .mu.g/mL to about 300 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is from about 0.001
.mu.g/mL to about 128 .mu.g/mL. In some embodiments, the minimum
effective concentration (MEC) is from about 0.001 .mu.g/mL to about
32 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is from about 0.001 .mu.g/mL to about 16
.mu.g/mL. In some embodiments, the minimum effective concentration
(MEC) is from about 0.001 .mu.g/mL to about 1.0 .mu.g/mL. In some
embodiments, the minimum effective concentration (MEC) is from
about 0.001 .mu.g/mL to about 0.6 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is from about 0.001
.mu.g/mL to about 0.3 .mu.g/mL. In some embodiments, the minimum
effective concentration (MEC) is from about 0.001 .mu.g/mL to about
0.1 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is from about 0.008 .mu.g/mL to about 0.6
.mu.g/mL. In some embodiments, the minimum effective concentration
(MEC) is from about 0.008 .mu.g/mL to about 0.3 .mu.g/mL. In some
embodiments, the minimum effective concentration (MEC) is from
about 0.008 .mu.g/mL to about 0.06 .mu.g/mL.
[0133] In some embodiments, minimum effective concentration (MEC)
is about 0.001 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 0.005 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 0.010 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 0.015 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 0.020 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 0.030 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 0.040 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 0.050 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 0.060 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 0.070 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 0.080 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 0.090 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 0.100 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 0.125 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 0.200 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 0.250 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 0.300 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 0.400 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 0.500 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 0.600 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 0.700 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 0.75 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 0.800 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 0.900 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 1.000 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 1.500 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 2.000 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 2.500 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 3.000 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 4.000 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 8.000 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 10.000 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 16.00 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 20.00 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 30.00 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 32.00 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 40.00 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 60.00 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 80.00 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 100.00 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 120.00 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 128.00 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 150.00 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 200.00 .mu.g/mL. In some embodiments,
the minimum effective concentration (MEC) is about 300.00 .mu.g/mL.
In some embodiments, the minimum effective concentration (MEC) is
about 400.00 .mu.g/mL. In some embodiments, the minimum effective
concentration (MEC) is about 500.00 .mu.g/mL.
Particle Size
[0134] In some embodiments, the inhalation composition is
administered by the inhalation device as droplets or particles
having a mass median aerodynamic diameter (MMAD) from about 0.5
.mu.m to about 10 .mu.m. In some embodiments, the inhalation
composition is administered by the inhalation device as droplets or
particles having a mass median aerodynamic diameter (MMAD) from
about 0.5 .mu.m to about 5 .mu.m. In some embodiments, the
inhalation composition is administered by the inhalation device as
droplets or particles having a mass median aerodynamic diameter
(MMAD) from about 1 .mu.m to about 10 .mu.m. In some embodiments,
the inhalation composition is administered by the inhalation device
as droplets or particles having a mass median aerodynamic diameter
(MMAD) from about 1 .mu.m to about 5 .mu.m. In some embodiments,
the inhalation composition is administered by the inhalation device
as droplets or particles having a mass median aerodynamic diameter
(MMAD) from about 1 .mu.m to about 4 .mu.m. In some embodiments,
the inhalation composition is administered by the inhalation device
as droplets or particles having a mass median aerodynamic diameter
(MMAD) from about 1 .mu.m to about 3 .mu.m. In some embodiments,
the inhalation composition is administered by the inhalation device
as droplets or particles having a mass median aerodynamic diameter
(MMAD) from about 1 .mu.m to about 3 .mu.m. In some embodiments,
the inhalation composition is administered by the inhalation device
as droplets or particles having a mass median aerodynamic diameter
(MMAD) from about 2 .mu.m to about 3 .mu.m.
[0135] In some embodiments, the inhalation composition is
administered by the inhalation device as droplets or particles
having a mass median aerodynamic diameter (MMAD) of about 0.5
.mu.m. In some embodiments, the inhalation composition is
administered by the inhalation device as droplets or particles
having a mass median aerodynamic diameter (MMAD) of about 1 .mu.m.
In some embodiments, the inhalation composition is administered by
the inhalation device as droplets or particles having a mass median
aerodynamic diameter (MMAD) of about 2 .mu.m. In some embodiments,
the inhalation composition is administered by the inhalation device
as droplets or particles having a mass median aerodynamic diameter
(MMAD) of about 3 .mu.m. In some embodiments, the inhalation
composition is administered by the inhalation device as droplets or
particles having a mass median aerodynamic diameter (MMAD) of about
4 .mu.m. In some embodiments, the inhalation composition is
administered by the inhalation device as droplets or particles
having a mass median aerodynamic diameter (MMAD) of about 5 .mu.m.
In some embodiments, the inhalation composition is administered by
the inhalation device as droplets or particles having a mass median
aerodynamic diameter (MMAD) of about 6 .mu.m. In some embodiments,
the inhalation composition is administered by the inhalation device
as droplets or particles having a mass median aerodynamic diameter
(MMAD) of about 7 .mu.m. In some embodiments, the inhalation
composition is administered by the inhalation device as droplets or
particles having a mass median aerodynamic diameter (MMAD) of about
8 .mu.m. In some embodiments, the inhalation composition is
administered by the inhalation device as droplets or particles
having a mass median aerodynamic diameter (MMAD) of about 9 .mu.m.
In some embodiments, the inhalation composition is administered by
the inhalation device as droplets or particles having a mass median
aerodynamic diameter (MMAD) of about 10 .mu.m.
[0136] In some embodiments, the inhalation composition is
administered by the inhalation device as droplets or particles
having a GSD (geometric standard deviation) of about 1 to about 3.
In some embodiments, the inhalation composition is administered by
the inhalation device as droplets or particles having a GSD
(geometric standard deviation) of about 2 to about 3.
[0137] In some embodiments, the inhalation composition is
administered by the inhalation device as droplets or particles
having a GSD (geometric standard deviation) is about 1. In some
embodiments, the inhalation composition is administered by the
inhalation device as droplets or particles having a GSD (geometric
standard deviation) is about 2. In some embodiments, the inhalation
composition is administered by the inhalation device as droplets or
particles having a GSD (geometric standard deviation) is about
3.
Half-Life
[0138] In some embodiments, the half-life of the caspofungin, or a
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is about 1 hour to about 100 hours. In some
embodiments, the half-life of the caspofungin, or a polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung is about 1 hour to about 75 hours. In some embodiments,
the half-life of the caspofungin, or a polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung is about 1
hour to about 50 hours. In some embodiments, the half-life of the
caspofungin, or a polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is about 1 hour to about 20
hours. In some embodiments, the half-life of the caspofungin, or a
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is about 20 hours to about 50 hours. In some
embodiments, the half-life of the caspofungin, or a polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung is about 30 hours to about 50 hours. In some embodiments,
the half-life of the caspofungin, or a polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung is about 1
hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours,
about 6 hours, about 7 hours, about 8 hours, about 9 hours, about
10 hours, about 11 hours, about 12 hours, about 13 hours, about 14
hours, about 15 hours, about 16 hours, about 17 hours, about 18
hours, about 19 hours, about 20 hours, about 21 hours, about 22
hours, about 23 hours, about 24 hours, about 25 hours, about 26
hours, about 27 hours, about 28 hours, about 29 hours, about 30
hours, about 31 hours, about 32 hours, about 33 hours, about 34
hours, about 35 hours, about 36 hours, about 37 hours, about 38
hours, about 39 hours, about 40 hours, about 41 hours, about 42
hours, about 43 hours, about 44 hours, about 45 hours, about 50
hours, about 55 hours, about 60 hours, about 65 hours, about 70
hours, about 75 hours, about 80 hours, about 85 hours, about 90
hours, about 95 hours, or about 100 hours.
[0139] In some embodiments, the half-life of the caspofungin, or a
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than about 1 hour, greater than
about 2 hours, greater than about 3 hours, greater than about 4
hours, greater than about 5 hours, greater than about 6 hours,
greater than about 7 hours, greater than about 8 hours, greater
than about 9 hours, greater than about 10 hours, greater than about
11 hours, greater than about 12 hours, greater than about 13 hours,
greater than about 14 hours, greater than about 15 hours, greater
than about 16 hours, greater than about 17 hours, greater than
about 18 hours, greater than about 19 hours, greater than about 20
hours, greater than about 21 hours, greater than about 22 hours,
greater than about 23 hours, greater than about 24 hours, greater
than about 25 hours, greater than about 26 hours, greater than
about 27 hours, greater than about 28 hours, greater than about 29
hours, greater than about 30 hours, greater than about 31 hours,
greater than about 32 hours, greater than about 33 hours, greater
than about 34 hours, greater than about 35 hours, greater than
about 36 hours, greater than about 37 hours, greater than about 38
hours, greater than about 39 hours, greater than about 40 hours,
greater than about 41 hours, greater than about 42 hours, greater
than about 43 hours, greater than about 44 hours, greater than
about 45 hours, greater than about 50 hours, greater than about 55
hours, greater than about 60 hours, greater than about 65 hours,
greater than about 70 hours, greater than about 75 hours, greater
than about 80 hours, greater than about 85 hours, greater than
about 90 hours, greater than about 95 hours, or greater than about
100 hours.
[0140] In some embodiments, the half-life of the caspofungin, or a
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is less than about 1 hour, less than about 2
hours, less than about 3 hours, less than about 4 hours, less than
about 5 hours, less than about 6 hours, less than about 7 hours,
less than about 8 hours, less than about 9 hours, less than about
10 hours, less than about 11 hours, less than about 12 hours, less
than about 13 hours, less than about 14 hours, less than about 15
hours, less than about 16 hours, less than about 17 hours, less
than about 18 hours, less than about 19 hours, less than about 20
hours, less than about 21 hours, less than about 22 hours, less
than about 23 hours, less than about 24 hours, less than about 25
hours, less than about 26 hours, less than about 27 hours, less
than about 28 hours, less than about 29 hours, less than about 30
hours, less than about 31 hours, less than about 32 hours, less
than about 33 hours, less than about 34 hours, less than about 35
hours, less than about 36 hours, less than about 37 hours, less
than about 38 hours, less than about 39 hours, less than about 40
hours, less than about 41 hours, less than about 42 hours, less
than about 43 hours, less than about 44 hours, less than about 45
hours, less than about 50 hours, less than about 55 hours, less
than about 60 hours, less than about 65 hours, less than about 70
hours, less than about 75 hours, less than about 80 hours, less
than about 85 hours, less than about 90 hours, less than about 95
hours, or less than about 100 hours.
Stability
[0141] In some embodiments, the inhalation composition is stable
from at about -20.degree. C. to about 25.degree. C. In some
embodiments, the inhalation composition is stable from at about
5.degree. C. to about 25.degree. C. In some embodiments, the
inhalation composition is stable at about -20.degree. C. In some
embodiments, the inhalation composition is stable at about
-15.degree. C. In some embodiments, the inhalation composition is
stable at about -10.degree. C. In some embodiments, the inhalation
composition is stable at about -5.degree. C. In some embodiments,
the inhalation composition is stable at about 0.degree. C. In some
embodiments, the inhalation composition is stable at about
5.degree. C. In some embodiments, the inhalation composition is
stable at about 6.degree. C. In some embodiments, the inhalation
composition is stable at about 7.degree. C. In some embodiments,
the inhalation composition is stable at about 8.degree. C. In some
embodiments, the inhalation composition is stable at about
9.degree. C. In some embodiments, the inhalation composition is
stable at about 10.degree. C. In some embodiments, the inhalation
composition is stable at about 11.degree. C. In some embodiments,
the inhalation composition is stable at about 12.degree. C. In some
embodiments, the inhalation composition is stable at about
13.degree. C. In some embodiments, the inhalation composition is
stable at about 14.degree. C. In some embodiments, the inhalation
composition is stable at about 15.degree. C. In some embodiments,
the inhalation composition is stable at about 16.degree. C. In some
embodiments, the inhalation composition is stable at about
17.degree. C. In some embodiments, the inhalation composition is
stable at about 18.degree. C. In some embodiments, the inhalation
composition is stable at about 19.degree. C. In some embodiments,
the inhalation composition is stable at about 20.degree. C. In some
embodiments, the inhalation composition is stable at about
21.degree. C. In some embodiments, the inhalation composition is
stable at about 22.degree. C. In some embodiments, the inhalation
composition is stable at about 23.degree. C. In some embodiments,
the inhalation composition is stable at about 24.degree. C. In some
embodiments, the inhalation composition is stable at about
25.degree. C.
[0142] In some embodiments, the inhalation compositions disclosed
herein are stable for at least about 6 months to about 2 years. In
some embodiments, the inhalation composition disclosed herein is
stable for at least about 6 months. In some embodiments, the
inhalation composition disclosed herein is stable for at least
about 7 months. In some embodiments, the inhalation composition
disclosed herein is for at least about 8 months. In some
embodiments, the inhalation composition disclosed herein is stable
for at least about 9 months. In some embodiments, the inhalation
composition disclosed herein is stable for at least about 10
months. In some embodiments, the inhalation composition disclosed
herein is stable for at least about 11 months. In some embodiments,
the inhalation composition disclosed herein is stable for at least
about 12 months. In some embodiments, the inhalation composition
disclosed herein is stable for at least about 13 months. In some
embodiments, the inhalation composition disclosed herein is stable
for at least about 14 months. In some embodiments, the inhalation
composition disclosed herein is stable for at least about 15
months. In some embodiments, the inhalation composition disclosed
herein is stable for at least about 16 months. In some embodiments,
the inhalation composition disclosed herein is stable for at least
about 17 months. In some embodiments, the inhalation composition is
stable for at least about 18 months. In some embodiments, the
inhalation composition disclosed herein is stable for at least
about 19 months. In some embodiments, the inhalation composition
disclosed herein is stable for at least about 20 months. In some
embodiments, the inhalation composition disclosed herein is stable
for at least about 21 months. In some embodiments, the inhalation
composition disclosed herein is stable for at least about 22
months. In some embodiments, the inhalation composition disclosed
herein is stable for at least about 23 months. In some embodiments,
the inhalation composition disclosed herein is stable for at least
about 24 months (2 years).
pH
[0143] In some embodiments, the inhalation composition has a pH
from about 4.0 to about 8.5. In some embodiments, the inhalation
composition has a pH from about 4.0 to about 7.5. In some
embodiments, the inhalation composition has a pH from about 5.0 to
about 8.5. In some embodiments, the inhalation composition has a pH
from about 6.0 to about 7.5. In some embodiments, the inhalation
composition has a pH from about 7.0 to about 7.5. In some
embodiments, the inhalation composition has a pH of about 4.0. In
some embodiments, the inhalation composition has a pH of about 4.5.
In some embodiments, the inhalation composition has a pH of about
5.0. In some embodiments, the inhalation composition has a pH of
about 5.5. In some embodiments, the inhalation composition has a pH
of about 6.0. In some embodiments, the inhalation composition has a
pH of about 6.5. In some embodiments, the inhalation composition
has a pH of about 7.0. In some embodiments, the inhalation
composition has a pH of about 7.5. In some embodiments, the
inhalation composition has a pH of about 8.0. In some embodiments,
the inhalation composition has a pH of about 8.5.
Pulmonary Infections
[0144] Disclosed herein is a method for the prevention or treatment
of a pulmonary infection in the pulmonary system. In some
embodiments, the method is for treating a fungal infection caused
by Candida sp., and/or by Aspergillus sp., and/or by Pneumocystis
jirovecii. In some embodiments, the method is for treating an
infection caused by Candida sp., and/or by Aspergillus sp. In some
embodiments, the method is for treating a fungal infection caused
by Candida albicans, Candida tropicalis, Candida krusei, Candida
glabrata, Candida guilliermondii, or Candida parapsilosis. In some
embodiments, the method is for treating a fungal infection caused
by Candida albicans, Candida tropicalis, Candida krusei, or Candida
glabrata. In some embodiments, the method for treating a fungal
infection caused by Aspergillus fumigatus, Aspergillus flavus,
Aspergillus niger, or Aspergillus terreus. In some embodiments, the
method for treating a fungal infection is caused by Aspergillus
fumigatus, Aspergillus flavus, or Aspergillus niger.
[0145] In some embodiments, the method is for preventing a fungal
infection caused by Candida sp., and/or by Aspergillus sp., and/or
by Pneumocystis jirovecii. In some embodiments, the method is for
preventing an infection caused by Candida sp., and/or by
Aspergillus sp. In some embodiments, the method is for treating a
fungal infection caused by Candida albicans, Candida tropicalis,
Candida krusei, Candida glabrata, Candida guilliermondii, or
Candida parapsilosis. In some embodiments, the method is for
preventing a fungal infection caused by Candida albicans, Candida
tropicalis, Candida krusei, or Candida glabrata. In some
embodiments, the method for treating a fungal infection caused by
Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, or
Aspergillus terreus. In some embodiments, the method for preventing
a fungal infection is caused by Aspergillus fumigatus, Aspergillus
flavus, or Aspergillus niger.
[0146] In some embodiments, the subject is immunocompromised. In
some embodiments, the subject is a transplant recipient or a
subject undergoing cancer chemotherapy. In some embodiments, the
subject is a transplant recipient. In some embodiments, the subject
is undergoing cancer chemotherapy. In some embodiments, the subject
is a recipient of a hematopoietic stem-cell transplant, bone marrow
transplant, lung transplant, liver transplant, heart transplant,
kidney transplant, pancreas transplant or a combination thereof. In
some embodiments, the subject is a recipient of a hematopoietic
stem-cell transplant. In some embodiments, the subject is a
recipient of a bone marrow transplant. In some embodiments, the
subject is a recipient of a lung transplant. In some embodiments,
the subject is a recipient of a liver transplant. In some
embodiments, the subject is a recipient of a heart transplant. In
some embodiments, the subject is a recipient of a kidney
transplant. In some embodiments, the subject is a recipient of a
pancreas transplant.
Kits
[0147] Provided herein is a kit comprising a composition suitable
for administration via inhalation, wherein the composition
comprises caspofungin, or a polymorph, pharmaceutically acceptable
salt, hydrate, or solvate thereof, and wherein the composition is
essentially free of mannitol; and an inhalation device.
[0148] In some embodiments, the kit is used for preventing or
treating a fungal infection in the pulmonary system of a subject.
In some embodiments, the kit is used for preventing a fungal
infection in the pulmonary system of a subject. In some
embodiments, the kit is used for treating a fungal infection in the
pulmonary system of a subject.
[0149] In some embodiments, the kit is for treating a fungal
infection caused by Candida sp., and/or by Aspergillus sp., and/or
by Pneumocystis jirovecii. In some embodiments, the kit is for
treating an infection caused by Candida sp., and/or by Aspergillus
sp. In some embodiments, the kit is for treating a fungal infection
caused by Candida albicans, Candida tropicalis, Candida krusei,
Candida glabrata, Candida guilliermondii, or Candida parapsilosis.
In some embodiments, the kit is for treating a fungal infection
caused by Candida albicans, Candida tropicalis, Candida krusei, or
Candida glabrata. In some embodiments, the kit for treating a
fungal infection caused by Aspergillus fumigatus, Aspergillus
flavus, Aspergillus niger, or Aspergillus terreus. In some
embodiments, the kit is for treating a fungal infection caused by
Aspergillus fumigatus, Aspergillus flavus, or Aspergillus
niger.
[0150] In some embodiments, kit is for preventing a fungal
infection caused by Candida sp., and/or by Aspergillus sp., and/or
by Pneumocystis jirovecii. In some embodiments, the kit is for
preventing an infection caused by Candida sp., and/or by
Aspergillus sp. In some embodiments, the kit is for treating a
fungal infection caused by Candida albicans, Candida tropicalis,
Candida krusei, Candida glabrata, Candida guilliermondii, or
Candida parapsilosis. In some embodiments, the kit is for
preventing a fungal infection caused by Candida albicans, Candida
tropicalis, Candida krusei, or Candida glabrata. In some
embodiments, the kit for treating a fungal infection caused by
Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, or
Aspergillus terreus. In some embodiments, the kit is for preventing
a fungal infection caused by Aspergillus fumigatus, Aspergillus
flavus, or Aspergillus niger.
[0151] In some embodiments, the composition disclosed herein is
essentially free of mannitol. In some embodiments, the composition
disclosed herein is essentially free of sugar alcohol. In some
embodiments, the composition disclosed herein is essentially free
of sugar alcohol or sugar.
[0152] In some embodiments, the administration of the composition
provides a lung tissue concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof that is from about 1-fold to about 100-fold greater than
the concentration in the lung via intravenous administration at the
same delivery dose. In some embodiments, the administration of the
inhalation composition provides a lung tissue concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof that is from about 1-fold to about
90-fold greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the inhalation composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is from about
1-fold to about 80-fold greater than the concentration in the lung
via intravenous administration at the same delivery dose. In some
embodiments, the administration of the inhalation composition
provides a lung tissue concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof that is from about 1-fold to about 70-fold greater than the
concentration in the lung via intravenous administration at the
same delivery dose. In some embodiments, the administration of the
inhalation composition provides a lung tissue concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof that is from about 1-fold to about
60-fold greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is from about
1-fold to about 50-fold greater than the concentration in the lung
via intravenous administration at the same delivery dose. In some
embodiments, the administration of the inhalation composition
provides a lung tissue concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof that is from about 1-fold to about 40-fold greater than the
concentration in the lung via intravenous administration at the
same delivery dose. In some embodiments, the administration of the
inhalation composition provides a lung tissue concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof that is from about 1-fold to about
30-fold greater than the concentration in the lung via intravenous
administration at the same delivery dose. In some embodiments, the
administration of the composition provides a lung tissue
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof that is from about
1-fold to about 20-fold greater than the concentration in the lung
via intravenous administration at the same delivery dose. In some
embodiments, the administration of the composition provides a lung
tissue concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof that
is from about 1-fold to about 10-fold greater than the
concentration in the lung via intravenous administration at the
same delivery dose. In some embodiments, the administration of the
composition provides a lung tissue concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof that is from about 1-fold to about 5-fold greater
than the concentration in the lung via intravenous administration
at the same delivery dose.
[0153] In some embodiments, the administration of the composition
provides a lung tissue concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof that is about 1-fold greater than the concentration in the
lung via intravenous administration at the same delivery dose. In
some embodiments, the administration of the composition provides a
lung tissue concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof that
is about 5-fold greater than the concentration in the lung via
intravenous administration at the same delivery dose. In some
embodiments, the administration of the composition provides a lung
tissue concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof that
is about 10-fold greater than the concentration in the lung via
intravenous administration at the same delivery dose. In some
embodiments, the administration of the composition provides a lung
tissue concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof that
is about 20-fold greater than the concentration in the lung via
intravenous administration at the same delivery dose. In some
embodiments, the administration of the composition provides a lung
tissue concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof that
is about 30-fold greater than the concentration in the lung via
intravenous administration at the same delivery dose. In some
embodiments, the administration of the composition provides a lung
tissue concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof that
is about 40-fold greater than the concentration in the lung via
intravenous administration at the same delivery dose. In some
embodiments, the administration of the composition provides a lung
tissue concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof that
is about 50-fold greater than the concentration in the lung via
intravenous administration at the same delivery dose. In some
embodiments, the administration of the composition provides a lung
tissue concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof that
is about 60-fold greater than the concentration in the lung via
intravenous administration at the same delivery dose. In some
embodiments, the administration of the composition provides a lung
tissue concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof that
is about 70-fold greater than the concentration in the lung via
intravenous administration at the same delivery dose. In some
embodiments, the administration of the composition provides a lung
tissue concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof that
is about 80-fold greater than the concentration in the lung via
intravenous administration at the same delivery dose. In some
embodiments, the administration of the composition provides a lung
tissue concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof that
is about 90-fold greater than the concentration in the lung via
intravenous administration at the same delivery dose. In some
embodiments, the administration of the composition provides a lung
tissue concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof that
is about 100-fold greater than the concentration in the lung via
intravenous administration at the same delivery dose.
[0154] In some embodiments, the lung tissue concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof is greater than the concentration in
the lung via intravenous administration at the same delivery dose
for about 0.5 hour to about 336 hours, about 0.5 hour to about 168
hours, about 0.5 hour to about 144 hours, about 0.5 hour to about
120 hours, about 0.5 hour to about 96 hours, about 0.5 hour to
about 72 hours, about 0.5 hour to about 60 hours, about 0.5 hour to
about 48 hours, about 0.5 to about 36 hours, about 0.5 to about 24
hours, about 0.5 hour to about 12 hours, about 0.5 hour to about 6
hours, about 0.5 hour to about 3 hours, or about 0.5 hour to about
2 hours. In some embodiments, the lung tissue concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof is greater than the concentration in
the lung via intravenous administration at the same delivery dose
for 1 hour to about 336 hours, about 1 hour to about 168 hours,
about 1 hour to about 144 hours, about 1 hour to about 120 hours,
about 1 hour to about 96 hours, about 1 hour to about 72 hours,
about 1 hour to about 60 hours, about 1 hour to about 48 hours,
about 1 hour to about 36 hours, about 1 hour to about 24 hours,
about 1 hour to about 12 hours, about 1 hour to about 6 hours, for
about 1 hour to about 3 hours, or about 1 hour to about 2 hours. In
some embodiments, the lung tissue concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof is greater than the concentration in the lung via
intravenous administration at the same delivery dose for about 3
hours to about 336 hours, about 3 hours to about 168 hours, about 3
hours to about 144 hours, about 3 hours to about 120 hours, about 3
hours to about 96 hours, about 3 hours to about 72 hours, about 3
hours to about 60 hours, about 3 hours to about 48 hours, about 3
hours to about 36 hours, about 3 hours to about 24 hours, about 3
hours to about 12 hours, or about 3 hours to about 6 hours. In some
embodiments, the lung tissue concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof is greater than the concentration in the lung via
intravenous administration at the same delivery dose for about 6
hours to about 336 hours, about 6 hours to about 168 hours, about 6
hours to about 144 hours, about 6 hours to about 120 hours, about 6
hours to about 96 hours, about 6 hours to about 72 hours, about 6
hours to about 60 hours, about 6 hours to about 48 hours, about 6
hours to about 36 hours, about 6 hours to about 24 hours, or about
6 hours to about 12 hours.
[0155] In some embodiments, the lung tissue concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof is greater than the concentration in
the lung via intravenous administration at the same delivery dose
for about 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6
hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 18
hours, 24 hours, 32 hours, 48 hours, 72 hours, 96 hours, 120 hours,
144 hours, 168 hours, 240 hours, or 336 hours.
[0156] In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 1000-fold
greater than the concentration in the liver, kidney, spleen,
pancreas or plasma. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
500-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
200-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the inhalation composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 150-fold greater than the concentration in the
liver, kidney, spleen, pancreas or plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 120-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 110-fold
greater than the concentration in the liver, kidney, spleen,
pancreas or plasma. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
100-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the inhalation composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 90-fold greater than the concentration in the
liver, kidney, spleen, pancreas or plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 80-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 70-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
60-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
50-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the inhalation composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 40-fold greater than the concentration in the
liver, kidney, spleen, pancreas or plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 30-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 20-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 10-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 5-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma.
[0157] In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is about 1-fold greater than the concentration in the
liver, kidney, spleen, pancreas or plasma. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is about 2-fold
greater than the concentration in the liver, kidney, spleen,
pancreas or plasma. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is about 3-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 4-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is about 5-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 10-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is about 15-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 20-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is about 30-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 40-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is about 50-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 60-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is about 70-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 80-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is about 90-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 100-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the inhalation composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is about 110-fold
greater than the concentration in the liver, kidney, spleen,
pancreas or plasma. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung that is about 120-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is about 130-fold greater than the concentration in
the liver, kidney, spleen, pancreas or plasma. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 140-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the inhalation composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is about 150-fold
greater than the concentration in the liver, kidney, spleen,
pancreas or plasma. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is about 200-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 300-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is about 400-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 500-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is about 600-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 700-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is about 800-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
about 900-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is about 1000-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma.
[0158] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the liver,
kidney, spleen, pancreas, or plasma for about 0.5 hour to about 336
hours, 0.5 hour to about 168 hours, about 0.5 hour to about 144
hours, about 0.5 hour to about 120 hours, about 0.5 hour to about
96 hours, about 0.5 hour to about 72 hours, about 0.5 hour to about
60 hours, about 0.5 hour to about 48 hours, about 0.5 to about 36
hours, about 0.5 to about 24 hours, about 0.5 hour to about 12
hours, about 0.5 hour to about 6 hours, about 0.5 hour to about 3
hours, or about 0.5 hour to about 2 hours. In some embodiments, the
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung is greater
than the concentration in the liver, kidney, spleen, pancreas, or
plasma for about 1 hour to about 336 hours, about 1 hour to about
168 hours, about 1 hour to about 144 hours, about 1 hour to about
120 hours, about 1 hour to about 96 hours, about 1 hour to about 72
hours, about 1 hour to about 60 hours, about 1 hour to about 48
hours, about 1 hour to about 36 hours, about 1 hour to about 24
hours, about 1 hour to about 12 hours, about 1 hour to about 6
hours, for about 1 hour to about 3 hours, or about 1 hour to about
2 hours. In some embodiments, the concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung is greater than the concentration in
the liver, kidney, spleen, pancreas, or plasma for about 3 hours to
about 336 hours, about 3 hours to about 168 hours, about 3 hours to
about 144 hours, about 3 hours to about 120 hours, about 3 hours to
about 96 hours, about 3 hours to about 72 hours, about 3 hours to
about 60 hours, about 3 hours to about 48 hours, about 3 hours to
about 36 hours, about 3 hours to about 24 hours, about 3 hours to
about 12 hours, or about 3 hours to about 6 hours. In some
embodiments, the concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung is greater than the concentration in the liver, kidney,
spleen, pancreas, or plasma for about 6 hours to about 336 hours,
about 6 hours to about 168 hours, about 6 hours to about 144 hours,
about 6 hours to about 120 hours, about 6 hours to about 96 hours,
about 6 hours to about 72 hours, about 6 hours to about 60 hours,
about 6 hours to about 48 hours, about 6 hours to about 36 hours,
about 6 hours to about 24 hours, or about 6 hours to about 12
hours.
[0159] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the liver,
kidney, spleen, pancreas, or plasma for about 0.5 hour, 1 hour, 2
hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9
hours, 10 hours, 11 hours, 12 hours, 18 hours, 24 hours, 32 hours,
48 hours, 72 hours, 96 hours, 120 hours, 144 hours, 168 hours, 240
hours, or 336 hours.
[0160] In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 1000-fold
greater than the concentration in the liver. In some embodiments,
the administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 500-fold greater than the concentration in the
liver. In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 200-fold
greater than the concentration in the liver. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 150-fold greater than the
concentration in the liver. In some embodiments, the administration
of the inhalation composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 120-fold greater than the concentration in the
liver. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
110-fold greater than the concentration in the liver. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 100-fold greater than the
concentration in the liver. In some embodiments, the administration
of the inhalation composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 90-fold greater than the concentration in the
liver. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
80-fold greater than the concentration in the liver. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 70-fold greater
than the concentration in the liver. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 60-fold greater than the
concentration in the liver. In some embodiments, the administration
of the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
50-fold greater than the concentration in the liver. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 40-fold greater
than the concentration in the liver. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 30-fold greater than the
concentration in the liver. In some embodiments, the administration
of the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
20-fold greater than the concentration in the liver. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 10-fold greater than the
concentration in the liver. In some embodiments, the administration
of the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
5-fold greater than the concentration in the liver.
[0161] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the liver
for about 0.5 hour to about 336 hours, about 0.5 hour to about 168
hours, about 0.5 hour to about 144 hours, about 0.5 hour to about
120 hours, about 0.5 hour to about 96 hours, about 0.5 hour to
about 72 hours, about 0.5 hour to about 60 hours, about 0.5 hour to
about 48 hours, about 0.5 to about 36 hours, about 0.5 to about 24
hours, about 0.5 hour to about 12 hours, about 0.5 hour to about 6
hours, about 0.5 hour to about 3 hours, or about 0.5 hour to about
2 hours. In some embodiments, the concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung is greater than the concentration in
the liver for about 1 hour to about 336 hours, about 1 hour to
about 168 hours, about 1 hour to about 144 hours, about 1 hour to
about 120 hours, about 1 hour to about 96 hours, about 1 hour to
about 72 hours, about 1 hour to about 60 hours, about 1 hour to
about 48 hours, about 1 hour to about 36 hours, about 1 hour to
about 24 hours, about 1 hour to about 12 hours, about 1 hour to
about 6 hours, for about 1 hour to about 3 hours, or about 1 hour
to about 2 hours. In some embodiments, the concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is greater than the
concentration in the liver for about 3 hours to about 336 hours,
about 3 hours to about 168 hours, about 3 hours to about 144 hours,
about 3 hours to about 120 hours, about 3 hours to about 96 hours,
about 3 hours to about 72 hours, about 3 hours to about 60 hours,
about 3 hours to about 48 hours, about 3 hours to about 36 hours,
about 3 hours to about 24 hours, about 3 hours to about 12 hours,
or about 3 hours to about 6 hours. In some embodiments, the
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung is greater
than the concentration in the liver for about 6 hours to about 336
hours, about 6 hours to about 168 hours, about 6 hours to about 144
hours, about 6 hours to about 120 hours, about 6 hours to about 96
hours, about 6 hours to about 72 hours, about 6 hours to about 60
hours, about 6 hours to about 48 hours, about 6 hours to about 36
hours, about 6 hours to about 24 hours, or about 6 hours to about
12 hours.
[0162] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the liver
for about 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6
hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 18
hours, 24 hours, 32 hours, 48 hours, 72 hours, 96 hours, 120 hours,
144 hours, 168 hours, 240 hours, or 336 hours.
[0163] In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 1000-fold
greater than the concentration in the kidney. In some embodiments,
the administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 500-fold greater than the concentration in the
kidney. In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 200-fold
greater than the concentration in the kidney. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 150-fold greater than the
concentration in the kidney. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 120-fold greater than the
concentration in the kidney. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 110-fold greater than the
concentration in the kidney. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 100-fold greater than the concentration in the
kidney. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
90-fold greater than the concentration in the kidney. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 80-fold greater
than the concentration in the kidney. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 70-fold greater than the
concentration in the kidney. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 60-fold greater than the
concentration in the kidney. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 50-fold greater than the concentration in the
kidney. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
40-fold greater than the concentration in the kidney. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 30-fold greater
than the concentration in the kidney. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 20-fold greater than the concentration in the
kidney. In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 10-fold greater
than the concentration in the kidney. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 5-fold greater than the concentration in the
kidney.
[0164] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the kidney
for about 0.5 hour to about 336 hours, about 0.5 hour to about 168
hours, about 0.5 hour to about 144 hours, about 0.5 hour to about
120 hours, about 0.5 hour to about 96 hours, about 0.5 hour to
about 72 hours, about 0.5 hour to about 60 hours, about 0.5 hour to
about 48 hours, about 0.5 to about 36 hours, about 0.5 to about 24
hours, about 0.5 hour to about 12 hours, about 0.5 hour to about 6
hours, about 0.5 hour to about 3 hours, or about 0.5 hour to about
2 hours. In some embodiments, the concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung is greater than the concentration in
the kidney for about 1 hour to about 336 hours, about 1 hour to
about 168 hours, about 1 hour to about 144 hours, about 1 hour to
about 120 hours, about 1 hour to about 96 hours, about 1 hour to
about 72 hours, about 1 hour to about 60 hours, about 1 hour to
about 48 hours, about 1 hour to about 36 hours, about 1 hour to
about 24 hours, about 1 hour to about 12 hours, about 1 hour to
about 6 hours, for about 1 hour to about 3 hours, or about 1 hour
to about 2 hours. In some embodiments, the concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is greater than the
concentration in the kidney for about 3 hours to about 336 hours,
about 3 hours to about 168 hours, about 3 hours to about 144 hours,
about 3 hours to about 120 hours, about 3 hours to about 96 hours,
about 3 hours to about 72 hours, about 3 hours to about 60 hours,
about 3 hours to about 48 hours, about 3 hours to about 36 hours,
about 3 hours to about 24 hours, about 3 hours to about 12 hours,
or about 3 hours to about 6 hours. In some embodiments, the
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung is greater
than the concentration in the kidney for about 6 hours to about 336
hours, about 6 hours to about 168 hours, about 6 hours to about 144
hours, about 6 hours to about 120 hours, about 6 hours to about 96
hours, about 6 hours to about 72 hours, about 6 hours to about 60
hours, about 6 hours to about 48 hours, about 6 hours to about 36
hours, about 6 hours to about 24 hours, or about 6 hours to about
12 hours.
[0165] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the kidney
for about 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6
hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 18
hours, 24 hours, 32 hours, 48 hours, 72 hours, 96 hours, 120 hours,
144 hours, 168 hours, 240 hours, or 336 hours.
[0166] In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 1000-fold
greater than the concentration in the spleen. In some embodiments,
the administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 500-fold greater than the concentration in the
spleen. In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 200-fold
greater than the concentration in the spleen. In some embodiments,
the administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 150-fold greater than the
concentration in the spleen. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 120-fold greater than the
concentration in the spleen. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 110-fold greater than the
concentration in the spleen. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 100-fold greater than the concentration in the
spleen. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
90-fold greater than the concentration in the spleen. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 80-fold greater
than the concentration in the spleen. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 70-fold greater than the
concentration in the spleen. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 60-fold greater than the
concentration in the spleen. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 50-fold greater than the concentration in the
spleen. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
40-fold greater than the concentration in the spleen. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 30-fold greater
than the concentration in the spleen. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 20-fold greater than the concentration in the
spleen. In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 10-fold greater
than the concentration in the spleen. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 5-fold greater than the concentration in the
spleen.
[0167] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the spleen
for about 0.5 hour to about 336 hours, about 0.5 hour to about 168
hours, about 0.5 hour to about 144 hours, about 0.5 hour to about
120 hours, about 0.5 hour to about 96 hours, about 0.5 hour to
about 72 hours, about 0.5 hour to about 60 hours, about 0.5 hour to
about 48 hours, about 0.5 to about 36 hours, about 0.5 to about 24
hours, about 0.5 hour to about 12 hours, about 0.5 hour to about 6
hours, about 0.5 hour to about 3 hours, or about 0.5 hour to about
2 hours. In some embodiments, the concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung is greater than the concentration in
the spleen for about 1 hour to about 336 hours, about 1 hour to
about 168 hours, about 1 hour to about 144 hours, about 1 hour to
about 120 hours, about 1 hour to about 96 hours, about 1 hour to
about 72 hours, about 1 hour to about 60 hours, about 1 hour to
about 48 hours, about 1 hour to about 36 hours, about 1 hour to
about 24 hours, about 1 hour to about 12 hours, about 1 hour to
about 6 hours, for about 1 hour to about 3 hours, or about 1 hour
to about 2 hours. In some embodiments, the concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is greater than the
concentration in the spleen for about 3 hours to about 336 hours,
about 3 hours to about 168 hours, about 3 hours to about 144 hours,
about 3 hours to about 120 hours, about 3 hours to about 96 hours,
about 3 hours to about 72 hours, about 3 hours to about 60 hours,
about 3 hours to about 48 hours, about 3 hours to about 36 hours,
about 3 hours to about 24 hours, about 3 hours to about 12 hours,
or about 3 hours to about 6 hours. In some embodiments, the
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung is greater
than the concentration in the spleen for about 6 hours to about 336
hours, about 6 hours to about 168 hours, about 6 hours to about 144
hours, about 6 hours to about 120 hours, about 6 hours to about 96
hours, about 6 hours to about 72 hours, about 6 hours to about 60
hours, about 6 hours to about 48 hours, about 6 hours to about 36
hours, about 6 hours to about 24 hours, or about 6 hours to about
12 hours.
[0168] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the spleen
for about 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6
hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 18
hours, 24 hours, 32 hours, 48 hours, 72 hours, 96 hours, 120 hours,
144 hours, 168 hours, 240 hours, or 336 hours.
[0169] In some embodiments, the administration of composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 1000-fold
greater than the concentration in the pancreas. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 500-fold greater than the
concentration in the pancreas. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 200-fold greater than the concentration in the
pancreas. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
150-fold greater than the concentration in the pancreas. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 120-fold
greater than the concentration in the pancreas. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 110-fold
greater than the concentration in the pancreas. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 100-fold greater than the
concentration in the pancreas. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 90-fold greater than the
concentration in the pancreas. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 80-fold greater than the
concentration in the pancreas. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 70-fold greater than the
concentration in the pancreas. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 60-fold greater than the
concentration in the pancreas. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 50-fold greater than the concentration in the
pancreas. In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
40-fold greater than the concentration in the pancreas. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 30-fold greater
than the concentration in the pancreas. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 20-fold greater than the concentration in the
pancreas. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
10-fold greater than the concentration in the pancreas. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 5-fold greater than the
concentration in the pancreas.
[0170] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the
pancreas for about 0.5 hour to about 336 hours, about 0.5 hour to
about 168 hours, about 0.5 hour to about 144 hours, about 0.5 hour
to about 120 hours, about 0.5 hour to about 96 hours, about 0.5
hour to about 72 hours, about 0.5 hour to about 60 hours, about 0.5
hour to about 48 hours, about 0.5 to about 36 hours, about 0.5 to
about 24 hours, about 0.5 hour to about 12 hours, about 0.5 hour to
about 6 hours, about 0.5 hour to about 3 hours, or about 0.5 hour
to about 2 hours. In some embodiments, the concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is greater than the
concentration in the pancreas for about 1 hour to about 336 hours,
about 1 hour to about 168 hours, about 1 hour to about 144 hours,
about 1 hour to about 120 hours, about 1 hour to about 96 hours,
about 1 hour to about 72 hours, about 1 hour to about 60 hours,
about 1 hour to about 48 hours, about 1 hour to about 36 hours,
about 1 hour to about 24 hours, about 1 hour to about 12 hours,
about 1 hour to about 6 hours, for about 1 hour to about 3 hours,
or about 1 hour to about 2 hours. In some embodiments, the
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung is greater
than the concentration in the pancreas for about 3 hours to about
336 hours, about 3 hours to about 168 hours, about 3 hours to about
144 hours, about 3 hours to about 120 hours, about 3 hours to about
96 hours, about 3 hours to about 72 hours, about 3 hours to about
60 hours, about 3 hours to about 48 hours, about 3 hours to about
36 hours, about 3 hours to about 24 hours, about 3 hours to about
12 hours, or about 3 hours to about 6 hours. In some embodiments,
the concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung is greater
than the concentration in the pancreas for about 6 hours to about
336 hours, about 6 hours to about 168 hours, about 6 hours to about
144 hours, about 6 hours to about 120 hours, about 6 hours to about
96 hours, about 6 hours to about 72 hours, about 6 hours to about
60 hours, about 6 hours to about 48 hours, about 6 hours to about
36 hours, about 6 hours to about 24 hours, or about 6 hours to
about 12 hours.
[0171] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the
pancreas for about 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 5
hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12
hours, 18 hours, 24 hours, 32 hours, 48 hours, 72 hours, 96 hours,
120 hours, 144 hours, 168 hours, 240 hours, or 336 hours.
[0172] In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 1000-fold
greater than the concentration in plasma. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 500-fold greater than the concentration in plasma.
In some embodiments, the administration of the composition provides
a concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 200-fold greater than the
concentration in plasma. In some embodiments, the administration of
the inhalation composition provides a concentration of caspofungin
or the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung that is from about 1-fold greater to
about 150-fold greater than the concentration in plasma. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 120-fold
greater than the concentration in plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 110-fold greater than the
concentration in plasma. In some embodiments, the administration of
the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
100-fold greater than the concentration in plasma. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 90-fold greater
than the concentration in plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 80-fold greater than the
concentration in plasma. In some embodiments, the administration of
the inhalation composition provides a concentration of caspofungin
or the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung that is from about 1-fold greater to
about 70-fold greater than the concentration in plasma. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 60-fold greater
than the concentration in plasma. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 50-fold greater than the concentration in plasma.
In some embodiments, the administration of the inhalation
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
40-fold greater than the concentration in plasma. In some
embodiments, the administration of the inhalation composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung that is from about 1-fold greater to about 30-fold greater
than the concentration in plasma. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung that is from about 1-fold
greater to about 20-fold greater than the concentration in plasma.
In some embodiments, the administration of the composition provides
a concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung that is
from about 1-fold greater to about 10-fold greater than the
concentration in plasma. In some embodiments, the administration of
the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung that is from about 1-fold greater to about
5-fold greater than the concentration in plasma.
[0173] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the plasma
for about 0.5 hour to about 336 hours, about 0.5 hour to about 168
hours, about 0.5 hour to about 144 hours, about 0.5 hour to about
120 hours, about 0.5 hour to about 96 hours, about 0.5 hour to
about 72 hours, about 0.5 hour to about 60 hours, about 0.5 hour to
about 48 hours, about 0.5 to about 36 hours, about 0.5 to about 24
hours, about 0.5 hour to about 12 hours, about 0.5 hour to about 6
hours, about 0.5 hour to about 3 hours, or about 0.5 hour to about
2 hours. In some embodiments, the concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung is greater than the concentration in
plasma for about 1 hour to about 336 hours, about 1 hour to about
168 hours, about 1 hour to about 144 hours, about 1 hour to about
120 hours, about 1 hour to about 96 hours, about 1 hour to about 72
hours, about 1 hour to about 60 hours, about 1 hour to about 48
hours, about 1 hour to about 36 hours, about 1 hour to about 24
hours, about 1 hour to about 12 hours, about 1 hour to about 6
hours, for about 1 hour to about 3 hours, or about 1 hour to about
2 hours. In some embodiments, the concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the lung is greater than the concentration in
the plasma for about 3 hours to about 336 hours, about 3 hours to
about 168 hours, about 3 hours to about 144 hours, about 3 hours to
about 120 hours, about 3 hours to about 96 hours, about 3 hours to
about 72 hours, about 3 hours to about 60 hours, about 3 hours to
about 48 hours, about 3 hours to about 36 hours, about 3 hours to
about 24 hours, about 3 hours to about 12 hours, or about 3 hours
to about 6 hours. In some embodiments, the concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is greater than the
concentration in the plasma for about 6 hours to about 336 hours,
about 6 hours to about 168 hours, about 6 hours to about 144 hours,
about 6 hours to about 120 hours, about 6 hours to about 96 hours,
about 6 hours to about 72 hours, about 6 hours to about 60 hours,
about 6 hours to about 48 hours, about 6 hours to about 36 hours,
about 6 hours to about 24 hours, or about 6 hours to about 12
hours.
[0174] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than the concentration in the plasma
for about 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6
hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 18
hours, 24 hours, 32 hours, 48 hours, 72 hours, 96 hours, 120 hours,
144 hours, 168 hours, 240 hours, or 336 hours.
[0175] In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages that is from about 5-fold greater to about
1000-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 500-fold greater than the concentration in the
liver, kidney, spleen, pancreas or plasma. In some embodiments, the
administration of the inhalation composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is from about 5-fold greater to about 200-fold
greater than the concentration in the liver, kidney, spleen,
pancreas or plasma. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is from about
5-fold greater to about 150-fold greater than the concentration in
the liver, kidney, spleen, pancreas or plasma. In some embodiments,
the administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
from about 5-fold greater to about 100-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is from about 5-fold greater to about 50-fold
greater than the concentration in the liver, kidney, spleen,
pancreas or plasma. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 20-fold greater than the concentration in the
liver, kidney, spleen, pancreas or plasma. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
from about 5-fold greater to about 10-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma.
[0176] In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages that is about 5-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 10-fold greater than the concentration in
the liver, kidney, spleen, pancreas or plasma. In some embodiments,
the administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 20-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 30-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma. In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages that is about 40-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 50-fold greater than the concentration in
the liver, kidney, spleen, pancreas or plasma. In some embodiments,
the administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 60-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 70-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma. In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages that is about 80-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 90-fold greater than the concentration in
the liver, kidney, spleen, pancreas or plasma. In some embodiments,
the administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 100-fold greater than the concentration in the liver, kidney,
spleen, pancreas or plasma. In some embodiments, the administration
of the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 150-fold greater
than the concentration in the liver, kidney, spleen, pancreas or
plasma. In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages that is about 200-fold greater than the
concentration in the liver, kidney, spleen, pancreas or plasma. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 300-fold greater than the concentration
in the liver, kidney, spleen, pancreas or plasma. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 400-fold greater than the concentration
in the liver, kidney, spleen, pancreas or plasma. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 500-fold greater than the concentration
in the liver, kidney, spleen, pancreas or plasma. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 600-fold greater than the concentration
in the liver, kidney, spleen, pancreas or plasma. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 700-fold greater than the concentration
in the liver, kidney, spleen, pancreas or plasma. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 800-fold greater than the concentration
in the liver, kidney, spleen, pancreas or plasma. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 900-fold greater than the concentration
in the liver, kidney, spleen, pancreas or plasma. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 1000-fold greater than the concentration
in the liver, kidney, spleen, pancreas or plasma.
[0177] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages is greater than the
concentration in the liver, kidney, spleen, pancreas, or plasma for
about 0.5 hour to about 336 hours, about 0.5 hour to about 168
hours, about 0.5 hour to about 144 hours, about 0.5 hour to about
120 hours, about 0.5 hour to about 96 hours, about 0.5 hour to
about 72 hours, about 0.5 hour to about 60 hours, about 0.5 hour to
about 48 hours, about 0.5 to about 36 hours, about 0.5 to about 24
hours, about 0.5 hour to about 12 hours, about 0.5 hour to about 6
hours, about 0.5 hour to about 3 hours, or about 0.5 hour to about
2 hours. In some embodiments, the concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages is greater than the
concentration in the liver, kidney, spleen, pancreas, or plasma for
about 1 hour to about 336 hours, about 1 hour to about 168 hours,
about 1 hour to about 144 hours, about 1 hour to about 120 hours,
about 1 hour to about 96 hours, about 1 hour to about 72 hours,
about 1 hour to about 60 hours, about 1 hour to about 48 hours,
about 1 hour to about 36 hours, about 1 hour to about 24 hours,
about 1 hour to about 12 hours, about 1 hour to about 6 hours, for
about 1 hour to about 3 hours, or about 1 hour to about 2 hours. In
some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages is greater than the
concentration in the liver, kidney, spleen, pancreas, or plasma for
about 3 hours to about 336 hours, about 3 hours to about 168 hours,
about 3 hours to about 144 hours, about 3 hours to about 120 hours,
about 3 hours to about 96 hours, about 3 hours to about 72 hours,
about 3 hours to about 60 hours, about 3 hours to about 48 hours,
about 3 hours to about 36 hours, about 3 hours to about 24 hours,
about 3 hours to about 12 hours, or about 3 hours to about 6 hours.
In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages is greater than the
concentration in the liver, kidney, spleen, pancreas, or plasma for
about 6 hours to about 336 hours, about 6 hours to about 168 hours,
about 6 hours to about 144 hours, about 6 hours to about 120 hours,
about 6 hours to about 96 hours, about 6 hours to about 72 hours,
about 6 hours to about 60 hours, about 6 hours to about 48 hours,
about 6 hours to about 36 hours, about 6 hours to about 24 hours,
or about 6 hours to about 12 hours.
[0178] In some embodiments, the concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages is greater than the
concentration in the liver, kidney, spleen, pancreas, or plasma for
about 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6
hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 18
hours, 24 hours, 32 hours, 48 hours, 72 hours, 96 hours, 120 hours,
144 hours, 168 hours, 240 hours, or 336 hours.
[0179] In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages that is from about 5-fold greater to about
1000-fold greater than the concentration in the liver. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is from about 5-fold greater to about 500-fold
greater than the concentration in the liver. In some embodiments,
the administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
from about 5-fold greater to about 100-fold greater than the
concentration in the liver. In some embodiments, the administration
of the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 50-fold greater than the concentration in the
liver. In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages that is from about 5-fold greater to about
20-fold greater than the concentration in the liver. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is from about 5-fold greater to about 10-fold
greater than the concentration in the liver.
[0180] In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages that is about 5-fold greater than the
concentration in the liver. In some embodiments, the administration
of the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 10-fold greater
than the concentration in the liver. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 20-fold greater than the concentration in the liver. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 30-fold greater than the concentration in
the liver. In some embodiments, the administration of the
inhalation composition provides a concentration of caspofungin or
the polymorph, pharmaceutically acceptable salt, hydrate, or
solvate thereof in the alveolar macrophages that is about 40-fold
greater than the concentration in the liver. In some embodiments,
the administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 50-fold greater than the concentration in the liver. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 60-fold greater than the concentration in
the liver. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 70-fold greater
than the concentration in the liver. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 80-fold greater than the concentration in the liver. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 90-fold greater than the concentration in
the liver. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 100-fold greater
than the concentration in the liver. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 200-fold greater than the concentration in the liver. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 300-fold greater than the concentration
in the liver. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 400-fold greater
than the concentration in the liver. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 500-fold greater than the concentration in the liver. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 600-fold greater than the concentration
in the liver. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 700-fold greater
than the concentration in the liver. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 800-fold greater than the concentration in the liver. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 900-fold greater than the concentration
in the liver. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 1000-fold greater
than the concentration in the liver.
[0181] In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages that is from about 5-fold greater to about
1000-fold greater than the concentration in the kidney. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is from about 5-fold greater to about 500-fold
greater than the concentration in the kidney. In some embodiments,
the administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
from about 5-fold greater to about 100-fold greater than the
concentration in the kidney. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
from about 5-fold greater to about 50-fold greater than the
concentration in the kidney. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
from about 5-fold greater to about 20-fold greater than the
concentration in the kidney. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
from about 5-fold greater to about 10-fold greater than the
concentration in the kidney.
[0182] In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages that is about 5-fold greater than the
concentration in the kidney. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 10-fold greater than the concentration in the kidney. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 20-fold greater than the concentration in
the kidney. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 30-fold greater
than the concentration in the kidney. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 40-fold greater than the concentration in the kidney. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 50-fold greater than the concentration in
the kidney. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 60-fold greater
than the concentration in the kidney. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 70-fold greater than the concentration in the kidney. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 80-fold greater than the concentration in
the kidney. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 90-fold greater
than the concentration in the kidney. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 100-fold greater than the concentration in the kidney. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 200-fold greater than the concentration
in the kidney. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 300-fold greater
than the concentration in the kidney. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 400-fold greater than the concentration in the kidney. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 500-fold greater than the concentration
in the kidney. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 600-fold greater
than the concentration in the kidney. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 700-fold greater than the concentration in the kidney. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 800-fold greater than the concentration
in the kidney. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 900-fold greater
than the concentration in the kidney. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 1000-fold greater than the concentration in the kidney.
[0183] In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages that is from about 5-fold greater to about
1000-fold greater than the concentration in the spleen. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is from about 5-fold greater to about 500-fold
greater than the concentration in the spleen. In some embodiments,
the administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
from about 5-fold greater to about 100-fold greater than the
concentration in the spleen. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
from about 5-fold greater to about 50-fold greater than the
concentration in the spleen. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
from about 5-fold greater to about 20-fold greater than the
concentration in the spleen. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
from about 5-fold greater to about 10-fold greater than the
concentration in the spleen.
[0184] In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages that is about 5-fold greater than the
concentration in the spleen. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 10-fold greater than the concentration in the spleen. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 20-fold greater than the concentration in
the spleen. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 30-fold greater
than the concentration in the spleen. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 40-fold greater than the concentration in the spleen. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 50-fold greater than the concentration in
the spleen. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 60-fold greater
than the concentration in the spleen. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 70-fold greater than the concentration in the spleen. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 80-fold greater than the concentration in
the spleen. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 90-fold greater
than the concentration in the spleen. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 100-fold greater than the concentration in the spleen. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 200-fold greater than the concentration
in the spleen. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 300-fold greater
than the concentration in the spleen. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 400-fold greater than the concentration in the spleen. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 500-fold greater than the concentration
in the spleen. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 600-fold greater
than the concentration in the spleen. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 700-fold greater than the concentration in the spleen. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 800-fold greater than the concentration
in the spleen. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 900-fold greater
than the concentration in the spleen. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 1000-fold greater than the concentration in the spleen.
[0185] In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages that is from about 5-fold greater to about
1000-fold greater than the concentration in the pancreas. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is from about 5-fold greater to about 500-fold
greater than the concentration in the pancreas. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is from about 5-fold greater to about 100-fold
greater than the concentration in the pancreas. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is from about 5-fold greater to about 50-fold
greater than the concentration in the pancreas. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is from about 5-fold greater to about 20-fold
greater than the concentration in the pancreas. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is from about 5-fold greater to about 10-fold
greater than the concentration in the pancreas.
[0186] In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages that is about 5-fold greater than the
concentration in the pancreas. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 10-fold greater than the concentration in the pancreas. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 20-fold greater than the concentration in
the pancreas. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 30-fold greater
than the concentration in the pancreas. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 40-fold greater than the concentration in the pancreas. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 50-fold greater than the concentration in
the pancreas. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 60-fold greater
than the concentration in the pancreas. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 70-fold greater than the concentration in the pancreas. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 80-fold greater than the concentration in
the pancreas. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 90-fold greater
than the concentration in the pancreas. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 100-fold greater than the concentration in the pancreas. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 200-fold greater than the concentration
in the pancreas. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 300-fold greater
than the concentration in the pancreas. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 400-fold greater than the concentration in the pancreas. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 500-fold greater than the concentration
in the pancreas. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 600-fold greater
than the concentration in the pancreas. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 700-fold greater than the concentration in the pancreas. In
some embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 800-fold greater than the concentration
in the pancreas. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 900-fold greater
than the concentration in the pancreas. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 1000-fold greater than the concentration in the pancreas.
[0187] In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages that is from about 5-fold greater to about
1000-fold greater than the concentration in plasma. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is from about 5-fold greater to about 500-fold
greater than the concentration in plasma. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
from about 5-fold greater to about 100-fold greater than the
concentration in plasma. In some embodiments, the administration of
the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is from about 5-fold
greater to about 50-fold greater than the concentration in plasma.
In some embodiments, the administration of the composition provides
a concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is from about 5-fold greater to about 20-fold
greater than the concentration in plasma. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
from about 5-fold greater to about 10-fold greater than the
concentration in plasma.
[0188] In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages that is about 5-fold greater than the
concentration in plasma. In some embodiments, the administration of
the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 10-fold greater
than the concentration in plasma. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages is about
20-fold greater than the concentration in plasma. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 30-fold greater than the concentration in
plasma. In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages that is about 40-fold greater than the
concentration in plasma. In some embodiments, the administration of
the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 50-fold greater
than the concentration in plasma. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 60-fold greater than the concentration in plasma. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 70-fold greater than the concentration in
plasma. In some embodiments, the administration of the composition
provides a concentration of caspofungin or the polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the alveolar macrophages is about 80-fold greater than the
concentration in plasma. In some embodiments, the administration of
the composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 90-fold greater
than the concentration in plasma. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 100-fold greater than the concentration in plasma. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 200-fold greater than the concentration
in plasma. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 300-fold greater
than the concentration in plasma. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 400-fold greater than the concentration in plasma. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 500-fold greater than the concentration
in plasma. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 600-fold greater
than the concentration in plasma. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 700-fold greater than the concentration in plasma. In some
embodiments, the administration of the composition provides a
concentration of caspofungin or the polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the alveolar
macrophages that is about 800-fold greater than the concentration
in plasma. In some embodiments, the administration of the
composition provides a concentration of caspofungin or the
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the alveolar macrophages that is about 900-fold greater
than the concentration in plasma. In some embodiments, the
administration of the composition provides a concentration of
caspofungin or the polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the alveolar macrophages that is
about 1000-fold greater than the concentration in plasma.
[0189] In some embodiments, the inhalation composition is
administered by the inhalation device as droplets or particles
having a mass median aerodynamic diameter (MMAD) from about 0.5
.mu.m to about 10 .mu.m. In some embodiments, the inhalation
composition is administered by the inhalation device as droplets or
particles having a mass median aerodynamic diameter (MMAD) from
about 0.5 .mu.m to about 5 .mu.m. In some embodiments, the
composition is administered by the device as droplets or particles
having a mass median aerodynamic diameter (MMAD) from about 1 .mu.m
to about 10 .mu.m. In some embodiments, the composition is
administered by the inhalation device as droplets or particles
having a mass median aerodynamic diameter (MMAD) from about 1 .mu.m
to about 5 .mu.m. In some embodiments, the inhalation composition
is administered by the inhalation device as droplets or particles
having a mass median aerodynamic diameter (MMAD) from about 1 .mu.m
to about 4 .mu.m. In some embodiments, the inhalation composition
is administered by the inhalation device as droplets or particles
having a mass median aerodynamic diameter (MMAD) from about 1 .mu.m
to about 3 .mu.m. In some embodiments, the composition is
administered by the inhalation device as droplets or particles
having a mass median aerodynamic diameter (MMAD) from about 2 .mu.m
to about 3 .mu.m.
[0190] In some embodiments, the inhalation composition is
administered by the inhalation device as droplets or particles
having a mass median aerodynamic diameter (MMAD) of about 0.5
.mu.m. In some embodiments, the composition is administered by the
inhalation device as droplets or particles having a mass median
aerodynamic diameter (MMAD) of about 1 .mu.m. In some embodiments,
the composition is administered by the inhalation device as
droplets or particles having a mass median aerodynamic diameter
(MMAD) of about 2 .mu.m. In some embodiments, the composition is
administered by the inhalation device as droplets or particles
having a mass median aerodynamic diameter (MMAD) of about 3 .mu.m.
In some embodiments, the composition is administered by the
inhalation device as droplets or particles having a mass median
aerodynamic diameter (MMAD) of about 4 .mu.m. In some embodiments,
the composition is administered by the inhalation device as
droplets or particles having a mass median aerodynamic diameter
(MMAD) of about 5 .mu.m. In some embodiments, the composition is
administered by the inhalation device as droplets or particles
having a mass median aerodynamic diameter (MMAD) of about 6 .mu.m.
In some embodiments, the composition is administered by the
inhalation device as droplets or particles having a mass median
aerodynamic diameter (MMAD) of about 7 .mu.m. In some embodiments,
the composition is administered by the inhalation device as
droplets or particles having a mass median aerodynamic diameter
(MMAD) of about 8 .mu.m. In some embodiments, the composition is
administered by the inhalation device as droplets or particles
having a mass median aerodynamic diameter (MMAD) of about 9 .mu.m.
In some embodiments, the composition is administered by the
inhalation device as droplets or particles having a mass median
aerodynamic diameter (MMAD) of about 10 .mu.m.
[0191] In some embodiments, the inhalation composition is
administered by the inhalation device as droplets or particles
having a GSD (geometric standard deviation) of about 1 to about 3.
In some embodiments, the inhalation composition is administered by
the inhalation device as droplets or particles having a GSD
(geometric standard deviation) of about 2 to about 3.
[0192] In some embodiments, the inhalation composition is
administered by the inhalation device as droplets or particles
having a GSD (geometric standard deviation) is about 1. In some
embodiments, the inhalation composition is administered by the
inhalation device as droplets or particles having a GSD (geometric
standard deviation) is about 2. In some embodiments, the inhalation
composition is administered by the inhalation device as droplets or
particles having a GSD (geometric standard deviation) is about
3.
[0193] In some embodiments, the half-life of the caspofungin, or a
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is about 1 hour to about 100 hours. In some
embodiments, the half-life of the caspofungin, or a polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung is about 1 hour to about 75 hours. In some embodiments,
the half-life of the caspofungin, or a polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung is about 1
hour to about 50 hours. In some embodiments, the half-life of the
caspofungin, or a polymorph, pharmaceutically acceptable salt,
hydrate, or solvate thereof in the lung is about 1 hour to about 20
hours. In some embodiments, the half-life of the caspofungin, or a
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is about 20 hours to about 50 hours. In some
embodiments, the half-life of the caspofungin, or a polymorph,
pharmaceutically acceptable salt, hydrate, or solvate thereof in
the lung is about 30 hours to about 50 hours. In some embodiments,
the half-life of the caspofungin, or a polymorph, pharmaceutically
acceptable salt, hydrate, or solvate thereof in the lung is about 1
hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours,
about 6 hours, about 7 hours, about 8 hours, about 9 hours, about
10 hours, about 11 hours, about 12 hours, about 13 hours, about 14
hours, about 15 hours, about 16 hours, about 17 hours, about 18
hours, about 19 hours, about 20 hours, about 21 hours, about 22
hours, about 23 hours, about 24 hours, about 25 hours, about 26
hours, about 27 hours, about 28 hours, about 29 hours, about 30
hours, about 31 hours, about 32 hours, about 33 hours, about 34
hours, about 35 hours, about 36 hours, about 37 hours, about 38
hours, about 39 hours, about 40 hours, about 41 hours, about 42
hours, about 43 hours, about 44 hours, about 45 hours, about 50
hours, about 55 hours, about 60 hours, about 65 hours, about 70
hours, about 75 hours, about 80 hours, about 85 hours, about 90
hours, about 95 hours, or about 100 hours.
[0194] In some embodiments, the half-life of the caspofungin, or a
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is greater than about 1 hour, greater than
about 2 hours, greater than about 3 hours, greater than about 4
hours, greater than about 5 hours, greater than about 6 hours,
greater than about 7 hours, greater than about 8 hours, greater
than about 9 hours, greater than about 10 hours, greater than about
11 hours, greater than about 12 hours, greater than about 13 hours,
greater than about 14 hours, greater than about 15 hours, greater
than about 16 hours, greater than about 17 hours, greater than
about 18 hours, greater than about 19 hours, greater than about 20
hours, greater than about 21 hours, greater than about 22 hours,
greater than about 23 hours, greater than about 24 hours, greater
than about 25 hours, greater than about 26 hours, greater than
about 27 hours, greater than about 28 hours, greater than about 29
hours, greater than about 30 hours, greater than about 31 hours,
greater than about 32 hours, greater than about 33 hours, greater
than about 34 hours, greater than about 35 hours, greater than
about 36 hours, greater than about 37 hours, greater than about 38
hours, greater than about 39 hours, greater than about 40 hours,
greater than about 41 hours, greater than about 42 hours, greater
than about 43 hours, greater than about 44 hours, greater than
about 45 hours, greater than about 50 hours, greater than about 55
hours, greater than about 60 hours, greater than about 65 hours,
greater than about 70 hours, greater than about 75 hours, greater
than about 80 hours, greater than about 85 hours, greater than
about 90 hours, greater than about 95 hours, or greater than about
100 hours.
[0195] In some embodiments, the half-life of the caspofungin, or a
polymorph, pharmaceutically acceptable salt, hydrate, or solvate
thereof in the lung is less than about 1 hour, less than about 2
hours, less than about 3 hours, less than about 4 hours, less than
about 5 hours, less than about 6 hours, less than about 7 hours,
less than about 8 hours, less than about 9 hours, less than about
10 hours, less than about 11 hours, less than about 12 hours, less
than about 13 hours, less than about 14 hours, less than about 15
hours, less than about 16 hours, less than about 17 hours, less
than about 18 hours, less than about 19 hours, less than about 20
hours, less than about 21 hours, less than about 22 hours, less
than about 23 hours, less than about 24 hours, less than about 25
hours, less than about 26 hours, less than about 27 hours, less
than about 28 hours, less than about 29 hours, less than about 30
hours, less than about 31 hours, less than about 32 hours, less
than about 33 hours, less than about 34 hours, less than about 35
hours, less than about 36 hours, less than about 37 hours, less
than about 38 hours, less than about 39 hours, less than about 40
hours, less than about 41 hours, less than about 42 hours, less
than about 43 hours, less than about 44 hours, less than about 45
hours, less than about 50 hours, less than about 55 hours, less
than about 60 hours, less than about 65 hours, less than about 70
hours, less than about 75 hours, less than about 80 hours, less
than about 85 hours, less than about 90 hours, less than about 95
hours, or less than about 100 hours.
[0196] In some embodiments, the inhalation composition is stable at
about -20.degree. C. to about 25.degree. C. In some embodiments,
the composition is stable from at about 5.degree. C. to about
25.degree. C. In some embodiments, the composition is stable at
about -20.degree. C. In some embodiments, the composition is stable
at about -15.degree. C. In some embodiments, the composition is
stable at about -10.degree. C. In some embodiments, the composition
is stable at about -5.degree. C. In some embodiments, the
composition is stable at about 0.degree. C. In some embodiments,
the composition is stable at about 5.degree. C. In some
embodiments, the composition is stable at about 6.degree. C. In
some embodiments, the composition is stable at about 7.degree. C.
In some embodiments, the composition is stable at about 8.degree.
C. In some embodiments, the composition is stable at about
9.degree. C. In some embodiments, the composition is stable at
about 10.degree. C. In some embodiments, the composition is stable
at about 11.degree. C. In some embodiments, the composition is
stable at about 12.degree. C. In some embodiments, the composition
is stable at about 13.degree. C. In some embodiments, the
composition is stable at about 14.degree. C. In some embodiments,
the composition is stable at about 15.degree. C. In some
embodiments, the composition is stable at about 16.degree. C. In
some embodiments, the composition is stable at about 17.degree. C.
In some embodiments, the composition is stable at about 18.degree.
C. In some embodiments, the composition is stable at about
19.degree. C. In some embodiments, the composition is stable at
about 20.degree. C. In some embodiments, the composition is stable
at about 21.degree. C. In some embodiments, the composition is
stable at about 22.degree. C. In some embodiments, the composition
is stable at about 23.degree. C. In some embodiments, the
composition is stable at about 24.degree. C. In some embodiments,
the composition is stable at about 25.degree. C.
[0197] In some embodiments, the compositions disclosed herein are
stable for at least about 6 months to about 2 years. In some
embodiments, the composition disclosed herein is stable for at
least about 6 months. In some embodiments, the composition
disclosed herein is stable for at least about 7 months. In some
embodiments, the composition disclosed herein is stable for at
least about 8 months. In some embodiments, the composition
disclosed herein is stable for at least about 9 months. In some
embodiments, the composition disclosed herein is stable for at
least about 10 months. In some embodiments, the composition
disclosed herein is stable for at least about 11 months. In some
embodiments, the composition disclosed herein is stable for at
least about 12 months. In some embodiments, the composition
disclosed herein is stable for at least about 13 months. In some
embodiments, the composition disclosed herein is stable for at
least about 14 months. In some embodiments, the composition
disclosed herein is stable for at least about 15 months. In some
embodiments, the composition disclosed herein is stable for at
least about 16 months. In some embodiments, the composition
disclosed herein is stable for at least about 17 months. In some
embodiments, the composition is stable for at least about 18
months. In some embodiments, the composition disclosed herein is
stable for at least about 19 months. In some embodiments, the
composition disclosed herein is stable for at least about 20
months. In some embodiments, the composition disclosed herein is
stable for at least about 21 months. In some embodiments, the
composition disclosed herein is stable for at least about 22
months. In some embodiments, the composition disclosed herein is
stable for at least about 23 months. In some embodiments, the
composition disclosed herein is stable for at least about 24 months
(2 years).
[0198] In some embodiments, the composition has a pH from about 4.0
to about 8.5. In some embodiments, the composition has a pH from
about 4.0 to about 7.5. In some embodiments, the composition has a
pH from about 5.0 to about 8.5. In some embodiments, the
composition has a pH from about 6.0 to about 7.5. In some
embodiments, the composition has a pH from about 7.0 to about 7.5.
In some embodiments, the composition has a pH of about 4.0. In some
embodiments, the composition has a pH of about 4.5. In some
embodiments, the composition has a pH of about 5.0. In some
embodiments, the composition has a pH of about 5.5. In some
embodiments, the composition has a pH of about 6.0. In some
embodiments, the composition has a pH of about 6.5. In some
embodiments, the composition has a pH of about 7.0. In some
embodiments, the composition has a pH of about 7.5. In some
embodiments, the composition has a pH of about 8.0. In some
embodiments, the composition has a pH of about 8.5.
[0199] Other embodiments and uses will be apparent to one skilled
in the art in light of the present disclosures. The following
examples are provided merely as illustrative of various embodiments
and shall not be construed to limit the present disclosure in any
way.
EXAMPLES
Example 1: Pharmacokinetic Studies with Caspofungin
Formulations
[0200] Experimental Design: Caspofungin was administered to rats at
a target dose of 2 mg/kg by nose only inhalation (by deposition) or
intravenously (IV) to determine the plasma and tissue
concentrations and pharmacokinetics.
[0201] Whole blood samples were collected from three animals per
time-point at approximately 0.5, 1, 2, 4, 8, 12, 24 and 48 hours
and 7 days after dose administration for plasma drug level
determination. Rats were anesthetized with 70% CO2/30% air and
blood was collected from the retro-orbital plexus and placed into
tubes containing anticoagulant (EDTA). Blood samples were placed on
ice immediately following collection and processed (i.e.,
centrifuged) to plasma. The samples were then stored frozen (at
approximately -70.degree. C.) until analyzed.
[0202] Tissue specimens (lung, liver and kidney) were collected
from three animals per time point at 0.5, 2, 24 and 48 hours and 7
days after dose administration. All tissue specimens were stored
frozen at approximately -70.degree. C. until analyzed.
[0203] Plasma and tissue samples were analyzed for levels of
caspofungin using high performance liquid chromatography-mass
spectrometry-mass spectrometry (LC-MS-MS) according to methods
established for the study.
[0204] Exposure of male rats to caspofungin via nose-only
inhalation or via intravenous injection resulted in no test-article
related mortality; no clinical signs of toxicity; no effects on
body weight; and no gross necropsy findings attributable to
exposure to the test article.
[0205] In Vivo Details: Thirty Sprague-Dawley derived rats
[Crl:CD.RTM.(CD)Br] were obtained from Charles River Laboratories,
Inc., Wilmington, Mass., for use in this study. The rats were 52
days of age (approximately 7.5 weeks) upon arrival. One day
following receipt, body weights of the rats ranged from 171 g to
213 g. The animals were held in quarantine for 7 days prior to
administration of the test article. Throughout the quarantine
period, animals were observed at least once daily for mortality or
evidence of a moribund state. Before being released from
quarantine, the animals were given a detailed, hand-held physical
examination to ensure their health and suitability as test
subjects. The test animals were approximately 8.5 weeks old at the
start of the first exposure to the test article.
[0206] During non-exposure periods of the study all animals were
housed in Lab Products Inc., polycarbonate "shoe-box" cages
(10.5''.times.19''.times.8''), with absorbent hardwood chip
bedding. The animals were double housed for the quarantine period),
in cages equipped with automatic water and food containers. Animals
were double housed for the treatment period in cages equipped with
automatic water and food containers. Following group assignment,
racks and cages were cleaned and sanitized.
[0207] Animal room environmental conditions were recorded at least
once daily throughout the quarantine and exposure periods.
Temperatures ranged from 20.degree. C. to 21.degree. C. throughout
the study, and relative humidity (% RH) values ranged from 46 to
56%. Fluorescent lighting in the animal room was provided on a
cycle of 12 hours of light followed by 12 hours of darkness (light
from approximately 6:00 a.m. to 6:00 p.m.).
[0208] To condition the animals to placement and restraint in the
nose-only exposure system and reduce stress during the exposure
phase, the animals were acclimated to the holding tubes by placing
each rat in a nose-only holding tube for approximately 45 minutes
one working day prior to exposure.
[0209] The study complied with all applicable sections of the
Animal Welfare Act (AWA; Title 9, Code of Federal Regulations), the
Public Health Service Policy on Humane Care and Use of Laboratory
Animals (National Institutes of Health's Office of Laboratory
Animal Welfare, 2002), and the Guide for the Care and Use of
Laboratory Animals (National Research Council, 2011). To the extent
possible, procedures used in this study were designed to avoid or
minimize discomfort, stress, and pain to animals.
[0210] The animals were fed Harlan's Certified Global 18% Protein
Rodent (2018C). Each certified lot of diet was analyzed for
contaminants to ensure that none are present at concentrations that
would be expected to interfere with the conduct or purpose of this
study. Analytical data from the lots of diet to be used in the
study are retained on file. Coarse-filtered City of Chicago water
was provided ad libitum to all rats via automatic watering system.
Supply water is analyzed periodically for bacterial contamination
and chemical composition (e.g., electrolytes, metals, etc.).
Test Article Preparation:
[0211] Solution for inhalation: A 10 mg/mL dosing solution was
prepared by dissolving 800 mg of caspofungin diacetate powder in 80
mL of 0.9% saline solution. The resulting solution was aseptically
filtered and kept refrigerated between 2-8.degree. C. until
used.
[0212] Solution for IV administration: A 2 mg/mL dosing solution
from commercially obtained Cancidas (containing 54.6 mg of
caspofungin diacetate) was prepared by a) adding into 10.8 mL of
0.9% saline into the Cancidas vial and swirling gently until the
powder dissolved. 10.0 mL of this solution was extracted and added
a 25 mL volumetric flask which was diluted to the mark with 0.9%
saline and mixed well. The resulting solution was aseptically
filtered and kept refrigerated between 2-8.degree. C. until
used.
[0213] Test Article Dosing: The animals were randomized into two
groups of 15 animals based on body weight. Each group was dosed as
shown in Table 1 below.
TABLE-US-00001 TABLE 1 Duration Number of Exposure Group Target
Dose Route (minutes) Animals I 2 mg/kg Inhalation 123 15 II 2 mg/kg
IV N/A 15
[0214] The dose targeted for deposition via inhalation was 2 mg/kg
and was calculated based on this equation:
Deposited dose=(C.times.RMV.times.T.times.DF)/BW
where C is the average caspofungin concentration in the exposure
atmosphere during the exposure period, RMV is the respiratory
minute volume, T is the exposure time, DF is the deposition
fraction (assumed to be 10% per FDA guidelines) and BW is the
average animal body weight on exposure day.
[0215] The dose for IV administration was calculated based on the
body weight of each animal
Delivered dose=W.times.2 mg/kg
where W is animal weight (kg).
Inhalation Exposure Methods:
[0216] Inhalation Exposure Laboratory: The inhalation exposure part
of the study was conducted in an inhalation facility. The supply
air to the laboratories was preconditioned and automatically
controlled with a thermostat and humidistat. Each flow-past
nose-only inhalation exposure chamber (Lab Products Inc., Seaford,
Del.) is comprised of 52 ports. The chambers were encased in an
acrylic enclosure to isolate the exposure chamber and protect
laboratory personnel. The test atmosphere inlet and exhaust
configurations provided a uniform and continuous stream of fresh
test atmosphere to the animals undergoing exposure. After flowing
out of the supply port, any excess test atmosphere, along with
exhaled air, is drawn into the chamber exhaust manifold without
entering other ports.
[0217] During the inhalation exposure, the animals were restrained
in nose-only holding tubes (CH Technologies, USA, Westwood, NJ).
Following confirmation of the correct animal number, each tube was
placed in a pre-designated port of the inhalation exposure chamber.
Chamber ports were rotated for each exposure; placement for each
exposure is documented in the study records. Animal tube loading
and unloading and tube insertion and removal from the chamber
manifold processes were performed according to laboratory standard
operating procedures that are designed to minimize stress to the
rats. The rats were observed frequently while restrained to ensure
that they remained in the tubes and were not in danger of injury.
At the end of each exposure, when the chamber was purged of the
test substance (less than one minute), the tubes with the animals
were removed. The rats were removed from the tubes and returned to
their home cages. The holding tubes were sanitized after each
use.
[0218] Test Atmosphere Generation: Test atmosphere at the desired
concentrations was generated by aerosolizing the test substance and
mixing it with compressed filtered air to produce a continuous
supply of test atmosphere. Test atmospheres were generated by
aerosolizing the test formulation with a commercially available
nebulizer using compressed air of breathable quality and which is
filtered with a compressed air filter and a carbon adsorber.
[0219] Exhaust from the exposure chambers was moved through a high
efficiency particulate air (HEPA) filter by a ring compressor and
exhausted outside the building. Inlet and exhaust flows to and from
the chamber were controlled and continuously monitored by
rotometers.
Test Atmosphere Monitoring:
[0220] Gravimetric Analysis:
[0221] The test atmosphere concentration in the exposure chamber
was determined gravimetrically each exposure by collecting test
atmosphere samples on filters placed in closed-face filter holders
in the breathing zone of the animals. The gravimetric sampling
train consisted of a pre-weighed filter in series with a dry-gas
meter connected to a constant flow vacuum pump. Samples were
collected at a constant flow rate equal to the port flow of the
delivery tube. The filter samples were weighed to determine the
aerosol mass collected. The dry-gas meter measured the
corresponding volume of chamber air sampled and the
weight-to-volume ratio was determined to obtain the aerosol mass
concentration.
[0222] Aerosol Particle Size Distribution:
[0223] Aerosol particle size distribution was determined once with
a quartz crystal microbalance (QCM) cascade impactor (California
Measurements Inc., Sierra Madre, Calif.) equipped with 10 stages to
collect size-segregated samples. The mass median aerodynamic
diameter (MMAD) and geometric standard deviation (GSD) were
calculated from the mass accumulated on each collection stage of
the QCM.
[0224] Temperature, Relative Humidity and Airflow Rate:
[0225] Inhalation exposure chamber temperature, relative humidity
and airflow rate (liters per minute; LPM) were measured and
recorded once during the exposure. The chamber temperature and
relative humidity were monitored with a hand-held thermohygrometer
(35612 series, Oakton Instruments, Vernon Hills, Ill.).
Intravenous Administration:
[0226] Animals in the IV dosing group received a single injection
via the tail vein at a dosing volume of 1 mL/kg.
Toxicology Methods:
[0227] Moribundity/Mortality Observations and Physical
Examinations/Clinical Observations: Prior to initiation of dosing
(exposure), animals were observed at least once daily for mortality
or evidence of moribundity. A detailed, hand-held physical
examination was conducted on all animals once during the quarantine
period (prior to randomization). During the treatment period, the
animals were observed daily for mortality or evidence of
moribundity; these checks were separated by a minimum of four
hours. Daily cage-side clinical observations were conducted during
exposure, and daily hand-held clinical observations were conducted
before and after exposure. Observations included, but were not
limited to the following: changes in the skin and fur, eyes, and
mucous membranes; effects on the respiratory, circulatory,
autonomic and central nervous systems; and effects on somatomotor
activity and behavior pattern.
Body Weights and Body Weight Changes: Body weights were determined
one day after animal receipt; at randomization; and prior to
exposure on Study Day 1, 2, 3 and 7 (as applicable based on
scheduled euthanization).
[0228] Plasma and Tissue Samples/Necropsy: Whole blood samples were
collected from three animals per time-point at approximately 0.5,
1, 2, 4, 8, 12, 24 and 48 hours and 7 days after dose
administration for plasma drug level determination. Rats were
anesthetized with 70% CO2/30% air and blood was collected from the
retro-orbital plexus and placed into tubes containing anticoagulant
(EDTA). Blood samples were placed on ice immediately following
collection and processed (i.e., centrifuged) to plasma. The samples
were then stored frozen (at approximately -70.degree. C.) until
analyzed. All study animals surviving to scheduled necropsy were
euthanized by an overdose of an intraperitoneal injection of sodium
pentobarbital at 35-45 mg/kg. Tissue specimens (lung, liver and
kidney) were collected from three animals per time point at 0.5, 2,
24 and 48 hours and 7 days after dose administration. All tissue
specimens were stored frozen at approximately -70.degree. C. until
analyzed.
Bioanalytical Method and Analysis:
[0229] Calibration and Internal Standards: The reference standard,
caspofungin acetate (lot number 02220902; Chunghwa Chemical
Synthesis & Biotech, Taiwan), was stored at approximately
-70.degree. C.; and used without further purification for the
preparation of calibration standards and quality control (QC)
samples for the determination of caspofungin in plasma and tissue
samples collected from this study. The internal standard
(caspofungin acetate-d4; lot number 10-GJF-162-1) was stored at
-20.degree. C.
[0230] Sample Preparation: For the determination of caspofungin in
plasma, a 100 .mu.L aliquot from each sample (in a 2 mL centrifuge
tube) was mixed with 0.3 mL of acetonitrile (ACN; Spectrum, New
Brunswick, N.J.) containing 150 ng of internal standard. After
shaking for five minutes, the sample was centrifuged at 4.degree.
C. for 10 minutes to remove precipitated proteins and supernatant
was transferred to an autosampler tube, diluted with 0.5 mL of
water, and vortex-mixed for instrumental analysis.
[0231] For the determination of caspofungin in tissue, samples
(lung--entire organ; liver--1 gram; kidneys--one organ) were finely
cut and extracted for analysis by adding 2.5 mL of ASTM Type I
water and shaking for approximately 0.5 hour, after which 2.5 mL of
acetonitrile (ACN; Spectrum, New Brunswick, N.J.) were added
following by shaking for another 0.5 hour. Subsequently, 100 .mu.L
of the supernatant was transferred to a 2 mL centrifuge tube and
processed for analysis using the same procedure as for plasma.
[0232] Freshly prepared caspofungin standard curves and quality
control (QC) samples were analyzed along with the study samples.
Instrument calibrators and QC samples were prepared by adding 10
.mu.L of a stock caspofungin solution in ACN/water (v/v 50/50) to
100 .mu.L of blank rat plasma (for both plasma and tissue samples).
Calibrator concentrations for plasma specimen analysis were
approximately 0.050, 0.10, 0.20, 0.50, 1.0, 2.5, 5.0 and 10
.mu.g/mL; QC samples were prepared at approximately 0.12, 4.0 and
8.0 .mu.g/mL. Calibrator concentrations for tissue specimen
analysis were approximately 1, 2, 5, 10, 20, 50 and 100 ng/sample;
QC samples were prepared at approximately 2.4, 40 and 80 ng/sample.
Calibrators and QC samples were processed for analysis following
the procedure described above.
[0233] Analytical Equipment and Conditions: Calibrator, QC and
study samples were analyzed under LC-MS-MS instrument conditions as
detailed in Table 2.
[0234] The retention time of caspofungin was approximately 2.3
minutes. Calibration curves were calculated from the linear
regression (weighting factor of 1/x.sup.2) of the caspofungin peak
area to internal standard peak area ratios versus caspofungin
concentration. Concentration of caspofungin in the samples was
determined using the peak area ratio and the regression parameters
of the calibration curve. Tissue results in ng were converted to
.mu.g/g using the amount of tissue extracted and the final extract
volume.
TABLE-US-00002 TABLE 2 Instrument Operating 4000 QTrap LC-MS-MS (AB
SCIEX, Conditions SYSTEM: Foster City, CA) equipped with a 1200
HPLC (Agilent Technologies, Wilmington, DE) HPLC CONDITIONS HPLC
Column: Kinetex Biphenyl 50 mm .times. 2.1 mm, 5 .mu.m, 100 .ANG.
(Phenomenex, Torrance, CA) Column Temperature 25.degree. C.
Injection Volume: 5 .mu.l Flow Rate: 300 .mu.L/min Mobile Phase A:
0.1% formic acid in water Mobile Phase B: 0.1% formic acid in
acetonitrile Time Mobile Phase A Mobile Phase B Program: (minutes)
(%) (%) 0.00 70 30 0.5 70 30 1.0 5 95 4.0 5 95 4.1 70 30 8.0 70 30
Run Time: 8 minutes Retention Time: Caspofungin and Internal
Standard - approximately 2.3 minutes MS-MS CONDITIONS Scan Type:
MRM Ion Source: Turbo Spray ESI Ion Spray Voltage: 5500 Volts
Polarity: Positive Ion Source Temperature: 550.degree. C. Collision
Energy: Caspofungin and Internal Standard: 20 Volts Ions monitored
(Q1.fwdarw.Q3): Caspofungin: 547.4 .fwdarw. 538.5; Internal
Standard: 550.3.fwdarw. 540.8 Resolution: Unit Data System: Analyst
.RTM. 1.6.3 (Applied Biosystems/ MDS Sciex, Foster City, CA)
[0235] Study Results: The pharmacokinetic experiment was performed
as described. The concentrations of caspofungin in plasma, lung,
kidney and liver tissues were determined and the results are
depicted in the following figures and tables described below.
[0236] FIG. 1 shows the pharmacokinetics of caspofungin in rat
plasma when delivered intravenously (dashed line) or via inhalation
(solid line) at 2 mg/kg. FIG. 2 shows the pharmacokinetics of
caspofungin in rat plasma when delivered intravenously (dashed
line) or via inhalation (solid line) at 2 mg/kg. FIG. 3 shows the
pharmacokinetics of caspofungin in rat lung tissue when delivered
intravenously (dashed line) or via inhalation (solid line) at 2
mg/kg. FIG. 4 shows the pharmacokinetics of caspofungin in rat
kidney tissue when delivered intravenously (dashed line) or via
inhalation (solid line) at 2 mg/kg. FIG. 5 shows the
pharmacokinetics of caspofungin in rat liver tissue when delivered
intravenously (dashed line) or via inhalation (solid line) at 2
mg/kg. FIG. 6 shows the relative weekly exposure per tissue,
Inhaled vs IV, from a single 2 mg/kg dose--a ratio of the 7 day AUC
for the inhaled route of delivery compared to the 7 day AUC for
intravenous administration. Tables 3-5 show the caspofungin
concentration as indicated below.
TABLE-US-00003 TABLE 3 Caspofungin Concentrations in Rat Lungs Time
(h) IV (.mu.g/g) Inhaled (.mu.g/g) Inhaled/IV 0.5 0.59 10.83 18.5 2
0.54 10.37 19.3 24 0.18 5.31 29.5 48 0.09 3.37 37.3 168 0.00 0.39
--
TABLE-US-00004 TABLE 4 Caspofungin Concentration in Rat Tissues
Following Inhaled Delivery at a dose of 2 mg/kg Time (h)
Lung(.mu.g/g) Plasma(.mu.g/mL) Kidney(.mu.g/g) Liver(.mu.g/g) 0.5
10.83 2.03 0.16 0.09 2 10.37 1.93 0.16 0.13 24 5.31 0.23 0.16 0.30
48 3.37 0.08 0.12 0.18 168 0.39 0.00 0.02 0.02
TABLE-US-00005 TABLE 5 Lung/Tissue Concentrations Ratios Following
Inhaled Delivery Time (h) Lung/Plasma Lung/Kidney Lung/Liver 0.5
5.3 69.1 115.0 2 5.4 64.7 77.8 24 22.9 32.4 17.6 48 43.8 28.8 18.9
168 -- 26.3 23.9
[0237] Table 6 shows the MIC and MEC for Aspergillus spp. isolate
susceptibility to caspofungin based from MIC data from Table 4,
Caspofungin Acetate FDA Advisory Committee Meeting Background,
Merck 2000 and MEC data from Espinel-Ingrof et al. Wild-Type MIC
Distributions and Epidemiological Cutoff Values for Caspofungin and
Aspergillus spp. for the CLSI Broth Microdilution Method,
Antimicrob. Agents Chemo., 2011, 55, 6, p 2855-2858.
TABLE-US-00006 TABLE 6 MIC.sub.90(.mu.g/mL) MEC (.mu.g/mL) Species
No. isolates Range Average.sup.a No. isolates Range Average.sup.b
Aspergillus 56 0.12-4 0.25 1691 0.016-32 0.25 fumigatus Aspergillus
flavus 13 0.06-2 0.2 432 0.016-32 0.06 Aspergillus nidulans 13
0.2-4 0.44 192 0.032-16 0.12 Aspergillus niger 10 0.06-0.5 0.14 440
0.016-2 0.06 Aspergillus terrus 11 0.06-.2 0.12 385 0.016-2 0.06
Aspergillus 75 0.032-2 0.12 versicolor .sup.aGeometric Mean MIC
.sup.bb. Mode - most frequent minimum effective concentration
(MEC)
[0238] Table 7 shows the MIC Candida spp. isolate susceptibility to
caspofungin based from Pfaller et al. Correlation of MIC with
Outcome for Candida Species Tested against Caspofungin,
Anidulafungin, and Micafungin: Analysis and Proposal for
Interpretive MIC Breakpoints, J. Clin Microbiol, 2008, 46, 8, p
2620-2629.
TABLE-US-00007 TABLE 7 No. Species isolates MIC.sub.90(.mu.g/mL)
Candida albicans 2869 0.06 Candida galbrata 747 0.12 Candida
tropicalis 625 0.06 Candida krusei 136 0.06 Candida parapsilosis
759 2 Candida guilliermondii 61 2
[0239] The half-life of caspofungin in the lung, as determined from
the studies described herein, is 39 hours i.e. every 39 hours 50%
of the remaining drug is eliminated from the lung. A projection of
the amount of caspofungin remaining in the lung following a time
period equivalent to one half-life is shown below in Table 8. The
lung concentration columns show two starting concentrations; one is
the concentration measured in the rat lung from the 2 mg/kg dose,
the second is the projected concentration that would result from an
inhaled dose of 7.2 mg/kg. To be effective the drug concentration
should remain above the MIC and MEC. The average MIC and MEC for
caspofungin versus Aspergillus fumigatus, the species most commonly
associated with Aspergillosis is 0.25 .mu.g/L.
TABLE-US-00008 TABLE 8 Drug Lung Concentration (.mu.g/g) Hours Days
Remaining 2 mg/kg 7.2 mg/kg 0 0 100% 10.8 39.0 39 1.6 50% 5.42 19.5
78 3.3 25% 2.71 9.75 117 4.9 13% 1.35 4.88 156 6.5 6% 0.68 2.44 195
8.1 3% 0.34 1.22 234 9.8 2% 0.17 0.61 273 11.4 1% 0.08 0.30 312
13.0 0.4%.sup. 0.04 0.15 351 14.6 0.2%.sup. 0.02 0.08
[0240] The measurement of the particles produced during the
inhalation experiment showed that they had a MMAD=1.15 .mu.m with a
GSD (geometric standard deviation) of 2.67.
Example 2: Comparative Tissue Distribution Studies of
Caspofungin
[0241] A pharmacokinetic study was performed in rats to investigate
the distribution of caspofungin parent compound to the organs most
associated with Aspergillosis and compound safety (i.e. lungs,
liver and kidney) when delivered either through an intravenous or
inhaled route. A comparison with the radiolabeled data from Stone
2004 (Stone, et. al. Disposition of Caspofungin: Role of
Distribution in Determining Pharmacokinetics in Plasma, Antimicrob.
Agents Chemo., 2004, 48, 3, p 815-823) is shown in Table 9. It is
clear that the amounts of caspofungin recovered from the IV dosed
study are substantially different from the previously reported
caspofungin concentrations. Not only are the distributions
significantly different, but they are in no way predictable.
TABLE-US-00009 TABLE 9 Plasma Kidney (.mu.g/mL) Lung (.mu.g/g)
(.mu.g/g) Liver (.mu.g/g) Time Stone IV Stone IV Stone IV Stone IV
(h) 2004.sup.a study.sup.b 2004.sup.a study.sup.b 2004.sup.a
study.sup.b 2004.sup.a study.sup.b 0.5 11 11.03 5.12 0.59 9.15 0.50
5.03 0.25 2 6.1 7.72 4.50 0.54 10.60 0.67 7.04 0.31 24 1.74 0.80
2.44 0.18 11.40 0.50 22.20 0.66 *Both studies dosed at 2 mg/kg
.sup.aquantities are of radiolabeled compound .sup.bquantities are
parent caspofungin acetate
Example 3: Prophylactic Efficacy of Aerosol Caspofungin in
Experimental Pulmonary Aspergillosis
[0242] The objective of the study is to determine the antifungal
efficacy of the caspofungin formulations administered via
inhalation therapy in the prophylaxis of invasive pulmonary
aspergillosis in rats.
[0243] The experimental procedures are performed according to the
procedures described in van de Cicogna et. al., Antimicrob. Agents
Chemother. 1997, 41, 259-261 with further modifications.
Caspofungin is used instead of amphotericin B.
[0244] The caspofungin formulation used herein include any one of
the formulations as described herein, such as those from Example 1,
or any one of the following formulations: Formulation 1:
caspofungin acetate
(4R,5S)-5-[(2-aminoethyl)amino]-N.sup.2-(10,12-dimethyl-loxotetradecyl)-4-
-hydroxy-L-ornithine]-5-[(3R)-3-hydroxy-L-ornithine] pneumocandin
B.sub.0 diacetate) (i.e. 50 mg or 70 mg), sucrose (i.e 34 mg or 54
mg), glacial acetic acid, sodium hydroxide; and Formulation 2:
caspofungin acetate
(4R,5S)-5-[(2-aminoethyl)amino]-N2-(10,12-dimethyl-loxotetradecyl)-4-hydr-
oxy-L-ornithine]-5-[(3R)-3-hydroxy-L-ornithine] pneumocandin B0
diacetate), glacial acetic acid, sodium hydroxide.
[0245] Male Sprague-Dawley rats (Charles River Breeding
Laboratories, Wilmington, Mass.) are fed a low-protein diet (8%
protein, Dyet, Bethelhem, Pa.) and are given a suitable amount of
tetracycline (i.e. 250 mg dissolved in 750 mL of drinking water) to
prevent bacterial infection. Furthermore, rats are treated with
subcutaneous injections of cortisone acetate (150 mg/kg of body
weight) three times a week under anesthesia with enflurane. These
injections are either given for two weeks until the day of
injection (trial 1) or throughout the duration of the experiment
(trial arm 2).
[0246] Aspergillus fumigatus H11-20 is obtained from a
steroid-treated rat dying from spontaneously acquired pulmonary
aspergillosis. Other clinical strains of Aspergillus fumigatus are
also suitable for these experiments. Suitable pores are obtained
from subculturing the organism on Sabouraud dextrose for an
appropriate time (i.e. 4 to 5 days) and are harvested with 0.02%
Tween 80 and washed with sterile saline. The final suspension
containing the desired amount of spores/mL, such as 10.sup.7
spores/mL, is prepared and confirmed by counting with a
hemacytometer.
[0247] General anesthesia in rats is induced with inhaled
enflurane, wherein a suitable amount of the Aspergillus spore
suspension (i.e., 0.1 mL to deliver 10.sup.6 spores) is injected
with a syringe to the exposed trachea. Wounds are closed surgical
staples.
[0248] The rats are administered the formulations of caspofungin as
described above with an inhalation device, such as a jet nebulizer
or an ultrasonic nebulizer, in a glass chamber. Rats are treated at
an appropriate time point before infection, such as 48 hours. The
estimated amount of drug inhaled by the rats is calculated from the
concentration of the product in the chamber, the minute volume of
the rats (lung volume times respiratory rate), and exposure
time.
[0249] For trial 1, rats (8-10 rats in each group) are either
treated with a placebo, such as sterile water, or with a suitable
dose of caspofungin at a suitable time period before infection
(i.e., 48 hours). Immunosuppressive treatments with cortisone
acetate are discontinued after time of infection. Rats in this
group are monitored for survival on daily basis for an appropriate
amount of time (i.e., 7 days).
[0250] For trial 2, rats (8-10 rats in each group) are either
treated with a placebo, such as sterile water or with an
appropriate dose of caspofungin at a suitable time period before
infection (i.e., 48 hours). Immunosuppressive treatments with
cortisone acetate are continued for the duration of the experiment
after infection (i.e., 14 days).
[0251] The outcome variables used to assess efficacy of this study
include but are not limited: survival of the infected rats during
therapy and after termination of therapy and caspofungin
concentration in the lung tissue and other organs (liver, kidney,
spleen, and pancreas) and plasma.
Example 4: Antifungal Efficacy of Caspofungin in Treatment of
Experimental Pulmonary Aspergillosis in Transiently Neutropenic
Rats
[0252] The objective of the study is to determine the antifungal
efficacy of the caspofungin formulations administered via
inhalation therapy in the treatment of invasive pulmonary
aspergillosis in transiently neutropenic rats.
[0253] The experimental procedures are performed according to the
procedures described in van de Sande et. al., Antimicrob. Agents
Chemother. 2008, 52, 1345-1350 with further modifications.
[0254] The caspofungin formulation used herein include any one of
the formulations as described herein, such as those from Example 1,
or any one of the following formulations: Formulation 1:
caspofungin acetate
(4R,5S)-5-[(2-aminoethyl)amino]-N.sup.2-(10,12-dimethyl-loxotetradecyl)-4-
-hydroxy-L-ornithine]-5-[(3R)-3-hydroxy-L-ornithine] pneumocandin
B.sub.0 diacetate) (i.e. 50 mg or 70 mg), sucrose (i.e 34 mg or 54
mg), glacial acetic acid, sodium hydroxide; and Formulation 2:
caspofungin acetate
(4R,5S)-5-[(2-aminoethyl)amino]-N2-(10,12-dimethyl-loxotetradecyl)-4-hydr-
oxy-L-ornithine]-5-[(3R)-3-hydroxy-L-ornithine] pneumocandin B0
diacetate), glacial acetic acid, sodium hydroxide.
[0255] A clinical strain of Aspergillus fumigatus is obtained from
a hemato-oncological patient with pulmonary aspergillosis. The
strain is passed through neutropenic rats and maintained on
Sabourand agar slants in order to maintain the strain's virulence.
The minimal inhibitory concentration (MIC) and minimal effective
concentration (MEC) of the strain used for this experiment against
caspofungin are determined accordingly.
Infection Model and Antifungal Treatment
[0256] The rat model of aerogenic left-sided invasive pulmonary
aspergillosis as described in van de Sande et. al., Antimicrob.
Agents Chemother. 2008, 52, 1345-1350 is used. Neutropenia is
induced by intraperitoneal administration of a suitable dose of
cyclophosphamide, such as 75 mg/kg, and is administered before
inoculation (i.e., 5 days) followed by administration of a suitable
dose prior to inoculation (i.e., 60 mg/kg 1 day before inoculation)
and several doses following inoculation (i.e., 50, 40, and 30 mg/kg
on days 3, 7, and 11 after fungal inoculation).
[0257] Fungal infection is established by intubation of the left
main bronchus while the rats are under general anesthesia. A
cannula is passed through the tube, and the left lobe is inoculated
with the appropriate amount of aspergillosis, such as
6.times.10.sup.4 conidia.
[0258] Antifungal therapy is initiated at a suitable time point
after inoculation, such as 16 h, 24 h, or 72 h after inoculation.
The rats are administered the formulations of caspofungin as
described above with an inhalation device, such as a jet nebulizer
or an ultrasonic nebulizer, in an appropriate dose (i.e., 4 mg/kg
or 10 mg/kg) and suitable dosing schedule, such as once a day, once
every two days, or once every three days. The antifungal therapy is
continued for a suitable amount of time, such as 7 days, 14 days,
or 21 days.
[0259] Outcome Variables
[0260] The outcome variables used to assess efficacy include but
not limited to following: survival of the infected rats during
therapy and after termination of therapy, pulmonary infarct score,
lung weight, residual, fungal burden (log CFU/gram), fungal growth
(log CFU/gram) in bronchoalveolar lavage fluid, computerized
tomograph (CT) scores, galactamannan index (GMI), and
histopathology.
Example 5: Antifungal Efficacy of Caspofungin for Prophylaxis of
Experimental Pulmonary Aspergillosis in Transiently Neutropenic
Rats
[0261] The objective of the study is to determine the antifungal
efficacy of the caspofungin formulations administered via
inhalation therapy in the prophylaxis of invasive pulmonary
aspergillosis in transiently neutropenic rats.
[0262] The experimental procedures are performed according to the
procedures described in van de Sande et. al., Antimicrob. Agents
Chemother. 2008, 52, 1345-1350 with further modifications.
[0263] The caspofungin formulation used herein include any one of
the formulations as described herein, such as those from Example 1,
or any one of the following formulations: Formulation 1:
caspofungin acetate
(4R,5S)-5-[(2-aminoethyl)amino]-N.sup.2-(10,12-dimethyl-loxotetradecyl)-4-
-hydroxy-L-ornithine]-5-[(3R)-3-hydroxy-L-ornithine] pneumocandin
B.sub.0 diacetate) (i.e. 50 mg or 70 mg), sucrose (i.e 34 mg or 54
mg), glacial acetic acid, sodium hydroxide; and Formulation 2:
caspofungin acetate
(4R,5S)-5-[(2-aminoethyl)amino]-N2-(10,12-dimethyl-loxotetradecyl)-4-hydr-
oxy-L-ornithine]-5-[(3R)-3-hydroxy-L-ornithine] pneumocandin B0
diacetate), glacial acetic acid, sodium hydroxide.
[0264] To assess the efficacy of caspofungin inhalation therapy for
the prophylaxis of pulmonary aspergillosis in a transiently
neutropenic rat model, the same methods used for the assessing the
therapeutic efficacy as described in Example 4 are utilized with
the following exceptions: caspofungin administration via inhalation
is started at a suitable time period before inoculation (i.e., 24
to 48 hours before infection); and a lower load of administered
inoculum is administered in order to simulate the low initial
tissue burden of A. fumigatus. Similar outcome variables as
described in Example 4 are used to assess efficacy.
* * * * *