U.S. patent application number 15/650437 was filed with the patent office on 2017-11-02 for tiotropium dry powders.
The applicant listed for this patent is PULMATRIX OPERATING COMPANY, INC.. Invention is credited to Wesley Dehaan, Diana Manzanedo, Jason M. Perry, Jean C. Sung, Brian Trautman.
Application Number | 20170312258 15/650437 |
Document ID | / |
Family ID | 50693973 |
Filed Date | 2017-11-02 |
United States Patent
Application |
20170312258 |
Kind Code |
A1 |
Sung; Jean C. ; et
al. |
November 2, 2017 |
TIOTROPIUM DRY POWDERS
Abstract
The present invention relates to respirable dry powder
comprising respirable dry particles that comprise sodium chloride,
leucine, and tiotropium bromide, wherein the sodium chloride is
about 60% to about 90%, the leucine is about 10% to about 40%, the
tiotropium bromide is about 0.01% to about 0.5%, and optionally one
or more additional therapeutic agents up to about 20%, wherein all
percentages are weight percentages on a dry basis and all the
components of the respirable dry particles amount to 100%. The
invention also relates to respirable dry powders that contain
respirable dry particles that comprise sodium chloride, leucine,
and tiotropium bromide, wherein the sodium chloride is 67% to 84%,
the leucine is 12% to 28%, the tiotropium bromide is about 0.01% to
about 0.5%, and optionally one or more additional therapeutic
agents up to about 20%, wherein all percentages are weight
percentages on a dry basis and all the components of the respirable
dry particles amount to 100%. The invention also relates to
respirable dry powders that contain respirable dry particles that
comprise about 79.5% to about 80.5% (w/w) sodium chloride, about
19.5% to about 20.5% (w/w) leucine, and about 0.01% to about 0.5%
(w/w) tiotropium bromide, and methods for treating a subject using
the respirable dry powders.
Inventors: |
Sung; Jean C.; (Cambridge,
MA) ; Manzanedo; Diana; (Cambridge, MA) ;
Perry; Jason M.; (Cambridge, MA) ; Dehaan;
Wesley; (Chelmsford, MA) ; Trautman; Brian;
(Arlington, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
PULMATRIX OPERATING COMPANY, INC. |
Lexington |
MA |
US |
|
|
Family ID: |
50693973 |
Appl. No.: |
15/650437 |
Filed: |
July 14, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14870736 |
Sep 30, 2015 |
9737518 |
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15650437 |
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PCT/US2014/025660 |
Mar 13, 2014 |
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14870736 |
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61874146 |
Sep 5, 2013 |
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61925400 |
Jan 9, 2014 |
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61807063 |
Apr 1, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 11/02 20180101;
A61K 31/439 20130101; A61K 45/06 20130101; Y02A 50/473 20180101;
A61P 11/06 20180101; A61K 31/57 20130101; Y02A 50/30 20180101; A61K
9/1611 20130101; A61P 11/00 20180101; A61P 43/00 20180101; Y02A
50/478 20180101; A61K 9/1617 20130101; A61K 9/0075 20130101; A61K
31/58 20130101; A61K 31/439 20130101; A61K 2300/00 20130101; A61K
31/58 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/439 20060101
A61K031/439; A61K 31/58 20060101 A61K031/58; A61K 31/57 20060101
A61K031/57; A61K 9/16 20060101 A61K009/16; A61K 9/16 20060101
A61K009/16; A61K 45/06 20060101 A61K045/06; A61K 9/00 20060101
A61K009/00 |
Claims
1. A receptacle comprising a respirable dry powder comprising
respirable dry particles that comprise sodium chloride, leucine,
and tiotropium bromide, wherein the sodium chloride is 75% to 82%,
the leucine is 15% to 25%, the tiotropium bromide is about 0.01% to
about 0.5%, and optionally one or more additional therapeutic
agents up to about 20%, wherein all percentages are weight
percentages on a dry basis and all the components of the respirable
dry particles amount to 100%, wherein the receptacle contains a
nominal dose of tiotropium between about 1.5 to about 12
micrograms.
2. The receptacle of claim 1, wherein the respirable dry powder has
a fine particle dose less than 5.0 microns of between about 1
microgram and about 5 micrograms of tiotropium.
3. The receptacle of claim 1, wherein the respirable dry powder has
a fine particle dose less than 4.4 microns of between about 1
microgram and about 4 micrograms of tiotropium.
4. The receptacle of claim 1, wherein the respirable dry powder has
a fine particle dose less than 4.4 microns of between about 1.5
micrograms and about 3.5 micrograms of tiotropium.
5. The receptacle of claim 1, wherein the receptacle is a capsule,
and wherein the capsule contains less than 6 mg of dry powder.
7. The receptacle of claim 1, wherein the respirable dry particles
have a volume median geometric diameter (VMGD) of about 5
micrometers or less.
8. The receptacle of claim 1, wherein the respirable dry powder has
a mass median aerodynamic diameter (MMAD) of between about 1 micron
and about 5 microns.
9. The receptacle of claim 1, wherein the respirable dry particles
have a 1/4 bar dispersibility ratio (1/4 bar) of less than 1.5 as
measured by laser diffraction.
10. The receptacle of claim 1, wherein the respirable dry particles
have a tap density greater than 0.4 g/cc to about 1.2
g/cm.sup.3.
11. The receptacle of claim 1, wherein the one or more additional
therapeutic agent is one or more corticosteroids.
12. A receptacle comprising a respirable dry powder comprising
respirable dry particles that comprise sodium chloride, leucine,
and tiotropium bromide, wherein the sodium chloride is 79.5% to
80.5%, the leucine is 19.5% to 20.5%, the tiotropium bromide is
about 0.01% to about 0.5%, and optionally one or more additional
therapeutic agents up to about 20%, wherein all percentages are
weight percentages on a dry basis and all the components of the
respirable dry particles amount to 100%, wherein the receptacle
contains a nominal dose of tiotropium between about 1.5 to about 12
micrograms.
13. A receptacle comprising a respirable dry powder comprising
respirable dry particles that comprise sodium chloride, leucine,
and tiotropium bromide, wherein the sodium chloride is 79.5% to
80.5%, the leucine is 19.5% to 20.5%, the tiotropium bromide is
about 0.01% to about 0.5%, and optionally one or more additional
therapeutic agents up to about 20%, wherein all percentages are
weight percentages on a dry basis and all the components of the
respirable dry particles amount to 100%, wherein the receptacle
contains a nominal dose of tiotropium between about 0.5 to about 6
micrograms
14. A method for treating a respiratory disease selected from the
group consisting of COPD, chronic bronchitis, emphysema, asthma,
cystic fibrosis, or non-cystic fibrosis bronchiectasis, comprising
administering to the respiratory tract of a patient in need thereof
an effective amount of a respirable dry powder of claim 1.
15. A method for treating or reducing the incidence or severity of
an acute exacerbation of a respiratory disease selected from the
group consisting of COPD, chronic bronchitis, emphysema, asthma,
cystic fibrosis, or non-cystic fibrosis bronchiectasis, comprising
administering to the respiratory tract of a patient in need thereof
an effective amount of a respirable dry powder of claim 1.
16. The method of claim 15, wherein the respiratory disease is
COPD.
17. A dry powder inhaler that contains the receptacle of claim 1,
wherein the dry powder inhaler is a capsule-based dry powder
inhaler or a blister-based dry powder inhaler.
18. The receptacle of claim 1, wherein the receptacle is a capsule
or a blister, and wherein the receptacle contains about 15 mg of
dry powder or less.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/870,736, filed Sep. 30, 2015, which is the
U.S. National Stage of International Application No.
PCT/US2014/025660, filed on Mar. 13, 2014, which claims the benefit
of U.S. Patent Application No. 61/807,063, filed on Apr. 1, 2013,
U.S. Patent Application No. 61/874,146, filed Sep. 5, 2013, and
U.S. Patent Application 61/925,400, filed Jan. 9, 2014, the entire
teachings of these applications are incorporated herein by
reference.
BACKGROUND
[0002] The chemical structure of tiotropium was first described in
U.S. Pat. Nos. 5,610,163 and RE39,820. Tiotropium salts include
salts containing cationic tiotropium with one of the following
anions: bromide, fluoride, chloride, iodine, C1-C4-alkylsulphate,
sulphate, hydrogen sulphate, phosphate, hydrogen phosphate,
di-hydrogen phosphate, nitrate, maleate, acetate, trifluoroacetate,
citrate, fumarate, tartrate, oxalate, succinate and benzoate,
C1-C4-alkylsulphonate, which may optionally be mono-, di- or
tri-substituted by fluorine at the alkyl group, or
phenylsulphonate, which may optionally be mono- or poly-substituted
by C1-C4-alkyl at the phenyl ring. Tiotropium bromide is an
anticholinergic providing therapeutic benefits, e.g. in the
treatment of COPD and asthma, and is the active ingredient in
SPIRIVA (tiotropium bromide) HANDIHALER (dry powder inhaler)
(Boehringer Ingelheim, Germany). Tiotropium bromide is known to
crystallize in various forms, such as crystalline anhydrous
(described e.g. in U.S. Pat. Nos. 6,608,055; 7,968,717; and
8,163,913 (Form 11)), crystalline monohydrate (described e.g. in
U.S. Pat. Nos. 6,777,423 and 6,908,928) and crystalline solvates
(described e.g. in U.S. Pat. No. 7,879,871). The various
crystalline forms of tiotropium can be distinguished by a number of
different assays, including X-ray Powder Diffraction (XRPD),
Differential scanning calorimetry (DSC), crystal structure, and
infrared (IR) spectrum analysis. Tiotropium can be synthesized
using a variety of methods which are well known in the art
(including, e.g. methods described in U.S. Pat. Nos. 6,486,321;
7,491,824; 7,662,963; and 8,344,143).
SUMMARY OF THE INVENTION
[0003] The invention relates to a respirable dry powder comprising
respirable dry particles that comprise sodium chloride, leucine,
and tiotropium bromide, wherein the sodium chloride is about 60% to
about 90%, the leucine is about 10% to about 40%, the tiotropium
bromide is about 0.01% to about 0.5%, and optionally one or more
additional therapeutic agents up to about 20%; preferably, the
sodium chloride is about 67% to about 84%, the leucine is about 12%
to about 28%, the tiotropium bromide is about 0.01% to about 0.5%,
and optionally one or more additional therapeutic agents up to
about 20%; more preferably, the sodium chloride is about 75% to
about 82% and the leucine is about 15% to about 25%; and most
preferably, the sodium chloride is about 79.5% to about 80.5% and
the leucine is about 19.5% to about 20.5%, where all the
percentages are weight percentages on a dry basis and all the
components of the respirable dry particles amount to 100%. The
invention also relates to a respirable dry powder comprising
respirable dry particles that comprise sodium chloride, leucine,
and tiotropium bromide, wherein the sodium chloride is about 65% to
about 86%, the leucine is about 10% to about 35%, the tiotropium
bromide is about 0.01% to about 0.5%, and optionally one or more
additional therapeutic agents, wherein the one or more additional
therapeutic agents is about 1% to about 10%, more preferably the
one or more additional therapeutic agents is about 3% to about 7%,
and most preferably the one or more additional therapeutic agents
is about 4% to about 5%, wherein all the percentages are weight
percentages on a dry basis and all the components of the respirable
dry particles amount to 100%.
[0004] The invention also relates to a respirable dry powder
comprising respirable dry particles consist of sodium chloride,
leucine, and tiotropium bromide, wherein the ratio of sodium
chloride to leucine is 2.5:1 to 8:1 (w/w), the tiotropium bromide
is about 0.01% to about 0.5%, and optionally one or more additional
therapeutic agent up to about 20%; preferably, the ratio of sodium
chloride to leucine is 3:1 to 6:1 (w/w); and most preferably, the
ratio of sodium chloride to leucine is about 4:1 (w/w), where all
percentages are weight percentages on a dry basis and all the
components of the respirable dry particles amount to 100%. The
invention also relates to a respirable dry powder comprising
respirable dry particles consist of sodium chloride, leucine, and
tiotropium bromide, wherein the ratio of sodium chloride to leucine
is 1.5:1 to 9:1 (w/w), the tiotropium bromide is about 0.01% to
about 0.5%, and optionally one or more additional therapeutic agent
up to about 20%; preferably, the ratio of sodium chloride to
leucine is 1.9:1 to 8.5:1 (w/w), where all percentages are weight
percentages on a dry basis and all the components of the respirable
dry particles amount to 100%.
[0005] The respirable dry powder comprising respirable dry
particles sometimes do not contain an additional therapeutic
agent.
[0006] The respirable dry powder comprising respirable dry
particles, at other times, do contain an additional therapeutic
agent of 20% or less of the formulation, by dry weight. The one or
more additional therapeutic agent may be present in an amount of
about 0.01% to about 10%, specifically, the one or more additional
therapeutic agent may be present in an amount of about 0.01% to
0.5%, an amount greater than 0.5% to 3%, or an amount greater than
3% to about 10%. The one or more additional therapeutic agent is
independently selected from the group consisting of one or more
corticosteroid, one or more long-acting beta agonist, one or more
short-acting beta agonist, one or more anti-inflammatory agent, one
or more bronchodilator, and any combination thereof.
[0007] The respirable dry powder comprising respirable dry
particles contains about 0.01% to about 0.5% tiotropium bromide, or
contains about 0.02% to about 0.25% tiotropium bromide, where the
percentages are weight percentages on a dry basis.
[0008] The respirable dry powder comprising respirable dry
particles have one or more of the following characteristics and/or
properties: a volume median geometric diameter (VMGD) about 10
micrometers or less, or about 1 micrometer to about 4 micrometers;
a tap density of at least about 0.45 g/cc, about 0.45 g/cc to about
1.2 g/cc, at least about 0.5 g/cc, at least about 0.55 g/cc, or at
least about 0.55 g/cc to about 1.0 g/cc; a mass median aerodynamic
diameter of between about 1 micron and about 5 microns, between
about 2 microns and about 5 microns, or preferably, between about
2.5 microns and about 4.5 microns; a fine particle dose less than
4.4 microns of between about 1 microgram and about 5 micrograms of
tiotropium, or about 2.0 micrograms and about 5.0 micrograms of
tiotropium; a ratio of the fine particle dose less than 2.0 microns
to the fine particle dose less than 4.4 microns of less than about
0.50, or preferably, less than about 0.35, or less than about 0.25;
a 1/4 bar dispersibility ratio of less than about 1.5, or less than
about 1.4, a 0.5/4 bar dispersibility ratio of about 1.5 or less,
all dispersibility ratios were measured by laser diffraction; an
FPF of the total dose less than 3.4 microns of about 25% or more,
between about 25% and about 60%, about 40% or more, or between
about 40% to about 60%; an FPF of the total dose less than 5.6
microns of about 45% or more, about 45% to about 80%, about 60% or
more, or about 60% to about 80%.
[0009] Also, they may have a tap density of at least about 0.4
g/cm.sup.3, a tap density of greater than 0.4 g/cm.sup.3, or
greater than 0.4 g/cm.sup.3 to about 1.2 g/cm.sup.3; an mass median
aerodynamic diameter (MMAD) of preferably between about 3 micron
and about 5 microns, or about 4 microns; or between about 3 microns
and about 6 microns, or, preferably, between about 4 microns and
about 6 microns, preferably, about 5 microns; a fine particle dose
less than 4.4 microns of between about 1 microgram and about 4
micrograms of tiotropium, or, preferably, between about 1.5
micrograms and 3.5 micrograms, about 2.0 micrograms, about 2.5
micrograms, or about 3.0 micrograms; a ratio of the fine particle
dose less than 2.0 microns to the fine particle dose less than 5.0
microns of less than about 0.50, or preferably, less than about
0.35, or preferably less than 0.25, less than 0.20, or less than
0.18.
[0010] The respirable dry powder comprising respirable dry
particles has a capsule emitted powder mass of at least 80% when
emitted from a passive dry powder inhaler that has a resistance of
about 0.036 sqrt(kPa)/liters per minute under the following
conditions; an inhalation energy of 2.3 Joules at a flow rate of 30
LPM using a size 3 capsule that contains a total mass of 10 mg,
said total mass consisting of the respirable dry particles, and
wherein the volume median geometric diameter of the respirable dry
particles emitted from the inhaler as measured by laser diffraction
is 5 microns or less.
[0011] The invention also relates to a method of treating a
respiratory disease and/or to a method of treating or reducing the
incidence or severity of an acute exacerbation of a respiratory
disease by administering to the respiratory tract of a patient in
need thereof the respiratory powder comprising respiratory
particles.
[0012] Additionally, the invention also relates to a method of
relieving the symptoms of a respiratory disease and/or a method of
improving the lung function of a patient with a respiratory disease
by administering to the respiratory tract of a patient in need
thereof the respiratory powder comprising respiratory particles.
Without wishing to be bound by theory, it is believed that
improving a patient's lung function over a period of time is a
long-term way to treat respiratory disease and/or to prevent acute
exacerbations.
[0013] The respirable dry powder comprising respirable dry
particles may be used 1) in treating a respiratory disease in an
individual, the use comprising administering to the respiratory
tract of the individual an effective amount of the respirable dry
powder, resulting in the treatment of a respiratory disease,
and/or, 2) in treating or reducing the incidence or severity of an
acute exacerbation of a respiratory disease in an individual, the
use comprising administering to the respiratory tract of the
individual an effective amount of the respirable dry powder,
resulting in the treatment or reduction in the incidence or
severity of an acute exacerbation of a respiratory disease.
[0014] Additionally, the respiratory dry powder comprising
respiratory dry particles may be used 1) in relieving the symptoms
of a respiratory disease, the use comprising administering to the
respiratory tract of the individual an effective amount of the
respirable dry powder, resulting in the relief of the symptoms of a
respiratory disease, and/or, 2) in improving the lung function of a
patient with a respiratory disease, the use comprising
administering to the respiratory tract of the individual an
effective amount of the respirable dry powder, resulting in an
improvement of the lung function of a patient with a respiratory
disease.
[0015] In some embodiments, the respiratory disease is COPD,
chronic bronchitis, emphysema, asthma, cystic fibrosis, or
non-cystic fibrosis bronchiectasis. The respiratory disease is
preferably COPD, chronic bronchitis, and/or emphysema.
[0016] The respirable dry powder comprising respirable dry
particles may be contained in a dry powder inhaler. The dry powder
inhaler may be a capsule-based dry powder inhaler, a blister-based
dry powder inhaler, or a reservoir-based dry powder inhaler. The
respirable dry powder comprising respirable dry particles may be
contained in a receptacle. The receptacle may be a capsule or a
blister, where the receptacle is suitable for any of the dry powder
inhalers listed above. The receptacle contains the respirable dry
powder of a mass of about 15 mg or less, about 11 mg or less, about
8.5 mg or less, about 6 mg or less, or about 4 mg or less. The
receptacle may contain the respirable dry powder of a mass of about
15 mg, 10 mg, 7.5 mg, 5 mg, 2.5 mg, or 1 mg. The receptacle may
contain a nominal dose of tiotropium between about 1.5 to about 12
micrograms, between about 3 to about 12 micrograms, between about 3
to about 9 micrograms, or between about 3 to about 6 micrograms.
The receptacle may contain a nominal dose of tiotropium of about
1.5 micrograms, about 3 micrograms, about 6 micrograms, about 9
micrograms, or about 12 micrograms. The receptacle can be contained
in a dry powder inhaler or can be packaged and/or sold
separately.
[0017] The respirable dry powder comprising respirable dry
particles may be contained in a dry powder inhaler. The dry powder
inhaler is preferably a capsule-based dry powder inhaler. More
preferably, the dry powder inhaler is selected from the RS01 family
of dry powder inhalers (Plastiape S.p.A., Italy). More preferably,
the dry powder inhaler is selected from the RS01 HR or the RS01
UHR2. In one aspect, the dry powder inhaler is not the RS01 HR.
Most preferably, the dry powder inhaler is the RS01 UHR2. The
respirable dry powder comprising respirable dry particles may be
contained in a receptacle. The receptacle is preferably a capsule.
Preferably, the capsule material is selected from gelatin and HPMC
(Hydroxypropyl methylcellulose). More preferably, the capsule
material is HPMC. In one aspect, the capsule material is not
gelatin. Preferably, the receptacle is a size 3 capsule. More
preferably the receptacle is a size 3, HPMC capsule. Most
preferably, the respirable dry powder comprising respirable dry
particles is contained in a size 3 HPMC capsule for use in the RS01
UHR2 dry powder inhaler. In one aspect, the respirable dry powder
consists of respirable dry particles.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 A) is a graph depicting the geometric mean of plasma
levels of tiotropium in pg/ml over time for exemplary Formulations
I, II, III, and IV, respectively. B) is a plot depicting the area
under the curve (AUC) for hours 0-2 after administration of
Formulations I, II, III, and IV, respectively, as
(pg.sub.tiotropium per hour)/ml.sub.serum.
[0019] FIG. 2 is a graph depicting mean change in FEV.sub.1 (forced
expiratory volume in one second) from baseline over time for
exemplary Formulations I, II, III, IV, and placebo,
respectively.
[0020] FIG. 3 is a graph of the aerodynamic size distributions at 4
kPA pressure drop for Formulation II at a 5.8 .mu.g nominal dose
and SPIRIVA (tiotropium bromide) HANDIHALER (dry powder inhaler) at
a 18 .mu.g nominal dose, illustrating a similar fine particle dose
(FPD) for Formulation II with a reduced nominal drug loading.
[0021] FIG. 4 is a graph showing that Formulation II has minimal
oral deposition versus the SPIRIVA (tiotropium bromide) HANDIHALER
(dry powder inhaler), reducing potential side effects.
[0022] FIG. 5 is a graph depicting reduced flow rate dependence of
Formulation II using the RS01 versus the SPIRIVA (tiotropium
bromide) HANDIHALER (dry powder inhaler) across a range of patient
relevant inhalation pressure drops.
[0023] FIG. 6 is a graph depicting the geometric mean of plasma
levels of tiotropium in pg/ml over time for exemplary Formulations
I, II, III and SPIRIVA (tiotropium bromide) HANDIHALER (dry powder
inhaler), respectively.
[0024] FIG. 7 is a graph depicting mean change in FEV.sub.1 (forced
expiratory volume in one second) from baseline over time for
exemplary Formulations I (3 micrograms nominal dose, also called "3
.mu.g"), II (6 micrograms nominal dose, also called "6 .mu.g"), III
(9 micrograms nominal dose, also called "9 .mu.g"), SPIRIVA
(tiotropium bromide) HANDIHALER (dry powder inhaler) and
placebo.
[0025] FIG. 8 is a graph of the aerodynamic size distributions at 4
kPA pressure drop for Formulation II delivered from the RS01 UHR2
at a 5.8 .mu.g nominal dose and SPIRIVA (tiotropium bromide)
HANDIHALER (dry powder inhaler) at a 18 .mu.g nominal dose,
illustrating a similar fine particle dose (FPD) for Formulation II
with a reduced nominal drug loading.
[0026] FIG. 9 is a graph showing that Formulation II delivered from
the RS01 UHR2 has minimal oral deposition versus the SPIRIVA
(tiotropium bromide) HANDIHALER (dry powder inhaler), reducing
potential side effects.
[0027] FIG. 10 is a graph depicting reduced flow rate dependence of
Formulation II delivered from the RS01 UHR2 versus the SPIRIVA
(tiotropium bromide) HANDIHALER (dry powder inhaler) across a range
of patient relevant inhalation pressure drops.
DETAILED DESCRIPTION OF THE INVENTION
[0028] The invention relates to respirable dry powders containing
respirable dry particles that comprise sodium chloride, leucine,
and tiotropium bromide, wherein the sodium chloride is about 60% to
about 90%, the leucine is about 10% to about 40%, the tiotropium
bromide is about 0.01% to about 0.5%, and optionally one or more
additional therapeutic agents up to about 20%; preferably, the
sodium chloride is about 67% to about 84%, the leucine is about 12%
to about 28%, the tiotropium bromide is about 0.01% to about 0.5%,
and optionally one or more additional therapeutic agents up to
about 20%; preferably, the sodium chloride is about 75% to about
82% and the leucine is about 15% to about 25%; and most preferably,
the sodium chloride is about 79.5% to about 80.5% and the leucine
is about 19.5% to about 20.5%, where all the percentages are weight
percentages on a dry basis and all the components of the respirable
dry particles amount to 100%. The invention also relates to a
respirable dry powder comprising respirable dry particles that
comprise sodium chloride, leucine, and tiotropium bromide, wherein
the sodium chloride is about 65% to about 86%, the leucine is about
10% to about 35%, the tiotropium bromide is about 0.01% to about
0.5%, and optionally one or more additional therapeutic agents,
wherein the one or more additional therapeutic agents is about 1%
to about 10%, more preferably the one or more additional
therapeutic agents is about 3% to about 7%, and most preferably the
one or more additional therapeutic agents is about 4% to about 5%,
wherein all the percentages are weight percentages on a dry basis
and all the components of the respirable dry particles amount to
100%.
[0029] The invention also relates to a respirable dry powder
comprising respirable dry particles consist of sodium chloride,
leucine, and tiotropium bromide, wherein the ratio of sodium
chloride to leucine is 2.5:1 to 8:1 (w/w), the tiotropium bromide
is about 0.01% to about 0.5%, and optionally one or more additional
therapeutic agent up to about 20%; preferably, the ratio of sodium
chloride to leucine is 3:1 to 6:1 (w/w); and most preferably, the
ratio of sodium chloride to leucine is about 4:1, where all
percentages are weight percentages on a dry basis and all the
components of the respirable dry particles amount to 100%. The
invention also relates to a respirable dry powder comprising
respirable dry particles consist of sodium chloride, leucine, and
tiotropium bromide, wherein the ratio of sodium chloride to leucine
is 1.5:1 to 9:1 (w/w), the tiotropium bromide is about 0.01% to
about 0.5%, and optionally one or more additional therapeutic agent
up to about 20%; preferably, the ratio of sodium chloride to
leucine is 1.9:1 to 8.5:1 (w/w), where all percentages are weight
percentages on a dry basis and all the components of the respirable
dry particles amount to 100%.
[0030] These respirable dry powders comprising respirable dry
particles may be manufactured from their components, in solutions
or suspensions that are aqueous and/or contain another solvent, by
spray drying or other comparable processes. The respirable dry
powders comprising respirable dry particles are relatively dry in
water and solvent content, small in geometric diameter, dense in
mass density, and dispersible in that they deagglomerate from each
other with a relatively low amount of energy. They have superior
aerosol properties such as a relatively small aerodynamic diameter,
a relatively high fine particle fraction and fine particle dose
below sizes that are relevant to lung deposition. These properties
are illustrated for two exemplary formulations in Example 1. Three
additional preferred respirable dry powders comprising respirable
dry particles that comprise sodium chloride, leucine and tiotropium
are described in Example 3. Despite the processing that takes place
to make the respirable dry powders comprising respirable dry
particles, the tiotropium bromide maintains its activity as is
demonstrated in the in vivo experiment described in Examples 2 and
4.
Definitions
[0031] As used herein, the term "about" refers to a relative range
of plus or minus 5% of a stated value, e.g., "about 20 mg" would be
"20 mg plus or minus 1 mg".
[0032] As used herein, the terms "administration" or
"administering" of respirable dry particles refers to introducing
respirable dry particles to the respiratory tract of a subject.
[0033] The term "capsule emitted powder mass" or "CEPM" as used
herein refers to the amount of dry powder formulation emitted from
a capsule or dose unit container during an inhalation maneuver.
CEPM is measured gravimetrically, typically by weighing a capsule
before and after the inhalation maneuver to determine the mass of
powder formulation removed. CEPM can be expressed either as the
mass of powder removed, in milligrams, or as a percentage of the
initial filled powder mass in the capsule prior to the inhalation
maneuver.
[0034] The term "dispersible" is a term of art that describes the
characteristic of a dry powder or dry particles to be dispelled
into a respirable aerosol. Dispersibility of a dry powder or dry
particles is expressed herein as the quotient of the volumetric
median geometric diameter (VMGD) measured at a dispersion (i.e.,
regulator) pressure of 1 bar divided by the VMGD measured at a
dispersion (i.e., regulator) pressure of 4 bar, or VMGD at 0.5 bar
divided by the VMGD at 4 bar as measured by laser diffraction, such
as with a HELOS/RODOS. These quotients are referred to herein as "1
bar/4 bar dispersibility ratio", and "0.5 bar/4 bar dispersibility
ratio", respectively, and dispersibility correlates with a low
quotient. For example, 1 bar/4 bar dispersibility ratio refers to
the VMGD of respirable dry particles or powders emitted from the
orifice of a RODOS dry powder disperser (or equivalent technique)
at about 1 bar, as measured by a HELOS or other laser diffraction
system, divided by the VMGD of the same respirable dry particles or
powders measured at 4 bar by HELOS/RODOS. Thus, a highly
dispersible dry powder or respirable dry particles will have a 1
bar/4 bar dispersibility ratio or 0.5 bar/4 bar dispersibility
ratio that is close to 1.0. Highly dispersible powders have a low
tendency to agglomerate, aggregate or clump together and/or, if
agglomerated, aggregated or clumped together, are easily dispersed
or de-agglomerated as they emit from an inhaler and are breathed in
by a subject. Dispersibility can also be assessed by measuring the
size emitted from an inhaler as a function of flowrate. As the flow
rate through the inhaler decreases, the amount of energy in the
airflow available to be transferred to the powder to disperse it
decreases. A highly dispersible powder will have its size
distribution as characterized aerodynamically by its mass median
aerodynamic diameter (MMAD) or geometrically by its VMGD, not
substantially increase over a range of flow rates typical of
inhalation by humans, such as about 15 to 60 LPM, or about 20 to 60
LPM. VMGD may also be called the volume median diameter (VMD),
.times.50, or Dv50.
[0035] The term "dry particles" as used herein refers to respirable
particles that may contain up to about 15% water or other solvent.
Preferably the dry powders contain water or other solvent up to
about 10%, up to about 5%, up to about 1%, or between 0.01% and 1%,
by weight of the dry particles, or can be substantially free of
water or other solvent, or be anhydrous.
[0036] The term "dry powders" as used herein refers to compositions
that comprise respirable dry particles. Preferably the respirable
dry powders contain water or other solvent up to about 10%, up to
about 5%, up to about 1%, or between 0.01% and 1%, by weight of the
respirable dry particles, or can be substantially free of water or
other solvent, or be anhydrous.
[0037] The term "effective amount," as used herein, refers to the
amount of agent needed to achieve the desired effect; improve or
prevent deterioration of respiratory function (e.g., improve forced
expiratory volume in 1 second (FEV.sub.1) and/or forced expiratory
volume in 1 second (FEV.sub.1) as a proportion of forced vital
capacity (FEV.sub.1/FVC)), reduce the occurrence of an acute
exacerbation of a respiratory disease, e.g., Chronic Obstructive
Pulmonary Disease (COPD), asthma, Cystic Fibrosis (CF), and non-CF
Bronchiectasis.
[0038] The actual effective amount for a particular use can vary
according to the particular dry powder or dry particle, the mode of
administration, and the age, weight, general health of the subject,
and severity of the symptoms or condition being treated. Suitable
amounts of dry powders and dry particles to be administered, and
dosage schedules for a particular patient can be determined by a
clinician of ordinary skill based on these and other
considerations.
[0039] As used herein, the term "emitted dose" or "ED" refers to an
indication of the delivery of a drug formulation from a suitable
inhaler device after a firing or dispersion event. More
specifically, for dry powder formulations, the ED is a measure of
the percentage of powder that is drawn out of a unit dose package
and that exits the mouthpiece of an inhaler device. The ED is
defined as the ratio of the dose delivered by an inhaler device to
the nominal dose (i.e., the mass of powder per unit dose placed
into a suitable inhaler device prior to firing). The ED is an
experimentally-measured parameter, and can be determined using the
method of USP Section 601 Aerosols, Metered-Dose Inhalers and Dry
Powder Inhalers, Delivered-Dose Uniformity, Sampling the Delivered
Dose from Dry Powder Inhalers, United States Pharmacopeia
convention, Rockville, Md., 13.sup.1h Revision, 222-225, 2007. This
method utilizes an in vitro device set up to mimic patient
dosing.
[0040] The terms "FPF (<5.6)," "FPF (<5.6 microns)," and
"fine particle fraction of less than 5.6 microns" as used herein,
refer to the fraction of a sample of dry particles that have an
aerodynamic diameter of less than 5.6 microns. For example, FPF
(<5.6) can be determined by dividing the mass of respirable dry
particles deposited on the stage two and on the final collection
filter of a two-stage collapsed Andersen Cascade Impactor (ACI) by
the mass of respirable dry particles weighed into a capsule for
delivery to the instrument. This parameter may also be identified
as "FPF_TD(<5.6)," where TD means total dose. A similar
measurement can be conducted using an eight-stage ACT. The
eight-stage ACI cutoffs are different at the standard 60 L/min
flowrate, but the FPF_TD(<5.6) can be extrapolated from the
eight-stage complete data set. The eight-stage ACI result can also
be calculated by the USP method of using the dose collected in the
ACI instead of what was in the capsule to determine FPF.
[0041] The terms "FPD (<4.4)", `FPD<4.4 .mu.m", FPD(<4.4
microns)" and "fine particle dose of less than 4.4 microns" as used
herein, refer to the mass of respirable dry powder particles that
have an aerodynamic diameter of less than 4.4 micrometers. For
example, FPD<4.4 .mu.m can be determined by using an eight-stage
ACI at the standard 60 L/min flowrate and summing the mass
deposited on the final collection filter, and stages 6, 5, 4, 3,
and 2 for a single dose of powder actuated into the ACI.
[0042] The terms "FPF (<5.0)", "FPF<5 .mu.m", "FPF (<5.0
microns)," and "fine particle fraction of less than 5.0 microns" as
used herein, refer to the fraction of a mass of respirable dry
particles that have an aerodynamic diameter of less than 5.0
micrometers. For example, FPF (<5.0) can be determined by using
an eight-stage ACI at the standard 60 L/min flow rate by
extrapolating from the eight-stage complete data set. This
parameter may also be identified as "FPF_TD(<5.0)," where TD
means total dose. When used in conjunction with a geometric size
distribution such as those given by a Malvern Spraytec, Malvern
Mastersizer or Sympatec HELOS particle sizer, "FPF (<5.0)"
refers to the fraction of a mass of respirable dry particles that
have a geometric diameter of less than 5.0 micrometers.
[0043] The terms "FPF (<3.4)," "FPF (<3.4 microns)," and
"fine particle fraction of less than 3.4 microns" as used herein,
refer to the fraction of a mass of respirable dry particles that
have an aerodynamic diameter of less than 3.4 microns. For example,
FPF (<3.4) can be determined by dividing the mass of respirable
dry particles deposited on the final collection filter of a
two-stage collapsed ACI by the total mass of respirable dry
particles weighed into a capsule for delivery to the instrument.
This parameter may also be identified as "FPF_TD(<3.4)," where
TD means total dose. A similar measurement can be conducted using
an eight-stage ACI. The eight-stage ACI result can also be
calculated by the USP method of using the dose collected in the ACI
instead of what was in the capsule to determine FPF.
[0044] "Hausner ratio" is a term of art that refers to the tap
density divided by the bulk density and typically correlates with
bulk powder flowability (i.e., an increase in the Hausner ratio
typically corresponds to a decrease in powder flowability
[0045] The term "respirable" as used herein refers to dry particles
or dry powders that are suitable for delivery to the respiratory
tract (e.g., pulmonary delivery) in a subject by inhalation.
Respirable dry powders or dry particles have a mass median
aerodynamic diameter (MMAD) of less than about 10 microns,
preferably about 5 microns or less.
[0046] As used herein, the term "respiratory tract" includes the
upper respiratory tract (e.g., nasal passages, nasal cavity,
throat, and pharynx), respiratory airways (e.g., larynx, trachea,
bronchi, and bronchioles) and lungs (e.g., respiratory bronchioles,
alveolar ducts, alveolar sacs, and alveoli).
[0047] The term "small" as used herein to describe respirable dry
particles refers to particles that have a volume median geometric
diameter (VMGD) of about 10 microns or less, preferably about 5
microns or less.
Dry Powders and Dry Particles
[0048] The invention relates to respirable dry powders and
respirable dry particles that contain tiotropium as an active
ingredient. The chemical structure of tiotropium was first
described in U.S. Pat. Nos. 5,610,163 and RE39,820. Tiotropium
salts include salts containing cationic tiotropium with one of the
following anions: bromide, fluoride, chloride, iodine,
C1-C4-alkylsulphate, sulphate, hydrogen sulphate, phosphate,
hydrogen phosphate, di-hydrogen phosphate, nitrate, maleate,
acetate, trifluoroacetate, citrate, fumarate, tartrate, oxalate,
succinate and benzoate, C1-C4-alkylsulphonate, which may optionally
be mono-, di- or tri-substituted by fluorine at the alkyl group, or
phenylsulphonate, which may optionally be mono- or poly-substituted
by C1-C4-alkyl at the phenyl ring. Tiotropium bromide is an
anticholinergic providing therapeutic benefits, e.g. in the
treatment of COPD and asthma, and is the active ingredient in
SPIRIVA (tiotropium bromide) HANDIHALER (dry powder inhaler)
(Boehringer Ingelheim, Germany). Tiotropium bromide is known to
crystallize in various forms, such as crystalline anhydrous
(described e.g. in U.S. Pat. Nos. 6,608,055; 7,968,717; and
8,163,913 (Form 11)), crystalline monohydrate (described e.g. in
U.S. Pat. Nos. 6,777,423 and 6,908,928) and crystalline solvates
(described e.g. in U.S. Pat. No. 7,879,871). The various
crystalline forms of tiotropium can be distinguished by a number of
different assays, including X-ray Powder Diffraction (XRPD),
Differential scanning calorimetry (DSC), crystal structure, and
infrared (IR) spectrum analysis. Tiotropium can be synthesized
using a variety of methods which are well known in the art
(including, e.g. methods described in U.S. Pat. Nos. 6,486,321;
7,491,824; 7,662,963; and 8,344,143).
[0049] The tiotropium is generally present in the respirable dry
powders and respirable dry particles in the form of tiotropium
bromide. In particular, the respirable dry powders comprise
respirable dry particles that contain, on a dry basis: [0050] about
79.5% (w/w) to about 80.5% (w/w) sodium chloride, about 19.5% (w/w)
to about 20.5% (w/w) leucine, and about 0.01% (w/w) to about 0.5%
(w/w) tiotropium bromide, and/or sodium chloride to leucine in a
weight ratio of about 4:1, and about 0.01% (w/w) to about 0.5%
(w/w) tiotropium bromide. For example, the invention provides
respirable dry powders referred to as Formulations I-V, listed in
Table 1.
TABLE-US-00001 [0050] TABLE 1 Tiotropium formulations Composition
(wt %, dry basis) Tiotropium Sodium Formulation Bromide Leucine
Chloride I 0.04 19.99 79.97 II 0.07 19.99 79.94 III 0.11 19.98
79.91 IV 0.14 19.97 79.89 V 0.22 19.96 79.82
[0051] Additionally, the tiotropium formulations may be adjusted to
allow for an additional therapeutic agent. In one embodiment, the
respirable dry powders comprise respirable dry particles that
contain, on a dry basis: about 60% to about 90% sodium chloride,
about 10% to about 40% leucine, about 0.01% to about 0.5%
tiotropium bromide, and optionally one or more additional
therapeutic agents up to about 20%. In another embodiment, the
respirable dry powders comprise respirable dry particles that
contain, on a dry basis: about 67% to about 84% sodium chloride,
about 12% to about 28% leucine, about 0.01 to about 0.5% tiotropium
bromide, and optionally one or more additional therapeutic agent up
to about 20%. Optionally, the sodium chloride content is about 75%
to about 82% and/or the leucine content is about 15% to about 25%.
The tiotropium bromide is preferably present in an amount between
about 0.02% and 0.25%, by weight on a dry basis. The one or more
additional therapeutic agent is preferably present in an amount
between about 0.01% to about 10%, more preferably between about
0.01% to 0.5%, greater than 0.5% to 3%, or greater than 3% to about
10%. In another embodiment, the respirable dry powder comprising
respirable dry particles that contain, on a dry basis, about 65% to
about 86% sodium chloride, about 10% to about 35% leucine, about
0.01% to about 0.5% tiotropium bromide, and optionally one or more
additional therapeutic agents, wherein the one or more additional
therapeutic agents is about 1% to about 10%, more preferably the
one or more additional therapeutic agents is about 3% to about 7%,
and most preferably the one or more additional therapeutic agents
is about 4% to about 5%. The tiotropium bromide formulations
described in this paragraph are collectively referred to as
"Expanded Tiotropium Formulations".
[0052] Additional preferred therapeutic combinations with
tiotroprium include corticosteroids, such as inhaled
corticosteroids (ICS), long-acting beta agonists (LABA),
short-acting beta agonists (SABA), anti-inflammatory agents, and
any combination thereof. A bifunctional muscarinic antagonist-beta2
agonist (MABA) is optionally included among these additional
therapeutic combinations. In a most preferred embodiment, the
tiotropium is combined with one or more ICS. Particularly preferred
therapeutic combinations with tiotroprium include: a) tiotropium
and corticosteroids, such as inhaled corticosteroids (ICS); b)
tiotropium and long-acting beta agonists (LABA); c) tiotropium and
short-acting beta agonists (SABA); d) tiotropium and
anti-inflammatory agents; e) tiotropium and MABA, 0 tiotropium and
a bronchodilator, and any combination thereof. Combinations thereof
include, but are not limited to, tiotropium and ICS and LABA.
[0053] Suitable corticosteroids, such as inhaled corticosteroids
(ICS), include budesonide, fluticasone, flunisolide, triamcinolone,
beclomethasone, mometasone, ciclesonide, dexamethasone, and the
like.
[0054] Tiotropium can be delivered once per day (QD) to patients,
so inhaled corticosteroids whose pharmacological data and dosing
regimen support administration once per day are preferred.
Preferred inhaled corticosteroids are fluticasone, e.g.,
fluticasone furoate, mometasone, e.g., mometasone furoate,
ciclesonide, and the like.
[0055] Suitable LABAs include salmeterol, formoterol and isomers
(e.g., arformoterol), clenbuterol, tulobuterol, vilanterol
(Revolair.TM.), indacaterol, carmoterol, isoproterenol, procaterol,
bambuterol, milveterol, olodaterol, and the like.
[0056] Suitable SABAs include albuterol, epinephrine, pirbuterol,
levalbuterol, metaproteronol, maxair, and the like.
[0057] Suitable MABAs include AZD 2115 (AstraZeneca), GSK961081
(GlaxoSmithKline), LAS190792 (Almirall), PF4348235 (Pfizer) and
PF3429281 (Pfizer).
[0058] Combinations of corticosteroids and LABAs include salmeterol
with fluticasone, formoterol with budesonide, formoterol with
fluticasone, formoterol with mometasone, indacaterol with
mometasone, and the like.
[0059] Suitable anti-inflammatory agents include leukotriene
inhibitors, phosphodiesterase 4 (PDE4) inhibitors, other
anti-inflammatory agents, and the like.
[0060] Other suitable anti-inflammatory agents are kinase
inhibitors.
[0061] Other anti-inflammatory agents include omalizumab (anti-IgE
immunoglobulin Daiichi Sankyo Company, Limited), Zolair (anti-IgE
immunoglobulin, Genentech Inc, Novartis AG, Roche Holding Ltd),
Solfa (LTD4 antagonist and phosphodiesterase inhibitor, Takeda
Pharmaceutical Company Limited), IL-13 and IL-13 receptor
inhibitors (such as AMG-317, MILR1444A, CAT-354, QAX576, IMA-638,
Anrukinzumab, IMA-026, MK-6105, DOM-0910, and the like), IL-4 and
IL-4 receptor inhibitors (such as Pitrakinra, AER-003, AIR-645,
APG-201, DOM-0919, and the like), IL-1 inhibitors such as
canakinumab, CRTh2 receptor antagonists such as AZD1981 (CRTh2
receptor antagonist, AstraZeneca), neutrophil elastase inhibitor
such as AZD9668 (neutrophil elastase inhibitor, from AstraZeneca),
P38 mitogen-activated protein kinases inhibitor, e.g., GW856553X
Losmapimod, GSK681323, GSK 856553, and GSK610677 (all P38 kinase
inhibitors, GlaxoSmithKline PLC), and PH-797804 (p38 kinase
inhibitor; Pfizer), Arofylline LAB ALMIRALL (PDE-4 inhibitor,
Laboratorios Almirall, S.A.), ABT761 (5-LO inhibitor, Abbott
Laboratories), Zyflo.RTM. (5-LO inhibitor, Abbott Laboratories),
BT061 (anti-CD4 mAb, Boehringer Ingelheim GmbH), BIBW 2948 BS (map
kinase inhibitor), Corus (inhaled lidocaine to decrease
eosinophils, Gilead Sciences Inc.), Prograf.RTM. (IL-2-mediated
T-cell activation inhibitor, Astellas Pharma), Bimosiamose PFIZER
INC (selectin inhibitor, Pfizer Inc), R411 (alpha4beta1/alpha4beta7
integrin antagonist, Roche Holdings Ltd), Tilade.RTM. (inflammatory
mediator inhibitor, Sanofi-Aventis), Orenica.RTM. (T-cell
co-stimulation inhibitor, Bristol-Myers Squibb Company),
Soliris.RTM. (anti-C5, Alexion Pharmaceuticals Inc), Entorken.RTM.
(Farmacija d.o.o.), Excellair.RTM. (Syk kinase siRNA, ZaBeCor
Pharmaceuticals, Baxter International Inc), KB003 (anti-GMCSF mAb,
KaloBios Pharmaceuticals), Cromolyn sodiums (inhibit release of
mast cell mediators): Cromolyn sodium BOEHRINGER (Boehringer
Ingelheim GmbH), Cromolyn sodium TEVA (Teva Pharmaceutical
Industries Ltd), Intal (Sanofi-Aventis), BI1744CL (oldaterol
(beta-2-adrenoceptor antagonist) and tiotropium, Boehringer
Ingelheim GmbH), NFkappa-B inhibitors, CXR2 antagaonists, HLE
inhibitors, HMG-CoA reductase inhibitors and the like.
[0062] Anti-inflammatory agents also include compounds that
inhibit/decrease cell signaling by inflammatory molecules like
cytokines (e.g., IL-1, IL-4, IL-5, IL-6, IL-9, IL-13, IL-18 IL-25,
IFN-.alpha., IFN-.beta., and others), CC chemokines CCL-1-CCL28
(some of which are also known as, for example, MCP-1, CCL2,
RANTES), CXC chemokines CXCL1-CXCL17 (some of which are also know
as, for example, IL-8, MIP-2), CXCR2, growth factors (e.g., GM-CSF,
NGF, SCF, TGF-.beta., EGF, VEGF and others) and/or their respective
receptors.
[0063] Some examples of the aforementioned anti-inflammatory
antagonists/inhibitors include ABN912 (MCP-1/CCL2, Novartis AG),
AMG761 (CCR4, Amgen Inc), Enbrel.RTM. (TNF, Amgen Inc, Wyeth),
huMAb OX40L GENENTECH (TNF superfamily, Genentech Inc, AstraZeneca
PLC), R4930 (TNF superfamily, Roche Holding Ltd),
SB683699/Firategrast (VLA4, GlaxoSmithKline PLC), CNT0148
(TNFalpha, Centocor, Inc, Johnson & Johnson, Schering-Plough
Corp); Canakinumab (IL-.quadrature.beta, Novartis); Israpafant
MITSUBISHI (PAF/IL-5, Mitsubishi Tanabe Pharma Corporation); IL-4
and IL-4 receptor antagonists/inhibitors: AMG317 (Amgen Inc),
BAY169996 (Bayer AG), AER-003 (Aerovance), APG-201 (Apogenix); IL-5
and IL-5 receptor antagonists/inhibitors: MEDI563 (AstraZeneca PLC,
MedImmune, Inc), Bosatria (GlaxoSmithKline PLC), Cinquil (Ception
Therapeutic), TMC120B (Mitsubishi Tanabe Pharma Corporation),
Bosatria (GlaxoSmithKline PLC), Reslizumab SCHERING
(Schering-Plough Corp); MEDI528 (IL-9, AstraZeneca, MedImmune,
Inc); IL-13 and IL-13 receptor antagonists/inhibitors: TNX650
GENENTECH (Genentech), CAT-354 (AstraZeneca PLC, MedImmune),
AMG-317 (Takeda Pharmaceutical Company Limited), MK6105 (Merck
& Co Inc), IMA-026 (Wyeth), IMA-638 Anrukinzumab (Wyeth),
MILR1444A/Lebrikizumab (Genentech), QAX576 (Novartis), CNTO-607
(Centocor), MK-6105 (Merck, CSL); Dual IL-4 and IL-13 inhibitors:
AIR645/ISIS369645 (ISIS Altair), DOM-0910 (GlaxoSmithKline,
Domantis), Pitrakinra/AER001/Aerovant.TM. (Aerovance Inc), AMG-317
(Amgen), and the like. CXCR2 antagonists include, for example,
Reparixin (Dompe S.P.A.), DF2162 (Dompe, S.P.A.), AZ-10397767
(AstraZeneca), SB656933 (GlaxoSmithKline PLC), SB332235
(GlaxoSmithKline PLC), SB468477 (GlaxoSmithKline PLC), and
SCH527123 (Schering-Plough Corp).
[0064] In Formulations I to V and/or in the Expanded Tiotropium
Formulations, the respirable dry powders and/or respirable dry
particles are preferably small, mass dense, and dispersible. To
measure volumetric median geometric diameter (VMGD), a laser
diffraction system may be used, e.g., a Spraytec system (particle
size analysis instrument, Malvern Instruments) and a HELOS/RODOS
system (laser diffraction sensor with dry dispensing unit, Sympatec
GmbH). The respirable dry particles of Formulations I to V have a
VMGD as measured by laser diffraction at the dispersion pressure
setting of 1.0 bar using a HELOS/RODOS system of about 10 microns
or less (e.g., about 0.5 .mu.m to about 10 .mu.m), about 5 microns
or less (e.g., about 0.5 .mu.m to about 5 .mu.m), about 4 .mu.m or
less (e.g., about 0.5 .mu.m to about 4 .mu.m), about 3 .mu.m or
less (e.g., about 0.5 .mu.m to about 3 .mu.m), about 1 .mu.m to
about 5 .mu.m, about 1 .mu.m to about 4 .mu.m, about 1.5 .mu.m to
about 3.5 .mu.m, about 2 .mu.m to about 5 .mu.m, about 2 .mu.m to
about 4 .mu.m, or about 2 .mu.m to about 3 .mu.m. Preferably the
VMGD is about 5 microns or less (e.g., about 1 .mu.m to about 5
.mu.m), or about 4 .mu.m or less (e.g., about 1 .mu.m to about 4
.mu.m).
[0065] The respirable dry powders and/or respirable dry particles
of Formulations I to V and/or the Expanded Tiotropium Formulations
are dispersible, and have 1 bar/4 bar and/or 0.5 bar/4 bar ratio of
less than about 2.0 (e.g., about 0.9 to less than about 2), about
1.7 or less (e.g., about 0.9 to about 1.7) about 1.5 or less (e.g.,
about 0.9 to about 1.5), about 1.4 or less (e.g., about 0.9 to
about 1.4), or about 1.3 or less (e.g., about 0.9 to about 1.3),
and preferably have a 1 bar/4 bar and/or a 0.5 bar/4 bar of about
1.5 or less (e.g., about 1.0 to about 1.5), and/or about 1.4 or
less (e.g., about 1.0 to about 1.4).
[0066] The respirable dry powders and/or respirable dry particles
of Formulations I to V and/or the Expanded Tiotropium Formulations
preferably have a tap density of at least about 0.45 g/cm.sup.3
(e.g., about 0.45 g/cm.sup.3 to about 1.2 g/cm.sup.3), at least
about 0.5 g/cm.sup.3 (e.g., about 0.5 g/cm.sup.3 to about 1.2
g/cm.sup.3), at least about 0.55 g/cm.sup.3 (e.g., about 0.55
g/cm.sup.3 to about 1.2 g/cm.sup.3), at least about 0.6 g/cm.sup.3
(e.g., about 0.6 g/cm.sup.3 to about 1.2 g/cm.sup.3), or at least
about 0.6 g/cm.sup.3 to about 1.0 g/cm.sup.3.
[0067] Also, the respirable dry powders and/or respirable dry
particles of Formulations I to V and/or the Expanded Tiotropium
Formulations may have a tap density of at least about 0.4
g/cm.sup.3, a tap density of greater than 0.4 g/cm.sup.3, or a tap
density greater than 0.4 g/cm.sup.3 to about 1.2 g/cm.sup.3.
[0068] The respirable dry powders and/or respirable dry particles
of Formulations I to V and/or the Expanded Tiotropium Formulations
have an MMAD of less than 10 microns (e.g., about 0.5 microns to
less than 10 microns), preferably an MMAD of about 5 microns or
less (e.g., about 1 micron to about 5 microns), about 2 microns to
about 5 microns, or about 2.5 microns to about 4.5 microns. In a
preferred embodiment, the MMAD is measured using a capsule based
passive dry powder inhaler (RS01 Model 7, High resistance Plastiape
S.p.A.), which had specific resistance of 0.036 sqrt(kPa)/liters
per minute, and as measured at 60 LPM, the preferred MMAD range is
about 2.9 microns to about 4.0 microns, and the most preferred MMAD
range is about 2.9 microns to about 3.5 microns.
[0069] In another preferred embodiment, the MMAD is measured using
a capsule based passive dry powder inhaler RS01 UHR2 (RS01 Model 7,
Ultrahigh resistance 2 (UHR2) Plastiape S.p.A.), which had specific
resistance of 0.048 sqrt(kPa)/liters per minute, and as measured at
39 LPM, the preferred MMAD range is about 3.0 microns to about 5.0
microns, and the most preferred MMAD range is about 3.8 microns to
about 4.3 microns.
[0070] The respirable dry powders and/or respirable dry particles
of Formulations I to V and/or the Expanded Tiotropium Formulations
have an FPF of less than about 5.6 microns (FPF<5.6 .mu.m) of
the total dose of at least about 35%, preferably at least about
45%, at least about 60%, between about 45% to about 80%, or between
about 60% and about 80%.
[0071] In addition, the respirable dry powders and/or respirable
dry particles of Formulations I to V and/or the Expanded Tiotropium
Formulations preferably have a FPF of less than about 3.4 microns
(FPF<3.4 .mu.m) of the total dose of at least about 20%,
preferably at least about 25%, at least about 30%, at least about
40%, between about 25% and about 60%, or between about 40% and
about 60%.
[0072] The respirable dry powders and/or respirable dry particles
of Formulations I to V and/or the Expanded Tiotropium Formulations
have a FPD of less than about 4.4 microns (FPD<4.4 .mu.m) of
between about 1 microgram and about 5 micrograms, or about 2.0
micrograms and about 5.0 micrograms.
[0073] The respirable dry powders and/or respirable dry particles
of Formulations I to V and/or the Expanded Tiotropium Formulations
have a FPD of less than about 4.4 microns (FPD<4.4 .mu.m) as a
percentage of the total dose of at least 30%, at least 35%, at
least 40%, at least 45%, at least 50%, at least 55%, or at least
60%.
[0074] In some aspects, the invention provides a method of
efficiently delivering a dose of tiotropium as a dry powder. The
efficiency of delivering a dose of tiotropium can be characterized
based on delivering an effective amount of tiotropium to the lungs
with a lower nominal dose filled into the capsule than from a
standard dry powder formulation such as SPIRIVA (tiotropium
bromide) HANDIHALER (dry powder inhaler) which has a nominal dose
of 18 micrograms of tiotropium. The efficiency of delivering a dose
of tiotropium can further be characterized by delivering a fine
particle dose similar to that of a capsule of SPIRIVA (tiotropium
bromide) HANDIHALER (dry powder inhaler) with a lower nominal dose
filled into the capsule. The efficiency of delivering a dose of
tiotropium can further be characterized by delivering a fine
particle dose less than about 4.4 microns (FPD<4.4 .mu.m)
similar to that of a capsule of SPIRIVA (tiotropium bromide)
HANDIHALER (dry powder inhaler) with a lower nominal dose filled
into the capsule.
[0075] The efficiency of delivering a dose of tiotropium can be
further characterized in an aspect of the current invention based
on delivering an effective amount of tiotropium to the lungs to
achieve a similar improvement in lung function, preferably, a
similar change in forced expiratory volume in one second
(FEV.sub.1), or, more preferably, a similar change in trough
FEV.sub.1 response at steady state as SPIRIVA (tiotropium bromide)
HANDIHALER (dry powder inhaler), but with a lower nominal dose than
SPIRIVA (tiotropium bromide) HANDIHALER (dry powder inhaler). In
one aspect, when measured in patients being administered the
respirable dry powders and/or respirable dry particles of
Formulations I to V and/or the Expanded Tiotropium Formulations in
the current invention; when the nominal dose of tiotropium in the
respirable dry powders and/or respirable dry particles of
Formulations I to V and/or the Expanded Tiotropium Formulations is
70% or less, 50% or less, or preferably 35% or less, 25% or less,
or 20% or less, 15% or less, 10% or less, or 5% or less of the
nominal dose of SPIRIVA (tiotropium bromide) HANDIHALER (dry powder
inhaler), which is 18 micrograms of tiotropium; the change in
FEV.sub.1 is about 80% or greater of the change in FEV.sub.1
observed in patients taking SPIRIVA (tiotropium bromide) HANDIHALER
(dry powder inhaler), preferably, about 85% or greater of the
change in FEV.sub.1 observed in patients taking SPIRIVA (tiotropium
bromide) HANDIHALER (dry powder inhaler), more preferably, 90% or
greater of the change in FEV.sub.1 observed for patients taking
SPIRIVA (tiotropium bromide) HANDIHALER (dry powder inhaler), or
most preferably, about 95% or greater of the change in FEV.sub.1
observed in patients taking SPIRIVA (tiotropium bromide) HANDIHALER
(dry powder inhaler).
[0076] In another aspect, when measured in patients being
administered the respirable dry powders and/or respirable dry
particles of Formulations I to V and/or the Expanded Tiotropium
Formulations in the current invention; when the nominal dose of
tiotropium in the respirable dry powders and/or respirable dry
particles of Formulations I to V and/or the Expanded Tiotropium
Formulations is 70% or less, 50% or less, or preferably 35% or
less, 25% or less; or 20% or less, 15% or less, 10% or less, or 5%
or less of the nominal dose of SPIRIVA (tiotropium bromide)
HANDIHALER (dry powder inhaler), which is 18 micrograms of
tiotropium; the change in trough FEV.sub.1 response at steady state
is about 80% or greater of the change in trough FEV.sub.1 response
at steady state observed in patients taking SPIRIVA (tiotropium
bromide) HANDIHALER (dry powder inhaler), preferably, about 85% or
greater of the change in trough FEV.sub.1 response at steady state
observed in patients taking SPIRIVA (tiotropium bromide) HANDIHALER
(dry powder inhaler), more preferably, 90% or greater of the change
in trough FEV.sub.1 response at steady state observed for patients
taking SPIRIVA (tiotropium bromide) HANDIHALER (dry powder
inhaler), or most preferably, about 95% or greater of the change in
trough FEV.sub.1 response at steady state observed in patients
taking SPIRIVA (tiotropium bromide) HANDIHALER (dry powder
inhaler).
[0077] In another aspect, when measured in patients being
administered the respirable dry powders and/or respirable dry
particles of Formulations I to V and/or the Expanded Tiotropium
Formulations in the current invention; when the nominal dose of
tiotropium in the respirable dry powders and/or respirable dry
particles of Formulations I to V and/or the Expanded Tiotropium
Formulations is 70% or less, 50% or less, or preferably 35% or
less, 25% or less; or, 20% or less, 15% or less, 10% or less, or 5%
or less of the nominal dose of SPIRIVA (tiotropium bromide)
HANDIHALER (dry powder inhaler), which is 18 micrograms of
tiotropium; the change in trough FEV.sub.1 response at steady state
is about 80 mL or greater, about 90 mL or greater, preferably about
100 mL or greater, about 110 mL or greater, about 120 mL or
greater.
[0078] The respirable dry powders and/or respirable dry particles
of Formulations I to V and/or the Expanded Tiotropium Formulations
can be contained in a receptacle that may contain about 15 mg, 10
mg, 7.5 mg, 5 mg, 2.5 mg, or 1 mg of mass of the respirable dry
powder. Such receptacles may contain a nominal dose of tiotropium
that ranges between about 3 to about 12 micrograms, between about 3
to about 9 micrograms, or between about 3 to about 6 micrograms. In
certain embodiments, the receptacle may contain a nominal dose of
tiotropium of about 3 micrograms, about 6 micrograms, about 9
micrograms, or about 12 micrograms. The receptacle can be contained
in a dry powder inhaler or can be packaged and/or sold
separately.
[0079] Furthermore, the receptacles may contain a nominal dose of
tiotropium that ranges between about 1.5 micrograms and 12
micrograms. In a certain embodiment, the receptacle may contain a
nominal dose of tiotropium of about 2 micrograms.
[0080] Furthermore, the receptacles may contain a nominal dose of
tiotropium that ranges from about 0.5 micrograms to about 6
micrograms, or from about 0.5 micrograms to about 3 micrograms, or
from about 1 microgram to about 3 micrograms. In a certain
embodiment, the receptacle may contain a nominal dose of tiotropium
of about 0.5 micrograms, about 1 microgram, about 1.5 micrograms,
or about 2.5 micrograms.
[0081] The respirable dry powders and/or respirable dry particles
of Formulations I to V and/or the Expanded Tiotropium Formulations
can have a water or solvent content of up to about 15% by weight of
the respirable dry powder or particle. For example, the water or
solvent content is up to about 10%, up to about 5%, or preferably
between about 0.1% and about 3%, between about 0.01% and 1%, or be
substantially free of water or other solvent, or be anhydrous.
[0082] The respirable dry powders and/or respirable dry particles
of Formulations I to V and/or the Expanded Tiotropium Formulations
can be administered with low inhalation energy. In order to relate
the dispersion of powder at different inhalation flow rates,
volumes, and from inhalers of different resistances, the energy
required to perform the inhalation maneuver can be calculated.
Inhalation energy can be calculated from the equation
E=R.sup.2Q.sup.2V where E is the inhalation energy in Joules, R is
the inhaler resistance in kPa.sup.1/2/LPM, Q is the steady flow
rate in L/min and V is the inhaled air volume in L.
[0083] The respirable dry powders and/or respirable dry particles
of Formulations I to V and/or the Expanded Tiotropium Formulations
are characterized by a high emitted dose (e.g., CEPM of at least
75%, at least 80%, at least 85%, at least 90%, at least 95%) from a
dry powder inhaler when a total inhalation energy of less than
about 5 Joules, less than about 3.5 Joules, less than about 2.4
Joules, less than about 2 Joules, less than about 1 Joule, less
than about 0.8 Joule, less than about 0.5 Joule, or less than about
0.3 Joule is applied to the dry powder inhaler. For example, an
emitted dose of at least 75%, at least 80%, at least 85%, at least
90%, at least 95% CEPM of any one of Formulations I to V contained
in a unit dose container, containing about 4 mg or more, about 6 mg
or more, about 11 mg or more, about 15 mg or more, about 20 mg or
more, about 30 mg or more, or about 4 mg to about 6 mg, about 6 mg
to about 11 mg, about 11 mg to about 15 mg, or about 15 mg to about
20 mg of the appropriate formulation, in a dry powder inhaler can
be achieved when a total inhalation energy of less than about 5
Joules, less than about 3.5 Joules, less than about 2 Joules, less
than about 1 Joule, less than about 0.8 Joule, less than about 0.5
Joule, or less than about 0.3 Joule is applied to the dry powder
inhaler.
[0084] In one aspect, The respirable dry powders and/or respirable
dry particles of Formulations I to V and/or the Expanded Tiotropium
Formulations are characterized by a capsule emitted powder mass of
at least 80% when emitted from a passive dry powder inhaler that
has a resistance of about 0.036 sqrt(kPa)/liters per minute under
the following conditions: an inhalation energy of 2.3 Joules at a
flow rate of 30 LPM using a size 3 capsule that contains a total
mass of 10 mg, said total mass consisting of the respirable dry
particles of any one of Formulations I to V, and wherein the volume
median geometric diameter of the respirable dry particles emitted
from the inhaler is 5 microns or less.
[0085] The dry powder can fill the unit dose container, or the unit
dose container can be at least 2% full, at least 5% full, at least
10% full, at least 20% full, at least 30% full, least 40% full, at
least 50% full, at least 60% full, at least 70% full, at least 80%
full, or at least 90% full. The unit dose container can be a
capsule (e.g., size 000, 00, 0E, 0, 1, 2, 3, and 4, with respective
volumetric capacities of 1.37 ml, 950 .mu.l, 770 .mu.l, 680 .mu.l,
480 .mu.l, 360 .mu.l, 270 .mu.l, and 200 .mu.l). The capsule is
preferably between about 2% full and about 10% full, between about
10% full and about 20% full. The unit dose container can be a
blister. The blister can be packaged as a single blister, or as
part of a set of blisters, for example, 7 blisters, 14 blisters, 28
blisters, or 30 blisters. The one or more blister is preferably at
least 30% full, at least 50% full, or at least 70% full.
[0086] Healthy adult populations are predicted to be able to
achieve inhalation energies ranging from 2.9 Joules for comfortable
inhalations to 22 Joules for maximum inhalations by using values of
peak inspiratory flow rate (PIFR) measured by Clarke et al.
(Journal of Aerosol Med, 6(2), p. 99-110, 1993) for the flow rate Q
from two inhaler resistances of 0.02 and 0.055 kPa.sup.1/2/LPM,
with an inhalation volume of 2 L based on both FDA guidance
documents for dry powder inhalers and on the work of Tiddens et al.
(Journal of Aerosol Med, 19(4), p. 456-465, 2006) who found adults
averaging 2.2 L inhaled volume through a variety of DPIs.
[0087] Mild, moderate and severe adult COPD patients are predicted
to be able to achieve maximum inhalation energies of 5.1 to 21
Joules, 5.2 to 19 Joules, and 2.3 to 18 Joules respectively. This
is again based on using measured PIFR values for the flow rate Q in
the equation for inhalation energy. The PIFR achievable for each
group is a function of the inhaler resistance that is being inhaled
through. The work of Broeders et al. (Eur Respir J, 18, p. 780-783,
2001) was used to predict maximum and minimum achievable PIFR
through 2 dry powder inhalers of resistances 0.021 and 0.032
kPa.sup.1/2/LPM for each.
[0088] Similarly, adult asthmatic patients are predicted to be able
to achieve maximum inhalation energies of 7.4 to 21 Joules based on
the same assumptions as the COPD population and PIFR data from
Broeders et al.
[0089] Healthy adults and children, COPD patients, asthmatic
patients ages 5 and above, and CF patients, for example, are
capable of providing sufficient inhalation energy to empty and
disperse the dry powder formulations of the invention.
[0090] An advantage of the invention is the production of powders
that disperse well across a wide range of flow rates and are
relatively flowrate independent. The respirable dry particles and
respirable dry powders of the invention enable the use of a simple,
passive DPI for a wide patient population.
[0091] In particular aspects, the invention is a respirable dry
powder containing respirable dry particles of any one of
Formulations I to V. In a further particular aspect, the respirable
dry powder containing respirable dry particles comprise i) about
79.5% to about 80.5% sodium chloride, ii) about 19.5% to about
20.5% leucine, and iii) about 0.01% to about 0.5% tiotropium
bromide, with all values are weight percentages. In an additional
particular aspect, the invention is a respirable dry powder
containing respirable dry particles that contain Expanded
Tiotropium Formulations.
[0092] The respirable dry powder containing respirable dry
particles of any one of formulations in the previous paragraph or
falling in any one of the formulation ranges in the previous
paragraph are characterized by: [0093] 1. VMGD at 1 bar as measured
using a HELOS/RODOS system is about 10 microns or less, preferably
between about 1 micron and about 5 microns, between about 1 micron
and about 4.0 microns, or between about 1.5 microns and about 3.5
microns; [0094] 2. 1 bar/4 bar of about 1.5 or less, about 1.4 or
less, or between about 1 and about 1.5, or between about 1 and
about 1.4; [0095] 3. 0.5 bar/4 bar of about 1.5 or less, about 1.4
or less, or between about 1 and about 1.5, or between about 1 and
about 1.4; [0096] 4. tap density of about 0.45 g/cm.sup.3 or
greater, between about 0.45 g/cm.sup.3 and about 1.2 g/cm.sup.3,
between 0.5 g/cm.sup.3 and about 1.2 g/cm.sup.3, between 0.55
g/cm.sup.3 and about 1.1 g/cm.sup.3, or between 0.6 g/cm.sup.3 and
about 1 g/cm.sup.3; [0097] 5. MMAD of about 10 microns or less,
preferably between about 1 micron and about 5 microns, or between
about 2.5 microns to about 4.5 microns; [0098] 6. FPF<5.6 of at
least about 45%, at least about 60%, or between about 60% and about
80%; [0099] 7. FPF<4.4 of at least about 35%, at least about
50%, or between about 50% and about 70%; [0100] 8. FPF<3.4 of at
least about 25%, at least about 40%, or between about 40% and about
60%; [0101] 9. FPD<4.4 of between about 1 microgram and about 5
micrograms of tiotropium, or between about 2.0 micrograms and about
5.0 micrograms of tiotropium; and/or [0102] 10. Ratio of the fine
particle dose less than 2.0 microns to the fine particle dose less
than 4.4 microns of less than about 0.50, less than about 0.35, or
less than about 0.25.
[0103] The respirable dry powder or respirable dry particles
described above can be further characterized by a water content of
less than 15% by weight, preferably less than 10%, less than 5%, or
most preferably less than 1%, all by weight. In addition, the
respirable dry powder or respirable dry particles of any one of
Formulations I to V are characterized by a capsule emitted powder
mass of at least 80% when emitted from a passive dry powder inhaler
that has a resistance of about 0.036 sqrt(kPa)/liters per minute
under the following conditions: an inhalation energy of 2.3 Joules
at a flow rate of 30 LPM using a size 3 capsule that contains a
total mass of 10 mg, said total mass consisting of the respirable
dry particles of any one of Formulations I to V, and wherein the
volume median geometric diameter of the respirable dry particles
emitted from the inhaler is 5 microns or less.
[0104] In another particular aspect, the invention is a respirable
dry powder containing respirable dry particles of a formulation
falling within one of the following ranges or specifically
identified formulation: [0105] about 60% to about 90% sodium
chloride, about 10% to about 40% leucine, about 0.01% to about 0.5%
tiotropium, and optionally one or more additional therapeutic
agents up to about 20%; [0106] about 65% to about 86% sodium
chloride, about 10% to about 35% leucine, about 0.01% to about 0.5%
tiotropium, and optionally one or more additional therapeutic
agents up to about 20%; [0107] preferably, about 67% to about 84%
sodium chloride, about 12% to about 28% leucine, about 0.01 to
about 0.5% tiotropium, and optionally one or more additional
therapeutic agent up to about 20%; [0108] more preferably, about
75% to about 82% sodium chloride, about 15% to about 25% leucine,
about 0.01 to about 0.5% tiotropium, and optionally one or more
additional therapeutic agent up to about 20%; or [0109] most
preferably, about 79.5% to about 80.5% sodium chloride, about 19.5%
to about 20.5% leucine, about 0.01 to about 0.5% tiotropium; or
Formulation I-V, where the weight percent of each component is
listed below in Table 1A:
TABLE-US-00002 [0109] TABLE 1A Tiotropium formulations Composition
(wt %, dry basis) Sodium Formulation Tiotropium Leucine Chloride I
0.04 19.99 79.97 II 0.07 19.99 79.94 III 0.11 19.98 79.91 IV 0.14
19.97 79.89 V 0.22 19.96 79.82
[0110] where all values are weight percent, and all of the
components of any particular formulation adds up to 100%; where the
tiotropium is preferably present in an amount between about 0.02%
and 0.25%, by weight on a dry basis, and where the one or more
additional therapeutic agent is preferably present in an amount
between about 0.01% to about 10%. Preferably, the additional
therapeutic agent is an inhaled corticosteroid (ICS). More
preferably, the ICS is chosen to match the dosing regimen of
tiotropium, which is administered once per day (QD), for example,
as indicated in the SPIRIVA (tiotropium bromide) HANDIHALER (dry
powder inhaler) package insert. The preferred inhaled
corticosteroids are fluticasone, such as fluticasone furoate,
mometasone, such as mometasone furoate, ciclesonide, and the like;
and the more preferred inhaled corticosteroids are fluticasone
furoate, mometasone furoate, or ciclesonide. The preferred weight
percentages on a dry basis of these inhaled corticosteroids are
from about 0.2% to about 4% for fluticasone furoate, from about
0.4% to about 10% for mometasone furoate, and from about 0.2% to
about 5% for ciclesonide. In a preferred aspect, only one ICS is
used in the formulation. [0111] In one aspect, the weight ratio
between sodium chloride and leucine is about 4:1. In one aspect,
the respirable dry powder consists of respirable dry particles. In
another aspect, the formulation does not contain another
therapeutic agent besides tiotropium.
[0112] The respirable dry powder comprising respirable dry
particles described by any of the ranges or specifically disclosed
formulations in the previous paragraph are characterized by: [0113]
1. VMGD at 1 bar as measured using a HELOS/RODOS system is about 10
microns or less, preferably between about 1 micron and about 5
microns, between about 1.0 micron and about 4.0 microns, or between
about 1.5 microns and about 3.5 microns, or between 2 microns and 5
microns, or between 2.5 microns and 4.5 microns; [0114] 2. 1 bar/4
bar of about 1.5 or less, about 1.4 or less, about 1.3 or less, or
between about 1 and about 1.5, or between about 1 and about 1.4, or
between about 1 and about 1.3; [0115] 3. 0.5 bar/4 bar of about 1.5
or less, about 1.4 or less, about 1.3 or less, or between about 1
and about 1.5, or between about 1 and about 1.4, or between about 1
and about 1.3; [0116] 4. tap density of greater than 0.4
g/cm.sup.3, greater than 0.4 g/cm.sup.3 to about 1.2 g/cm.sup.3,
about 0.45 g/cm.sup.3 or greater, between about 0.45 g/cm.sup.3 and
about 1.2 g/cm.sup.3, between 0.5 g/cm.sup.3 and about 1.2
g/cm.sup.3, between 0.55 g/cm.sup.3 and about 1.1 g/cm.sup.3, or
between 0.6 g/cm.sup.3 and about 1 g/cm.sup.3; [0117] 5. MMAD of
about 10 microns or less, preferably between about 1 micron and
about 5 microns, between about 2.5 microns to about 4.5 microns, or
between 3.0 microns and 5.0 microns; [0118] 6. FPF<5.0 of at
least about 45%, at least about 60%, or between about 60% and about
80%; [0119] 7. FPF<4.4 of at least about 35%, at least about
50%, or between about 50% and about 70%; [0120] 8. FPF<3.4 of at
least about 25%, at least about 40%, or between about 40% and about
60%; [0121] 9. FPD<4.4 of between about 1 microgram and about 5
micrograms of tiotropium, between about 2.0 micrograms and about
5.0 micrograms of tiotropium, or, preferably, between 2.0
micrograms and 4.0 micrograms; [0122] 10. FPD<5.0 of between
about 1 microgram and about 5 micrograms of tiotropium, between
about 2.0 micrograms and about 5.0 micrograms of tiotropium, or,
preferably, between 2.0 micrograms and 4.0 micrograms; [0123] 11.
Ratio of the fine particle dose less than 2.0 microns to the fine
particle dose less than 4.4 microns of less than about 0.50, less
than about 0.35, less than about 0.30; preferably, less than about
0.25, less than about 0.20, less than about 0.18, or about 0.15 or
less; [0124] 12. Ratio of the fine particle dose less than 2.0
microns to the fine particle dose less than 5.0 microns of less
than about 0.50, less than about 0.35, less than about 0.30;
preferably, less than about 0.25, less than about 0.20, less than
about 0.18, or about 0.15 or less; [0125] 13. A water content, on a
weight basis, of less than 15%, less than 10%, preferably less than
5%, or most preferably less than 1%; [0126] 14. A CEPM of at least
80% when emitted from a passive dry powder inhaler that has a
resistance of about 0.036 sqrt(kPa)/liters per minute under the
following conditions: an inhalation energy of 2.3 Joules at a flow
rate of 30 LPM using a size 3 capsule that contains a total mass of
10 mg of the respirable dry powder comprising respirable dry
particles described by any of the ranges or specifically disclosed
formulations in the previous paragraph, and wherein the VMGD of the
respirable dry particles emitted from the inhaler is 5 microns or
less; [0127] 15. A emitted dose of at least 70%, at least 75%, at
least 80%, or at least 85% when emitted from a passive dry powder
inhaler that has a resistance of about 0.036 sqrt(kPa)/liters per
minute under the following conditions: an inhalation energy of 2.3
Joules at a flow rate of 30 LPM using a size 3 capsule that
contains a total mass of 10 mg of the respirable dry powder
comprising respirable dry particles described by any of the ranges
or specifically disclosed formulations in the previous paragraph,
and wherein the VMGD of the respirable dry particles emitted from
the inhaler is 5 microns or less; [0128] 16. A CEPM of at least 80%
when emitted from a passive dry powder inhaler that has a
resistance of about 0.048 sqrt(kPa)/liters per minute under the
following conditions: an inhalation energy of 1.8 Joules at a flow
rate of 20 LPM using a size 3 capsule that contains a total mass of
5 mg of the respirable dry powder comprising respirable dry
particles described by any of the ranges or specifically disclosed
formulations in the previous paragraph, and wherein the VMGD of the
respirable dry particles emitted from the inhaler is 5 microns or
less; and/or [0129] 17. A emitted dose of at least 65%, at least
70%, at least 75%, at least 80%, or at least 85% when emitted from
a passive dry powder inhaler that has a resistance of about 0.048
sqrt(kPa)/liters per minute under the following conditions: an
inhalation energy of 1.8 Joules at a flow rate of 20 LPM using a
size 3 capsule that contains a total mass of 5 mg of the respirable
dry powder comprising respirable dry particles described by any of
the ranges or specifically disclosed formulations in the previous
paragraph, and wherein the VMGD of the respirable dry particles
emitted from the inhaler is 5 microns or less.
[0130] The respirable dry powder comprising respirable dry
particles described by any of the ranges or specifically disclosed
formulations, characterized in the previous paragraph, may be
filled into a receptacle, for example a capsule or a blister. When
the receptacle is a capsule, the capsule is, for example, a size 2
or a size 3 capsule, and is preferably a size 3 capsule. The
capsule material may be, for example, gelatin or HPMC
(Hydroxypropyl methylcellulose), and is preferably HPMC.
[0131] The respirable dry powder comprising respirable dry
particles described and characterized above may be contained in a
dry powder inhaler (DPI). The DPI may be a capsule-based DPI or a
blister-based DPI, and is preferably a capsule-based DPI. More
preferably, the dry powder inhaler is selected from the RS01 family
of dry powder inhalers (Plastiape S.p.A., Italy). More preferably,
the dry powder inhaler is selected from the RS01 HR or the RS01
UHR2. Most preferably, the dry powder inhaler is the RS01 UHR2. In
one aspect, the dry powder inhaler is not the RS01 HR.
[0132] When the respirable dry powder comprising respirable dry
particles described and characterized above is contained in a
receptacle, the receptacle may contain a mass of the respirable dry
powder comprising respirable dry particles between about 8 mg and
about 12 mg, between about 5.5 mg and about 9.5 mg, between about
3.5 mg and about 6.5 mg, between about 1.5 mg and 4.5 mg, or
between 0.5 mg and 2.5 mg; and, preferably, between about 3.5 mg
and about 6.5 mg; or about 15 milligrams, about 10 milligrams,
about 7.5 milligrams, about 5 milligrams, about 2.5 milligrams, or
about 1 milligrams; preferably, a mass of about 5 milligrams.
Alternatively or additionally, when the respirable dry powder
comprising respirable dry particles is contained in a receptacle,
the receptacle may contain a nominal dose of tiotropium between
about 1.5 micrograms to about 12 micrograms, between about 3 to
about 12 micrograms, between about 3 to about 6 micrograms;
preferably, from about 0.5 micrograms to about 6 micrograms, or
from about 0.5 micrograms to about 3 micrograms, or about 1
microgram to about 3 micrograms; or a nominal dose of tiotropium of
about 12 micrograms, about 9 micrograms, preferably, about 6
micrograms, about 4 micrograms; or, more preferably about 3
micrograms, about 2 micrograms or about 1 microgram.
[0133] When the respirable dry powder comprising respirable dry
particles described and characterized above is administered to a
patient; when the nominal dose of tiotropium is 70% or less, 50% or
less, or preferably 35% or less, 25% or less; or 20% or less, 15%
or less, 10% or less, or 5% or less of the nominal dose of SPIRIVA
(tiotropium bromide) HANDIHALER (dry powder inhaler), which is 18
micrograms of tiotropium; the change in trough FEV.sub.1 response
at steady state is about 80% or greater of the change in trough
FEV.sub.1 response at steady state observed in patients taking
SPIRIVA (tiotropium bromide) HANDIHALER (dry powder inhaler),
preferably, about 85% or greater of the change in trough FEV.sub.1
response at steady state observed in patients taking SPIRIVA
(tiotropium bromide) HANDIHALER (dry powder inhaler), more
preferably, 90% or greater of the change in trough FEV.sub.1
response at steady state observed for patients taking SPIRIVA
(tiotropium bromide) HANDIHALER (dry powder inhaler), or most
preferably, about 95% or greater of the change in trough FEV.sub.1
response at steady state observed in patients taking SPIRIVA
(tiotropium bromide) HANDIHALER (dry powder inhaler). Alternatively
or in addition, when the respirable dry powder comprising
respirable dry particles described and characterized above is
administered to a patient; when the nominal dose of tiotropium is
70% or less, 50% or less, or preferably 35% or less, 25% or less;
or, 20% or less, 15% or less, 10% or less, or 5% or less of the
nominal dose of SPIRIVA (tiotropium bromide) HANDIHALER (dry powder
inhaler), which is 18 micrograms of tiotropium; the change in
trough FEV.sub.1 response at steady state is about 80 mL or
greater, about 90 mL or greater, preferably about 100 mL or
greater, about 110 mL or greater, about 120 mL or greater. The
patient described above may be a patient with a respiratory
disease, such as COPD, chronic bronchitis, emphysema, asthma,
cystic fibrosis, or non-cystic fibrosis bronchiectasis. Preferably,
the respiratory disease is COPD, chronic bronchitis, and/or
emphysema. The respirable dry powder comprising respirable dry
particles described and characterized above may be administered to
a patient to reduce the incidence or severity of an acute
exacerbation of a respiratory disease, to relieve the symptoms of a
respiratory disease, and/or to improve the lung function of a
patient with a respiratory disease.
Methods for Preparing Dry Powders and Dry Particles
[0134] The respirable dry particles and dry powders can be prepared
using any suitable method. Many suitable methods for preparing
respirable dry powders and particles are conventional in the art,
and include single and double emulsion solvent evaporation, spray
drying, spray-freeze drying, milling (e.g., jet milling), blending,
solvent extraction, solvent evaporation, phase separation, simple
and complex coacervation, interfacial polymerization, suitable
methods that involve the use of supercritical carbon dioxide
(CO.sub.2), sonocrystalliztion, nanoparticle aggregate formation
and other suitable methods, including combinations thereof.
Respirable dry particles can be made using methods for making
microspheres or microcapsules known in the art. These methods can
be employed under conditions that result in the formation of
respirable dry particles with desired aerodynamic properties (e.g.,
aerodynamic diameter and geometric diameter). If desired,
respirable dry particles with desired properties, such as size and
density, can be selected using suitable methods, such as
sieving.
[0135] Suitable methods for selecting respirable dry particles with
desired properties, such as size and density, include wet sieving,
dry sieving, and aerodynamic classifiers (such as cyclones).
[0136] The respirable dry particles are preferably spray dried.
Suitable spray-drying techniques are described, for example, by K.
Masters in "Spray Drying Handbook", John Wiley & Sons, New York
(1984). Generally, during spray-drying, heat from a hot gas such as
heated air or nitrogen is used to evaporate a solvent from droplets
formed by atomizing a continuous liquid feed. When hot air is used,
the moisture in the air is at least partially removed before its
use. When nitrogen is used, the nitrogen gas can be run "dry",
meaning that no additional water vapor is combined with the gas. If
desired the moisture level of the nitrogen or air can be set before
the beginning of spray dry run at a fixed value above "dry"
nitrogen. If desired, the spray drying or other instruments, e.g.,
jet milling instrument, used to prepare the dry particles can
include an inline geometric particle sizer that determines a
geometric diameter of the respirable dry particles as they are
being produced, and/or an inline aerodynamic particle sizer that
determines the aerodynamic diameter of the respirable dry particles
as they are being produced.
[0137] For spray drying, solutions, emulsions or suspensions that
contain the components of the dry particles to be produced in a
suitable solvent (e.g., aqueous solvent, organic solvent,
aqueous-organic mixture or emulsion) are distributed to a drying
vessel via an atomization device. For example, a nozzle or a rotary
atomizer may be used to distribute the solution or suspension to
the drying vessel. The nozzle can be a two-fluid nozzle, which is
in an internal mixing setup or an external mixing setup.
Alternatively, a rotary atomizer having a 4- or 24-vaned wheel may
be used. Examples of suitable spray dryers that can be outfitted
with either a rotary atomizer or a nozzle, include, a Mobile Minor
Spray Dryer or the Model PSD-1, both manufactured by GEA Niro, Inc.
(Denmark). Actual spray drying conditions will vary depending, in
part, on the composition of the spray drying solution or suspension
and material flow rates. The person of ordinary skill will be able
to determine appropriate conditions based on the compositions of
the solution, emulsion or suspension to be spray dried, the desired
particle properties and other factors. In general, the inlet
temperature to the spray dryer is about 90.degree. C. to about
300.degree. C., and preferably is about 220.degree. C. to about
285.degree. C. Another preferable range is between 130.degree. C.
to about 200.degree. C. The spray dryer outlet temperature will
vary depending upon such factors as the feed temperature and the
properties of the materials being dried. Generally, the outlet
temperature is about 50.degree. C. to about 150.degree. C.,
preferably about 90.degree. C. to about 120.degree. C., or about
98.degree. C. to about 108.degree. C. Another preferable range is
between 65.degree. C. to about 110.degree. C., preferably about
75.degree. C. to about 100.degree. C. If desired, the respirable
dry particles that are produced can be fractionated by volumetric
size, for example, using a sieve, or fractioned by aerodynamic
size, for example, using a cyclone, and/or further separated
according to density using techniques known to those of skill in
the art.
[0138] Additional examples of spray dryers include the ProCepT
Formatrix R&D spray dryer (ProCepT nv, Zelzate, Belgium). BuCHI
B-290 MINI SPRAY DRYER (BUCHI Labortechnik AG, Flawil,
Switzerland). An additional preferred range for the inlet
temperature to the spray dryer is about 180.degree. C. to about
285.degree. C. An additional preferred range for the outlet
temperature from the spray dryer is about 40.degree. C. to about
110.degree. C., more preferably about 50.degree. C. to about
90.degree. C.
[0139] To prepare the respirable dry particles of the invention,
generally, a solution, emulsion or suspension that contains the
desired components of the dry powder (i.e., a feed stock) is
prepared and spray dried under suitable conditions. Preferably, the
dissolved or suspended solids concentration in the feed stock is at
least about 1 g/L, at least about 2 g/L, at least about 5 g/L, at
least about 10 g/L, at least about 15 g/L, at least about 20 g/L,
at least about 30 g/L, at least about 40 g/L, at least about 50
g/L, at least about 60 g/L, at least about 70 g/L, at least about
80 g/L, at least about 90 g/L, or at least about 100 g/L. The feed
stock can be provided by preparing a single solution or suspension
by dissolving or suspending suitable components (e.g., salts,
excipients, other active ingredients) in a suitable solvent. The
solvent, emulsion or suspension can be prepared using any suitable
methods, such as bulk mixing of dry and/or liquid components or
static mixing of liquid components to form a combination. For
example, a hydrophilic component (e.g., an aqueous solution) and a
hydrophobic component (e.g., an organic solution) can be combined
using a static mixer to form a combination. The combination can
then be atomized to produce droplets, which are dried to form
respirable dry particles. Preferably, the atomizing step is
performed immediately after the components are combined in the
static mixer. Alternatively, the atomizing step is performed on a
bulk mixed solution.
[0140] The feed stock, or components of the feed stock, can be
prepared using any suitable solvent, such as an organic solvent, an
aqueous solvent or mixtures thereof. Suitable organic solvents that
can be employed include but are not limited to alcohols such as,
for example, ethanol, methanol, propanol, isopropanol, butanols,
and others. Other organic solvents include but are not limited to
perfluorocarbons, dichloromethane, chloroform, ether, ethyl
acetate, methyl tert-butyl ether and others. Co-solvents that can
be employed include an aqueous solvent and an organic solvent, such
as, but not limited to, the organic solvents as described above.
Aqueous solvents include water and buffered solutions.
[0141] The feed stock or components of the feed stock can have any
desired pH, viscosity or other properties. If desired, a pH buffer
can be added to the solvent or co-solvent or to the formed mixture.
Generally, the pH of the mixture ranges from about 3 to about
8.
[0142] Respirable dry particles and dry powders can be fabricated
and then separated, for example, by filtration or centrifugation by
means of a cyclone, to provide a particle sample with a preselected
size distribution. For example, greater than about 30%, greater
than about 40%, greater than about 50%, greater than about 60%,
greater than about 70%, greater than about 80%, or greater than
about 90% of the respirable dry particles in a sample can have a
diameter within a selected range. The selected range within which a
certain percentage of the respirable dry particles fall can be, for
example, any of the size ranges described herein, such as between
about 0.1 to about 3 microns VMGD.
[0143] The invention also relates to respirable dry powders or
respirable dry particles produced by preparing a feedstock
solution, emulsion or suspension and spray drying the feedstock
according to the methods described herein. The feedstock can be
prepared using (a) sodium chloride in an amount of about 79.5% to
about 80.5% by weight (e.g., of total solutes used for preparing
the feedstock) and (b) leucine in an amount of at least about 19.5%
to about 20.5% by weight (e.g., of total solutes used for preparing
the feedstock) and tiotropium bromide in an amount of about 0.01%
to about 0.5% by weight (e.g., of total solutes used for preparing
the feedstock). All weight percentages are given on a dry
(anhydrous) basis.
[0144] In an embodiment, the respirable dry powders or respirable
dry particles of the invention can be obtained by (1) preparing a
feedstock comprising (a) a dry solute containing in percent by
weight of the total dry solute about 79.5% to about 80.5% sodium
chloride, about 19.5% to about 20.5% leucine, and about 0.01% to
about 0.5% tiotropium bromide, and (b) one or more suitable
solvents for dissolution of the solute and formation of the
feedstock, and (2) spray drying the feedstock. Various methods
(e.g., static mixing, bulk mixing) can be used for mixing the
solutes and solvents to prepare feedstocks, which are known in the
art. If desired, other suitable methods of mixing may be used. For
example, additional components that cause or facilitate the mixing
can be included in the feedstock. For example, carbon dioxide
produces fizzing or effervescence and thus can serve to promote
physical mixing of the solute and solvents.
[0145] The diameter of the respirable dry particles, for example,
their VMGD, can be measured using an electrical zone sensing
instrument such as a Multisizer IIe (Coulter Electronic, Luton,
Beds, England), or a laser diffraction instrument such as a HELOS
system (Sympatec, Princeton, N.J.) or a Mastersizer system
(Malvern, Worcestershire, UK). Other instruments for measuring
particle geometric diameter are well known in the art. The diameter
of respirable dry particles in a sample will range depending upon
factors such as particle composition and methods of synthesis. The
distribution of size of respirable dry particles in a sample can be
selected to permit optimal deposition within targeted sites within
the respiratory system.
[0146] Experimentally, aerodynamic diameter can be determined using
time of flight (TOF) measurements. For example, an instrument such
as the Aerosol Particle Sizer (APS) Spectrometer (TSI Inc.,
Shoreview, Minn.) can be used to measure aerodynamic diameter. The
APS measures the time taken for individual respirable dry particles
to pass between two fixed laser beams.
[0147] Aerodynamic diameter also can be experimentally determined
directly using conventional gravitational settling methods, in
which the time required for a sample of respirable dry particles to
settle a certain distance is measured. Indirect methods for
measuring the mass median aerodynamic diameter include the Andersen
Cascade Impactor (ACI), next generation impactor (NGI), and the
multi-stage liquid impinger (MSLI) methods. The methods and
instruments for measuring particle aerodynamic diameter are well
known in the art.
[0148] Tap density is a measure of the envelope mass density
characterizing a particle. Tap density is accepted in the field as
an approximation of the envelope mass density of a particle. The
envelope mass density of a particle of a statistically isotropic
shape is defined as the mass of the particle divided by the minimum
sphere envelope volume within which it can be enclosed. Features
which can contribute to low tap density include irregular surface
texture, high particle cohesiveness and porous structure. Tap
density can be measured by using instruments known to those skilled
in the art such as the Dual Platform Microprocessor Controlled Tap
Density Tester (Vankel, N.C.), a GeoPyc.TM. instrument
(Micrometrics Instrument Corp., Norcross, Ga.), or SOTAX Tap
Density Tester model TD2 (SOTAX Corp., Horsham, Pa.). Tap density
can be determined using the method of USP Bulk Density and Tapped
Density, United States Pharmacopeia convention, Rockville, Md.,
10.sup.th Supplement, 4950-4951, 1999.
[0149] Fine particle fraction can be used as one way to
characterize the aerosol performance of a dispersed powder. Fine
particle fraction describes the size distribution of airborne
respirable dry particles. Gravimetric analysis, using a Cascade
impactor, is one method of measuring the size distribution, or fine
particle fraction, of airborne respirable dry particles. The
Andersen Cascade Impactor (ACI) is an eight-stage impactor that can
separate aerosols into nine distinct fractions based on aerodynamic
size. The size cutoffs of each stage are dependent upon the flow
rate at which the ACI is operated. The ACI is made up of multiple
stages consisting of a series of nozzles (i.e., a jet plate) and an
impaction surface (i.e., an impaction disc). At each stage an
aerosol stream passes through the nozzles and impinges upon the
surface. Respirable dry particles in the aerosol stream with a
large enough inertia will impact upon the plate. Smaller respirable
dry particles that do not have enough inertia to impact on the
plate will remain in the aerosol stream and be carried to the next
stage. Each successive stage of the ACI has a higher aerosol
velocity in the nozzles so that smaller respirable dry particles
can be collected at each successive stage. Specifically, an
eight-stage ACI is calibrated so that the fraction of powder that
is collected on stage 2 and all lower stages including the final
collection filter is composed of respirable dry particles that have
an aerodynamic diameter of less than 4.4 microns. The airflow at
such a calibration is approximately 60 L/min.
[0150] If desired, a two-stage collapsed ACI can also be used to
measure fine particle fraction. The two-stage collapsed ACI
consists of only stages 0 and 2 of the eight-stage ACI, as well as
the final collection filter, and allows for the collection of two
separate powder fractions. Specifically, a two-stage collapsed ACI
is calibrated so that the fraction of powder that is collected on
stage two is composed of respirable dry particles that have an
aerodynamic diameter of less than 5.6 microns and greater than 3.4
microns. The fraction of powder passing stage two and depositing on
the final collection filter is thus composed of respirable dry
particles having an aerodynamic diameter of less than 3.4 microns.
The airflow at such a calibration is approximately 60 L/min.
[0151] The FPF(<5.6) has been demonstrated to correlate to the
fraction of the powder that is able to make it into the lungs of
the patient, while the FPF(<3.4) has been demonstrated to
correlate to the fraction of the powder that reaches the deep lung
of a patient. These correlations provide a quantitative indicator
that can be used for particle optimization.
[0152] Emitted dose can be determined using the method of USP
Section 601 Aerosols, Metered-Dose Inhalers and Dry Powder
Inhalers, Delivered-Dose Uniformity, Sampling the Delivered Dose
from Dry Powder Inhalers, United States Pharmacopeia convention,
Rockville, Md., 13.sup.th Revision, 222-225, 2007. This method
utilizes an in vitro device set up to mimic patient dosing.
[0153] An ACI can be used to approximate the emitted dose, which
herein is called gravimetric recovered dose and analytical
recovered dose. "Gravimetric recovered dose" is defined as the
ratio of the powder weighed on all stage filters of the ACI to the
nominal dose. "Analytical recovered dose" is defined as the ratio
of the powder recovered from rinsing all stages, all stage filters,
and the induction port of the ACI to the nominal dose.
[0154] Another way to approximate emitted dose is to determine how
much powder leaves its container, e.g. capsule or blister, upon
actuation of a dry powder inhaler (DPI). This takes into account
the percentage leaving the capsule, but does not take into account
any powder depositing on the DPI. The emitted powder mass is the
difference in the weight of the capsule with the dose before
inhaler actuation and the weight of the capsule after inhaler
actuation. This measurement can be called the capsule emitted
powder mass (CEPM) or sometimes termed "shot-weight".
[0155] A Multi-Stage Liquid Impinger (MSLI) is another device that
can be used to measure fine particle fraction. The Multi-Stage
Liquid Impinger operates on the same principles as the ACI,
although instead of eight stages, MSLI has five. Additionally, each
MSLI stage consists of an ethanol-wetted glass frit instead of a
solid plate. The wetted stage is used to prevent particle bounce
and re-entrainment, which can occur when using the ACI.
[0156] The Next Generation Pharmaceutical Impactor (NGI) is a
particle-classifying cascade impactor for testing metered-dose,
dry-powder, and similar inhaler devices.
[0157] The geometric particle size distribution can be measured for
the respirable dry powder after being emitted from a dry powder
inhaler (DPI) by use of a laser diffraction instrument such as the
Malvern Spraytec. With the inhaler mounted in the open-bench
configuration, an airtight seal is made to the air inlet side of
the DPI, causing the outlet aerosol to pass perpendicularly through
the laser beam as an external flow. In this way, known flow rates
can be blown through the DPI by positive pressure to empty the DPI.
The resulting geometric particle size distribution of the aerosol
is measured by the photodetectors with samples typically taken at
1000 Hz for the duration of the inhalation and the Dv50, GSD,
FPF<5.0 .mu.m measured and averaged over the duration of the
inhalation.
[0158] Water content of the respirable dry powder or respirable dry
particles can be measured by a Karl Fisher titration machine, or by
a Thermogravimetric Analysis or Thermal Gravimetric Analysis (TGA).
Karl Fischer titration uses coulometric or volumetric titration to
determine trace amounts of water in a sample. TGA is a method of
thermal analysis in which changes in weight of materials are
measured as a function of temperature (with constant heating rate),
or as a function of time (with constant temperature and/or constant
mass loss). TGA may be used to determine the water content or
residual solvent content of the material being tested.
[0159] The invention also relates to a respirable dry powder or
respirable dry particles produced using any of the methods
described herein.
[0160] The respirable dry particles of the invention can also be
characterized by the chemical, physical, aerosol, and solid-state
stability of the therapeutic agents and excipients that the
respirable dry particles comprise. The chemical stability of the
constituent salts can affect important characteristics of the
respirable particles including shelf-life, proper storage
conditions, and acceptable environments for administration,
biological compatibility, and effectiveness of the salts. Chemical
stability can be assessed using techniques well known in the art.
One example of a technique that can be used to assess chemical
stability is reverse phase high performance liquid chromatography
(RP-HPLC).
Therapeutic Use and Methods
[0161] The respirable dry powders and respirable dry particles of
the present invention are suited for administration to the
respiratory tract. The dry powders and dry particles of the
invention can be administered to a subject in need thereof for the
treatment of respiratory (e.g., pulmonary) diseases, such as
chronic bronchitis, emphysema, chronic obstructive pulmonary
disease, asthma, airway hyper responsiveness, seasonal allergic
allergy, bronchiectasis, cystic fibrosis, pulmonary parenchymal
inflammatory conditions and the like, and for the treatment,
reduction in incidence or severity, and/or prevention of acute
exacerbations of these chronic diseases, such as exacerbations
caused by viral infections (e.g., influenza virus, parainfluenza
virus, respiratory syncytial virus, rhinovirus, adenovirus,
metapneumovirus, coxsackie virus, echo virus, corona virus, herpes
virus, cytomegalovirus, and the like), bacterial infections (e.g.,
Streptococcus pneumoniae, which is commonly referred to as
pneumococcus, Staphylococcus aureus, Burkholderis ssp.,
Streptococcus agalactiae, Haemophilus influenzae, Haemophilus
parainfluenzae, Klebsiella pneumoniae, Escherichia coli,
Pseudomonas aeruginosa, Moraxella catarrhalis, Chlamydophila
pneumoniae, Mycoplasma pneumoniae, Legionella pneumophila, Serratia
marcescens, Mycobacterium tuberculosis, Bordetella pertussis, and
the like), fungal infections (e.g., Histoplasma capsulatum,
Cryptococcus neoformans, Pneumocystis jiroveci, Coccidioides
immitis, and the like) or parasitic infections (e.g., Toxoplasma
gondii, Strongyloides stercoralis, and the like), or environmental
allergens and irritants (e.g., aeroallergens, including pollen and
cat dander, airborne particulates, and the like). In a preferred
embodiment, the pulmonary disease is chronic bronchitis, emphysema,
or chronic obstructive pulmonary disease. If desired, the
respirable dry powders and respirable dry particles can be
administered orally.
[0162] In another preferred embodiment, the pulmonary disease is
asthma.
[0163] In some aspects, the invention is a method for treating
pulmonary diseases, such as chronic bronchitis, emphysema, chronic
obstructive pulmonary disease, asthma, airway hyper responsiveness,
seasonal allergic allergy, bronchiectasis, cystic fibrosis and the
like, comprising administering to the respiratory tract of a
subject in need thereof an effective amount of respirable dry
particles or dry powder, as described herein. In a preferred
embodiment, the pulmonary disease is chronic bronchitis, emphysema,
or chronic obstructive pulmonary disease.
[0164] In another preferred embodiment, the pulmonary disease is
asthma.
[0165] In other aspects, the invention is a method for the
treatment, reduction in incidence or severity, or prevention of
acute exacerbations of a chronic pulmonary disease, such as chronic
bronchitis, emphysema, chronic obstructive pulmonary disease,
asthma, airway hyper responsiveness, seasonal allergic allergy,
bronchiectasis, cystic fibrosis and the like, comprising
administering to the respiratory tract of a subject in need thereof
an effective amount of respirable dry particles or dry powder, as
described herein. In a preferred embodiment, the pulmonary disease
is chronic bronchitis, emphysema, or chronic obstructive pulmonary
disease.
[0166] In another preferred embodiment, the pulmonary disease is
asthma.
[0167] In other aspects, the invention is a method for reducing
inflammation comprising administering to the respiratory tract of a
subject in need thereof an effective amount of respirable dry
particles or dry powders as described herein. Thus, the respirable
dry particles and dry powders can be used to broadly prevent or
treat acute and/or chronic inflammation and, in particular,
inflammation that characterizes a number of pulmonary diseases and
conditions including, chronic bronchitis, emphysema, chronic
obstructive pulmonary disease (COPD), asthma, airway hyper
responsiveness, seasonal allergic allergy, bronchiectasis, cystic
fibrosis (CF), pulmonary parenchymal inflammatory
diseases/conditions, and the like. In a preferred embodiment, the
pulmonary disease is chronic bronchitis, emphysema, or chronic
obstructive pulmonary disease. The dry particles and dry powders
can be administered to prevent or treat both the inflammation
inherent to diseases like COPD, asthma, and CF and the increased
inflammation caused by acute exacerbations of the diseases, both of
which play a primary role in the pathogenesis of those
diseases.
[0168] In a preferred embodiment, the pulmonary disease is chronic
bronchitis, emphysema, or chronic obstructive pulmonary disease. In
another preferred embodiment, the pulmonary disease is asthma.
[0169] In other aspects, the invention is a method for relieving
the symptoms of a respiratory disease and/or a chronic pulmonary
disease, such as chronic bronchitis, emphysema, chronic obstructive
pulmonary disease, asthma, airway hyper responsiveness, seasonal
allergic allergy, bronchiectasis, cystic fibrosis and the like,
comprising administering to the respiratory tract of a subject in
need thereof an effective amount of respirable dry particles or dry
powder, as described herein. In a preferred embodiment, the
pulmonary disease is chronic bronchitis, emphysema, or chronic
obstructive pulmonary disease. In another preferred embodiment, the
pulmonary disease is asthma.
[0170] In other aspects, the invention is a method for improving
lung function of a patient with a respiratory disease and/or a
chronic pulmonary disease, such as chronic bronchitis, emphysema,
chronic obstructive pulmonary disease, asthma, airway hyper
responsiveness, seasonal allergic allergy, bronchiectasis, cystic
fibrosis and the like, comprising administering to the respiratory
tract of a subject in need thereof an effective amount of
respirable dry particles or dry powder, as described herein.
Without wishing to be bound by theory, improving a patient's lung
function over a period of time is a long-term way to treat a
respiratory disease and to prevent acute exacerbations. In a
preferred embodiment, the pulmonary disease is chronic bronchitis,
emphysema, or chronic obstructive pulmonary disease. In another
preferred embodiment, the pulmonary disease is asthma.
[0171] The respirable dry particles and dry powders can be
administered to the respiratory tract of a subject in need thereof
using any suitable method, such as instillation techniques, and/or
an inhalation device, such as a dry powder inhaler (DPI) or metered
dose inhaler (MDI). A number of DPIs are available, such as, the
inhalers disclosed is U.S. Pat. Nos. 4,995,385 and 4,069,819,
Spinhaler.RTM. (Fisons, Loughborough, U.K.), Rotahalers.RTM.,
Diskhaler.RTM. and Diskus.RTM. (GlaxoSmithKline, Research Triangle
Technology Park, N.C.), FlowCaps.RTM. (Hovione, Loures, Portugal),
Inhalators.RTM. (Boehringer-Ingelheim, Germany), Aerolizer.RTM.
(Novartis, Switzerland), high-resistance and low-resistance RS-01
(Plastiape, Italy) and others known to those skilled in the
art.
[0172] The following scientific journal articles are incorporated
by reference for their thorough overview of the following dry
powder inhaler (DPI) configurations: 1) Single-dose Capsule DPI, 2)
Multi-dose Blister DPI, and 3) Multi-dose Reservoir DPI. N. Islam,
E. Gladki, "Dry powder inhalers (DPIs) A review of device
reliability and innovation", International Journal of
Pharmaceuticals, 360(2008):1-11. H. Chystyn, "Diskus Review",
International Journal of Clinical Practice, June 2007, 61, 6,
1022-1036. H. Steckel, B. Muller, "In vitro evaluation of dry
powder inhalers I: drug deposition of commonly used devices",
International Journal of Pharmaceuticals, 154(1997):19-29. Some
representative capsule-based DPI units are RS-01 (Plastiape,
Italy), Turbospin.RTM. (PH&T, Italy), Brezhaler.RTM. (Novartis,
Switzerland), Aerolizer (Novartis, Switzerland), Podhaler.RTM.
(Novartis, Switzerland), HandiHaler.RTM. (Boehringer Ingelheim,
Germany), AIR.RTM. (Civitas, Massachusetts), Dose One.RTM. (Dose
One, Maine), and Eclipse.RTM. (Rhone Poulenc Rorer). Some
representative unit dose DPIs are Conix.RTM. (3M, Minnesota),
Cricket.RTM. (Mannkind, California), Dreamboat.RTM. (Mannkind,
California), Occoris.RTM. (Team Consulting, Cambridge, UK),
Solis.RTM. (Sandoz), Trivair.RTM. (Trimel Biopharma, Canada),
Twincaps.RTM. (Hovione, Loures, Portugal). Some representative
blister-based DPI units are Diskus.RTM. (GlaxoSmithKline (GSK),
UK), Diskhaler.RTM. (GSK), Taper Dry.RTM. (3M, Minnisota),
Gemini.RTM. (GSK), Twincer.RTM. (University of Groningen,
Netherlands), Aspirair.RTM. (Vectura, UK), AcuBreathe.RTM.
(Respirics, Minnisota, USA), Exubra.RTM. (Novartis, Switzerland),
Gyrohaler.RTM. (Vectura, UK), Omnihaler.RTM. (Vectura, UK),
Microdose.RTM. (Microdose Therapeutix, USA), Multihaler.RTM.
(Cipla, India) Prohaler.RTM. (Aptar), Technohaler.RTM. (Vectura,
UK), and Xcelovair.RTM. (Mylan, Pennsylvania). Some representative
reservoir-based DPI units are Clickhaler.RTM. (Vectura), Next
DPI.RTM. (Chiesi), Easyhaler.RTM. (Orion), Novolizer.RTM. (Meda),
Pulmojet.RTM. (sanofi-aventis), Pulvinal.RTM. (Chiesi),
Skyehaler.RTM. (Skyepharma), Duohaler.RTM. (Vectura), Taifun.RTM.
(Akela), Flexhaler.RTM. (AstraZeneca, Sweden), Turbuhaler.RTM.
(AstraZeneca, Sweden), and Twisthaler.RTM. (Merck), and others
known to those skilled in the art.
[0173] Generally, inhalation devices (e.g., DPIs) are able to
deliver a maximum amount of dry powder or dry particles in a single
inhalation, which is related to the capacity of the blisters,
capsules (e.g. size 000, 00, 0E, 0, 1, 2, 3, and 4, with respective
volumetric capacities of 1.37 ml, 950 .mu.l, 770 .mu.l, 680 .mu.l,
480 .mu.l, 360 .mu.l, 270 .mu.l, and 200 .mu.l) or other means that
contain the dry particles or dry powders within the inhaler.
Preferably, the blister has a volume of about 360 microliters or
less, about 270 microliters or less, or more preferably, about 200
microliters or less, about 150 microliters or less, or about 100
microliters or less. Preferably, the capsule is a size 2 capsule,
or a size 4 capsule. More preferably, the capsule is a size 3
capsule. Accordingly, delivery of a desired dose or effective
amount may require two or more inhalations. Preferably, each dose
that is administered to a subject in need thereof contains an
effective amount of respirable dry particles or dry powder and is
administered using no more than about 4 inhalations. For example,
each dose of respirable dry particles or dry powder can be
administered in a single inhalation or 2, 3, or 4 inhalations. The
respirable dry particles and dry powders are preferably
administered in a single, breath-activated step using a passive
DPI. When this type of device is used, the energy of the subject's
inhalation both disperses the respirable dry particles and draws
them into the respiratory tract.
[0174] The respirable dry particles or dry powders can be
preferably delivered by inhalation to a desired area within the
respiratory tract, as desired. It is well-known that particles with
an aerodynamic diameter (MMAD) of about 1 micron to about 3
microns, can be delivered to the deep lung. Larger MMAD, for
example, from about 3 microns to about 5 microns can be delivered
to the central and upper airways. Therefore, without wished to be
bound by theory, the invention has a MMAD of about 1 micron to
about 5 microns, and preferentially, about 2.5 microns to about 4.5
microns, which preferentially deposits more of the therapeutic dose
in the central airways than in the upper airways or in the deep
lung.
[0175] For dry powder inhalers, oral cavity deposition is dominated
by inertial impaction and so characterized by the aerosol's Stokes
number (DeHaan et al. Journal of Aerosol Science, 35 (3), 309-331,
2003). For equivalent inhaler geometry, breathing pattern and oral
cavity geometry, the Stokes number, and so the oral cavity
deposition, is primarily affected by the aerodynamic size of the
inhaled powder. Hence, factors which contribute to oral deposition
of a powder include the size distribution of the individual
particles and the dispersibility of the powder. If the MMAD of the
individual particles is too large, e.g. above 5 .mu.m, then an
increasing percentage of powder will deposit in the oral cavity.
Likewise, if a powder has poor dispersibility, it is an indication
that the particles will leave the dry powder inhaler and enter the
oral cavity as agglomerates. Agglomerated powder will perform
aerodynamically like an individual particle as large as the
agglomerate, therefore even if the individual particles are small
(e.g., MMAD of 5 microns or less), the size distribution of the
inhaled powder may have an MMAD of greater than 5 leading to
enhanced oral cavity deposition.
[0176] Therefore, it is desirable to have a powder in which the
particles are small, dense, and dispersible such that the powders
consistently deposit in the desired region of the respiratory
tract. For example, the respirable dry powders comprising
respirable dry particles have a MMAD of about 5 microns or less,
between about 1 micron and about 5 microns, preferably between
about 2.5 microns and about 4.5 microns; are dense particles, for
example have a high tap density and/or envelope density are
desired, such as about 0.45 g/cc or more, about 0.45 g/cc to about
1.2 g/cc, about 0.5 g/cc or more, about 0.55 g/cc or more, about
0.55 g/cc to about 1.0 g/cc, or about 0.6 g/cc to about 1.0 g/cc;
and are highly dispersible (e.g. 1/4 bar or alternatively, 0.5/4
bar of less than about 2.0, and preferably about 1.5 or less, or
about 1.4 or less). The tap density and/or envelop density and MMAD
are related theoretically to the VMGD by means of the following
formula: MMAD=VMGD*sqrt(envelope density or tap density). If it is
desired to deliver a high mass of therapeutic using a fixed volume
dosing container, then, particles of higher tap density and/or
envelope density are desired.
[0177] The respirable dry powders comprising respirable dry
particles may also have a tap density of at least about 0.4
g/cm.sup.3, a tap density of greater than 0.4 g/cm.sup.3, or a tap
density of greater than 0.4 g/cm.sup.3 to about 1.2 g/cm.sup.3.
[0178] The respirable dry powders and respirable dry particles of
the invention can be employed in compositions suitable for drug
delivery via the respiratory system. For example, such compositions
can include blends of the respirable dry particles of the invention
and one or more other dry particles or powders, such as dry
particles or powders that contain another active agent, or that
consist of or consist essentially of one or more pharmaceutically
acceptable excipients. The respirable dry powder can include blends
of the dry particles with lactose, such as large lactose carrier
particles that are greater than 10 microns, 20 microns to 500
microns, and preferably between 25 microns and 250 microns.
[0179] Respirable dry powders and respirable dry particles suitable
for use in the methods of the invention can travel through the
upper airways (i.e., the oropharynx and larynx), the lower airways,
which include the trachea followed by bifurcations into the bronchi
and bronchioli, and through the terminal bronchioli which in turn
divide into respiratory bronchioli leading then to the ultimate
respiratory zone, the alveoli or the deep lung. In one embodiment
of the invention, most of the mass of respirable dry powders or
particles deposit in the deep lung. In another embodiment of the
invention, delivery is primarily to the central airways. In another
embodiment, delivery is to the upper airways. In a preferred
embodiment, most of the mass of the respirable dry powders or
particles deposit in the conducting airways.
[0180] Suitable intervals between doses that provide the desired
therapeutic effect can be determined based on the severity of the
condition, overall well being of the subject and the subject's
tolerance to respirable dry particles and dry powders and other
considerations. Based on these and other considerations, a
clinician can determine appropriate intervals between doses.
Generally, respirable dry particles and respirable dry powders are
administered once, twice or three times a day, as needed.
[0181] If desired or indicated, the respirable dry particles and
respirable dry powders described herein can be administered with
one or more other therapeutic agents. The other therapeutic agents
can be administered by any suitable route, such as orally,
parenterally (e.g., intravenous, intra-arterial, intramuscular, or
subcutaneous injection), topically, by inhalation (e.g.,
intrabronchial, intranasal or oral inhalation, intranasal drops),
rectally, vaginally, and the like. The respirable dry particles and
dry powders can be administered before, substantially concurrently
with, or subsequent to administration of the other therapeutic
agent. Preferably, the respirable dry particles and dry powders and
the other therapeutic agent are administered so as to provide
substantial overlap of their pharmacologic activities.
EXEMPLIFICATION
[0182] Materials used in the following Examples and their sources
are listed below. Sodium chloride, and L-leucine were obtained from
Sigma-Aldrich Co. (St. Louis, Mo.), Spectrum Chemicals (Gardena,
Calif.), or Merck (Darmstadt, Germany). Tiotropium bromide was
obtained from RIA International (East Hanover, N.J.). Ultrapure
(Type II ASTM) water was from a water purification system
(Millipore Corp., Billerica, Mass.), or equivalent.
[0183] Methods:
[0184] Geometric or Volume Diameter.
[0185] Volume median diameter (.times.50 or Dv50), which may also
be referred to as volume median geometric diameter (VMGD), was
determined using a laser diffraction technique. The equipment
consisted of a HELOS diffractometer and a RODOS dry powder
disperser (Sympatec, Inc., Princeton, N.J.). The RODOS disperser
applies a shear force to a sample of particles, controlled by the
regulator pressure (typically set at 1.0 bar with maximum orifice
ring pressure) of the incoming compressed dry air. The pressure
settings may be varied to vary the amount of energy used to
disperse the powder. For example, the dispersion energy may be
modulated by changing the regulator pressure from 0.2 bar to 4.0
bar. Powder sample is dispensed from a microspatula into the RODOS
funnel. The dispersed particles travel through a laser beam where
the resulting diffracted light pattern produced is collected,
typically using an R1 lens, by a series of detectors. The ensemble
diffraction pattern is then translated into a volume-based particle
size distribution using the Fraunhofer diffraction model, on the
basis that smaller particles diffract light at larger angles. Using
this method, geometric standard deviation (GSD) for the volume
diameter was also determined.
[0186] Volume median diameter can also be measured using a method
where the powder is emitted from a dry powder inhaler device. The
equipment consisted of a Spraytec laser diffraction particle size
system (Malvern, Worcestershire, UK), "Spraytec". Powder
formulations were filled into size 3 HPMC capsules (Capsugel
V-Caps) by hand with the fill weight measured gravimetrically using
an analytical balance (Mettler Tolerdo X5205). A capsule based
passive dry powder inhaler (RS01 Model 7, High resistance Plastiape
S.p.A.) was used which had a specific resistance of 0.036
kPa.sup.1/2LPM.sup.-1. Flow rate and inhaled volume were set using
a timer controlled solenoid valve with flow control valve (TPK2000,
Copley Scientific). Capsules were placed in the dry powder inhaler,
punctured and the inhaler sealed inside a cylinder. The cylinder
was connected to a positive pressure air source with steady air
flow through the system measured with a mass flow meter and its
duration controlled with a timer controlled solenoid valve. The
exit of the dry powder inhaler was exposed to room pressure and the
resulting aerosol jet passed through the laser of the diffraction
particle sizer (Spraytec) in its open bench configuration before
being captured by a vacuum extractor. The steady air flow rate
through the system was initiated using the solenoid valve and the
particle size distribution was measured via the Spraytec at 1 kHz
for the duration of the single inhalation maneuver with a minimum
of 2 seconds. Particle size distribution parameters calculated
included the volume median diameter (Dv50) and the geometric
standard deviation (GSD) and the fine particle fraction (FPF) of
particles less than 5 micrometers in diameter. At the completion of
the inhalation duration, the dry powder inhaler was opened, the
capsule removed and re-weighed to calculate the mass of powder that
had been emitted from the capsule during the inhalation duration
(capsule emitted powder mass or CEPM).
[0187] Fine Particle Fraction.
[0188] The aerodynamic properties of the powders dispersed from an
inhaler device were assessed with an Mk-II 1 ACFM Andersen Cascade
Impactor (Copley Scientific Limited, Nottingham, UK) (ACI) or a
Next Generation Impactor (Copley Scientific Limited, Nottingham,
UK) (NGI). The ACI instrument was run in controlled environmental
conditions of 18 to 25.degree. C. and relative humidity (RH)
between 25 and 35%. The instrument consists of eight stages that
separate aerosol particles based on inertial impaction. At each
stage, the aerosol stream passes through a set of nozzles and
impinges on a corresponding impaction plate. Particles having small
enough inertia will continue with the aerosol stream to the next
stage, while the remaining particles will impact upon the plate. At
each successive stage, the aerosol passes through nozzles at a
higher velocity and aerodynamically smaller particles are collected
on the plate. After the aerosol passes through the final stage, a
filter collects the smallest particles that remain, called the
"final collection filter". Gravimetric and/or chemical analyses can
then be performed to determine the particle size distribution. A
short stack cascade impactor, also referred to as a collapsed
cascade impactor, is also utilized to allow for reduced labor time
to evaluate two aerodynamic particle size cut-points. With this
collapsed cascade impactor, stages are eliminated except those
required to establish fine and coarse particle fractions.
[0189] The impaction techniques utilized allowed for the collection
of two or eight separate powder fractions. The capsules (HPMC, Size
3; Capsugel Vcaps, Peapack, N.J.) were hand filled with powder to a
specific weight and placed in a hand-held, breath-activated dry
powder inhaler (DPI) device, the high resistance RS01 DPI
(Plastiape, Osnago, Italy). The capsule was punctured and the
powder was drawn through the cascade impactor operated at a flow
rate of 60.0 L/min for 2.0 s. At this flowrate, the calibrated
cut-off diameters for the eight stages are 8.6, 6.5, 4.4, 3.3, 2.0,
1.1, 0.5 and 0.3 microns and for the two stages used with the short
stack cascade impactor, based on the Andersen Cascade Impactor, the
cut-off diameters are 5.6 microns and 3.4 microns. The fractions
were collected by placing filters in the apparatus and determining
the amount of powder that impinged on them by gravimetric
measurements or chemical measurements on an HPLC. The fine particle
fraction of the total dose of powder (FPF.sub.TD) less than or
equal to an effective cut-off aerodynamic diameter was calculated
by dividing the powder mass recovered from the desired stages of
the impactor by the total particle mass in the capsule. Results are
reported for the eight-stage normal stack cascade impactor as the
fine particle fraction of less than 4.4 microns (FPF.sub.TD<4.4
microns) and the fine particle fraction of less than 2.0 microns
(FPF.sub.TD<2.0 microns), and the two-stage short stack cascade
impactor as the fine particle fraction of less than 5.6 microns
(FPF.sub.TD<5.6 microns) and the fine particle fraction of less
than 3.4 microns (FPF.sub.TD<3.4 microns). The fine particle
fraction can alternatively be calculated relative to the recovered
or emitted dose of powder by dividing the powder mass recovered
from the desired stages of the impactor by the total powder mass
recovered in the impactor.
[0190] Similarly, for FPF measurements utilizing the NGI, the NGI
instrument was run in controlled environmental conditions of 18 to
25.degree. C. and relative humidity (RH) between 25 and 35%. The
instrument consists of seven stages that separate aerosol particles
based on inertial impaction and can be operated at a variety of air
flow rates. At each stage, the aerosol stream passes through a set
of nozzles and impinges on a corresponding impaction surface.
Particles having small enough inertia will continue with the
aerosol stream to the next stage, while the remaining particles
will impact upon the surface. At each successive stage, the aerosol
passes through nozzles at a higher velocity and aerodynamically
smaller particles are collected on the plate. After the aerosol
passes through the final stage, a micro-orifice collector collects
the smallest particles that remain. Chemical analyses can then be
performed to determine the particle size distribution. The capsules
(HPMC, Size 3; Capsugel Vcaps, Peapack, N.J.) were hand filled with
powder to a specific weight and placed in a hand-held,
breath-activated dry powder inhaler (DPI) device, the high
resistance RS01 DPI (Plastiape, Osnago, Italy). The capsule was
punctured and the powder was drawn through the cascade impactor
operated at a specified flow rate for 2.0 Liters of inhaled air. At
the specified flow rate, the cut-off diameters for the stages were
calculated. The fractions were collected by placing wetted filters
in the apparatus and determining the amount of powder that impinged
on them by chemical measurements on an HPLC. The fine particle
fraction of the total dose of powder (FPF.sub.TD) less than or
equal to an effective cut-off aerodynamic diameter was calculated
by dividing the powder mass recovered from the desired stages of
the impactor by the total particle mass in the capsule. Results are
reported for the NGI as the fine particle fraction of less than 5.0
microns (FPF.sub.TD<5.0 microns)
[0191] Aerodynamic Diameter.
[0192] Mass median aerodynamic diameter (MMAD) was determined using
the information obtained by the Andersen Cascade Impactor (ACI).
The cumulative mass under the stage cut-off diameter is calculated
for each stage and normalized by the recovered dose of powder. The
MMAD of the powder is then calculated by linear interpolation of
the stage cut-off diameters that bracket the 50th percentile. An
alternative method of measuring the MMAD is with the Next
Generation Pharmaceutical Impactor (NGI). Like the ACI, the MMAD is
calculated with the cumulative mass under the stage cut-off
diameter is calculated for each stage and normalized by the
recovered dose of powder. The MMAD of the powder is then calculated
by linear interpolation of the stage cut-off diameters that bracket
the 50th percentile.
[0193] Fine Particle Dose.
[0194] The fine particle dose (FPD) is determined using the
information obtained from the ACI. Alternatively, the FPD is
determined using the information obtained from the NGI. The fine
particle dose indicates the mass of one or more therapeutics in a
specific size range and can be used to predict the mass which will
reach a certain region in the respiratory tract. The fine particle
dose can be measured gravimetrically or chemically. If measured
gravimetrically, since the dry particles are assumed to be
homogenous, the mass of the powder on each stage and collection
filter can be multiplied by the fraction of therapeutic agent in
the formulation to determine the mass of therapeutic. If measured
chemically, the powder from each stage or filter is collected,
separated, and assayed for example on an HPLC to determine the
content of the therapeutic. The cumulative mass deposited on the
final collection filter, and stages 6, 5, 4, 3, and 2 for a single
dose of powder, contained in one or more capsules, actuated into
the ACI is equal to the fine particle dose less than 4.4 microns
(FPD<4.4 microns). The cumulative mass deposited on the final
collection filter, and stages 6, 5 and 4 for a single dose of
powder, contained in one or more capsules, actuated into the ACI is
equal to the fine particle dose less than 2.0 microns (FPD<2.0
microns). The quotient of these two values is expressed as
FPD<2.0 .mu.m/FPD<4.4 .mu.m. The higher the ratio, the higher
the percentage of therapeutic that enters the lungs which is
expected to penetrate to the alveolar regions of the lung. The
lower the ratio, the lower the percentage of therapeutic that
enters the lungs, which is expected to penetrate to the alveolar
regions of the lung. For some therapies that target the central or
conducting airways, a lower ratio such as less than 40%, less than
30%, or less than 20% is desired. For other therapies that target
the deep lung, a higher ratio such as 40% or greater, 50% or
greater, or 60% or greater is desired. Similarly, for FPD
measurements utilizing the NGI, the NGI instrument was run as
described in the Fine Particle Fraction description in the
Exemplification section. The cumulative mass deposited on each of
the stages at the specified flow rate is calculated and the
cumulative mass corresponding to a 5.0 micrometer diameter particle
is interpolated. This cumulative mass for a single dose of powder,
contained in one or more capsules, actuated into the NGI is equal
to the fine particle dose less than 5.0 microns (FPD<5.0
microns).
[0195] Emitted Geometric or Volume Diameter.
[0196] The volume median diameter (Dv50) of the powder after it is
emitted from a dry powder inhaler, which may also be referred to as
volume median geometric diameter (VMGD), was determined using a
laser diffraction technique via the Spraytec diffractometer
(Malvern, Inc.). Powder was filled into size 3 capsules (V-Caps,
Capsugel) and placed in a capsule based dry powder inhaler (RS01
Model 7 High resistance, Plastiape, Italy), or DPI, and the DPI
sealed inside a cylinder. The cylinder was connected to a positive
pressure air source with steady air flow through the system
measured with a mass flow meter and its duration controlled with a
timer controlled solenoid valve. The exit of the dry powder inhaler
was exposed to room pressure and the resulting aerosol jet passed
through the laser of the diffraction particle sizer (Spraytec) in
its open bench configuration before being captured by a vacuum
extractor. The steady air flow rate through the system was
initiated using the solenoid valve. A steady air flow rate was
drawn through the DPI typically at 60 L/min for a set duration,
typically of 2 seconds. Alternatively, the air flow rate drawn
through the DPI was sometimes run at 15 L/min, 20 L/min, or 30
L/min. The resulting geometric particle size distribution of the
aerosol was calculated from the software based on the measured
scatter pattern on the photodetectors with samples typically taken
at 1000 Hz for the duration of the inhalation. The Dv50, GSD,
FPF<5.0 .mu.m measured were then averaged over the duration of
the inhalation.
[0197] The Emitted Dose (ED) refers to the mass of therapeutic
which exits a suitable inhaler device after a firing or dispersion
event. The ED is determined using a method based on USP Section 601
Aerosols, Metered-Dose Inhalers and Dry Powder Inhalers,
Delivered-Dose Uniformity, Sampling the Delivered Dose from Dry
Powder Inhalers, United States Pharmacopeia convention, Rockville,
Md., 13th Revision, 222-225, 2007. Contents of capsules are
dispersed using the RS01 HR inhaler at a pressure drop of 4 kPa and
a typical flow rate of 60 LPM and the emitted powder is collected
on a filter in a filter holder sampling apparatus. The sampling
apparatus is rinsed with a suitable solvent such as water and
analyzed using an HPLC method. For gravimetric analysis a shorter
length filter holder sampling apparatus is used to reduce
deposition in the apparatus and the filter is weighed before and
after to determine the mass of powder delivered from the DPI to the
filter. The emitted dose of therapeutic is then calculated based on
the content of therapeutic in the delivered powder. Emitted dose
can be reported as the mass of therapeutic delivered from the DPI
or as a percentage of the filled dose.
[0198] Capsule Emitted Powder Mass.
[0199] A measure of the emission properties of the powders was
determined by using the information obtained from the Andersen
Cascade Impactor tests or emitted geometric diameter by Spraytec.
The filled capsule weight was recorded at the beginning of the run
and the final capsule weight was recorded after the completion of
the run. The difference in weight represented the amount of powder
emitted from the capsule (CEPM or capsule emitted powder mass). The
CEPM was reported as a mass of powder or as a percent by dividing
the amount of powder emitted from the capsule by the total initial
particle mass in the capsule. While the standard CEPM was measured
at 60 L/min, it was also measured at 15 L/min, 20 L/min, or 30
L/min.
[0200] Tap Density.
[0201] Tap density was measured using a modified method requiring
smaller powder quantities, following USP <616> with the
substitution of a 1.5 cc microcentrifuge tube (Eppendorf AG,
Hamburg, Germany) or a 0.3 cc section of a disposable serological
polystyrene micropipette (Grenier Bio-One, Monroe, N.C.) with
polyethylene caps (Kimble Chase, Vineland, N.J.) to cap both ends
and hold the powder. Instruments for measuring tap density, known
to those skilled in the art, include but are not limited to the
Dual Platform Microprocessor Controlled Tap Density Tester (Vankel,
Cary, N.C.) or a SOTAX Tap Density Tester model TD2 (Horsham, Pa.).
Tap density is a standard, approximated measure of the envelope
mass density. The envelope mass density of an isotropic particle is
defined as the mass of the particle divided by the minimum
spherical envelope volume within which it can be enclosed.
[0202] Bulk Density.
[0203] Bulk density was estimated prior to tap density measurement
procedure by dividing the weight of the powder by the volume of the
powder, as estimated using the volumetric measuring device.
[0204] Thermogravimetric Analysis.
[0205] Thermogravimetric analysis (TGA) was performed using a
Thermogravimetric Analyzer Q500 (TA Instruments, New Castle, Del.).
The samples were placed into an open aluminum DSC pan with the tare
weight previously recorded by the instrument. The following method
was employed: Ramp 10.00.degree. C./min from ambient
(.about.35.degree. C.) to 200.degree. C. The weight loss was
reported as a function of temperature up to 150.degree. C. TGA
allows for the calculation of the water content of the dry
powder.
[0206] Tiotropium Content Using HPLC.
[0207] Tiotropium content was measured using a high-performance
liquid chromatography (HPLC) system with an ultraviolet (UV)
detector. The HPLC method was performed using an HPLC system with
UV detection (HPLC-UV; Waters, Milford, Mass.) with Waters Xterra
MS C18 column (5 .mu.m, 3.times.100 mm; Waters, Milford, Mass.) to
identify and quantify tiotropium in a range of 0.03 .mu.g/mL to
1.27 .mu.g/mL. The HPLC-UV system was set up with 100 .mu.L
injection volume, 40.degree. C. column temperature, 240 nm
detection wavelength, and isocratic elution with a mobile phase of
0.1% trifluoroacetic acid (Fisher Scientific, Pittsburgh, Pa.) and
acetonitrile (Fisher Scientific, Pittsburgh, Pa.) (85:15) to
determine tiotropium content in a 10 minute run time. Results are
reported as both tiotropium and tiotropium bromide content.
[0208] Liquid Feedstock Preparation for Spray Drying.
[0209] Spray drying homogenous particles requires that the
ingredients of interest be solubilized in solution or suspended in
a uniform and stable suspension. Sodium chloride, leucine and
tiotropium bromide are sufficiently water-soluble to prepare
suitable spray drying solutions. Alternatively, ethanol or another
organic solvent can be used
[0210] Spray Drying Using Niro Spray Dryer.
[0211] Dry powders were produced by spray drying utilizing a Niro
Mobile Minor spray dryer (GEA Process Engineering Inc., Columbia,
Md.) with powder collection from a cyclone, a product filter or
both. Atomization of the liquid feed was performed using a
co-current two-fluid nozzle either from Niro (GEA Process
Engineering Inc., Columbia, Md.) or a Spraying Systems (Carol
Stream, Ill.) two-fluid nozzle with gas cap 67147 and fluid cap
2850SS, although other two-fluid nozzle setups are also possible.
In some embodiments, the two-fluid nozzle can be in an internal
mixing setup or an external mixing setup. Additional atomization
techniques include rotary atomization or a pressure nozzle. The
liquid feed was fed using gear pumps (Cole-Parmer Instrument
Company, Vernon Hills, Ill.) directly into the two-fluid nozzle or
into a static mixer (Charles Ross & Son Company, Hauppauge,
N.Y.) immediately before introduction into the two-fluid nozzle. An
additional liquid feed technique includes feeding from a
pressurized vessel. Nitrogen or air may be used as the drying gas,
provided that moisture in the air is at least partially removed
before its use. Pressurized nitrogen or air can be used as the
atomization gas feed to the two-fluid nozzle. The process gas inlet
temperature can range from 70.degree. C. to 300.degree. C. and
outlet temperature from 30.degree. C. to 120.degree. C. with a
liquid feedstock rate of 10 mL/min to 100 mL/min. The gas supplying
the two-fluid atomizer can vary depending on nozzle selection and
for the Niro co-current two-fluid nozzle can range from 5 kg/hr to
50 kg/hr or for the Spraying Systems two-fluid nozzle with gas cap
67147 and fluid cap 2850SS can range from 30 g/min to 150 g/min.
The atomization gas rate can be set to achieve a certain gas to
liquid mass ratio, which directly affects the droplet size created.
The pressure inside the drying drum can range from +3 "WC to -6
"WC. Spray dried powders can be collected in a container at the
outlet of the cyclone, onto a cartridge or baghouse filter, or from
both a cyclone and a cartridge or baghouse filter.
[0212] Process gas as used in these descriptions refers to the
drying gas. The two-fluid Spraying Systems nozzles were a 1/4J
series of nozzles.
[0213] Spray Drying Using Buchi Spray Dryer.
[0214] Dry powders were prepared by spray drying on a Buchi B-290
Mini Spray Dryer (BUCHI Labortechnik AG, Flawil, Switzerland) with
powder collection from either a standard or High Performance
cyclone. The system was run either with air or nitrogen as the
drying and atomization gas in open-loop (single pass) mode. When
run using air, the system used the Buchi B-296 dehumidifier to
ensure stable temperature and humidity of the air used to spray
dry. Furthermore, when the relative humidity in the room exceeded
30% RH, an external LG dehumidifier (model 49007903, LG
Electronics, Englewood Cliffs, N.J.) was run constantly. When run
using nitrogen, a pressurized source of nitrogen was used.
Furthermore, the aspirator of the system was adjusted to maintain
the system pressure at -2.0'' water column. Atomization of the
liquid feed utilized a Buchi two-fluid nozzle with a 1.5 mm
diameter or a Schlick 970-0 atomizer with a 0.5 mm liquid insert
(Dusen-Schlick GmbH, Coburg, Germany). Inlet temperature of the
process gas can range from 100.degree. C. to 220.degree. C. and
outlet temperature from 30.degree. C. to 120.degree. C. with a
liquid feedstock flowrate of 3 mL/min to 10 mL/min. The two-fluid
atomizing gas ranges from 25 mm to 45 mm (300 LPH to 530 LPH) for
the Buchi two-fluid nozzle and for the Schlick atomizer an
atomizing air pressure of upwards of 0.3 bar. The aspirator rate
ranges from 50% to 100%.
[0215] Spray Drying Using ProCepT Formatrix.
[0216] Dry powders were prepared by spray drying on a ProCepT
Formatrix R&D spray dryer (ProCepT nv, Zelzate, Belgium). The
system was run in open loop configuration using room air in a
manufacturing suite controlled to <60% RH. The drying gas flow
rate can range from 0.2 to 0.5 m.sup.3/min. The bi-fluid nozzle was
equipped for atomization with liquid tips from 0.15-1.2 mm. The
atomization gas pressure could vary from about 0.5 bar to 6 bar.
The system was equipped with either the small or medium cyclone.
The inlet temperature of the spray dryer can range from about
100.degree. C. to 190.degree. C., with an outlet temperature from
about 40.degree. C. to about 95.degree. C. The liquid feedstock
flowrate can range from about 0.1 to 15 mL/min. Process parameters
were controlled via the ProCepT human-machine interface (HMI) and
all parameters were recorded electronically.
[0217] Clinical Measurements.
[0218] Clinical measurements reported below include the maximal
concentration for tiotropium in the bloodstream (C.sub.max), the
area under the curve for tiotropium in the bloodstream (AUC), and
forced expiratory volume in one second of a patient (FEV.sub.1).
C.sub.max is the maximum concentration of a therapeutic agent, such
as tiotropium, in the bloodstream. It provides pharmacokinetic (PK)
information. It is measured as picograms per milliliter (pg/mL).
AUC indicates the total systemic exposure of an individual to a
therapeutic agent, such as tiotropium, over the stated timeframe.
Herein, AUC was measured over the following timeframes, 0-2 hours,
0-6 hours, and 0-24 hours. AUC is measure in picogram-hours per
milliliter (pg*hr/mL). FEV.sub.1 is the forced expiratory volume in
one second of a person, and can be used to determine the effect of
administration of a therapeutic, such as tiotropium, to a patient.
It provides pharmacodynamic (PD) information. FEV.sub.1 is measured
in liters (L).
Example 1. Tiotropium and Salt-Containing Dry Powder
Formulations
A. Powder Preparation.
[0219] Feedstock solutions were prepared and used to manufacture
dry powders comprised of neat, dry particles containing tiotropium
bromide, sodium chloride, and leucine. Powders were prepared in
triplicate. Table 2 lists the components of the feedstock
formulations used in preparation of the dry powders comprised of
dry particles. Weight percentages are given on a dry basis.
TABLE-US-00003 TABLE 2 Feedstock compositions Formulation Feedstock
Composition (w/w), dry basis I 0.04% tiotropium bromide (TioB),
79.97% sodium chloride, 19.99% leucine V 0.22% tiotropium bromide
(TioB), 79.82% sodium chloride, 19.96% leucine
[0220] The feedstock solutions that were used to spray dry
particles were made as follows. For Formulation I, the liquid
feedstock was batch mixed, the total solids concentration was 30
g/L, the amount of tiotropium bromide in solution was 0.012 g/L,
the amount of sodium chloride in the solution was 23.990 g/L, the
amount of leucine in the solution was 5.998 g/L, and the final
aqueous feedstock was clear. For Formulation V, the liquid
feedstock was batch mixed, the total solids concentration was 30
g/L, the amount of tiotropium bromide in solution was 0.066 g/L,
the amount of sodium chloride in the solution was 23.947 g/L, the
amount of leucine in the solution was 5.989 g/L, and the final
feedstock was clear. Feedstock volumes ranged from 0.720 to 1.800
L, which supported manufacturing campaigns from 2 to 5 hours.
[0221] Dry powders of Formulations I and V were manufactured from
these feedstocks by spray drying on the Buchi B-290 Mini Spray
Dryer (BUCHI Labortechnik AG, Flawil, Switzerland) with cyclone
powder collection. The system was run in open-loop (single pass)
mode using nitrogen as the drying and atomization gas. Atomization
of the liquid feed utilized a Schlick 970-0 atomizer with a 0.5 mm
liquid insert. The aspirator of the system was adjusted to maintain
the system pressure at -2.0'' water column.
[0222] The following spray drying conditions were followed to
manufacture the dry powders. For Formulations I and V, the liquid
feedstock solids concentration was 30 g/L, the process gas inlet
temperature was 178.degree. C. to 182.degree. C., the process gas
outlet temperature was 77.degree. C., the drying gas flowrate was
18.0 kg/hr, the atomization gas flowrate was 1.824 kg/hr, the
atomization gas backpressure at the atomizer inlet was 34 psig to
37 psig and the liquid feedstock flowrate was 6.0 mL/min. The
resulting dry powder formulations are reported in Table 3.
TABLE-US-00004 TABLE 3 Dry Powder compositions, dry basis
Formulation Dry Powder Composition (w/w), dry basis I 0.04%
tiotropium bromide (TioB), 79.97% sodium chloride, 19.99% leucine V
0.22% tiotropium bromide (TioB), 79.82% sodium chloride, 19.96%
leucine
B. Powder Characterization.
[0223] The size and density characteristics are found in Table 4.
The VMGD of Formulations I and V using the RODOS at a dispersion
energy of 1 bar were both 2.30 micrometers, with a standard
deviation of 0.04 and 0.03, respectively, indicating the process
was reproducible over the triplicate spray drying productions. The
span at 1 bar of 1.45 and 1.47 for Formulations I and V,
respectively, indicates a relatively narrow size distribution. The
1 bar/4 bar dispersibility ratio of 1.21 and 1.22 for Formulations
I and V, respectively, and the 0.5 bar/4 bar dispersibility ratio
of 1.29 for both formulations indicate that they are relatively
independent of dispersion energy, a desirable characteristic which
allows the relatively similar therapeutic dose to be administered
to a varying patient population.
[0224] The geometric particle size and capsule emitted powder mass
(CEPM) measured and/or calculated at 60 liters per minute (LPM) and
20 LPM simulated patient flow rates were measured for the two
formulations and reported in Table 4. Formulations I and V both had
a CEPM of 100% at 60 LPM and 97% at 20 LPM. Formulation I had a
Dv50 of 2.43 microns at 60 LPM and 2.63 microns at 20 LPM, and
Formulation V had a Dv50 of 2.39 microns at 60 LPM and 2.62 microns
at 20 LPM. The small change in CEPM and geometric size from 60 LPM
to 20 LPM indicates that the dry powder formulations are relatively
independent of patient inspiratory flowrate, indicating that
patients breathing in at varying flow rates would receive a
relatively similar therapeutic dose.
[0225] The aerodynamic particle size, fine particle fractions and
fine particle doses measured and/or calculated with a two-stage
and/or eight-stage Anderson Cascade Impactor (ACI-2 and ACI-8) are
reported in Table 4. The fine particle fraction of the total dose
less than 2.0, 3.4, 4.4, and 5.6 microns for Formulation I were
14%, 44%, 56.7%, and 72%, respectively, and for Formulation V were
14%, 45%, 58.8%, and 73%, respectively. It should be noted that the
ACI-2 was run with just 1 capsule containing about 10 mg of dry
powder while the ACI-8 was run with 2 capsules, totaling 20 mg of
dry powder. The fine particle dose less than 4.4 micrometers
(FPD<4.4) for Formulation I and V were 3.77 micrograms of
tiotropium and 21.65 micrograms of tiotropium delivered from 2
capsules of 10 mg of powder each or 1.89 micrograms and 10.82
micrograms per capsule respectively.
[0226] The fine particle dose for Formulation I and V both indicate
a high percentage of the nominal dose which is filled into the
capsule reaches the impactor stages (57% and 59%) and so would be
predicted to be delivered to the lungs. This reflects a significant
improvement in efficiency of the inventive formulations over the
commercially available lactose blend-based dry powder SPIRIVA
(tiotropium bromide) HANDIHALER (dry powder inhaler) product. The
SPIRIVA (tiotropium bromide) HANDIHALER (dry powder inhaler)
product has a nominal dose of 18 micrograms of tiotropium filled
into each capsule dose but delivers a fine particle dose
(FPD<4.4) of between 2.5 and 3.7 micrograms for each filled
capsule, as calculated from Shur et al., AAPS Journal, 2012 and
Chodosh et al., Journal of Aerosol Medicine, 2001
[0227] The MMAD of Formulation I and V were 3.20 microns and 3.17
microns, respectively, indicating deposition in the central and
conducting airways. The "FPD<2.0 micron/FPD<4.4 micron"
ratios for Formulation I and V were 25% and 24%, respectively,
indicating that 75% and 76%, respectively, of the FPD less than 4.4
microns has an FPD of 2.0 microns or greater, another indication
that the majority of the dry powder should deposit in the central
and conducting airways.
[0228] Properties relating to the bulk and tap densities of the
formulations are reported in Table 4. The bulk density of both
formulations was 0.26 g/cc and the tap density of Formulation I was
0.68 g/cc and of Formulation V was 0.69 g/cc. For Formulations I
and V, the Hausner ratios were 2.58 and 2.70, respectively, and the
Carr Index was 61.22 and 62.57, respectively.
[0229] The water contents of Formulations I and V were measured
with TGA and are reported in Table 4. They are 0.07% and 0.08%,
respectively.
[0230] The tiotropium bromide contents of Formulations I and V were
measured with HPLC-UV and are reported in Table 4. They are 0.040%
and 0.221%, respectively.
TABLE-US-00005 TABLE 4 Formulations I and V Size and Density
Characteristics Formulation I Formulation V Test n = 3 Lots n = 3
Lots Method Parameter Unit mean .+-. SD mean .+-. SD Geometric
x50/dg @ (.mu.m) 2.30 .+-. 0.04 2.30 .+-. 0.03 Particle 0.5 bar
Size GSD @ 0.5 bar -- 1.66 .+-. 0.04 1.66 .+-. 0.02 using a RODOS/
HELOS Span @ 0.5 bar -- 1.45 .+-. 0.03 1.47 .+-. 0.06 x50/dg @ 1
bar (.mu.m) 2.17 .+-. 0.04 2.17 .+-. 0.03 GSD @ 1 bar -- 1.66 .+-.
0.02 1.67 .+-. 0.03 Span @ 1 bar -- 1.45 .+-. 0.03 1.48 .+-. 0.04
x50/dg @ 4 bar (.mu.m) 1.79 .+-. 0.02 1.78 .+-. 0.01 GSD @ 4 bar --
1.76 .+-. 0.02 1.93 .+-. 0.16 Span @ 4 bar -- 1.51 .+-. 0.04 1.58
.+-. 0.09 1/4 bar -- 1.21 .+-. 0.02 1.22 .+-. 0.02 0.5/4 bar --
1.29 .+-. 0.02 1.29 .+-. 0.01 Geometric CEPM @ (%) 100 .+-. 0 100
.+-. 0 Particle 60LPM Size Dv50 @ (.mu.m) 2.43 .+-. 0.07 2.39 .+-.
0.06 using a 60LPM Spraytec GSD @ 60 -- 1.89 .+-. 0.06 1.86 .+-.
0.05 LPM Span @ 60 -- 1.99 .+-. 0.09 1.91 .+-. 0.11 LPM CEPM @ (%)
97 .+-. 1 97 .+-. 1 20LPM Dv50 @ (.mu.m) 2.63 .+-. 0.11 2.62 .+-.
0.06 20LPM GSD @ 20 -- 1.75 .+-. 0.04 1.76 .+-. 0.03 LPM Span @ 20
-- 1.73 .+-. 0.10 1.78 .+-. 0.07 LPM Aero- Powder (mg) 10.02 .+-.
0.08 10.03 .+-. 0.08 dynamic weight Particle CEPM (%) 98 .+-. 0 98
.+-. 1 Size using FPF_TD (%) 44 .+-. 2 45 .+-. 4 an ACI-2 <3.4
.mu.m FPF_TD (%) 72 .+-. 2 73 .+-. 2 <5.6 .mu.m Mass (%) 77 .+-.
2 79 .+-. 1 collected Aero- Powder (mg) 20.04 .+-. 0.11 20.13 .+-.
0.13 dynamic weight Particle (two Size using approx. 10 mg an ACI-8
capsules) -1 (mg) 0.20 .+-. 0.02 0.21 .+-. 0.02 0 (mg) 0.77 .+-.
0.08 0.69 .+-. 0.10 1 (mg) 2.71 .+-. 0.15 2.66 .+-. 0.28 2 (mg)
3.41 .+-. 0.18 3.59 .+-. 0.16 3 (mg) 5.15 .+-. 0.33 5.38 .+-. 0.20
4 (mg) 1.54 .+-. 0.21 1.55 .+-. 0.17 5 (mg) 0.40 .+-. 0.09 0.47
.+-. 0.08 6 (mg) 0.32 .+-. 0.10 0.35 .+-. 0.04 F (mg) 0.53 .+-.
0.15 0.50 .+-. 0.15 MMAD (.mu.m) 3.20 .+-. 0.10 3.17 .+-. 0.08 GSD
-- 1.75 .+-. 0.08 1.73 .+-. 0.03 FPD <2.0 (mg) 2.79 .+-. 0.33
2.87 .+-. 0.18 .mu.m FPF_TD <2.0 (%) 14 .+-. 2 14 .+-. 1 .mu.m
FPD <4.4 .mu.m (mg) 11.35 .+-. 0.37 11.84 .+-. 0.23 FPD <4.4
.mu.m (.mu.g 3.77 .+-. 0.12 21.65 .+-. 0.43 Tio) FPF_TD <4.4 (%)
57 .+-. 2 59 .+-. 1 .mu.m FPD <2.0 .mu.m/ -- 0.25 .+-. 0.02 0.24
.+-. 0.01 FPD <4.4 .mu.m Densities Bulk (g/cc) 0.26 .+-. 0.02
0.26 .+-. 0.02 density Tapped (g/cc) 0.68 .+-. 0.08 0.69 .+-. 0.06
density Hausner -- 2.58 .+-. 0.12 2.70 .+-. 0.34 ratio Carr Index
-- 61.22 .+-. 1.81 62.57 .+-. 4.99 TGA (Water Water (%) 0.07 .+-.
0.02 0.08 .+-. 0.03 content) Content Tiotropium Tiotropium (%)
0.040 .+-. 0 0.221 .+-. 0 Bromide Bromide Content Content using
HPLC
Example 2. Formulation V Reduces Specific Airway Resistance
Following Methylcholine Challenge in Healthy Mice
[0231] In order to determine efficacy of tiotropium bromide present
in Formulation V, pulmonary function testing was conducted in
healthy mice one hour following treatment with Formulation V.
Treatments were made in a whole body exposure chamber using a
capsule based dry powder inhaler system. Dose was varied by
changing the number of capsules used for each exposure, in this
case 2 or 3, 90 mg capsules for an estimated expected dose of 4.4
.mu.g or 6.6 .mu.g tiotropium bromide, respectively. Pulmonary
function testing was conducted by measuring the specific airway
resistance (sRaw) in mice through dual chamber plethysmography.
Baseline sRaw measurements were taken for 5 minutes, followed by 5
minutes of measurement after nebulization of 0 mg/ml and 100 mg/ml
methylcholine chloride (MCh) dissolved in 0.9% sodium chloride into
the head chamber.
[0232] The results are shown in Table 5. Treatment with both 4.4
.mu.g and 6.6 .mu.g tiotropium bromide resulted in a more that 40%
reduction in sRaw in comparison with untreated mice, p=0.035 and
p=0.032, respectively, following challenge with 100 mg/ml MCh.
There were no significant changes in sRaw at baseline or following
challenge with 0 mg/ml MCh. It is known from the literature, e.g.,
"Effect of tiotropium bromide on airway inflammation and remodeling
in a mouse model of asthma", Clinical and Experimental Allergy
40:1266-1275), that tiotropium bromide results in enhanced
pulmonary function during MCh challenge by antagonizing the M3
muscarinic receptor, the same receptor that recognizes MCh,
ultimately leading to bronchoconstriction. Additionally, it has
been demonstrated that tiotropium bromide enhanced pulmonary
function, resulting in lower sRaw values, for animals and humans
challenged with inhaled MCh in 0.9% sodium chloride. The results
reported in Table 5, specifically unchanged sRaw values at baseline
and 0 mg/ml in conjunction with a significant reduction of sRaw
after 100 mg/ml MCh challenge. Formulation V reduced sRaw following
MCh challenge in healthy mice.
TABLE-US-00006 TABLE 5 MCh challenge following Formulation V
treatment in healthy mice. sRaw (cmH.sub.2O s) 4.4 micrograms 6.6
micrograms Challenge Untreated tiotropium bromide tiotropium
bromide Baseline 5.33 .+-. 1.20 4.68 .+-. 0.29 4.62 .+-. 0.49 0
mg/ml 5.43 .+-. 1.34 4.16 .+-. 0.55 5.60 .+-. 2.06 MCh 100 mg/ml
13.75 .+-. 3.13 8.23 .+-. 3.75* 8.26 .+-. 3.55* MCh Data are
represented as Mean .+-. SD; *p < 0.05
Example 3. Dry Powder Formulations Containing Tiotropium in
Combination with Additional Pharmaceutically Active Agents
[0233] A. Powder Preparation.
[0234] Feedstock solutions were prepared in order to manufacture
dry powders comprised of dry particles containing a sodium salt, a
non-salt excipient, tiotropium and optionally additional
pharmaceutical active agents. Table 6 lists the components of the
feedstock formulations used in preparation of the dry powders
comprised of dry particles. Weight percentages are given on a dry
basis.
TABLE-US-00007 TABLE 6 Feedstock compositions of sodium-salt with
tiotropium and in combination with other pharmaceutically active
agents. % % % Salt Excipient Drug load load load Formulation Salt
(w/w) Excipient (w/w) Drug (w/w) VI Sodium 65.42 Leucine 34.47
Tiotropium 0.113 Chloride Bromide (TioB) VII Sodium 85.31 Leucine
10.0 FP/SX/TioB 4.0/0.58/0.113 Chloride VIII Sodium 65.42 Leucine
29.89 FP/SX/TioB 4.0/0.58/0.113 Chloride
[0235] The feedstock solutions were made according to the
parameters in Tables 7 and 8.
TABLE-US-00008 TABLE 7 Formulation Conditions Formulation: VI VII
Total solids (g) 3 10 Total volume water (L) 0.3 0.4 Total solids
concentration (g/L) 10 10 Amount of NaCl in 1 L (g) 6.542 8.531
Amount leucine in 1 L (g) 3.447 1.0 Amount FP in 1 L (g) 0 0.4
Amount SX in 1 L (g) 0 0.058 Amount TioB in 1 L (g) 0.0113
0.0113
TABLE-US-00009 TABLE 8 Formulation Conditions Formulation: VIII
Total solids (g) 4 Total volume water (L) 0.4 Total solids
concentration 10 (g/L) Amount of NaCl in 1 L (g) 6.542 Amount of
NaSulf in 1 L 0 (g) Amount of NaCit in 1 L 0 (g) Amount leucine in
1 L (g) 2.989 Amount mannitol in 1 L 0 (g) Amount FP in 1 L (g) 0.4
Amount SX in 1 L (g) 0.058 Amount TioB in 1 L (g) 0.0113 Amount
Insulin in 1 L (g) 0 Amount IgG in 1 L (g) 0
[0236] For all formulations, the liquid feedstock was batch
mixed
[0237] Formulation VI through VIII dry powders were produced by
spray drying on the Buchi B-290 Mini Spray Dryer (BUCHI
Labortechnik AG, Flawil, Switzerland) with powder collection from a
High Performance cyclone in a 60 mL glass vessel. The system used
the Buchi B-296 dehumidifier and an external LG dehumidifier (model
49007903, LG Electronics, Englewood Cliffs, N.J.) was run
constantly. Atomization of the liquid feed utilized a Buchi
two-fluid nozzle with a 1.5 mm diameter. The two-fluid atomizing
gas was set at 40 mm (667 LPH). The aspirator rate was set to 80%
(32 m.sup.3/h) for Formulation VI; 70% for Formulations VII, and
VIII. Air was used as the drying gas and the atomization gas. Table
9 below includes details about the spray drying conditions.
TABLE-US-00010 TABLE 9 Spray Drying Process Conditions Formulation
Process Parameters VI VII VIII Liquid feedstock solids
concentration 10 10 10 (g/L) Process gas inlet temperature
(.degree. C.) 115 180 180 Process gas outlet temperature (.degree.
C.) 67-68 74-75 71-74 Process gas flowrate (liter/hr, LPH) 667 667
667 Atomization gas flowrate 32 29 29 (meters.sup.3/hr) Liquid
feedstock flowrate (mL/min) 2.5 10 12.1
[0238] B. Powder Characterization.
[0239] Powder physical and aerosol properties are summarized in
Tables 10 to 14 below. Values with .+-. indicate standard deviation
of the value reported. Two-stage ACI-2 results are reported in
Table 10 for FPF.sub.TD<3.4 .mu.m and FPF.sub.TD<5.6 .mu.m.
Formulations VI through VIII had a FPF.sub.TD<3.4 .mu.m greater
than 20% and a FPF.sub.TD<3.4 .mu.m greater than 30%.
Formulation VI had a FPF.sub.TD<3.4 .mu.m greater than 45%.
Formulations VI through VIII had a FPF.sub.TD<5.6 .mu.m greater
than 40% and a FPF.sub.TD<5.6 .mu.m of greater than 60%.
TABLE-US-00011 TABLE 10 Aerodynamic properties ACI-2 FPF.sub.TD
<3.4 .mu.m FPF.sub.TD <5.6 .mu.m Formulation % % VI 53.96%
.+-. 1.44% 73.00% .+-. 1.80% VII 40.29% .+-. 0.28% 65.33% .+-.
0.41% VIII 37.80% .+-. 2.97% 62.74% .+-. 2.47%
[0240] Formulations VI through VIII had a tapped density greater
than 0.35 g/cc, and Formulations VI and VII had a tapped density
greater than 0.40 g/cc. Formulations VI and VII had a tapped
density greater than 0.50 g/cc. Formulations VI through VIII had a
Hausner Ratio greater than or equal to 1.5. Formulations VII and
VIII had a Hausner Ratios greater than 2.0. Formulation VII had a
Hausner Ratio of 3.07 (see Table 11).
TABLE-US-00012 TABLE 11 Density properties Density Bulk Tapped
Hausner Formulation g/cc g/cc Ratio VI 0.34 .+-. 0.01 0.52 .+-.
0.05 1.54 VII 0.17 .+-. 0 0.52 .+-. 0.04 3.07 VIII 0.18 .+-. 0.01
0.37 .+-. 0.06 2.09
[0241] Table 12 shows that Formulations VI through VIII had Dv50 of
less than 2.0 microns at 60 LPM. Formulations VI through VIII had a
Dv50 of less than 6.0 .mu.m at 15 LPM. Formulations VII had a Dv50
of less than 5.0 .mu.m at 15 LPM.
TABLE-US-00013 TABLE 12 Geometric Diameters Dispersibility -
Spraytec @ 60 LPM @ 15 LPM Formulation Dv50 (.mu.m) GSD Dv50
(.mu.m) GSD VI 1.28 .+-. 0.08 5.59 .+-. 0.18 5.85 .+-. 0.18 4.04
.+-. 0.10 VII 1.55 .+-. 0.07 5.02 .+-. 0.34 4.23 .+-. 0.10 3.20
.+-. 0.25 VIII 1.70 .+-. 0.07 4.47 .+-. 0.25 5.09 .+-. 0.20 3.27
.+-. 0.11
[0242] Table 13 shows that Formulations VI through VIII had a
capsule emitted particle mass (CEPM) of greater than 96% at 60 LPM.
Formulations VI through VIII had a CEPM of greater than 90% at 15
LPM.
TABLE-US-00014 TABLE 13 Dispersibility properties Dispersibility -
CEPM @ 60 LPM @ 15 LPM Formulation CEPM CEPM VI 99.33% .+-. 0.40%
96.92% .+-. 0.81% VII 97.46% .+-. 0.14% 95.94% .+-. 0.55% VIII
99.47% .+-. 0.14% 97.92% .+-. 0.41%
[0243] Table 14 shows that Formulations VI through VIII had a Dv50
of less than 2.0 when using the RODOS at a 1.0 bar setting.
Formulations VI through VIII had a RODOS Ratio for 0.5 bar/4 bar of
less than 1.4, and Formulations VI and VIII had a RODOS Ratio for
0.5 bar/4 bar of less than 1.3. Formulations VI through VIII had a
RODOS Ratio for 1 bar/4 bar of less than or equal to about 1.1.
TABLE-US-00015 TABLE 14 Dispersibility properties (Geometric
diameter using RODOS) RODOS 0.5 bar 1.0 bar 4.0 bar Dv50 Dv50 Dv50
Form. (.mu.m) GSD (.mu.m) GSD (.mu.m) GSD 0.5/4 bar 1/4 bar VI 1.66
2.16 1.46 2.06 1.36 1.92 1.22 1.07 VII 1.87 1.95 1.48 1.78 1.37
1.78 1.36 1.08 VIII 1.95 1.96 1.74 1.93 1.6 1.91 1.22 1.09
Example 4. Effect of a Monovalent Cation-Based Dry Powder of
Tiotropium Bromide (Formulation VI) on Airway Hyperreactivity in an
Ovalbumin Mouse Model of Allergic Asthma
[0244] An ovalbumin mouse model of allergic asthma, protocols for
sensitization and subsequent challenging with OVA, and pulmonary
function testing are described in Examples 6 to 8 of PCT
Publication No. WO 2012/044736 "Monovalent Cation Dry Powders" and
are incorporated by reference herein in their entirety.
[0245] It was known from the literature that tiotropium bromide
(TioB) enhances pulmonary function, resulting in lower sRaw values,
for animals and human beings challenged with methacholine chloride
(MCh) in 0.9% sodium chloride for inhalation. (Ohta, S. et al.
(2010), "Effect of tiotropium bromide on airway inflammation and
remodeling in a mouse model of asthma", Clinical and Experimental
Allergy 40:1266-1275).
[0246] While the effects of TioB on sRaw were known from the
literature, the effect of co-formulating the TioB formulation with
a sodium salt was unknown. Formulation VI (34.47% leucine, 65.42%
NaCi and 0.113% tiotropium bromide, w/w on a dry basis) was tested,
and compared to Placebo-B dry powder (98% leucine, 2% NaCl, w/w on
a dry basis). Results from pulmonary function testing are shown in
Table 15.
TABLE-US-00016 TABLE 15 Effect on specific airway resistance of
Formulation VI. Placebo-B Formulation VI Specific Airway Resistance
[cm H.sub.2O .times. s] (Standard Condition Deviation) Baseline 2.6
(1.5) 4.7 (1.0) PBS 2.9 (1.5) 5.2 (0.8) 50 mg/ml MCh 21.0 (12.0)
5.4 (1.0) 100 mg/ml MCh 18.0 (12.8) 6.3 (2.0)
[0247] These data show that Formulation VI significantly reduced
sRaw during MCh challenge compared to Placebo-B (p<0.00001).
Example 5. Pharmacokinetic (PK) and Pharmacodynamics (PD) Effects
of Monovalent Cation-Based Dry Powders of Tiotropium Bromide
(Formulations I-IV)
[0248] In a pilot study, four doses (two per cohort) of a
monovalent cation-based dry powder of tiotropium bromide,
Formulations I-IV, were evaluated. Plasma levels of tiotropium
bromide were measured over time (FIG. 1) and the bronchodilatory
effect was measured (FIG. 2). Subjects were moderate to severe COPD
patients. Single-doses of Formulations I-IV and matching placebo
were administered in a double-blind inter-leaving cross-over
design. The study was designed to enroll a total of 24 COPD
subjects randomised to 2 cohorts of 12 each taking part in a 2 way
dosing regimen. Within each cohort up to 10 subjects were to
receive the active agent (Formulations I-IV comprising tiotropium
bromide) and 2 were to receive placebo. Formulation I provides a
nominal dose of 3 .mu.g, Formulation II provides a nominal dose of
6 .mu.g, Formulation III provides a nominal dose of 9 .mu.g, and
Formulation IV provides a nominal dose of 12 .mu.g, as indicated in
Table 16.
[0249] Data used in this example, including the tables and figures,
represent unaudited data from a clinical trial. Formulations used
in this example were manufactured with a ProCepT Formatrix R&D
spray dryer.
TABLE-US-00017 TABLE 16 Formulations I-IV and Placebo. Nominal Dose
Composition (wt %) in 10 mg Tiotropium Sodium Fill Weight
Formulation Bromide Leucine Chloride (.mu.g tiotropium) I 0.04
19.99 79.97 3 II 0.07 19.99 79.94 6 III 0.11 19.98 79.91 9 IV 0.14
19.97 79.89 12 Placebo 0.00 20.00 80.00 0
[0250] Cohort 1 received Formulation I or placebo during the first
treatment period (12 subjects: 2 placebo, 10 Formulation I),
followed by a wash out period of a minimum of seven days. After a
safety review, Cohort 2 received Formulation II or placebo during
the first treatment period (12 subjects: 2 placebo, 10 Formulation
II), followed by a wash out period of a minimum of seven days.
After a safety review and the washout period, Cohort 1 returned to
receive Formulation III or placebo for the second treatment period
(11 subjects: 2 placebo, 9 Formulation III). After a final safety
review and a washout period, Cohort 2 returned to receive
Formulation IV or placebo for the second treatment period (10
subjects: 2 placebo, 8 Formulation IV).
[0251] Serum levels of tiotropium bromide were determined using
LC-MS/MS (Liquid chromatography-tandem mass spectrometry) methods
well known in the art, e.g. as described in Nilsson et al. PLoS
One, 5(7):e11411 (2010). The following analytes were detected:
TABLE-US-00018 TABLE 17 Tiotropium analytes. Precursor Product
Analyte ion (m/z) ion (m/z) Tiotropium 392.1 152.1 Tiotropium-D3
395.2 155.2
[0252] Pulmonary function tests were performed using a standard
calibrated spirometer. As a measure of the bronchodilatory effects
of Formulations I-IV in human subjects, FEV.sub.1 (forced
expiratory volume in one second) was used. The predicted FEV.sub.1
was obtained using the normal prediction equations by the ERS
(European Respiratory Society) adjusting for race, gender and age.
Quanjer et al. "Lung volume and forced ventilatory flows." Eur
Respir J. 6: Suppl. 16, 5-40 (1993). Spirometry measurements were
conducted in accordance with ATS/ERS (American Thoracic
Society/European Respiratory Society) 2005 guidelines. The single
highest FEV.sub.1 and the single highest FVC (forced vital
capacity) values from acceptable and repeatable maneuvers were
reported and the FEV.sub.1/FVC ratio determined.
[0253] Unaudited data obtained from the pilot study suggest that
tiotropium bromide, exemplified by Formulations I-IV, was
effectively delivered to the lungs in monovalent cation-based dry
powders, and tiotropium bromide could be measured in the blood.
FIG. 1A depicts the geometric mean PK profile of each nominal dose
level (Formulations I-IV, 3 .mu.g, 6 .mu.g, 9 .mu.g, and 12 .mu.g,
respectively) over a period of 6 hours. The maximal concentration
for tiotropium (C.sub.max) was detected at about 5 minutes after
administration. This profile is consistent with the PK profile of
SPIRIVA (tiotropium bromide) HANDIHALER (dry powder inhaler). FIG.
1B depicts the mean area under the curve (AUC.sub.0-2h) for each
Formulation, I-IV. For comparison, the known profile of single
doses of SPIRIVA (tiotropium bromide) HANDIHALER (dry powder
inhaler) is indicated by a grey boxed area. The data for SPIRIVA
(tiotropium bromide) HANDIHALER (dry powder inhaler) may be
obtained from the FDA's website:
www.accessdata.fda.gov/scripts/cder/drugsatfda/. The AUC.sub.0-2h
for Formulations I-IV bracket the profile of SPIRIVA (tiotropium
bromide) HANDIHALER (dry powder inhaler).
[0254] FIG. 2 depicts pharmacodynamic data that suggest that
Formulations I-IV all improved pulmonary function, each exerting a
measurable bronchodilatory effect as measured by increased peak
FEV.sub.1 over the first 6 h after dosing and increased trough
FEV.sub.1 24 h after dosing. Formulation I (a nominal dose of 3
.mu.g tiotropium) resulted in a measurable and sustained increase
in FEV.sub.1. Formulations II-IV (nominal doses of 6, 9, and 12
.mu.g tiotropium, respectively) resulted in larger improvements in
FEV.sub.1 compared to Formulation I. The profiles obtained for
Formulations II-IV were fairly similar. The single dose improvement
in lung function of Formulations I-IV are comparable to single dose
SPIRIVA (tiotropium bromide) HANDIHALER (dry powder inhaler) lung
function improvement, as described, e.g. by Maesen et al.,
"Tiotropium bromide, a new long-acting antimuscarinic
bronchodilator: a pharmacodynamics study in patients with chronic
obstructive pulmonary disease (COPD)" Eur. Respir. J, 8:1506-13
(1995). However, the improvements can be obtained at significantly
lower nominal doses when compared to the SPIRIVA (tiotropium
bromide) HANDIHALER (dry powder inhaler) product.
Example 6. An In Vitro Testing Comparing the Aerodynamic Particle
Sizes of Tiotropium Bromide Formulation II to the SPIRIVA
(Tiotropium Bromide) HANDIHALER (Dry Powder Inhaler)
[0255] In vitro mass median aerodynamic diameter (MMAD) testing,
also referred to as aerodynamic particle size distribution (aPSD)
testing, was performed which compared Formulation II to the SPIRIVA
(tiotropium bromide) HANDIHALER (dry powder inhaler). The goals of
this study were i) to inform the development of a formulation that
achieved similar fine particle dose delivery across a range of flow
rates relevant for COPD patients and ii) to determine if
Formulation II, representative of all the Formulations I-IV, was
less dependent on a patient's inspiratory flow rate than the
SPIRIVA (tiotropium bromide) HANDIHALER (dry powder inhaler). This
MMAD testing was performed across a range of flow rates relevant to
the intended COPD patient population.
[0256] Formulation II was produced and filled into size 3 HPMC
capsules for dispersion in the RS01 dry powder inhaler. SPIRIVA
(tiotropium bromide) was procured and dispersed from the HANDIHALER
(dry powder inhaler). A multi-stage next-generation impactor (NGI)
was used to determine the mass distributed at various aerodynamic
diameters, the fine particle fraction (FPF) less than 5 micrometers
in diameter, and the fine particle dose (FPD) less than 5
micrometers in diameter. Due to the differing airflow resistance of
the two dry powder inhalers, the formulations were compared at
similar pressure drops across the inhaler rather than at the same
air flow rate. The distributions are shown at a 4 kPa pressure drop
across each dry powder inhaler. (See FIG. 3 and Table 18 below) For
Formulation II using the RS01 HR device, this pressure drop
correlated to an inspiratory flow rate of 60 LPM. For SPIRIVA
(tiotropium bromide) HANDIHALER (dry powder inhaler), this pressure
drop correlated to an inspiratory flow rate of 39 LPM. Testing was
performed with replicates, n=5 for the Formulation II using the
RS01 HR inhaler and n=3 for SPIRIVA (tiotropium bromide) HANDIHALER
(dry powder inhaler). Similar aerodynamic particle size
distributions are seen for the 2 products and the fine particle
dose (FPD<5.0 .mu.m) was found to be comparable for Formulation
II using the RS01 inhaler and the SPIRIVA (tiotropium bromide)
HANDIHALER (dry powder inhaler), even though the nominal dose of
Formulation II was 5.8 micrograms and the nominal dose of SPIRIVA
(tiotropium bromide) HANDIHALER (dry powder inhaler) was 18
micrograms. This means that the delivery efficiency for Formulation
II using the RS01 inhaler was over three times more efficient that
the SPIRIVA (tiotropium bromide) HANDIHALER (dry powder inhaler).
This result is further illustrated by the difference in the fine
particle fraction (FPF<5.0 .mu.m) relative to the nominal dose,
which was 54.8% for Formulation II in the RS01 HR, and 15.0% for
SPIRIVA (tiotropium bromide) HANDIHALER (dry powder inhaler). (See
Table 19 below.) The loss of drug product for the SPIRIVA
(tiotropium bromide) HANDIHALER (dry powder inhaler) was attributed
to the relatively higher amounts of the therapeutic left in the
capsule, device, mouthpiece adapter, induction port and
pre-separator. (See FIG. 4 and Table 20 below) A pre-separator was
not included in NGI testing with Formulation II with the RS01
inhaler because carrier particles were not present in the
spray-dried formulation.
TABLE-US-00019 TABLE 18 Tiotropium mass distribution by stage of
the NGI at 4 kPa for both Formulation II using the RS01 inhaler per
5.8 .mu.g tiotropium nominal dose and the SPIRIVA (tiotropium
bromide) HANDIHALER (dry powder inhaler) per 18 microgram (.mu.g)
nominal dose. SPIRIVA (tiotropium bromide) Formulation II using
HANDIHALER the RS01 inhaler at (dry powder inhaler) at Tiotropium
mass 60 LPM and 5.8 .mu.g 39 LPM and 18 .mu.g distribution by
nominal dose nominal dose stage of the NGI (.mu.g tiotropium)
(.mu.g tiotropium) Stage 1 0.15 .+-. 0.03 0.25 .+-. 0.01 Stage 2
0.97 .+-. 0.12 0.81 .+-. 0.13 Stage 3 1.31 .+-. 0.09 1.42 .+-. 0.11
Stage 4 0.87 .+-. 0.16 1.32 .+-. 0.10 Stage 5 0.59 .+-. 0.04 0.29
.+-. 0.02 Stage 6 0.26 .+-. 0.04 0.04 .+-. 0.01 Stage 7 0.05 0.04
Micro-Orifice 0.05 0.04 Collector After Filter 0.00 0.02
TABLE-US-00020 TABLE 19 Tiotropium nominal dose and FPF less than
5.0 microns as a percentage of the nominal dose using the RS01
inhaler and the SPIRIVA (tiotropium bromide) HANDIHALER (dry powder
inhaler). SPIRIVA Formulation II (tiotropium bromide) using the
RS01 HANDIHALER inhaler (dry powder inhaler) Nominal Dose (.mu.g
tiotropium) 5.8 18 FPF (<5.0 microns) as a 54.8 .+-. 2.8 15.0
.+-. 1.2 percentage of the Nominal Dose
TABLE-US-00021 TABLE 20 Tiotropium mass distribution on various
components before entering the NGI at 4 kPa for both Formulation II
using the RS01 inhaler and the SPIRIVA (tiotropium bromide)
HANDIHALER (dry powder inhaler). SPIRIVA (tiotropium bromide)
Formulation II using HANDIHALER Powder distribution the RS01
inhaler at (dry powder inhaler) at on various 60 LPM and 5.8 .mu.g
39 LPM and 18 .mu.g components before nominal dose nominal dose
entering the NGI (.mu.g tiotropium) (.mu.g tiotropium) Capsule 0.09
.+-. 0.00 6.42 .+-. 0.53 Dry Powder Inhaler 0.23 .+-. 0.01 1.68
Mouthpiece Adapter, 0.63 .+-. 0.04 5.23 0.27 Induction Port and
Pre-separator
[0257] Aerosol testing was performed over a range of peak
inspiratory flows (PIP) relevant to the intended COPD patient
population. A flow rate range 20 L/min to 55 L/min, with a
mid-point of 39 L/min was selected for testing SPIRIVA (tiotropium
bromide) HANDIHALER (dry powder inhaler), which spans the PIF range
that was measured for COPD patients with the product and is
specified in the United States product package insert for SPIRIVA
(tiotropium bromide) HANDIHALER (dry powder inhaler). For
Formulation II, the corresponding flow rate range was calculated
from the SPIRIVA (tiotropium bromide) HANDIHALER (dry powder
inhaler) range by matching differential pressure based on the
different resistances of the DPIs, resulting in a PIF range of 28
L/min to 84 L/min with a mid-point of 60 LPM. The DPI used for
Formulation II was the RS01 HR inhaler, while the DPI used for the
SPIRIVA (tiotropium bromide) product was the HANDIHALER (dry powder
inhaler).
[0258] Formulation II was produced and filled into size 3 HPMC
capsules for dispersion in the RS01 dry powder inhaler. SPIRIVA
(tiotropium bromide) was procured and dispersed from the HANDIHALER
(dry powder inhaler). Fine particle dose (FPD<5.0 microns) is
shown at 1, 4, and 8 kPa pressure drops across the dry powder
inhaler for Formulation II and SPIRIVA (tiotropium bromide)
HANDIHALER (dry powder inhaler) as determined using an NGI. Fine
particle dose was found to be less sensitive to flow rate for
Formulation II compared to the SPIRIVA (tiotropium bromide)
HANDIHALER (dry powder inhaler). The flow rate dependence of the
fine particle dose (less than 5 micrometers) for both products is
shown in FIG. 5 and Table 21 (n=3-5 replicates; values presented
are the mean.+-.standard deviation). Formulation II using the RS01
HR inhaler was found to be less sensitive to the patient's
simulated inspiratory flow rate, even at the low DPI pressure drop
of 1 kPa. These results indicate that Formulation II using the RS01
would provide both improved efficiency in delivery of the nominal
dose compared to SPIRIVA (tiotropium bromide) HANDIHALER (dry
powder inhaler) and more consistent lung delivery across the
patient population, including those with low PIF due to highly
compromised lungs.
TABLE-US-00022 TABLE 21 Flow rate dependence of Formulation II
using the RS01 versus the SPIRIVA (tiotropium bromide) HANDIHALER
(dry powder inhaler) FPD (<5.0 microns) in micrograms of
Tiotropium SPIRIVA (tiotropium bromide) Formulation II using
HANDIHALER the RS01 HR inhaler (dry powder inhaler) DPI Pressure at
5.8 .mu.g at 18 .mu.g Drop (kPa) nominal dose nominal dose 1 3.41
.+-. 0.13 1.61 .+-. 0.22 4 3.19 .+-. 0.17 2.70 .+-. 0.22 8 3.26
.+-. 0.06 2.85 .+-. 0.33 Note: N = 3 replicates for both inhalers
at all conditions, except that N = 5 for the RS01 at the 4 kPa
condition.
Example 7. Pharmacokinetic (PK) and Pharmacodynamics (PD) Effects
of Monovalent Cation-Based Dry Powders of Tiotropium Bromide
(Formulations
[0259] In a Phase Ib study, three dose strengths of a monovalent
cation-based dry powder of tiotropium bromide, Formulations I-III,
were evaluated. This study was designed to enroll up to 40 COPD
patients in a randomized, double blind, 5-way single-dose crossover
study. Formulations I-III, placebo, and open label comparator
product were the 5 arms of the study. There was a 7 day minimum
washout period between doses. Plasma levels of tiotropium bromide
were measured over time (see FIG. 6 and Table 23) and the
bronchodilatory effect was measured (FIG. 7). Subjects were
moderate to severe COPD patients. Formulation I provides a nominal
dose of 3 .mu.g, Formulation II provides a nominal dose of 6 .mu.g,
and Formulation III provides a nominal dose of 9 .mu.g, as
indicated in Table 22.
TABLE-US-00023 TABLE 22 Formulations I-III, Placebo and SPIRIVA
(tiotropium bromide) HANDIHALER (dry powder inhaler) loadings.
Nominal Dose Composition (wt %) in 10 mg Tiotropium Sodium Fill
Weight Formulation Bromide Leucine Chloride (.mu.g tiotropium) I
0.04 19.99 79.97 3 II 0.07 19.99 79.94 6 III 0.11 19.98 79.91 9
Placebo 0.00 20.00 80.00 0
TABLE-US-00024 TABLE 23 Serum PK values at Cmax and AUC values over
varying timeframes. SPIRIVA 3 6 9 (tiotropium bromide) micro-
micro- micro- HANDIHALER grams grams grams (dry powder inhaler)
C.sub.max 7.98 15.9 30.1 7.24 AUC.sub.0-2 4.79 10.1 17.6 6.65
AUC.sub.0-6 6.09 14.9 25.5 12.5 AUC.sub.0-24 6.38 18.1 36 18.2
Note: All time points and Cmax are in pg/mL and the AUC is in
pg*hr/mL
[0260] Serum levels of tiotropium bromide were determined using
LC-MS/MS (Liquid chromatography-tandem mass spectrometry) methods
well known in the art, e.g. as described in Nilsson et al. PLoS
One, 5(7):e11411 (2010). The following analytes were detected
(Table 24):
TABLE-US-00025 TABLE 24 Tiotropium analytes. Precursor Production
Analyte ion (m/z) (m/z) Tiotropium 392.1 152.1 Tiotropium-D3 395.2
155.2
[0261] Pulmonary function tests were performed using a standard
calibrated spirometer. As a measure of the bronchodilatory effects
of Formulations I-III in human subjects, FEV.sub.1 (forced
expiratory volume in one second) was used. The predicted FEV.sub.1
was obtained using the normal prediction equations by the ERS
(European Respiratory Society) adjusting for race, gender and age.
Quanjer et al. "Lung volume and forced ventilatory flows." Eur
Respir J. 6: Suppl. 16, 5-40 (1993). Spirometry measurements were
conducted in accordance with ATS/ERS (American Thoracic
Society/European Respiratory Society) 2005 guidelines. The single
highest FEV.sub.1 and the single highest FVC (forced vital
capacity) values from acceptable and repeatable maneuvers were
reported and the FEV.sub.1/FVC ratio determined. Data is reported
in FIG. 7.
[0262] Unaudited data obtained from the Phase Ib study suggest that
tiotropium bromide, exemplified by Formulations I-III, was
effectively delivered to the lungs in monovalent cation-based dry
powders, and tiotropium bromide could be measured in the blood.
[0263] FIG. 6 depicts the geometric mean PK profile of each nominal
dose level (Formulations I-III, 3 .mu.g, 6 .mu.g, 9 .mu.g,
respectively), and the SPIRIVA (tiotropium bromide) HANDIHALER (dry
powder inhaler) over a period of 6 hours. The maximal concentration
for tiotropium (C.sub.max) was detected at about 5 minutes after
administration. SPIRIVA (tiotropium bromide) HANDIHALER (dry powder
inhaler). Serum levels for Formulations I-III increased with dose
and exhibited similar kinetics to the SPIRIVA (tiotropium bromide)
HANDIHALER (dry powder inhaler). The C.sub.max and the AUC.sub.0-2h
are similar between Formulation I and the SPIRIVA (tiotropium
bromide) HANDIHALER (dry powder inhaler). AUC.sub.0-24h are similar
between Formulation II and the SPIRIVA (tiotropium bromide)
HANDIHALER (dry powder inhaler).
[0264] FIG. 7 depicts pharmacodynamic data that suggest that
Formulations I-III all improved pulmonary function, each exerting a
measurable bronchodilatory effect as measured by increased peak
FEV.sub.1 over the first 6 h after dosing and increased trough
FEV.sub.1 24 h after dosing. Formulations I-III each resulted in a
measurable and sustained increase in FEV.sub.1, with the data
showing significant and sustained increases in FEV.sub.1 compared
to the placebo. Formulation I matched the changes in FEV.sub.1 to
the SPIRIVA (tiotropium bromide) HANDIHALER (dry powder inhaler),
both in "peak" and "trough" improvements. Formulations II and III
result in a greater improvement in lung function than SPIRIVA
(tiotropium bromide) HANDIHALER (dry powder inhaler).
[0265] This clinical data demonstrate the ability to match lung
dose of SPIRIVA (tiotropium bromide) HANDIHALER (dry powder
inhaler) with a significantly lower nominal dose. Formulation I is
comparable to SPIRIVA (tiotropium bromide) HANDIHALER (dry powder
inhaler) across multiple parameters and achieves a similar
improvement in lung function to SPIRIVA (tiotropium bromide)
HANDIHALER (dry powder inhaler) with significantly lower total
systemic exposure. Formulation II, which has a similar total
systemic exposure to SPIRIVA (tiotropium bromide) HANDIHALER (dry
powder inhaler) as seen by AUC.sub.0-24h results in better lung
function improvements at the same exposure dose.
[0266] A. Audited Clinical Data
[0267] As mentioned above in this example, the results presented
were from unaudited data obtained from the Phase Ib study. Below is
a presentation of the audited data from the same Phase Ib study as
was presented earlier in this example, which support the
observations and conclusions written above. The data above
represent unaudited clinical data. It is noted that data in Tables
23 and 25 and FIG. 6 are geometric mean values, and data in Table
26 and FIG. 7 are mean values. It is noted that the SPIRIVA
(tiotropium bromide) HANDIHALER (dry powder inhaler) was the
comparator to Formulations I-III in the clinical trial. SPIRIVA
(tiotropium bromide) HANDIHALER (dry powder inhaler) has a nominal
dose of tiotropium of 18 micrograms, which is blended with 5.5 mg
of lactose monohydrate, and has essentially a 5.5 mg capsule fill
weight.
TABLE-US-00026 TABLE 25 Serum PK values at C.sub.max and AUC values
SPIRIVA Formula- Formula- Formula- (tiotropium bromide) tion tion
tion HANDIHALER I II III (dry powder inhaler) C.sub.max 7.85 15.9
29.6 7.22 SD 6.84 13.4 18.9 6.85 AUC.sub.0-2 h 4.70 9.08 15.8 6.56
SD 2.80 5.27 7.56 3.82 AUC.sub.0-6 h 6.94 14.2 24.2 14.0 SD 4.19
7.15 10.8 6.69 AUC.sub.0-24 h 8.77 21.2 38.0 24.7 SD 7.00 12.0 18.4
12.8 Note: All time points and Cmax are in pg/mL and the AUC is in
pg*hr/mL (Values reported as geometric mean values. SD = Standard
Deviation)
[0268] Table 25 reports the audited clinical data for the serum PK
values (C.sub.max and AUC) for different time periods up to 24
hours after dosing. The C.sub.max value of Formulation I was 7.85
pg/mL.+-.6.84 pg/mL and closely matched that of SPIRIVA (tiotropium
bromide) HANDIHALER (dry powder inhaler), which was 7.22 pg/mL f
6.85 pg/mL. The C.sub.max values of Formulation II and III were
15.9 pg/mL.+-.13.4 pg/mL and 29.6 pg/mL.+-.18.9 pg/mL,
respectively, which were both greater than C.sub.max of SPIRIVA
(tiotropium bromide) HANDIHALER (dry powder inhaler). The
AUC.sub.0-24 of Formulation I was 8.77.+-.7.00 pg*hr/mL, which was
about 1/3 the AUC.sub.0-24h of SPIRIVA (tiotropium bromide)
HANDIHALER (dry powder inhaler), which was 24.7.+-.12.8 pg*hr/mL.
This means that the systemic exposure of Formulation I was about
1/3 that of SPIRIVA (tiotropium bromide) HANDIHALER (dry powder
inhaler). The AUC.sub.0-24h of Formulation II was 21.2.+-.12.0
pg*hr/mL, which was about the same AUC.sub.0-24h of SPIRIVA
(tiotropium bromide) HANDIHALER (dry powder inhaler), which was
24.7.+-.12.8 pg*hr/mL. This means that the systemic exposure of
Formulation II was about the same as that of SPIRIVA (tiotropium
bromide) HANDIHALER (dry powder inhaler). The AUC.sub.0-24h of
Formulation III was 38.0.+-.18.4 pg*hr/mL, which was greater than
the AUC.sub.0-24h of SPIRIVA (tiotropium bromide) HANDIHALER (dry
powder inhaler) This means that the systemic exposure of
Formulation III was greater than that of SPIRIVA (tiotropium
bromide) HANDIHALER (dry powder inhaler).
[0269] The audited clinical data presented in Table 25 confirm the
conclusions made from the unaudited data presented in Table 23 and
FIG. 6.
TABLE-US-00027 TABLE 26 Absolute Value in FEV.sub.1 and FEV.sub.1
Change from Baseline at 6 hours and 24 hours after dosing. Formula-
Formula- Formula- SPIRIVA tion 1 tion 2 tion 2 (tiotropium bromide)
(3 micro- (6 micro- (9 micro- HANDIHALER Placebo grams) grams)
grams) (dry powder inhaler) Pre-dose FEV.sub.1 1.297 1.321 1.282
1.296 1.288 (t = 0 hours) (L) SD 0.366 0.370 0.369 0.348 0.373
Absolute FEV.sub.1 1.311 1.561 1.577 1.588 1.529 (t = 6 hours) (L)
SD 0.373 0.445 0.443 0.419 0.437 Change in FEV.sub.1 0.014 0.239
0.294 0.292 0.240 at t = 6 hours (L) SD 0.112 0.163 0.166 0.168
0.189 Absolute FEV.sub.1 at Trough 1.299 1.472 1.500 1.494 1.458 (t
= 24 hours) (L) SD 0.366 0.392 0.421 0.387 0.357 Change in
FEV.sub.1 at Trough 0.001 0.151 0.218 0.198 0.169 (t = 24 hours)
(L) SD 0.100 0.120 0.145 0.164 0.157 (Values reported as mean
values. SD = Standard Deviation)
[0270] Table 26 reports the audited clinical data for the FEV.sub.1
values over varying time-points up to 24 hours. At the 6 hour time
point, administration of Formulation I had caused a change in
FEV.sub.1 of 0.239 L.+-.0.163 L which closely matched the result
observed for SPIRIVA (tiotropium bromide) HANDIHALER (dry powder
inhaler), which had caused a change in FEV.sub.1 of 0.240
L.+-.0.189 L, indicating a similar lung function improvement at 6
hours. Formulations II and III had caused a change in FEV.sub.1 of
0.294 L.+-.0.166 L and 0.292 L.+-.0.168 L, respectively, both of
which are greater than the change in FEV1 of 0.240 L 0.189 L
observed for SPIRIVA (tiotropium bromide) HANDIHALER (dry powder
inhaler), indicating a greater lung function improvement at 6
hours. At the 24 hours time point, which was the trough FEV.sub.1
observation point, administration of Formulation I had caused a
change in FEV.sub.1 of 0.151 L.+-.0.120 L which was slightly less
than the result observed for SPIRIVA (tiotropium bromide)
HANDIHALER (dry powder inhaler), which had caused a change in
FEV.sub.1 of 0.169 L.+-.0.157 L, indicating that Formulation I
caused an improvement in lung function at 24 hours, but was
slightly less than observed for SPIRIVA (tiotropium bromide)
HANDIHALER (dry powder inhaler). Formulations II and III had caused
a change in FEV.sub.1 of 0.218 L.+-.0.145 L and 0.198 L.+-.0.164 L,
respectively, both of which are greater than the change in FEV1 of
0.169 L.+-.0.157 L observed for SPIRIVA (tiotropium bromide)
HANDIHALER (dry powder inhaler), indicating a greater improvement
in lung function at 24 hours.
[0271] The audited clinical data presented in Table 26 confirm the
conclusions made from the unaudited data presented in FIG. 7.
[0272] Both the unaudited and audited data obtained from the Phase
Ib study suggest that tiotropium bromide, exemplified by
Formulations I-III, was effectively delivered to the lungs in
monovalent cation-based dry powders, and that tiotropium bromide
could be measured in the blood. The audited clinical data closely
matched the unaudited clinical data and served to confirm the
conclusions drawn from the unaudited data.
[0273] These clinical data demonstrate the ability to match lung
dose of SPIRIVA (tiotropium bromide) HANDIHALER (dry powder
inhaler) with a significantly lower nominal dose. Formulation I was
comparable to SPIRIVA (tiotropium bromide) HANDIHALER (dry powder
inhaler) in lung function improvement over the 24 hour time period,
SPIRIVA (tiotropium bromide) HANDIHALER (dry powder inhaler) as
demonstrated by the similar improvements in FEV.sub.1 at the 6 hour
timepoint and 24 hour trough timepoint. This similar lung function
improvement was achieved with similar values for C.sub.max, yet
with a significantly lower total systemic exposure, as seen by
AUC.sub.0-24h results of about 1/3 that observed for SPIRIVA
(tiotropium bromide) HANDIHALER (dry powder inhaler). Formulation
II, which has a similar total systemic exposure to SPIRIVA
(tiotropium bromide) HANDIHALER (dry powder inhaler) as seen by
AUC.sub.0-24h results in better lung function improvements at the
same exposure dose, for example, FEV.sub.1 change at 6 hours and at
the 24 hour trough timepoint.
Example 8. An In Vitro Testing Comparing the Aerodynamic Particle
Sizes of Tiotropium Bromide Formulation II from the RS01 UHR2 to
the SPIRIVA (Tiotropium Bromide) HANDIHALER (Dry Powder
Inhaler)
[0274] The example above was substantially repeated, as described
in Example 6, with a different model of dry powder inhaler
delivering Formulation II. In Example 6, Formulation II was
delivered using the RS01 HR dry powder inhaler while in the current
example, Formulation II was delivered from the RS01 UHR2 dry powder
inhaler which has a higher resistance to airflow than the RS01 HR
model. In vitro aerodynamic particle size distribution (aPSD)
testing was performed which compared Formulation II delivered form
the RS01 UHR2 dry powder inhaler to the SPIRIVA (tiotropium
bromide) HANDIHALER (dry powder inhaler). The goals of this study
were i) to inform the development of a formulation that achieved
similar fine particle dose delivery across a range of flow rates
relevant for COPD patients and ii) to determine if Formulation II,
representative of all the Formulations I-IV, was less dependent on
a patient's inspiratory flow rate than the SPIRIVA (tiotropium
bromide) HANDIHALER (dry powder inhaler). This aPSD testing was
performed across a range of flow rates relevant to the intended
COPD patient population.
[0275] Formulation II was produced and filled into size 3 HPMC
capsules for dispersion in the RS01 UHR2 dry powder inhaler.
SPIRIVA (tiotropium bromide) was procured and dispersed from the
HANDIHALER (dry powder inhaler). A multi-stage next-generation
impactor (NGI) was used to determine the mass median aerodynamic
diameters, the fine particle fraction (FPF) less than 5 micrometers
in diameter, and the fine particle dose (FPD) less than 5
micrometers in diameter. As both the RS01 UHR2 and SPIRIVA
(tiotropium bromide) HANDIHALER (dry powder inhaler) dry powder
inhaler have the similar airflow resistances, the formulations were
compared at the same air flow rates and so similar pressure drops
across the inhaler. The particle size distributions are shown at a
4 kPa pressure drop across each dry powder inhaler, which
corresponds to 39 LPM through each dry powder inhaler. (See FIG. 8
and Table 27 below) Testing was performed with replicates, n=3 for
the Formulation II using the RS01 UHR2 inhaler and n=3 for SPIRIVA
(tiotropium bromide) HANDIHALER (dry powder inhaler). Similar
aerodynamic particle size distributions are seen for the 3 products
and the fine particle dose (FPD<5.0 .mu.m) was found to be
comparable for Formulation II using the RS01 inhaler and the
SPIRIVA (tiotropium bromide) HANDIHALER (dry powder inhaler), even
though the nominal dose of Formulation II was 5.8 micrograms and
the nominal dose of SPIRIVA (tiotropium bromide) HANDIHALER (dry
powder inhaler) was 18 micrograms. This means that the delivery
efficiency for Formulation II using the RS01 UHR2 inhaler was over
three times more efficient that the SPIRIVA (tiotropium bromide)
HANDIHALER (dry powder inhaler). This result is further illustrated
by the difference in the fine particle fraction (FPF<5.0 .mu.m)
relative to the nominal dose, which was 51.4% for Formulation II in
the RS01 UHR2 and 15.0% for SPIRIVA (tiotropium bromide) HANDIHALER
(dry powder inhaler). (See Table 28 below.) The loss of drug
product for the SPIRIVA (tiotropium bromide) HANDIHALER (dry powder
inhaler) was attributed to the relatively higher amounts of the
therapeutic left in the capsule, device, mouthpiece adapter,
induction port and pre-separator. (See FIG. 9 and Table 29 below) A
pre-separator was not included in NGI testing with Formulation II
with the RS01 UHR2 inhaler because carrier particles were not
present in the spray-dried formulation.
TABLE-US-00028 TABLE 27 Tiotropium mass distribution by stage of
the NGI at 4 kPa for Formulation II using the RS01 UHR2 inhaler per
5.8 .mu.g tiotropium nominal dose and the SPIRIVA (tiotropium
bromide) HANDIHALER (dry powder inhaler) per 18 .mu.g nominal dose.
SPIRIVA Formulation II (tiotropium bromide) using the RS01
HANDIHALER UHR2 inhaler at (dry powder inhaler) at Tiotropium mass
39 LPM and 5.8 .mu.g 39 LPM and 18 .mu.g distribution by nominal
dose nominal dose stage of the NGI (.mu.g tiotropium) (.mu.g
tiotropium) Stage 1 0.07 .+-. 0.02 0.25 .+-. 0.01 Stage 2 0.51 .+-.
0.06 0.81 .+-. 0.13 Stage 3 1.21 .+-. 0.02 1.42 .+-. 0.11 Stage 4
1.21 .+-. 0.15 1.32 .+-. 0.10 Stage 5 0.87 .+-. 0.07 0.29 .+-. 0.02
Stage 6 0.18 .+-. 0.05 0.04 .+-. 0.01 Stage 7 0 0.04 Micro-Orifice
0.02 0.04 Collector After Filter 0 0.02
TABLE-US-00029 TABLE 28 Tiotropium nominal dose and FPF less than
5.0 microns as a percentage of the nominal dose using the RS01 UHR2
inhaler and the SPIRIVA (tiotropium bromide) HANDIHALER (dry powder
inhaler). SPIRIVA Formulation II (tiotropium bromide) using the
RS01 HANDIHALER UHR2 inhaler (dry powder inhaler) Nominal Dose
(.mu.g tiotropium) 5.8 18 FPF (<5.0 microns) as a 54.1 .+-. 3.3
15.0 .+-. 1.2 percentage of the Nominal Dose
TABLE-US-00030 TABLE 29 Tiotropium mass distribution on various
components before entering the NGI at 4 kPa for Formulation II
using the RS01 UHR2 inhaler and the SPIRIVA (tiotropium bromide)
HANDIHALER (dry powder inhaler). SPIRIVA Formulation II using
(tiotropium bromide) the RS01 UHR2 HANDIHALER Powder distribution
inhaler at (dry powder inhaler) at on various 39 LPM and 5.8 .mu.g
39 LPM and 18 .mu.g components before nominal dose nominal dose
entering the NGI (.mu.g tiotropium) (.mu.g tiotropium) Capsule 0.12
.+-. 0.00 6.42 .+-. 0.53 Dry Powder Inhaler 0.34 .+-. 0.02 1.68
Mouthpiece Adapter, 0.50 .+-. 0.02 5.23 0.27 Induction Port and
Pre-separator
[0276] Aerosol testing was performed over a range of peak
inspiratory flows (PIF) relevant to the intended COPD patient
population. A flow rate range 20 L/min to 55 L/min, with a
mid-point of 39 L/min (corresponding to 1, 4 and 8 kPa) was
selected for testing SPIRIVA (tiotropium bromide) HANDIHALER (dry
powder inhaler) and Formulation II from the RS01 UHR2, which spans
the PIF range that was measured for COPD patients with the product
and is specified in the United States product package insert for
SPIRIVA (tiotropium bromide) HANDIHALER (dry powder inhaler).
[0277] Formulation II was produced and filled into size 3 HPMC
capsules for dispersion in the RS01 UHR2 dry powder inhaler.
SPIRIVA (tiotropium bromide) was procured and dispersed from the
HANDIHALER (dry powder inhaler). Fine particle dose (FPD<5.0
microns) is shown at 1, 4, and 8 kPa pressure drops across the dry
powder inhaler for Formulation II from both RS01 inhalers and
SPIRIVA (tiotropium bromide) HANDIHALER (dry powder inhaler) as
determined using an NGI. Fine particle dose was found to be less
sensitive to flow rate for Formulation II in the RS01 UHR2 inhaler
compared to the SPIRIVA (tiotropium bromide) HANDIHALER (dry powder
inhaler). The flow rate dependence of the fine particle dose (less
than 5 micrometers) for both products is shown in FIG. 10 and Table
30 (n=3 replicates; values presented are the mean.+-.standard
deviation). Formulation II using the RS01 UHR2 inhaler was found to
be less sensitive to the patient's simulated inspiratory flow rate,
even at the low DPI pressure drop of 1 kPa. These results indicate
that Formulation II using the RS01 UHR2 inhaler would provide both
improved efficiency in delivery of the nominal dose compared to
SPIRIVA (tiotropium bromide) HANDIHALER (dry powder inhaler) and
more consistent lung delivery across the patient population,
including those with low PIF due to highly compromised lungs.
TABLE-US-00031 TABLE 30 Flow rate dependence of Formulation II
using the RS01 UHR2 versus the SPIRIVA (tiotropium bromide)
HANDIHALER (dry powder inhaler) FPD (<5.0 microns) in micrograms
of Tiotropium SPIRIVA Formulation II using (tiotropium bromide) the
RS01 UHR2 HANDIHALER inhaler (dry powder inhaler) DPI Pressure at
5.8 .mu.g at 18 .mu.g Drop (kPa) nominal dose nominal dose 1 3.14
.+-. 0.07 1.61 .+-. 0.22 4 3.15 .+-. 0.19 2.70 .+-. 0.22 8 3.24
.+-. 0.20 2.85 .+-. 0.33
* * * * *
References