U.S. patent application number 15/102957 was filed with the patent office on 2016-11-03 for pde5 inhibitor powder formulations and methods relating thereto.
This patent application is currently assigned to Respira Therapeutics, Inc.. The applicant listed for this patent is RESPIRA THERAPEUTICS, INC.. Invention is credited to Robert Curtis, Dan Deaton, Aileen Gibbons, James Hannon, Stephen Lermer, Revati Shreeniwas, Hugh Smyth, Pravin Soni, Zhen Xu.
Application Number | 20160317542 15/102957 |
Document ID | / |
Family ID | 53371777 |
Filed Date | 2016-11-03 |
United States Patent
Application |
20160317542 |
Kind Code |
A1 |
Xu; Zhen ; et al. |
November 3, 2016 |
PDE5 INHIBITOR POWDER FORMULATIONS AND METHODS RELATING THERETO
Abstract
Novel dry powder compositions comprising and methods relating
thereto are provided. The dry powder compositions comprise PDE5
inhibitors, such as vardenafil, or pharmaceutically acceptable
salts or esters thereof. The dry powder compositions may optionally
include an carrier/excipient. The concentration of active agent may
be at least about 2% by weight. Methods of aerosolizing the dry
powder compositions and using them to treat various diseases are
also disclosed.
Inventors: |
Xu; Zhen; (Albuquerque,
NM) ; Smyth; Hugh; (West Lake Hills, TX) ;
Gibbons; Aileen; (New York, NY) ; Shreeniwas;
Revati; (Palo Alto, CA) ; Soni; Pravin;
(Sunnyvale, CA) ; Deaton; Dan; (Apex, NC) ;
Hannon; James; (Albuquerque, NM) ; Lermer;
Stephen; (Austin, TX) ; Curtis; Robert; (Santa
Fe, NM) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
RESPIRA THERAPEUTICS, INC. |
Albuquerque |
NM |
US |
|
|
Assignee: |
Respira Therapeutics, Inc.
Albuquerque
NM
|
Family ID: |
53371777 |
Appl. No.: |
15/102957 |
Filed: |
December 9, 2014 |
PCT Filed: |
December 9, 2014 |
PCT NO: |
PCT/US2014/069392 |
371 Date: |
June 9, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61913744 |
Dec 9, 2013 |
|
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|
61913734 |
Dec 9, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/26 20130101;
A61K 31/166 20130101; A61K 31/53 20130101; A61M 15/0008 20140204;
A61K 9/0075 20130101; A61K 31/4985 20130101; A61K 31/519 20130101;
A61M 2202/064 20130101; A61K 31/506 20130101 |
International
Class: |
A61K 31/53 20060101
A61K031/53; A61K 47/26 20060101 A61K047/26; A61M 15/00 20060101
A61M015/00; A61K 9/00 20060101 A61K009/00 |
Claims
1. A powder pharmaceutical composition comprising a) at least about
2% by weight of a PDE5 inhibitor or a pharmaceutically acceptable
salt or ester thereof relative to the total weight of the overall
pharmaceutical composition, and b) at least one pharmaceutically
acceptable carrier.
2. The powder pharmaceutical composition of claim 1, wherein the
PDE5 inhibitor is at least one of vardenafil, sildenafil,
tadalafil, avanafil, benzamidenafil, lodenafil, mirodenafil,
udenafil, or zaprinast, or a pharmaceutically acceptable salt or
ester thereof.
3. The powder pharmaceutical composition of claim 1, wherein the
composition comprises at least about 2% to about 20% by weight of
the PDE5 inhibitor.
4. The powder pharmaceutical composition of claim 1, wherein the
composition comprises at least about 2% to about 20% by weight of
vardenafil or a pharmaceutically acceptable salt or ester
thereof.
5. The powder pharmaceutical composition of claim 1, wherein the at
least one pharmaceutically acceptable carrier comprises lactose,
mannitol, trehalose, or starch.
6. The powder pharmaceutical composition of claim 5, wherein the at
least one pharmaceutically acceptable carrier comprises at least
one of a mono-, di- or polysaccharide, or their derivatives,
calcium stearate, magnesium stearate, leucine or its derivatives,
lecithin, human serum albumin, polylysine, polyarginine, or other
force control agents, or combinations thereof.
7. The powder pharmaceutical composition of claim 1, wherein the
PDE5 inhibitor or a pharmaceutically acceptable salt or ester is
micronized.
8. The powder pharmaceutical composition of claim 1, wherein the
composition is packaged to have a nominal load of about 3 mg to 30
mg.
9. The powder pharmaceutical composition of claim 1, wherein the
composition is packaged to have a nominal dose of at least about
0.25 mg.
10. The powder pharmaceutical composition of claim 1, wherein the
composition is packaged to have a delivered dose of at least about
0.075 mg.
11. A method of aerosolizing a powder pharmaceutical composition
comprising a) at least 2% by weight of a PDE5 inhibitor, or a
pharmaceutically acceptable salt or ester thereof, relative to the
total weight of the overall pharmaceutical composition, and b) at
least one pharmaceutically acceptable carrier, the method
comprising: providing an inhaler comprising a dispersion chamber
having an inlet and an outlet, the dispersion chamber containing an
actuator that is movable reciprocatable along a longitudinal axis
of the dispersion chamber; and inducing air flow through the outlet
channel to cause air and the powder pharmaceutical composition to
enter into the dispersion chamber from the inlet, and to cause the
actuator to oscillate within the dispersion chamber to assist in
dispersing the powder pharmaceutical composition from the outlet
for delivery to a subject through the outlet.
12. The method of claim 11, wherein the PDE5 inhibitor is at least
one of vardenafil, sildenafil, tadalafil, avanafil, benzamidenafil,
lodenafil, mirodenafil, udenafil, or zaprinast, or a
pharmaceutically acceptable salt or ester thereof.
13. The method of claim 11, wherein the composition comprises at
least about 2% to about 20% by weight of the PDE5 inhibitor.
14. The method of claim 11, wherein the composition comprises at
least about 2% to about 20% by weight of vardenafil or a
pharmaceutically acceptable salt or ester thereof.
15. The method of claim 11, wherein the at least one
pharmaceutically acceptable carrier comprises lactose, mannitol,
trehalose, or starch.
16. The method of claim 11, wherein the at least one
pharmaceutically acceptable carrier comprises at least one of a
mono-, di- or poly-saccharide, or their derivatives, calcium
stearate, magnesium stearate, leucine or its derivatives, lecithin,
human serum albumin, polylysine, polyarginine, or other force
control agents, or combinations thereof.
17. The method of claim 11, wherein the composition has a mass
median aerodynamic diameter of between 0.5 .mu.m and 5 .mu.m upon
aerosolization.
18. The method of claim 11, wherein the composition has a fine
particle fraction of at least about 20% upon aerosolization.
19. The method of claim 11, wherein the composition has an emitted
dose of at least about 40% upon aerosolization.
20. The method of claim 11, wherein the powdered medicament is
stored within a storage compartment, and wherein the powder
pharmaceutical composition is transferred from the storage
compartment, through the inlet and into the dispersion chamber.
21. The method of claim 11, wherein the inlet is in fluid
communication with an initial chamber, and wherein the powder
pharmaceutical composition is received into the initial chamber
prior to passing through the inlet and into the dispersion
chamber.
22. A method of treating a disease in a subject in need thereof,
the method comprising administering to the subject via a pulmonary
route an effective amount of a powder pharmaceutical composition
comprising a) at least about 2% of a PDE5 inhibitor, or a
pharmaceutically acceptable salt or ester thereof, by weight
relative to the total weight of the overall pharmaceutical
composition dose, and b) at least one pharmaceutically acceptable
carrier.
23. The method of claim 22, wherein the disease is a lung disease
or a heart disease.
24. The method of claim 23, wherein the lung disease is pulmonary
hypertension or cystic fibrosis.
25. The method of claim 23, wherein the heart disease is congestive
heart failure.
26. The method of claim 22, wherein the powder pharmaceutical
composition is administered as an aerosol.
27. The method of claim 22, wherein the powder pharmaceutical
composition is administered using a dry powder inhaler or a metered
dose inhaler.
28. The method of claim 22, wherein the powder pharmaceutical
composition is administered by providing an inhaler comprising a
dispersion chamber having an inlet and an outlet, the dispersion
chamber containing an actuator that is movable reciprocatable along
a longitudinal axis of the dispersion chamber; and inducing air
flow through the outlet channel to cause air and the powder
pharmaceutical composition to enter into the dispersion chamber
from the inlet, and to cause the actuator to oscillate within the
dispersion chamber to assist in dispersing the powder
pharmaceutical composition from the outlet for delivery to a
subject through the outlet.
29. The method of claim 22, wherein the PDE5 inhibitor is at least
one of vardenafil, sildenafil, tadalafil, avanafil, benzamidenafil,
lodenafil, mirodenafil, udenafil, or zaprinast, or a
pharmaceutically acceptable salt or ester thereof.
30. The method of claim 22, wherein the composition comprises at
least about 2% to about 20% by weight of the PDE5 inhibitor.
31. The method of claim 22, wherein the composition comprises at
least about 2% to about 20% by weight of vardenafil or a
pharmaceutically acceptable salt or ester thereof.
32. The method of claim 22, wherein the composition further
comprises at least one pharmaceutically acceptable salt, and
wherein the at least one pharmaceutically acceptable carrier
comprises lactose, mannitol, trehalose, or starch.
33. The method of claim 22, wherein the composition further
comprises at least one pharmaceutically acceptable salt, and
wherein the at least one pharmaceutically acceptable carrier
comprises at least one of a mono-, di- or poly-saccharide, or their
derivatives, calcium stearate, magnesium stearate, leucine or its
derivatives, lecithin, human serum albumin, polylysine,
polyarginine, or other force control agents, or combinations
thereof.
34. The method of claim 22, wherein a delivered dose of about 0.25
mg to about 20 mg is delivered to the subject upon aerosolization.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims priority under 35 U.S.C.
119(e) to U.S. Provisional Application Nos. 61/913,734 and
61/913,744, both filed Dec. 9, 2013, and both of which are hereby
incorporated by reference in their entireties herein.
FIELD
[0002] The invention relates to powder formulations of PDE5
inhibitors and methods relating thereto.
BACKGROUND
[0003] Phosphodiesterase type 5 inhibitors (PDE5 inhibitors) block
the degradative action of cGMP-specific phosphodiesterase type 5
(PDE5) on cyclic GMP in the smooth muscle cells lining the blood
vessels supplying the corpus cavernosum of the penis. These drugs,
including vardenafil (Levitra.TM.), sildenafil (Viagra.TM.), and
tadalafil (Cialis.TM.), are administered orally for the treatment
of erectile dysfunction and were the first effective oral treatment
available for the condition.
[0004] PDE5 inhibitors have also been studied for other clinical
use as well, including cardiovascular and heart diseases. For
example, because PDE5 is also present in the arterial wall smooth
muscle within the lungs, PDE5 inhibitors have also been explored
for lung diseases such as pulmonary hypertension and cystic
fibrosis. Pulmonary arterial hypertension, a disease characterized
by sustained elevations of pulmonary artery pressure, which leads
to an increased incidence of failure of the right ventricle of the
heart, which in turn can result in the blood vessels in the lungs
become overloaded with fluid. Two oral PDE5 inhibitors, sildenafil
(Revatio.TM.) and tadalafil (Adcirca.TM.), are approved for the
treatment of pulmonary arterial hypertension. PDE5 inhibitors have
been found to have activity as both a corrector and potentiator of
CFTR protein abnormalities in animal models of cystic fibrosis
disease. (Lubamba et al., Am. J. Respir. Crit. Care Med. (2008)
177:506-515, Lubamba et al., J. Cystic Fibrosis (2012) 11:266-273).
Sildenafil has also been studied as a potential anti-inflammatory
treatment for cystic fibrosis. Oral PDE5 inhibitors have also been
reported to have anti-remodeling properties and to improve cardiac
inotropism, independent of afterload changes, with a good safety
profile. (Giannetta et al., BMC Medicine (2014) 12:185). However,
oral administration of PDE5 inhibitors results in poor and variable
bioavailability and also extensive metabolism in the liver.
(Sandqvist et al., Eur. J. Clin. Pharmacol. (2013) 69:197-207;
Mehrotra, Intl. J. Impotence Res. (2007) 19:253-264.) If oral doses
are increased beyond certain levels, the incidence of systemic side
effects increase which prevents the acceptable use of these drugs.
(Levitra EMEA Scientific Discussion Document, 2005)
[0005] In view of the limitations presented by oral administration
formulations of PDE5 inhibitors, there is a continuing need for
further improvement in pharmaceutical preparations that deliver
increased drug doses to the lung.
BRIEF SUMMARY
[0006] In one aspect, provided is a powder pharmaceutical
composition comprising a) at least about 2% by weight of a PDE5
inhibitor or a pharmaceutically acceptable salt or ester thereof
relative to the total weight of the overall pharmaceutical
composition, and b) at least one pharmaceutically acceptable
carrier.
[0007] In another aspect, provided is a method of aerosolizing a
powder pharmaceutical composition comprising a) at least 2% by
weight of a PDE5 inhibitor, or a pharmaceutically acceptable salt
or ester thereof, relative to the total weight of the overall
pharmaceutical composition, and b) at least one pharmaceutically
acceptable carrier, the method comprising: providing an inhaler
comprising a dispersion chamber having an inlet and an outlet, the
dispersion chamber containing an actuator that is movable
reciprocatable along a longitudinal axis of the dispersion chamber;
and inducing air flow through the outlet channel to cause air and
the powder pharmaceutical composition to enter into the dispersion
chamber from the inlet, and to cause the actuator to oscillate
within the dispersion chamber to assist in dispersing the powder
pharmaceutical composition from the outlet for delivery to a
subject through the outlet.
[0008] In another aspect, provided is a method of treating a
disease in a subject in need thereof, the method comprising
administering to the subject via a pulmonary route an effective
amount of a powder pharmaceutical composition comprising a) at
least about 2% of a PDE5 inhibitor, or a pharmaceutically
acceptable salt or ester thereof, by weight relative to the total
weight of the overall pharmaceutical composition dose, and b) at
least one pharmaceutically acceptable carrier.
[0009] It will be appreciated from a review of the remainder of
this application that further methods and compositions are also
part of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] FIG. 1 illustrates a .sup.1H NMR spectrometry spectrum for
VarHCl.3H.sub.2O (top) and Var(HCl).sub.2.xH.sub.2O (bottom)
according to certain aspects.
[0011] FIG. 2 illustrates a .sup.13C NMR spectrometry spectrum for
Var(HCl).sub.2.xH.sub.2O (top) and VarHCl.3H.sub.2O (bottom)
according to certain aspects.
[0012] FIG. 3 illustrates the results of pH titration analysis for
Var(HCl).sub.2, VarHCl, and VarBase according to some aspects.
[0013] FIGS. 4A-4F illustrates the results of instrinsic stability
testing of VarHCl.3H.sub.2O as assessed by a HPLC high performance
liquid chromatography (HPLC) according to certain aspects. FIG. 4A
shows a HPLC trace for VarHCl.3H.sub.2O as obtained from the
manufacturer. FIG. 4B and FIG. 4C show HPLC traces for
VarHCl.3H.sub.2O following acid degradation in 1N HCl at r.t. for
48 hr and in 1N HCl at 60.degree. C. for 4 hr, respectively. FIG.
4D and FIG. 4E show HPLC traces for VarHCl.3H.sub.2O following
basic degradation in 1N NaOH at r.t. for 48 hr and in 1N NaOH at
60.degree. C. for 4 hr, respectively. FIG. 4F shows an HPLC trace
for VarHCl.3H.sub.2O following oxidative degradation in 6%
H.sub.2O.sub.2 at r.t. for 48 hr.
[0014] FIGS. 5A-5D illustrate the results of
VarHCl.3H.sub.2O-lactose (1:1) formulation blend stability at
different temperatures and humidities as assessed by HPLC according
to some aspects. FIG. 5A shows a HPLC trace of the formulation
stored pouched at 25.degree. C. and 60% relative humidity (RH).
FIG. 5B shows a HPLC trace of the formulation stored pouched at
40.degree. C. and 75% RH. FIG. 5C shows a HPLC trace of the
formulation stored open to ambient environment at 40.degree. C. and
75% RH. FIG. 5D shows a HPLC trace of the formulation prior to
storage (control).
[0015] FIGS. 6A-6C illustrates the particle size distribution of
micronized Var(HCl).sub.2.xH.sub.2O, VarBase, and VarHCl.xH.sub.2O,
respectively, according to certain aspects.
[0016] FIGS. 7A-7C provide scanning electron microscopy (SEM)
images of micronized Var(HCl).sub.2.xH.sub.2O, VarBase, and
VarHCl.xH.sub.2O, respectively, according to certain aspects.
[0017] FIGS. 8A-8C illustrate the results of differential scanning
calorimetry (DSC) analysis to assess the thermal properties of
micronized vardenafil compounds according to certain aspects. FIG.
8A shows the DSC thermogram for Var(HCl).sub.2.xH.sub.2O. FIG. 8B
shows the DSC thermogram for VarBase. FIG. 8C shows the DSC
thermogram for VarHCl.xH.sub.2O.
[0018] FIGS. 9A-9D illustrate dynamic vapor sorption (DVS) analysis
of micronized vardenafil compounds to assess moisture sorption and
desorption behavior according to certain aspects. FIGS. 9A and 9B
show the DVS isotherm plot for micronized Var(HCl).sub.2.xH.sub.2O
and micronized VarBase, respectively. DVS isotherm plots for
micronized VarHCl.xH.sub.2O are shown in FIG. 9C and FIG. 9D, with
the Y axis reflecting either percent change in mass or the
stoichiometric water sorption and desorption profiles (ratio of
H.sub.2O vapor absorbed to dry VarHCl (mol/mol)).
[0019] FIG. 10 illustrates thermogravimetric analysis (TGA) of
micronized Var(HCl).sub.2.xH.sub.2O to assess mass loss according
to certain aspects.
[0020] FIGS. 11A-11C illustrate results of x-ray powder diffraction
(XRPD) analysis assessing crystalline forms of vardenafil
formulations after micronization. FIGS. 10A, 10B, and 10C show the
diffractograms for micronized Var(HCl).sub.2.xH.sub.2O, micronized
VarBase, and micronized VarHCl.xH.sub.2O, respectively.
[0021] FIG. 12 and illustrates an exemplary conditions for
preparation of a 5% Var(HCl).sub.2.xH.sub.2O and lactose blend
formulation. Components were hand blended and then mixed in a
shaker-mixer at 22 rpm-, 49 rpm, and 99 rpm for 5 min, 10 min, 15
min, and 20 min. Extend of blend uniformity was assessed by the
coefficient of variation (% CV) sampling.
[0022] FIG. 13 is a block diagram of a method of aerosolizing a
powder pharmaceutical composition according to some aspects.
[0023] FIG. 14A shows a cross-section of an exemplary tubular body
having an inlet and a dispersion chamber according to some aspects.
FIG. 14B shows a bead position with a chamber of the tubular body
of FIG. 14A according to some aspects.
[0024] FIGS. 15A-15B illustrates the aerosol performance of a range
of high dose Var(HCl).sub.2.xH.sub.2O-lactose blend formulations
according to some aspects. FIG. 15A shows a strong correlation of
emitted dose (ED (%) and API concentration (% w/w) of 20%, 40%,
60%, and 80% API blend formulations. The amount of powder
deposition in the inhaler device was also assessed and
well-correlated with API concentration as shown in FIG. 15B.
[0025] FIG. 16 is a block diagram of a method of treating a disease
in a mammal in need thereof with a powder pharmaceutical
composition according to some aspects.
DETAILED DESCRIPTION
I. Definitions
[0026] The singular forms "a," "an," and, "the" include plural
references unless the context clearly dictates otherwise. Thus, for
example, reference to a compound refers to one or more compounds or
at least one compound. As such, the terms "a" (or "an"), "one or
more," and "at least one" can be used interchangeably herein.
[0027] The phrase "about" as used herein is used to provide
flexibility to a numerical range endpoint by providing that a given
value may be "a little above" or "a little below" the endpoint
accounting for variations one might see in measurements taken among
different instruments, samples, and sample preparations.
[0028] As used herein, the terms "formulation" and "composition"
are used interchangeably and refer to a mixture of at least one
compound, element, or molecule. In some aspects the terms
"formulation" and "composition" may be used to refer to a mixture
of one or more active agents with one or more carrier or other
excipients.
[0029] The terms "therapeutic agent," "active agent," "active
pharmaceutical ingredient," "API," "pharmaceutically active agent,"
and "pharmaceutical," and "drug" are used interchangeably herein to
refer to a substance having a pharmaceutical, pharmacological,
psychosomatic, or therapeutic effect. Further, when these terms are
used, or when a particular active agent is specifically identified
by name or category, it is understood that such recitation is
intended to include the active agent per se, as well as
pharmaceutically acceptable, pharmacologically active derivatives
thereof, or compounds significantly related thereto, including
without limitation, salts, pharmaceutically acceptable salts,
N-oxides, prodrugs, active metabolites, isomers, fragments,
solvates (such as hydrates), polymorphs, pseudopolymorphs, and
esters. Suitable agents for use in the formulations described
herein include, without limitation, compounds which have the
formula (I):
##STR00001##
The compound of Formula I is chemically identified as
2-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylphenyl]-5-methyl-7-propyl-1H-
-imidazo[5,1-i][1,2,4]triazin-4-one, also known as vardenafil. In
particular, the compounds include the chemical forms as set forth
in Formulas (2), (3), and (4) above, including vardenafil base
(VarBase), salts (mono and bis), such as hydrogen chloride salts,
and hydrates (mono, di-, tri-hyrdates), as well as different
polymorphs.
[0030] As used herein, the term "treating" refers to providing an
appropriate dose of a therapeutic agent to a subject suffering from
an ailment.
[0031] As used herein, the term "condition" refers to a disease
state for which the compounds, compositions and methods of the
present disclosure are being used to treat.
[0032] As used herein, "subject" refers to a mammal that may
benefit from the administration of a drug composition or method of
this invention. Examples of subjects include humans, and may also
include other animals such as horses, pigs, cattle, dogs, cats,
rabbits, rats, mice and aquatic mammals. In one specific aspect, a
subject is a human.
[0033] As used herein, an "effective amount" or a "therapeutically
effective amount" of a drug refers to a non-toxic, but sufficient
amount of the drug, to achieve therapeutic results in treating a
condition for which the drug is known to be effective. It is
understood that various biological factors may affect the ability
of a substance to perform its intended task. Therefore, an
"effective amount" or a "therapeutically effective amount" may be
dependent in some instances on such biological factors. Further,
while the achievement of therapeutic effects may be measured by a
physician or other qualified medical personnel using evaluations
known in the art, it is recognized that individual variation and
response to treatments may make the achievement of therapeutic
effects a somewhat subjective decision. The determination of an
effective amount is well within the ordinary skill in the art of
pharmaceutical sciences and medicine. See, for example, Meiner and
Tonascia, "Clinical Trials: Design, Conduct, and Analysis,"
Monographs in Epidemiology and Biostatistics, Vol. 8 (1986),
incorporated herein by reference.
[0034] As used herein, "pharmaceutically acceptable carrier,"
"carrier," and "excipient" may be used interchangeably, and refer
to any inert and pharmaceutically acceptable material that has
substantially no biological activity, and makes up a substantial
part of the formulation.
[0035] As used herein, the terms "administration," and
"administering" refer to the manner in which an active agent is
presented to a subject. Administration can be accomplished by
various art-known routes such as oral, parenteral, transdermal,
inhalation, implantation, etc.
[0036] The term "pulmonary administration" represents any method of
administration in which an active agent can be administered through
the pulmonary route by inhaling an aerosolized liquid or powder
form (nasally or orally). Such aerosolized liquid or powder forms
are traditionally intended to substantially release and or deliver
the active agent to the mucosal membrane and epithelium of the
lungs. In the context of this disclosure, the active agent is in
powder form.
[0037] The term "nominal load" or "total load" refers to the total
amount of formulation packaged or partitioned for administration to
a subject. For example, the nominal load is the total amount of
powder formulation that is enclosed in a capsule for use with an
inhaler.
[0038] The term "nominal dose" or "total dose" refers to the total
amount or mass of active agent packaged or partitioned for
administration to a subject. For example, the nominal dose is the
total amount of active agent that is enclosed in a capsule for use
with an inhaler.
[0039] The term "emitted dose" (ED (%)) refers to the mass of an
active agent that is emitted from a dry powder inhaler
aerosolization device as a percentage of a nominal dose mass.
Powder that exhibits high flow rate often results in higher ED
(%).
[0040] The term "fine particle fraction" or "fine particle fraction
from the emitted dose" (% FPF(ED)) refers to the mass of active
agent having an aerodynamic diameter below about about 5 .mu.m as a
percentage of an emitted dose mass. Typically, the cutoff size is
less than or equal to an aerodynamic diameter of about 5 .mu.m but,
depending on the experimental conditions, can be around 6.4 .mu.m.
The FPF is often used to evaluate the efficiency of aerosol
deaggregation.
[0041] The term "respirable fraction" (RF (%)) is the mass of an
active agent that is below a certain aerodynamic cutoff size as a
percentage of a nominal dose mass. Also known as the fine particle
fraction from the total dose (FPF(TD)). Fine particle fraction may
also be calculated as a percentage of the emitted dose (FPF(ED)).
The respirable fraction represents the proportion of powder aerosol
that can enter the deep respiratory tract. Typically, the RF cutoff
size is an aerodynamic diameter of less than about 10 .mu.m,
preferably less than about 7 .mu.m, and most preferably less than
or about 5 .mu.m. For example, depending on the experimental
conditions, the cutoff size RF can be around 6.4 .mu.m. The
respirable fraction may be determined using an inertial sampling
device.
[0042] The aerodynamic diameter (D.sub.ae) is a spherical
equivalent diameter and derives from the equivalence between the
inhaled particle and a sphere of unit density (.rho..sub.o)
undergoing sedimentation at the same rate as per the following
formula:
D ae = D v ( .rho. x .rho. o ) ( Eq . 1 ) ##EQU00001##
where D.sub.v is the volume-equivalent diameter, .rho. is the
particle density and .chi. is the shape factor. Hence, the
aerodynamic behavior depends on particle geometry, density and
volume diameter: a small spherical particle with a high density
will behave aerodynamically as a bigger particle, being poorly
transported in the lower airways. The D.sub.ae can be improved
reducing the volume diameter and the density or increasing the
shape factor of the particles, by means of different processes.
[0043] The term "mass median aerodynamic diameter" (MMAD) refers to
the mass median aerodynamic diameter of airborne particles at which
50% of particles by mass are larger and 50% are smaller. In other
words, it is the median of the aerodynamic particle size
distribution as a function of particle mass. The percentages of
mass less than the stated aerodynamic diameters versus the
aerodynamic diameters are plotted logarithmically. The MMAD is
taken as the intersection of the line with the 50% cumulative
percent. Computational methods can also be applied.
[0044] As used herein, a plurality of items, structural elements,
compositional elements, and/or materials may be presented in a
common list for convenience. However, these lists should be
construed as though each member of the list is individually
identified as a separate and unique member. Thus, no individual
member of such list should be construed as a de facto equivalent of
any other member of the same list solely based on their
presentation in a common group without indications to the
contrary.
[0045] Concentrations, amounts, and other numerical data may be
expressed or presented herein in a range format. It is to be
understood that such a range format is used merely for convenience
and brevity and thus should be interpreted flexibly to include not
only the numerical values explicitly recited as the limits of the
range, but also to include all the individual numerical values or
sub-ranges encompassed within that range as if each numerical value
and sub-range is explicitly recited. As an illustration, a
numerical range of "about 1 to about 5" should be interpreted to
include not only the explicitly recited values of about 1 to about
5, but also include individual values and sub-ranges within the
indicated range. Thus, included in this numerical range are
individual values such as 2, 3, and 4 and sub-ranges such as from
1-3, from 2-4, and from 3-5, etc., as well as 1, 2, 3, 4, and 5,
individually.
[0046] This same principle applies to ranges reciting only one
numerical value as a minimum or a maximum. Furthermore, such an
interpretation should apply regardless of the breadth of the range
or the characteristics being described.
II. Formulations
[0047] Provided are dry powder pharmaceutical compositions of PDE5
inhibitors and pharmaceutically acceptable salts and esters
thereof. The compositions include at least about 2% by weight of
active agent and at least one pharmaceutically acceptable
carrier.
[0048] In one aspect, provided is a powder pharmaceutical
composition comprising a) at least about 2% by weight of a PDE5
inhibitor or a pharmaceutically acceptable salt or ester thereof
relative to the total weight of the overall pharmaceutical
composition, and b) at least one pharmaceutically acceptable
carrier. In one aspect, the PDE5 inhibitor may be at least one of
vardenafil, sildenafil, tadalafil, avanafil, benzamidenafil,
lodenafil, mirodenafil, udenafil, or zaprinast, or a
pharmaceutically acceptable salt or ester thereof. In one aspect,
the composition may include at least about 2% to about 20% by
weight of the PDE5 inhibitor. In one aspect, the composition may
include at least about 2% to about 20% by weight of vardenafil or a
pharmaceutically acceptable salt or ester thereof. In one aspect,
the at least one pharmaceutically acceptable carrier may include
lactose, mannitol, trehalose, or starch. In one aspect, the at
least one pharmaceutically acceptable carrier may include at least
one of a mono-, di- or poly-saccharide, or their derivatives,
calcium stearate, magnesium stearate, leucine or its derivatives,
lecithin, human serum albumin, polylysine, polyarginine, or other
force control agents, or combinations thereof. In one aspect, the
PDE5 inhibitor or a pharmaceutically acceptable salt or ester may
be micronized. In one aspect, the composition may be packaged to
have a nominal load of about 3 mg to 30 mg. In one aspect, the
composition may be packaged to have a nominal dose of at least
about 0.25 mg. In one aspect, the composition may be packaged to
have a delivered dose of at least about 0.075 mg.
[0049] In one aspect, provided is a method of aerosolizing a powder
pharmaceutical composition comprising a) at least 2% by weight of a
PDE5 inhibitor, or a pharmaceutically acceptable salt or ester
thereof, relative to the total weight of the overall pharmaceutical
composition, and b) at least one pharmaceutically acceptable
carrier, the method comprising: providing an inhaler comprising a
dispersion chamber having an inlet and an outlet, the dispersion
chamber containing an actuator that is movable reciprocatable along
a longitudinal axis of the dispersion chamber; and inducing air
flow through the outlet channel to cause air and the powder
pharmaceutical composition to enter into the dispersion chamber
from the inlet, and to cause the actuator to oscillate within the
dispersion chamber to assist in dispersing the powder
pharmaceutical composition from the outlet for delivery to a
subject through the outlet. In various aspects, the powder
pharmaceutical composition may have one or more of the properties
recited in the previous paragraph. In one aspect, the composition
may have a mass median aerodynamic diameter of between 0.5 .mu.m
and 5 .mu.m upon aerosolization. In one aspect, the composition may
have a fine particle fraction of at least about 20% upon
aerosolization. In one aspect, the composition may have an emitted
dose of at least about 40% upon aerosolization. In one aspect, the
powdered medicament may be stored within a storage compartment (of
the inhaler), and wherein the powder pharmaceutical composition is
transferred from the storage compartment, through the inlet and
into the dispersion chamber. In one aspect, the inlet may be in
fluid communication with an initial chamber, and wherein the powder
pharmaceutical composition is received into the initial chamber
prior to passing through the inlet and into the dispersion
chamber.
[0050] In one aspect, provided is a method of treating a disease in
a subject in need thereof, the method comprising administering to
the subject via a pulmonary route an effective amount of a powder
pharmaceutical composition comprising a) at least about 2% of a
PDE5 inhibitor, or a pharmaceutically acceptable salt or ester
thereof, by weight relative to the total weight of the overall
pharmaceutical composition dose, and b) at least one
pharmaceutically acceptable carrier. In one aspect, the disease may
be a lung disease or a heart disease. For example, in some aspects,
the lung disease may be pulmonary arterial hypertension or cystic
fibrosis. In other aspects, the heart disease may be congestive
heart failure. In various aspects, the powder pharmaceutical
composition may have one or more of the properties recited in the
previous paragraphs. In one aspect, the powder pharmaceutical
composition may be administered as an aerosol. In another aspect,
the powder pharmaceutical composition may be administered using a
dry powder inhaler or a metered dose inhaler. For example, in some
aspects, the powder pharmaceutical composition may be administered
by providing an inhaler comprising a dispersion chamber having an
inlet and an outlet, the dispersion chamber containing an actuator
that is movable reciprocatable along a longitudinal axis of the
dispersion chamber; and inducing air flow through the outlet
channel to cause air and the powder pharmaceutical composition to
enter into the dispersion chamber from the inlet, and to cause the
actuator to oscillate within the dispersion chamber to assist in
dispersing the powder pharmaceutical composition from the outlet
for delivery to a subject through the outlet. In one aspect, a
delivered dose of about 0.25 mg to about 20 mg may be delivered to
the subject upon aerosolization.
Active Agents
[0051] In one aspect, the active agent of the pharmaceutical
composition may a PDE5 inhibitor. Examples of PDE5 inhibitors
include, but are not limited to, vardenafil, sildenafil, tadalafil,
avanafil, benzamidenafil, lodenafil, mirodenafil, udenafil,
zaprinast, or any of their pharmaceutically acceptable salts,
esters, or derivatives. In one aspect, the active agent may be
vardenafil, in all of its suitable forms, which has the formula
(I):
##STR00002##
The compound of Formula (I) is chemically identified as
2-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylphenyl]-5-methyl-7-propyl-1H-
-imidazo[5,1-i][1,2,4]triazin-4-one. Two polymorphic structures
have been known for the free base of vardenafil described by
Formula (I) (Form I described in WO/1999/024433 and Form II
described in U.S. Pat. No. 7,977,478). Vardenafil can further form
salts, which are described by general chemical Formula (II),
wherein HA stands for any acid (as described in WO/2013/075680).
The majority of solid forms of vardenafil are the respective
hydrochlorides and their hydrates (as described in U.S. Pat. Nos.
6,362,178 and 7,977,478; Haning et al., Bioorg. Med. Chem. Lett. 12
(2002) 865-868), which are described by general Formula (III). The
hydrochloride trihydrate (as described in U.S. Pat. Nos. 6,362,178
and 8,273,876, WO/2002/050076) described by chemical Formula (IV),
is the form of vardenafil that has been used for preparing oral
dosage forms (WO/2010/130393, WO/2008/151811, WO/2005/110420,
WO/2004/006894). An amorphous form of vardenafil hydrochloride
trihydrate has been described (U.S. Pat. No. 7,977,478), as well as
a thermodynamically stable crystalline form used in preparing
dosage forms (U.S. Pat. No. 8,273,876). The crystalline hydrate
according to Formula (IV) is instable due to possible loss of
crystal water in using this salt for preparation of a dosage form
(U.S. Pat. No. 8,273,876), but also in any inappropriate
manipulation with this salt during its preparation.
[0052] For example, the active agent may be vardenafil as shown in
Formula (I) (also referred to herein as VarBase), sildenafil,
tadalafil, avanafil, benzamidenafil, lodenafil, mirodenafil,
udenafil, or zaprinast, as well as pharmaceutically acceptable,
pharmacologically active derivatives thereof, or compounds
significantly related thereto, including without limitation, salts,
pharmaceutically acceptable salts, N-oxides, prodrugs, active
metabolites, isomers, fragments, solvates, including hydrates,
polymorphs, pseudopolymorphs, esters, etc. In some instances, the
term "active agent" includes all pharmaceutically acceptable forms
of vardenafil or the other PDE5 inhibitors described herein. For
example, the active agent can be in an isomeric mixture. In
addition, the active agent can be in a solvated form such as a
hydrate. Any form of the active agent is suitable for use in the
compositions of the present invention, such as, for example, a
pharmaceutically acceptable salt of the active agent, a free acid
of the active agent, or a mixture thereof. In some instances, the
term "active agent" may include all pharmaceutically acceptable
salts, derivatives, esters, and analogs of vardenafil or the other
PDE5 inhibitors listed herein, as well as combinations thereof.
[0053] In some aspects, the active agent may be a vardenafil
compound having the chemical forms as set forth in Formulas (I),
(II), (III), or (IV) above. For example, the pharmaceutically
acceptable salts of vardenafil may include, without limitation,
hydrogen chloride salt forms thereof and the like. For example,
where the vardenafil salt (VarSalt) is hydrogen chloride, the
mono-hydrogen chloride may be represented by Formulas (II) or (IV).
When unhydrated, the mono-hydrogen chloride form may be represented
by Formula (II), also referred to herein as VarHCl. When this form
in fully hydrated, it is represented by Formula (IV), also referred
to herein as VarHCl.3H.sub.2O. When partially hydrated, it is
represented by Formula (III), also referred to herein as
VarHCl.xH.sub.2O, where "x" represents undetermined amount of bound
water between 0-3. The di-hydrogen chloride form of vardenafil can
be represented by Formulas (II) or (III). When unhydrated, the
di-hydrogen chloride form may be represented by Formula (II), also
referred to herein as Var(HCl).sub.2. When hydrated, this form is
represented by Formula (III), which is referred to herein as
Var(HCl).sub.2.xH.sub.2O, as this form is unstable and readily
loses water molecules.
[0054] In certain aspects, active agent may be present in different
crystal forms. The different crystalline forms of the same compound
can have an impact on one or more physical properties, such as
stability, solubility, melting point, bulk density, flow
properties, bioavailability, etc. For example, vardenafil base as
shown in Formula (I) has two polymorphic forms.
[0055] The solid powder forms of active agent may be characterized
by one or more of several techniques including differential
scanning calorimetry (DSC), thermogravimetric analysis (TGA),
dynamic vapor sorption (DVS), x-ray powder diffraction (XRPD), and
Karl Fischer (KF) titration, and pH titration. The active agents
may also be assessed in liquid form by nuclear magnetic resonance
(NMR). Further, combinations of such techniques may be used to
describe the invention. For example, one or more XRPD patterns
combined with one or more DVS plots may be used to describe one or
more solid forms of the active agents in a way that differentiates
them from each other, including the various forms of different PDE5
inhibitors (such as salts, esters, and hydrates).
[0056] Although it characterizes a form, it is not necessary to
rely only upon an entire diffraction pattern or spectrum to
characterize an active agent. Those of ordinary skill in the
pharmaceutical arts recognize that a subset of a diffraction
pattern, spectrum, or plot may be used to characterize an active
agent provided that subset distinguishes the active agent from the
other forms. Thus, one or more X-ray powder diffraction pattern
alone may be used to characterize an active agent. Likewise, one or
more DVS or DSC plots alone may be used to characterize an active
agent. Likewise, one or more pH titration analyses may be used to
characterize an active agent. Likewise, one or more NMR spectra
alone may be used to characterize an active agent. Such
characterizations are done by comparing the XRPD, DSC, DVS, TGA,
NMR data amongst the forms to determine characteristic peaks.
[0057] One may also combine data from other techniques in such a
characterization. Thus, one may rely upon one or more XRPD pattern
and, for example, one or more NMR spectrum, HPLC trace, DSC and/or
DVS plot, TGA data, Karl Fischer analyses, or pH analyses, to
characterize an active agent. For example, if one or more X-ray
diffraction peak characterizes an active agent, one could also
consider HPLC, DSC, DVS, TGA, NMR, KF titration, and pH titration
data to characterize the active agent. In particular, combining
multiple techniques for analysis of an active agent forms can be
advantageous to confirm chemical identity of the active agent.
[0058] For example, as shown in Table 2, HPLC analysis combined
with Karl Fischer titration can identify the chemical forms of
vardenafil as Var(HCl).sub.2.xH.sub.2O and not VarHCl.xH.sub.2O. In
some instances, elemental analysis of carbon, hydrogen, and
nitrogen can identify different chemical forms of vardenafil based
on their molecular formulas. For example, for VarBase and
vardenafil HCl salts (VarSalts) and hydrates, the following
equations may be used:
Water equation : 18 y 488.6 + 36.5 y + 18 x ( Eq . 2 ) CHN equation
: 488.6 - 64 - 32 - x + 2 y 488.6 + 36.5 y + 18 x ( Eq . 3 )
##EQU00002##
where y is the number of HCl molecules bound to the vardenafil
molecule and x is the number of water molecules bound to the
vardenafil molecule. For other salts, the equations may be modified
to account for the elements of the salt. In another example, NMR
analysis may be performed to identify chemical shifts
characteristic of different vardenafil forms. The NMR analysis may
be either .sup.1H NMR analysis or .sup.13C NMR analysis as shown in
FIG. 1 and FIG. 2. In some instances, d.sub.6-DMSO can be used as a
solvent. For example, by .sup.1H NMR analysis, VarHCl.3H.sub.2O can
be identified by a methyl peak shifted to 2.472 ppm and triplet
(doublet+singlet) around 8 ppm as shown in FIG. 1. In another
example, by .sup.1H NMR analysis, Var(HCl).sub.2.xH.sub.2O can be
identified by a methyl peak shifted to 2.604 ppm and a quintet
(triplet+doublet) around 8 ppm as shown in FIG. 1.
[0059] In some instances, active agents may be characterized and
distinguished using DSC as shown in FIGS. 8A-8C. For example,
Var(HCl).sub.2.xH.sub.2O may be characterized by a onset of glass
transition at about 50.degree. C. that ended at about 110.degree.
C., a small endothermic peak at about 140.degree. C., and two large
endothermic peaks at 222.degree. C. and 294.degree. C. In another
example, VarBase may be identified by a heat of fusion temperature
of 190.degree. C., with an onset temperature of about 177.degree.
C. when the scanning rate was set at 10.degree. C./min, and
degradation peaks when the temperature is raised above 250.degree.
C. In some instances, the melting temperature of the vardenafil
forms as determined by DSC may identify different forms of VarBase.
In another example, Var(HCl).sub.2.xH.sub.2O may be identified by a
large endothermic peak at 107.degree. C., and onset temperature of
about 50-60.degree. C., and a heat of fusion temperature of about
199.degree. C. In other instances, active agents may be
characterized and distinguished using DVS as shown in FIGS. 9A-9D,
TGA as shown in FIG. 10, and XRPD as shown in FIGS. 11A-11C.
Excipients
[0060] The disclosed dry powder compositions can additionally
include a carrier/excipient. Dry powder compositions may contain a
powder mix for inhalation of the active ingredient and a suitable
powder base (a carrier, a diluent, and/or an excipient substance)
such as mono-, di or poly-saccharides (for example, lactose,
mannitol, trehalose, or starch). In certain cases, the carrier may
form from about 1% to about 95% by weight of the formulation. In
some instances, the powder base may act as a carrier, a diluent
that aids in dispensing the active agent, and a fluidizing agent to
assist dispersion of the active agent.
[0061] In some instances, lactose may be a suitable powder base for
use with PDE5 inhibitor dry powder compositions. In some instances,
lactose is a suitable carrier for vardenafil formulations for
pulmonary administration because it does not react with vardenafil
as shown, for example, in FIGS. 5A-5D for VarHCl.3H.sub.2O. In some
cases, vardenafil-lactose blends are chemically stable even though
lactose is a reducing sugar that could react via a Maillard
chemical reaction with the amines in vardenafil. The lactose may
be, for example, alpha-lactose monohydrate, anhydrous
alpha-lactose, anhydrous beta-lactose, or a blend thereof (for
example, 70-80% anhydrous beta-lactose and 20-30% anhydrous
alpha-lactose). In some instances, lactose (or other powder base)
may be sieved, milled, micronized, or some combination thereof. The
lactose may comprise a fine lactose fraction. The fine lactose
fraction is defined as the fraction of lactose having a particle
size of less than 7 .mu.m, such as less than 6 .mu.m, for example
less than 5 .mu.m. The particle size of the fine lactose fraction
may be less than 4.5 .mu.m. The fine lactose fraction, if present,
may comprise 2% to 50% by weight of the total lactose component,
such as 5% to 10% by weight fine lactose, for example 4.5% by
weight fine lactose. In some cases, lactose of different size
fractions may be combined in a dry powder composition. In some
instances, the particle size of the carrier will be much greater
than that of the active agent. For example, the lactose (or other
powder base) may have average diameter of between about 2 .mu.m to
about 250 .mu.m, more preferably about 5 .mu.m to about 150 .mu.m,
or more preferably about 60 .mu.m to about 90 .mu.m. These sizes
can be determined by laser diffraction obtaining an equivalent
volume diameter, or by other sizing methods such as sieving.
[0062] The disclosed dry powder compositions may also include, in
addition to the active ingredient and carrier, a further excipient
(a ternary agent) such as a mono-, di or poly-saccharides and their
derivatives, calcium stearate or magnesium stearate, leucine and
its derivatives, lecithin, human serum albumin, polylysine,
polyarginine, and other force control agents. In some instances, if
magnesium stearate is present in the composition, it may be present
in an amount of about 0.2% to 2%, such as 0.6% to 2% or 0.5% to
1.75%, or 0.6%, 0.75%, 1%, 1.25% or 1.5% w/w, based on the total
weight of the composition. The magnesium stearate may have a
particle size in the range 1 .mu.m to 50 .mu.m, and more
particularly 1 .mu.m to 20 .mu.m.
[0063] Alternatively, in some instances, the dry powder composition
contains pure active agent, without any carriers or excipients.
Dosage Forms
[0064] In one aspect, the disclosed compositions may take the form
of dry powders suitable for pulmonary administration via
inhalation.
[0065] Dry powder dosage forms of PDE5 inhibitors (such vardenafil,
sildenafil, tadalafil, avanafil, benzamidenafil, lodenafil,
mirodenafil, udenafil, or zaprinast, or pharmaceutically acceptable
salts or esters thereof) and a pharmaceutically acceptable carrier
as described herein offer advantages over other traditional
formulations for oral administration (such as tablets, capsules,
and liquids administered by swallowing). For example,
administration by inhalation of the dry powder formulation
overcomes the dosing limitations of oral administrations because
higher concentrations of the active agent can be delivered to the
site of action (lungs) without the side effects seen with systemic
administration. Similarly, administration by inhalation may even
allow the use of these agents in patients who are unable to
tolerate these drugs because of hypotension, drug interactions in
the liver or other systemic adverse effects, including systemic
toxicities associated with chronic daily use, which arise with
traditional dosage forms for oral administration.
[0066] As used herein, the term "dosage form" refers to physically
discrete units suitable as unitary dosages for human subjects and
other mammals, each unit containing a predetermined quantity
(nominal dose) of therapeutic agent calculated to produce the
desired onset, tolerability, and therapeutic effects, in
association with one or more suitable pharmaceutical excipients
such as carriers. Methods for preparing such dosage forms are known
or will be apparent to those skilled in the art. The dosage form to
be administered will, in any event, contain a quantity of the
therapeutic agent in a therapeutically effective amount for relief
of the condition being treated when administered in accordance with
the teachings of this disclosure.
[0067] In some instances, the disclosed compositions may comprise
from about 2% to about 100%. In some instances, about 2%, about 3%,
about 4%, about 5%, about 10%, about 15%, about 20%, about 25%,
about 30%, about 35%, about 40%, about 45%, about 50%, about 55%,
about 60%, about 65%, about 70%, about 75%, about 80%, about 85%,
about 90%, about 95%, or about 100% by weight of the active agent
may be used (in whatever chosen form). In some cases, the
compositions comprise about 5% to about 50%, or about 2% to about
20% by weight of the active agent. One skilled in the art
understands that the foregoing percentages will vary depending upon
the particular source of active agent utilized, the amount of
active agent desired in the final formulation, and the aerosol
performance of the final formulation.
[0068] In some instances, the compositions may comprise at least
about 2% by weight of the active agent, such as, for example, at
least about 2% to about 20% by weight of the active agent. For
example, as shown in Tables 6-8, the concentration of the active
agent may be 5% to 20% in dry compositions with an acceptable
carrier for pulmonary administration (such as lactose). In other
instances, the concentration of active agent may be greater than
20%. For example, as shown in FIG. 15A, the active agent
concentration may be anywhere from 20% to 100% active agent. For
example, in some instances, the composition may 100% pure active
agent, or nearly 100% pure active agent as shown, for example, in
Table 5. In certain instances, for example as shown in FIG. 15A,
the emitted dose of a composition upon aerosolization may decrease
as the concentration of active agent increases. In some cases, this
may be due to deposition of the active agent onto the inhaler
device used for aerosolization as shown, for example in FIG. 15B.
However, this may vary based on the configuration of the inhaler
device used for aerosolization.
[0069] In another aspect, the dry powder formulation may exhibit
long term stability. In some instances, this is in contrast to
vardenafil in aqueous solutions, which may be more prone to acidic,
basic, or oxidative degradation as shown in FIGS. 4A-4F. For
example, the dry powder compositions may be stored to reduce the
possibility of either dehydration or exposure to moisture in the
air. The compositions may also be stable when stored at room
temperature. For example, the composition may be stable at room
temperature for at least 1 month, or at least 3 months, or at least
6 months as shown in FIGS. 5A-5D. In some instances, the
composition may be stable at room temperature for about 1 year or
about two years. In some instances, the dry powder composition
contain primarily pure active agent. In other instances, the dry
powder composition may contain at least 50%, such as, for example,
at least 90%, pharmaceutically acceptable carrier/excipient. In
some instances, the excipient may include lactose.
[0070] The disclosed dry powder compositions are generally
aerosolizable for the purposes of administration as a dry powder
dispersion. Suitable devices for aerosolization include dry powder
inhaler and metered dose inhalers. Such devices function to emit a
dispersion of the formulation contained within the device. The
characteristics of the emitted dispersion, particularly the aerosol
performance of the composition, are properties that relate in part
to the dry powder composition.
Preparation of Dry Powder Formulations
[0071] Any suitable methods can be used to mix the formulation
comprising the active agent as described, for example, in
Remington: The Science and Practice of Pharmacy, 25.sup.th Edition.
In some instances, the active agent and carrier are combined, mixed
and the mixture may be directly packaged for aerosolization (such
as in a capsule). In certain instances, the active agent and
carrier are combined and mixed using the method of geometric
dilution as generally known in the art. In one aspect, disclosed is
a method of producing a powder pharmaceutical composition
comprising the active agent, by contacting at least about 2% of the
active agent by weight relative to the total weight of the overall
pharmaceutical composition with at least one pharmaceutically
acceptable carrier. In some instances, the active agent may be a
PDE5 inhibitor, such as vardenafil, or a pharmaceutically
acceptable salt, ester, or solvate thereof as described herein. In
some instances, the active agent may be at least about 2% by weight
of the composition, or some other amount as described above.
[0072] Active ingredients for administration by inhalation
generally have a controlled particle size. The optimum particle
size for inhalation into the bronchial system is usually 1-10
.mu.m, preferably 1-5 .mu.m. Particles having a size above 20 .mu.m
are generally too large when inhaled to reach the small airways. To
achieve the desired particle size for the active agent, the
compound as produced may be size reduced by conventional means,
such as by micronization. Micronization of the active agent or of
all formulation components can be performed using any suitable
commercially available apparatus such as those described in
Remington: The Science and Practice of Pharmacy, 25.sup.th Edition.
For example, micronization may be performed by air jet
micronization, spiral milling, controlled precipitation,
high-pressure homogenization, spray drying, or cryo-milling. The
desired fraction may be separated out by air classification or
sieving. Preferably, the active agent particles will be
crystalline. In some instances, the active agent alone can be
micronized prior to mixing. In some instances, as shown in FIGS.
6A-6C and summarized in Table 3, vardenafil compounds may be
micronized within the respirable range. For example, the D.sub.v50
of the micronized particles may be between about 1 .mu.m and about
2 .mu.m with a span of about 0.25 to about 1.6.
[0073] In certain cases, it may be desirable to increase the
particle size of the active agent (for example, after
micronization), which can be performed, for example, by
granulation.
[0074] In some aspects, mixing is performed by agitating the
components of the dry powder formulations to produce a mixture
having a uniform concentration of active agent. For example, the
components may be combined and then mixed such as by a low shear or
high shear blender and/or agitated at high speed using a mechanical
mixer. In some instances, the components may be mixed at an
agitation speed of about 20 rpm, about 50 rpm, or about 100 rpm. In
some instances, the components are mixed at an agitation speed of
about 99-100 rpm. The components should be mixed for a sufficient
time to ensure uniformity of the blend. For example, the components
may be mixed for at least 5 min, 10 min, 15 min, or 20 min. In some
instances, after an initial mixing step, blend uniformity of the
mixture may be assessed and, if necessary, the mixture may be
agitated for an additional period of time until the desired blend
uniformity is achieved. Blend uniformity may be assessed as the
coefficient of variability for samples assessed throughout the
mixture. In some instances, the dry powder composition after mixing
has a coefficient of variation of no more than about 5% or, in some
instances, no more than about 10%. In one example, as shown in FIG.
12, a 5% blend of Var(HCl).sub.2.xH.sub.2O and lactose had a blend
uniformity (% coefficient of variation) less than about 5% when
mixed for about 5-20 min at about 100 rpm.
[0075] Following mixing, a relaxation or de-energizing step may be
performed to allow the powder blend to discharge built up
electrostatic charges from handling. This step may involve
incubation at a certain temperature from room temperature to near
50.degree. C. for a predetermined time from 1 day to 30 days, or
exposure to a controlled humidity air source for a controlled time
period, or some other method of charge dissipation commonly known.
Alternatively, an ionizing source that produces approximately equal
amounts of positive and negative ions may be used to dissipate
charge.
[0076] Once the dry powder composition is obtained, it may be
packaged into individual doses suitable for administration via
inhalation. The formulation may be transferred into individual
doses using a dosing system that is commonly used to fill capsules,
blister cavities, reservoirs, and containers. Following filling of
the doses, the powder is ready for dosing from an inhaler device.
In some instances, the formulation may be packaged in a blister
dose containment system. For example, capsule material may include
a gelatin or HPMC (hydroxypropylmethylcellulose) capsule dose
containment system. In general, the capsules may each contain one
dose, or multiple capsules can be used to contain the equivalent of
one dose. Examples of commercial dry powder inhaler products where
the powder is stored in capsules include the FORADIL.RTM.
Aerolizer.RTM., the SPIRIVA.RTM. HandiHaler.RTM., and the
VENTOLIN.RTM. Rotahaler (GSK). In some instances, the formulation
may be packaged in individual blisters, where one blister may
contain one dose. Examples of commercial dry powder inhaler
products where the powder is stored in blister dose containment
systems include the FLOVENT.RTM. Diskus.RTM., SEREVENT.RTM.
Diskus.RTM., and the ADVAIR.RTM. Diskus.RTM.. In some instances,
the formulation may be packaged into a reservoir, where a
particular reservoir may contain sufficient powder for multiple
doses. Examples of commercial dry powder inhaler products where the
powder is stored in reservoirs include the ASMANEX.RTM.
Twisthaler.RTM., SYMBICORT.RTM. Turbuhaler.RTM. and the
Budelin.RTM. Novolizer.RTM.. Still other embodiments are possible.
In some instances, the composition may be packaged to have a
nominal load of about 3 mg to 30 mg. Based on the aerosol
performance properties and concentration of the active agent in the
dry powder composition, the composition may be packaged to have a
delivered dose of at least about 0.1 mg to about 20 mg, or at least
about 0.25 mg to about 20 mg, or at least about 0.5 mg to about 10
mg, or at least about 0.1 mg, about 0.25 mg, 0.5 mg, about 1 mg,
about 5 mg, about 10 mg, about 15 mg, or about 20 mg. In some
instances, the composition may be packaged to have a delivered dose
of about 0.25 mg to 20 mg, including delivered doses in the range
of about 0.25 mg to about 5 mg, about 0.25 mg to about 2 mg, about
0.25 mg to about 3 mg, about 0.25 mg to about 4 mg, about 1 mg to
about 5 mg, about 2 mg to about 8 mg, about 2 mg to about 12 mg,
and about 5 mg to about 15 mg.
III. Methods of Administration
[0077] The compositions disclosed herein are useful in therapeutic
applications, such as for treating pulmonary hypertension, cystic
fibrosis, and congestive heart failure. Importantly, the
compositions of the present invention provide the rapid and
predictable delivery of an active agent in the lungs that should
increase the bioavailability of the active agent, overcoming the
limitations of oral dosing and reducing risk of drug interactions
and systemic side effects. In particular, the delivery of the
therapeutic agent optimizes absorption within the lungs. As a
result, the therapeutic agent can reach the site of action locally
in the lung, or in systemic circulation, in a substantially shorter
period of time and at a substantially higher local lung
concentration than with traditional oral (for example, tablet)
administration. Also, as elevated oral doses may be associated with
increased systemic side effects, administration of the dry powder
composition via the pulmonary route may permit higher
concentrations of active agent to be administered than with oral
administration.
[0078] In addition, the dry powder compositions disclosed herein
offer advantages over compositions for oral administration. In
particular, vardenafil exhibits a good balance between
lipophilicity (relatively low) and solubility (relatively high),
which is desirable for a dry powder formulation for pulmonary
delivery to facilitate cellular uptake, lung residence time, and
metabolism within the airways. An advantage of inhaled compositions
over oral dosage forms may be the short time until effects are
observed. The short onset of action can be important for many
diseases. Another advantage of dry powder formulations for
inhalation is avoiding metabolism in the liver and side effects
associated therewith at high concentrations of active agent.
[0079] Administration of the compositions disclosed herein is
preferably carried out via any of the accepted modes of pulmonary
administration, particularly oral dry powder inhalation. In some
instances, the composition may be administered through the mouth or
through the nasal passages. Suitable devices for administration of
the dry powder composition include dry powder inhalers and metered
dose inhalers.
[0080] FIG. 13 is a block diagram illustrating methods for
aerosolizing such dry powder compositions according to certain
aspects. As a first step 1301 of the method 1300, a powder
pharmaceutical composition comprising a) at least 2% by weight of a
PDE5 inhibitor, or a pharmaceutically acceptable salt or ester
thereof, relative to the total weight of the overall pharmaceutical
composition, and b) at least one pharmaceutically acceptable
carrier may be provided. Step 1302 illustrates that an inhaler
comprising a dispersion chamber having an inlet and an outlet, the
dispersion chamber containing an actuator that is movable
reciprocatable along a longitudinal axis of the dispersion chamber
may be provided. Steps 1301 and 1302 may be performed in any order
or simultaneously. As shown in step 1303, air flow is induced
through the outlet channel to cause air and the powder
pharmaceutical composition to enter into the dispersion chamber
from the inlet, and to cause the actuator to oscillate within the
dispersion chamber to assist in dispersing the powder
pharmaceutical composition from the outlet for delivery to a
subject through the outlet. In some instances, the powdered
medicament may be stored within a storage compartment (of the
inhaler), and wherein the powder pharmaceutical composition is
transferred from the storage compartment, through the inlet and
into the dispersion chamber. In certain cases, the inlet may be in
fluid communication with an initial chamber, and wherein the powder
pharmaceutical composition is received into the initial chamber
prior to passing through the inlet and into the dispersion
chamber.
[0081] In practice, a patient may prime an aerosolization device by
puncturing the container holding the formulation (such as a capsule
or blister) that is contained within a powder reservoir, or the
patient may transfer drug from the powder reservoir into the
inhalation portion of the device, and then inhale. Inhalation by a
patient draws the powder through the inhaler device where powder
entrainment results in dilation, fluidization, and at least the
partial de-agglomerating of powder aggregates and micro aggregates
and then dispersion of the API powder aerosol (in other words,
aerosolization). This approach may be useful for effectively
dispersing both pure drug-powder formulations where there are no
carrier particles are present and traditional binary or ternary
carrier-based formulations.
[0082] Exemplary devices for use in administering the dry powder
composition include dry powder inhalers and metered dose inhalers
such as, but not limited to Twisthaler.RTM. (Merck), Diskus.RTM.
(GSK), Handihaler.RTM. (BI), Aerolizer.RTM., Turbuhaler.RTM.
(AstraZeneca), Flexhaler.RTM. (Astrazeneca), Neohaler.RTM.
(Breezhaler.RTM.) (Novartis), Easyhaler.RTM. (Orion),
Novolizer.RTM. (Meda Pharma), Rotahaler.RTM. (GSK), and others. As
known to those skilled in the art, difference devices will have
different performance characteristics based on the device
resistance, deaggregation mechanisms, adhesion of drug to the
internal flow channels, ability of the patient to coordinate and
inhale, among other factors.
[0083] In another aspect, the dry powder compositions may be
administered using a dry powder inhaler or a metered dose inhaler
that comprises a dry powder deaggregator, also referred to as a
powder dispersion mechanism. Exemplary powder dispersion mechanisms
are described in U.S. Patent Publication Nos. 2013/0340754 and
2013/0340747, which are incorporated herein by reference in their
entirety. In some instances, such powder dispersion mechanisms may
comprise of a bead positioned within a chamber that is arranged and
configured to induce a sudden, rapid, or otherwise abrupt expansion
of a flow stream upon entering the chamber. In general, the chamber
may be coupled to any form or type of dose containment system or
source that supplies powdered active agent into the chamber.
Referring now to FIG. 14A, a cross-section of an example tubular
body 100 having an inlet 102 and a dispersion chamber 104 is shown
according to the principles of the present disclosure. In this
example, a fluid (air) flow path of the inlet 102 is defined by a
first internal diameter 106, and a fluid (air) flow path of the
chamber 104 is defined by a second internal diameter 108. Although
shown approximately constant in FIG. 14A, at least one of the first
internal diameter 106 and the second internal diameter 108 may vary
in dimension as defined with respect to a longitudinal axis L of
the tubular body 100. In addition to providing desirable fluid flow
characteristics, as discussed further below, these configurable
dimensions may be defined such as to provide for a draft angle for
injection molding.
[0084] For example, referring now additionally to FIG. 14B, a bead
302 may be positioned within the chamber 104 of the tubular body
100 of FIG. 14A. In this example, the bead 302 may be approximately
spherical, at least on the macroscale, and oscillate in a manner
similar to that described in U.S. Pat. No. 8,651,104, which is
herein incorporated by reference in its entirety. Further, a
relationship between the diameter 304 of the bead 302, the first
internal diameter 106 of the inlet 102, and the second internal
diameter 108 of the chamber 104 may be as described in U.S. Patent
Publication Nos. 2013/0340754 and 2013/0340747, which are
incorporated herein by reference in their entirety.
[0085] In some instances, the powder dispersion mechanism may be
coupled to a dry powder inhaler or metered dose inhaler such as a
commercially available device. The dispersion mechanism (dispersion
chamber) may be adapted to receive an aerosolized powdered active
agent from an inlet channel such as described, for example, in U.S.
Patent Publication Nos. 2013/0340754, which is incorporated herein
by reference in its entirety. The powder dispersion mechanism (dry
powder deaggregator) may be adapted to receive at least a portion
of the aerosolized powdered active agent from the first chamber of
the inhaler. The powder dispersion mechanism may include a
dispersion chamber that may hold an actuator that is movable within
the dispersion chamber along a longitudinal axis. The dry powder
inhaler may include an outlet channel through which air and
powdered active agent exit the inhaler to be delivered to a
subject. A geometry of the inhaler may be such that a flow profile
is generated within the dispersion chamber that causes the actuator
to oscillate along the longitudinal axis, enabling the oscillating
actuator to effectively disperse powdered medicament received in
the dispersion chamber for delivery to the patient through the
outlet channel.
[0086] In one example, the powder dispersion mechanism may have an
inlet diameter of about 2.72 mm and an oscillation chamber length
and diameter of about 10 mm and about 5.89 mm, respectively. In
some instances, the powder dispersion mechanism may include a bead
having a diameter of 4 mm in the chamber. In some instances, the
bead may have a density of about 0.9 mg/mm.sup.3. In some
instances, the bead may be made of polypropylene or a similar
material. In some instances, the powder dispersion mechanism can be
coupled with a commercial inhaler or other component to form a
delivery system for aerosolization of the dry powder compositions.
In some cases, the delivery system may work at effectively at
different airflow rates and pressure drops within the range of
normal physiological inhalation for a subject such as, for example,
about 40 to about 60 L/min and about 2 to about 4 kPa.
[0087] In certain instances, a dry powder inhaler system may be
used to aerosolize and administer the dry powder formulation. The
dry powder inhaler system may include a receptacle containing an
amount of powdered active agent. The dry powder inhaler system may
include an inlet channel that is adapted to receive air and
powdered active agent from the receptacle. The dry powder inhaler
system may include a first chamber that is adapted to receive air
and powdered active agent from the inlet channel. A volume of the
first chamber may be greater than volume of the inlet channel. The
dry powder inhaler system may include a dispersion chamber that is
adapted to receive air and powdered medicament from the first
chamber. The dispersion chamber may hold an actuator that is
movable within the dispersion chamber along a longitudinal axis.
The dry powder inhaler system may include an outlet channel through
which air and powdered active agent exit the dispersion chamber to
be delivered to a patient. A geometry of the system may be such
that a flow profile is generated within the system that causes the
actuator to oscillate along the longitudinal axis, enabling the
oscillating actuator to effectively disperse powdered medicament
received in the dispersion chamber for delivery to the patient
through the outlet channel.
[0088] In one aspect, a method for aerosolizing a powdered
medicament is disclosed. The method may include providing an
inhaler comprising a first chamber, and a dispersion chamber, the
dispersion chamber containing an actuator that is movable within
the dispersion chamber along a longitudinal axis, and an outlet
channel. The method may include inducing air flow through the
outlet channel to cause air and powdered medicament to enter into
the first chamber through the inlet channel into the dispersion
chamber, and to cause the actuator to oscillate within the
dispersion chamber to effectively disperse powdered medicament
passing through the first chamber and the dispersion chamber to be
entrained by the air and delivered to the patient through the
outlet channel.
[0089] Several different parameters are used as measures of the
aerosol performance of a dry powder formulation under certain
airflow and pressure drop conditions. For example, the emitted
dose" (ED (%)) of a formulation refers to the mass of an active
agent that is emitted from a dry powder inhaler aerosolization
device as a percentage of a nominal dose mass. Powder formulations
that exhibit better powder flow properties often result in higher
ED (%). Another parameter is the respirable fraction (RF (%)) of
the formulation, which is the mass of an active agent that is below
a certain aerodynamic cutoff size as a percentage of a nominal dose
mass. Fine particle fraction is the mass of active agent having an
aerodynamic diameter below about about 5 .mu.m as a percentage of
an emitted dose mass. This response is often used to evaluate the
efficiency of aerosol deaggregation. For example, the % FPF(ED) may
be the percentage of an active agent of a formulation having an
aerodynamic diameter at or below about 5 .mu.m. The respirable
fraction represents the proportion of powder aerosol active agent
that can enter the deep respiratory tract. Another parameter is
mass median aerodynamic diameter (MMAD). The MMAD is the median of
the distribution of airborne particle mass with respect to the
aerodynamic diameter. Airflow conditions are generally selected to
span the range of physiological inhalation capabilities of a
subject. For example, for a human subject, the pressure drop for an
inhalation may be in the range of about 0.5 kPa to about 8 kPa,
more typically within the range of about 1 kPa to about 4 kPa, and
including airflow rates of about 5 L/min to about 120 L/min, more
typically in the range of about 15 L/min to about 100 L/min.
[0090] In some instances, the dry powder composition may have an
emitted dose of at least about 20%, about 25%, about 30%, about
35%, about 40%, about 50%, about 55%, about 60%, about 65%, about
70%, about 75%, about 80%, about 85%, about 90%, or about 95% upon
aerosolization. In one example, as shown in Table 5, pure active
agent compositions may have an emitted dose of at least about 65%
for VarBase, at least about 25% for Var(HCl).sub.2.xH.sub.2O, at
least about 70% for Var(HCl).sub.2.xH.sub.2O (rehydrated), and at
least about 40% for VarHCl.xH.sub.2O. In some cases, the active
agent may be micronized. In some instances, nominal dose may not
impact emitted dose of pure active agent compositions. In another
example, as shown in Tables 6-8, dry powder compositions of
vardenafil compounds plus a carrier, such as lactose, may have
emitted doses that are, on average, somewhat higher than the pure
active agent compositions. For example, a 5%
Var(HCl).sub.2.xH.sub.2O composition may have an emitted dose of at
least about 75% regardless of whether the nominal load used for
aerosolization was 10 mg or 20 mg as shown in Table 6. In another
example, 5% and 20% Var(HCl).sub.2.xH.sub.2O compositions may have
an emitted dose of at least about 80% as shown in Table 7. In
another example, 5% and 20% VarBase and VarHCl.xH.sub.2O
compositions may have emitted doses of at least about 70% as shown
in Table 8.
[0091] In certain cases, the dry powder composition may have a fine
particle fraction of at least about 20%, about 25%, about 30%,
about 35%, about 40%, about 50%, about 55%, about 60%, about 65%,
about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%
upon aerosolization. In some instances, composition of pure active
agent may have a fine particle fraction of at least about 20% as
shown in Table 5. For example, as shown in Table 5, pure active
agent compositions may have an emitted dose of at least about
35-60% for VarBase, at least about 85-90% for
Var(HCl).sub.2.xH.sub.2O, at least about 60-65% for
Var(HCl).sub.2.xH.sub.2O (rehydrated), and at least about 65-70%
for VarHCl.xH.sub.2O. In some cases, a composition of a vardenafil
compound and a carrier (such as lactose) may have a fine particle
fraction of at least about 40-50% as shown in Tables 6-8. For
example, a 5% Var(HCl).sub.2.xH.sub.2O composition may have a fine
particle fraction of at least about 65-70% regardless of whether
the nominal load used for aerosolization was 10 mg or 20 mg as
shown in Table 6. In another example, 5% and 20%
Var(HCl).sub.2.xH.sub.2O compositions may have a fine particle
fraction of at least about 65-80% as shown in Table 7. In some
instances, increasing the concentration of active agent (such as
Var(HCl).sub.2 xH.sub.2O) in the composition may increase the fine
particle fraction upon aerosolization. In another example, 5% and
20% VarBase and VarHCl.xH.sub.2O compositions may have a fine
particle fractions of at least about 40-70% as shown in Table 8. In
some instances, increasing the active agent (such as VarBase and
VarHCl.xH.sub.2O) in the composition may increase the fine particle
fraction upon aerosolization. In some instances, VarHCl.xH.sub.2O
has a slightly higher respirable fraction upon aerosolization than
VarBase.
[0092] In certain cases, the dry powder composition may have a
respirable fraction of at least about 20%, about 25%, about 30%,
about 35%, about 40%, about 50%, about 55%, about 60%, about 65%,
or about 70%, upon aerosolization. In one example, as shown in
Table 5, pure active agent compositions may have a respirable
fraction of at least about 25% or 45% for VarBase depending on
nominal dose (10 mg vs 3 mg), at least about 20% for
Var(HCl).sub.2.xH.sub.2O (regardless of nominal dose, 10 mg vs 3
mg), at least about 45% for Var(HCl).sub.2.xH.sub.2O (rehydrated),
and at least about 30% for VarHCl.xH.sub.2O. In some cases, the
active agent may be micronized. In another example, a 5%
Var(HCl).sub.2.xH.sub.2O composition may have a respirable fraction
of at least about 50% regardless of whether the nominal load used
for aerosolization was 10 mg or 20 mg as shown in Table 6. In
another example, 5% and 20% Var(HCl).sub.2.xH.sub.2O compositions
may have a respirable fraction of at least about 50-60% as shown in
Table 7. In some instances, increasing the concentration of the
active agent may diminish the respirable fraction of the
composition (such as VarHCl.xH.sub.2O) upon aerosolization. In
another example, 5% and 20% VarBase and VarHCl.xH.sub.2O
compositions may have respirable fractions of at least about 25-50%
as shown in Table 8. In some instances, increasing the
concentration of the active agent (such as VarBase and
VarHCl.xH.sub.2O) may diminish the respirable fraction of the
composition upon aerosolization.
[0093] In some instances, the MMAD of the composition is less than
about 10 .mu.m, less than about 5 .mu.m, or less than about 3
.mu.m, upon aerosolization. For example, upon aerosolization, the
compositions may have a mass median aerodynamic diameter (MMAD) of
between about 0.5 .mu.m and about 8 .mu.m, such as, for example,
between about 1 .mu.m and about 2 .mu.m, between about 1 .mu.m and
about 3 .mu.m, between about 0.5 .mu.m and about 4 .mu.m, or
between about 0.5 .mu.m and about 5 .mu.m, or other ranges therein.
In some instances, as shown in Tables 6-7 and 9, the composition
may have a relatively small MMAD of about 0.7 to about 1.5 .mu.m,
including about 0.7 .mu.m to about 1.5 .mu.m, about 0.8 .mu.m to
about 0.85 .mu.m, about 0.8 .mu.m to about 0.95 .mu.m, and about
0.9 .mu.m to about 1.2 .mu.m.
[0094] In certain cases, the dry composition formulations may have
similar aerosolization properties at both high and low airflow
rates. This may reduce variability in dosing (due to inhalation
variability). For example, as shown in Table 9, a 5%
Var(HCl).sub.2.xH.sub.2O composition has similar emitted dose and
respirable fraction upon aerosolization at both 2 kPa and 4 kPa
airflow using a dry powder inhaler.
[0095] Upon inhalation, some portion of the dry powder composition,
particularly the active agent, is emitted from a delivery system,
such as an inhaler, upon aerosolization of the dry powder
composition. Generally, the term delivered dose refers to the
percentage mass emitted dose (ED (%)) as a function of the nominal
dose mass in the delivery system. In some instances, upon
aerosolization and inhalation, the composition may have a delivered
dose of about 0.25 mg to 20 mg, including delivered doses in the
range of about 0.25 mg to about 5 mg, about 0.25 mg to about 2 mg,
about 0.25 mg to about 3 mg, about 0.25 mg to about 4 mg, about 1
mg to about 5 mg, about 2 mg to about 8 mg, about 2 mg to about 12
mg, and about 5 mg to about 15 mg. In some instances, upon
aerosolization, the composition may have a delivered dose of at
least about 0.1 mg to about 20 mg, or at least about 0.25 mg to
about 20 mg, or at least about 0.5 mg to about 10 mg, or at least
about 0.1 mg, about 0.25 mg, 0.5 mg, about 1 mg, about 5 mg, about
10 mg, about 15 mg, or about 20 mg.
[0096] One issue relating to use of inhalers for pulmonary
administration of dry powder composition is that, in some
instances, depending on the mechanism by which the inhaler
components operate (for example, the capsule piercing mechanism),
an amount of the composition may be deposited within the device and
not emitted. For example, as shown in FIGS. 15A and 15B, deposition
of active agent increased approximately linearly as active agent
concentration increased for one type of dry powder inhaler.
[0097] In some instances, the dry powder composition is formulated
and packaged to have substantial delivered (emitted) dose
uniformity. The uniformity of the emitted dose reflects the safety,
quality, and efficacy of the dry powder compositions. In some
instances, the composition may have a delivered dose uniformity of
about 75% to about 125% target dose over 2-60 inhalations.
[0098] The percent recovery (% recvy) is a way to check the mass
balance before and after dose delivery by capturing and measuring
the amount of drug discharged from an inhaler to verify accuracy of
analysis. In some instances, the total mass of drug collected in
all of the components divided by the total number of minimum
recommended doses discharged is not less than 75% and not more than
125% of the average minimum recommended dose determined during
testing for delivered-dose uniformity. See USP <601>. In some
instances, the percent recovery of the dry powder formulation is at
least about 95% or at least about 100%, for example, as shown in
Table 5 and Table 8, for various dry compositions with different
active agents and concentrations and nominal loads.
IV. Methods of Treatment
[0099] The compositions disclosed herein have particular utility in
the area of human and veterinary therapeutics. In one aspect, a
method of treating a disease in a mammal in need thereof is
provided, the method comprising administering to the mammal via a
pulmonary route an effective amount of a powder pharmaceutical
composition comprising a) at least about 2% of a PDE5 inhibitor, or
a pharmaceutically acceptable salt or ester thereof, by weight
relative to the total weight of the overall pharmaceutical
composition dose, and b) at least one pharmaceutically acceptable
carrier. The dry powder formulations and methods described herein
provide improved methods of treating certain diseases that are
currently treated only with oral formulations that are swallowed.
In some instances, the disease may be a lung disease such as
pulmonary hypertension or cystic fibrosis. For example the lung
disease may be pulmonary arterial hypertension. In some cases, the
disease may be a heart disease. For example, the heart disease may
be congestive heart failure/disease.
[0100] PDE5 inhibitors are used to augment the action of endogenous
nitric oxide resulting in vasodilatation and reduction of smooth
muscle proliferation in patients with pulmonary hypertension.
Pulmonary hypertension includes, but is not limited to, pulmonary
arterial hypertension, primary pulmonary hypertension, secondary
pulmonary hypertension, familial pulmonary hypertension, sporadic
pulmonary hypertension, precapillary pulmonary hypertension,
pulmonary artery hypertension, idiopathic pulmonary hypertension,
thrombotic pulmonary arteriopathy, plexogenic pulmonary
arteriopathy and pulmonary hypertension associated with or related
to, left ventricular dysfunction, mitral valvular disease,
constrictive pericarditis, aortic stenosis, cardiomyopathy,
mediastinal fibrosis, anomalous pulmonary venous drainage,
pulmonary venoocclusive disease, collagen vascular disease,
congenital heart disease, congenital heart disease, pulmonary venus
hypertension, chronic obstructive pulmonary disease, interstitial
lung disease, lung fibrosis, sleep-disordered breathing,
alveolarhyperventilation disorder, chronic exposure to high
altitude, neonatal lung disease, alveolar-capillary dysplasia,
sickle cell disease, other coagulation disorders, chronic
thromboemboli, connective tissue disease, lupus, schistosomiasis,
sarcoidosis or pulmonary capillary hemangiomatosis.
[0101] Cystic fibrosis is caused by a defective or missing CFTR
protein resulting from mutations in the CFTR gene. There are more
than 1,800 The F508del mutation, results in a "trafficking" defect,
in which the CFTR protein does not reach the cell surface in
sufficient quantities. The absence of working CFTR proteins results
in poor flow of salt and water into and out of cells in a number of
organs, which results in a thick, sticky mucus that builds up and
blocks the airways of in the lungs, causing chronic lung
infections, inflammation and progressive lung damage. While cystic
fibrosis is caused by mutations in the CTFR gene, cGMP has a key
role in the cell and regulates many aspects of proper CFTR
functioning. cGMP is metabolized by the PDE5 enzyme. Thus, in some
instances, PDE5 inhibitors may maintain and control levels of cGMP,
which, in turn, may modulate CFTR and improve CTFR function. PDE5
inhibitors have also been shown to exhibit anti-inflammatory and
anti-pseudomonal activity in preclinical models. (Poschet et al.
2007 Lung Cell. Molec. Physiol. 293(3):L712-L719) For example, oral
sildenafil, a PDE5i, has reduced biomarkers of lung inflammation in
clinical trials in adult CF patients with F508del mutation.
(Taylor-Cousar et al., Abstract A94, Therapeutic & Diagnostic
Adv. Cystic Fibrosis 2013, p. A2066.)
[0102] PDE5 expression appears to be increased in a number of
myocardial disease states, including chronic myopathies involving
myocyte or ventricular hypertrophy. (Schwartz et al. 2012 JACC
59(1):9-15) In hypertrophied myocardium, PDE5 inhibitors increase
cGMP, which inhibits phosphodiesterase-3 and thereby increases
cyclic adenosine monophosphate. (cAMP). cAMP in turn activates
protein kinase A, which increases intracellular calcium and
contractility (Schwartz). PDE5 inhibitors were found to improve
hemodynamic and clinical parameters in patients with congestive
heart disease in a number of small trials (Schwartz). Small trials
in patients with congestive heart disease demonstrated the greatest
benefit of PDE5Is in patients with secondary PAH and right
ventricular failure (Lewis et al. 2007 Circulation 116:1555-1562;
Melenovsky et al. 2009 J. Am. Coll. Cardiol. 54:595-600.).
[0103] In some cases, the delivery of dry powder formulations of
PDE5 inhibitors may be more efficient that oral dose formulations
by creating a high local lung concentration of the active agent,
potentially yielding a quicker onset of action with likely
comparable or enhanced efficacy with fewer side effects.
[0104] Local delivery of PDE5i directly into the lung may
circumvent poor oral bioavailability and provide even greater
selectivity of effect by delivering high local lung concentrations
with lower total dose exposure with the potential for greater
efficacy. Administration of dry powder formulations via inhalation
are also advantageous because the route of administration allows
avoidance of extensive first pass hepatic metabolism and drug-drug
interaction with CYP3A inducers/inhibitors. Many drugs used to
treat lung diseases (such a cystic fibrosis and pulmonary
hypertension) can be metabolized using this enzyme system and,
therefore, are susceptible to interactions or contraindications.
Inhalation delivery may avoid the severity of these interactions
because avoidance of first pass metabolism, while the lower
administered dose (but higher lung tissue dose) may minimize the
potential for interactions Inhalation delivery may also avoid
adverse side effects associated with orally administered PDE5
inhibitor formulations, such as hypotension, hearing or visual
improvement, headache, dyspepsia, flushing, insomnia, erythema,
dyspnea, rhinitis, diarrhea, myalgia, pyrexia, gastritis,
sinusitis, paraesthesia. For example, in many chronic obstructive
pulmonary disease (COPD) patients, ventilation/perfusion (V/Q)
mismatch may preclude the use of oral PDE5 inhibitor formulations
as these patients generally have some degree of hypoxic
vasoconstriction that can be worsened by the action of PDE5
inhibitors and other adverse effects, particularly in patients with
moderately severe COPD. In some instances, a dry powder PDE5
inhibitor formulation with low oral and throat deposition and
swallowing may better target the active agent to the ventilated
areas of the lung, controlling the pulmonary hypertension while
avoiding increasing V/Q mismatch and hypoxia. Thus, in some
instances, administration of PDE5 inhibitors via a pulmonary route
may be useful for treating subjects who are unable to tolerate
clinically useful doses of oral formulations because of
hypotension, drug interactions or other systemic adverse
effects.
[0105] In some instances, lower doses of dry powder formulations
(as compared to oral doses for swallowing) may be administered to a
subject. In some instances, similar doses of the dry powder
formulations as used for oral doses for swallowing may be
administered to a subject, wherein, because the drug is
administered directly to the target site, there may be a reduction
in systemic drug levels using a dry powder inhaler formulation.
This may lead to a reduction of systemic toxicities associated with
chronic daily use (headache, lowered blood pressure, cardiovascular
effects anterior ischemic optic neuropathy, priapism,
vaso-occlusive crises.
[0106] In general, orally administered PDE5 inhibitors dissolve in
the digestive tract and are absorbed into the blood stream. Upon
reaching the pulmonary circulation, the PDE5 compound diffuses
across the vascular endothelium into the surrounding smooth muscle
cells, where it inhibits the PDE5 enzyme present in the
intracellular fluid of the muscle cells, resulting in a dilatory
effect on the pulmonary arteries and arterioles. In contrast, in
some instances, inhaled powder formulation of PDE5 inhibitors are
expected to take a more direct route after deposition in the lumen
of pulmonary airways, diffusing across the airway walls into the
vascular smooth muscle cells where it acts on the PDE5 enzyme and
may result in a dilatory effect on the pulmonary arteries and
arterioles. Thus, in some instances, for example, in the context of
pulmonary hypertension, the target area of the lung for powder
delivery is the deep lung where the pulmonary vasculature has
smooth muscle cells upon which the active agent can exert its
pharmacological effects. In some instances, effective delivery to
this area of the lung may require smaller aerodynamic particle size
ranges (typically greater than 1 micron on average, for example,
between 1-5 microns MMAD, or between about 1-3 microns MMAD) for
the aerosolized active agent. In other instances, for example, in
the context of cystic fibrosis, the target tissue is the airway
epithelial (such as the ciliated airways), particularly those
affected by defective CFTR protein. In some instances, effective
delivery to this area of the lung may require aerodynamic particle
size ranges of between about 1 to about 5 microns in aerodynamic
diameter, about 2 to about 6 microns. or about 2 to about 7
microns. In some instances, the dry powder formulations provided in
this disclosure have an MMAD in the appropriate size range for
delivery to the deeper parts of the lung.
[0107] In some instances, pulmonary delivery with higher
aerosolization efficiencies (such as, for example, about 70% FPF),
may allow less mouth and throat deposition upon aerosolization and
inhalation by a subject. As mouth and throat deposited drug is
swallowed and will be absorbed similarly to orally administered
formulation, reducing swallowing by achieving efficient
aerosolization may reduce the incidence of systemic effects.
[0108] In certain instances, a delivered dose of about 0.25 mg to
about 20 mg may be delivered to the subject upon aerosolization.
For example, in some instances, typical doses for treatment of
pulmonary hypertension will be about 0.5 mg to about 20 mg of
active agent, depending on patient disease category, disease stage,
and other health aspects of the subjects such as, for example,
medication, patient age, etc. In some instances, the inhaled dose
required to attain efficacy in a human subject with pulmonary
hypertension delivered via a high efficiency inhaler device may be
about 1/10th to 1/20th the oral dose, or 0.25 mg to 0.5 mg,
possibly 0.1 mg to 3 mg of active agent delivered to the deep lung.
In another example, in some instances, typical doses for treatment
of cystic fibrosis will be about 0.5 mg to about 30 mg of active
agent, depending on patient genetic factors (such as type of CTFR
mutation), disease stage, and other health aspects of the subjects
such as, for example, medication, patient age, etc. For example, in
some instances, typical doses for treatment of myocardial diseases
will be about 0.5 mg to about 20 mg of active agent, depending on
patient disease category, disease stage, and other health aspects
of the subjects such as, for example, medication, patient age,
etc.
[0109] FIG. 16 is a block diagram illustrating methods of treating
a disease in a mammal in need thereof according to some aspects. As
shown in step 1801 of method 1800, a subject with a disease in need
of treatment is provided. In one aspect, the disease may be a lung
disease or a heart disease. For example, in some aspects, the lung
disease may be pulmonary hypertension or cystic fibrosis. In other
aspects, the heart disease may be congestive heart failure. As
shown in step 1802, the method further includes administering to
the subject via a pulmonary route an effective amount of a powder
pharmaceutical composition comprising a) at least about 2% of a
PDE5 inhibitor, or a pharmaceutically acceptable salt or ester
thereof, by weight relative to the total weight of the overall
pharmaceutical composition dose, and b) at least one
pharmaceutically acceptable carrier. In some instances, the powder
pharmaceutical composition may be administered as an aerosol. For
example, in some cases, the powder pharmaceutical composition may
be administered using a dry powder inhaler or a metered dose
inhaler. For example, in some instances, the powder pharmaceutical
composition may be administered by providing an inhaler comprising
a dispersion chamber having an inlet and an outlet, the dispersion
chamber containing an actuator that is movable reciprocatable along
a longitudinal axis of the dispersion chamber; and inducing air
flow through the outlet channel to cause air and the powder
pharmaceutical composition to enter into the dispersion chamber
from the inlet, and to cause the actuator to oscillate within the
dispersion chamber to assist in dispersing the powder
pharmaceutical composition from the outlet for delivery to a
subject through the outlet.
[0110] The foregoing description of certain aspects and features,
including illustrated embodiments, has been presented only for the
purpose of illustration and description and is not intended to be
exhaustive or to limit the disclosure to the precise forms
disclosed. Numerous modifications, adaptations, and uses thereof
will be apparent to those skilled in the art without departing from
the scope of the disclosure. Certain features that are described in
this specification in the context of separate embodiments can also
be implemented in combination in a single implementation.
Conversely, various features that are described in the context of a
single implementation can also be implemented in multiple ways
separately or in any suitable subcombination. Moreover, although
features may be described above as acting in certain combinations,
one or more features from a combination can in some cases be
excised from the combination, and the combination may be directed
to a subcombination or variation of a subcombination. Thus,
particular embodiments have been described. Other embodiments are
within the scope of the disclosure.
[0111] The following examples are intended for illustration only,
are not intended to limit the scope of this disclosure. The
contents of all U.S. patents and other references referred to in
this application are hereby incorporated by reference herein in
their entirety.
Examples
Example 1
Identification of Vardenafil Compounds
[0112] In view of the range of vardenafil forms, including salts
and hydrates, as well as the limitation of conventional chemical
identification methods, it is not straightforward to identify the
form of vardenafil sold commercially or described in the art. For
example, both anhydrous VarHCl (vardenafil hydrochloride) and
Var(HCl).sub.2 (vardenafil dihydrochloride) can stoichiometrically
obtain 1-3 bound water molecules to form hydrates. Among them,
crystalline VarHCl.3H.sub.2O is the thermodynamically stable form
that has been used in commercial formulations. However, VarHCl and
Var(HCl).sub.2 can be difficult to differentiate from each other by
each individual analytical method such as high performance liquid
chromatography (HPLC), ultraviolet spectrophotometer (UV), mass
spectroscopy (MS), Infra-red (IR), elemental analysis (CHN) and
chloride ion analysis. For example, the molecular weight of
Var(HCl).sub.2.xH.sub.2O (579.55 g/mol) and VarHCl.3H.sub.2O
(579.12 g/mol) are nearly identical. As such, differentiating
between these molecules by any individual mass related analytical
techniques reliably may not be possible. In fact, Applicants have
found that several reputable chemical suppliers have mistakenly
sold Var(HCl).sub.2.xH.sub.2O (vardenafil dihydrochloride hydrate)
as VarHCl.3H.sub.2O (vardenafil hydrochloride trihydrate).
[0113] Testing methods were developed to ensure the ability to
identify and differentiate the chemical identity of vardenafil
forms for use in preparation of formulations. As described further
below, the methods are: HPLC quantification coupled with Karl
Fischer (KF) titration (Section A), elemental analysis (C, H, N)
coupled with KF (Section B), NMR (.sup.1H and .sup.13C) (Section
C), and pH titration assessment (Section D). For example, as shown
below, these methods were used to differentiate
Var(HCl).sub.2.xH.sub.2O and VarHCl.xH.sub.2O.
[0114] A. HPLC Quantification Coupled with Karl Fischer (KF)
Titration
[0115] While HPLC columns can be used to separate vardenafil
compounds (active pharmaceutical ingredients; APIs) based on their
polarity, this is not how HPLC was used to characterize the
vardenafil compounds. The principle of this method is that the HPLC
area under the curve (AUC) for the vardenafil portion of VarHCl and
Var(HCl).sub.2 are the same as VarBase (488.61 g/mol) when the same
mass of compounds are compared. The H.sup.+ and Cl.sup.-ions in the
vardenafil compounds will not be detected and reflected in AUC.
Thus, when the same mass of the vardenafil compounds are weighed
and analyzed by HPLC, the values of AUC quantified by HPLC will
show VarBase>VarHCl>Var(HCl).sub.2 because part of the mass
(H.sup.+ and Cl.sup.-) in VarHCl and Var(HCl).sub.2 will not
contribute to the AUC, as shown below in Table 1. By comparing the
AUC ratio of VarHCl/VarBase or Var(HCl).sub.2/VarBase, the number
of HCl in vardenafil salts can be determined. Karl Fischer
titration was performed using coulometric titration to determine
trace amounts of water in the sample.
TABLE-US-00001 TABLE 1 Exemplary Vardenafil Forms and Theoretical
Water Content Substance MW (g/mol) % VarBase Water (%) VarBase
488.61 100.0 0 VarHCl 525.07 93.1 0 VarHCl.cndot.H.sub.2O 543.09
90.0 3.32 VarHCl.cndot.2H.sub.2O 561.10 87.1 6.42
VarHCl.cndot.3H.sub.2O 579.12 84.4 9.33 Var(HCl).sub.2 561.54 87.0
0 Var(HCl).sub.2.cndot.H.sub.2O 579.55 84.3 3.11
Var(HCl).sub.2.cndot.2H.sub.2O 597.57 81.8 6.03
Var(HCl).sub.2.cndot.3H.sub.2O 615.59 79.4 8.78
[0116] There are four assumptions for applying this method: [0117]
1) All APIs are 100% pure. [0118] 2) The API dry weight (anhydrate
VarHCl and Var(HCl).sub.2) is used for the mass calculation. This
requires dehydration of raw material by heating in vacuo. [0119] 3)
If there are any residual water contents (both unbound and bound
water), they can be accurately quantified by KF. [0120] 4) The HPLC
method (column, mobile phase, buffer, etc.) does not change
throughout the testing.
[0121] HPLC analysis was performed using an Agilent 1260 Infinity
series module HPLC system with appropriate columns and buffers
(acidic aqueous and acidic organic mobile phases). The column
temperature was maintained at 40.degree. C. and the detection was
monitored at a wavelength of 215 nm.
[0122] VarBase and a vardenafil salt hydrate (VarSalt) were
purchased and analyzed using the above-described method. The
results are shown in Table 2. Based on the dry weight and AUC, the
amount of vardenafil in the salt is 87.2% of that in VarBase. This
is consistent with the percent API of Var(HCl).sub.2, which is
calculated to have a percent API of 87.1% as shown in Table 1
above. Thus, although the VarSalt was claimed to VarHCl.3H.sub.2O,
this analysis shows that the compound was actually
Var(HCl).sub.2.xH.sub.2O.
TABLE-US-00002 TABLE 2 HPLC + KF Analysis of VarSalt and VarBase
VarSalt VarBase API Weight (mg) 3.002 3.008 Water Content (%) 3.485
1.658 API Dry Weight (mg) 2.897 2.958 Diluent Volume (mL) 20 20 API
Concentration (mcg/mL) 144.9 147.9 AUC 4707.8 5509.1 AUC/mcg/mL
32.5 37.2 AUC/mcg/mL ratio 0.872 N/A (VarSalt/VarBase)
[0123] B. Elemental Analysis of C, N, and H Coupled with Karl
Fischer (KF) Titration
[0124] Elemental analysis can determine the mass fraction of
carbon, hydrogen, nitrogen and other heteroatoms (generally
referred to as CHNX). The most common elemental analysis
accomplished by combustion analysis is for carbon, hydrogen,
nitrogen, which is referred to herein as CHN analysis. Commercial
VarSalt was purchased for this analysis. The amount of water in the
vardenafil compound was also accurately determined by KF titration
before the CHN analysis was performed to ensure accuracy. The
elemental analysis showed a % C value of 45.88, a % H value of 5.92
and a % N value of 13.87, within an error margin of .+-.0.3%. The
water content was measured using a coulometric KF titrator, and the
result was 6.92%. Based on this analysis, the VarSalt appeared to
have approximately 2 HCl molecules and 2 water molecules,
indicating that the VarSalt was likely Var(HCl).sub.2.2H.sub.2O (or
possibly a mixture of dihydrate and trihydrate forms).
[0125] C. Nuclear Magnetic Resonance (NMR) (.sup.1H and
.sup.13C)
[0126] VarHCl.3H.sub.2O and Var(HCl).sub.2.xH.sub.2O (VarHCl and
Var(HCl).sub.2 in solution) have generally been deemed as
indistinguishable using NMR. For example, U.S. Pat. No. 6,362,178
describes that the chemical shift for VarHCl.3H.sub.2O (Example 20)
and Var(HCl).sub.2.xH.sub.2O (Example 337) are identical by .sup.1H
NMR, as set forth below. [0127] 200 MHz .sup.1H-NMR (DMSO-d.sub.6):
0.96, t, 3H; 1.22, t, 3H; 1.36, t, 3H; 1.82, sex., 2H; 2.61, s, 3H;
2.88, m, 2H; 3.08, m, 6H; 3.50, m, 2H; 3.70, m, 2H, 4.25, quart.,
2H; 7.48, d, 1H; 7.95, m, 2H; 11.42, s, 1H; 12.45, s, 1H. This is
problematic because many vendors provide only the .sup.1H NMR in
the Certificate of Analysis for vardenafil and, thus, may not be
correctly distinguishing between VarHCl.3H.sub.2O and
Var(HCl).sub.2.xH.sub.2O.
[0128] To identify spectral characteristics that could be used to
identify VarHCl.3H.sub.2O and Var(HCl).sub.2.xH.sub.2O, both
.sup.1H and .sup.13C NMR were performed. The spectra are shown in
FIG. 1. The results showed that VarHCl.3H.sub.2O (top) and
Var(HCl).sub.2.xH.sub.2O (bottom) can be readily distinguished from
NMR, using d.sub.6-DMSO as solvent. For example, in the .sup.1H
NMR, a characteristic methyl peak showed a chemical shift of 2.472
ppm for VarHCl.3H.sub.2O, while the same methyl peak shifted to
2.604 ppm for Var(HCl).sub.2.xH.sub.2O. De-shielding causes a
methyl group shift from 2.472 to 2.604. At around 8 ppm, two of the
three protons in the benzene ring of vardenafil showed a triplet
(doublet+singlet) for VarHCl.3H.sub.2O, while the same protons
showed a quintet (triplet+doublet) for Var(HCl).sub.2
xH.sub.2O.
[0129] The result of .sup.13C NMR clearly shows that the chemical
shift of a large number of carbon signals at different ppm. Spectra
for .sup.13C NMR in d.sub.6-DMSO analysis of
Var(HCl).sub.2.xH.sub.2O (top) and VarHCl.3H.sub.2O (bottom) are
shown in FIG. 2.
[0130] This is the first reporting of differences in the NMR
spectrum of VarHCl.3H.sub.2O and Var(HCl).sub.2.xH.sub.2O. This
method can be used, alone or in conjunction with other analytical
methods to identify and characterize vardenafil compound
preparations. For example, based on this analytical method, it is
apparent that the vardenafil salt described in U.S. Pat. No.
6,362,178 (Example 20) is misidentified and is actually
Var(HCl).sub.2.xH.sub.2O.
[0131] D. pH Titration
[0132] Perhaps the easiest way to distinguish Var(HCl).sub.2,
VarHCl, and VarBase is by means of pH titration analysis. The
experiment was performed at ambient condition (22.5.degree. C. and
31% RH). One gram of Var(HCl).sub.2.xH.sub.2O was dissolved in 15
mL pure H.sub.2O in a beaker. NaOH solution (10%) was added in 20
.mu.L stepwise increments while the solution was stirred
vigorously. The pH and temperature was recorded 20 sec after each
addition of NaOH solution. The results of this analysis are shown
in FIG. 3.
[0133] The result showed that the initial pH was 2.15 at
22.5.degree. C. The pH increased slowly until precipitation
appeared. The pH dropped accordingly when VarHCl was gradually
precipitated from the solution until the pH reached 3.9. A rapid
increase in pH was observed, indicating all VarHCl was
precipitated. The pH reached a plateau at 5.2 and dropped to 4.6,
indicating the conversion of VarHCl to VarBase. All VarBase was
precipitated when a sharp change of pH occurred from 5.3 to 10.9.
Continued addition of 10% NaOH resulted in the dissolution of all
precipitate and the conversion of VarBase to the sodium salt of
vardenafil (NaVar). Thus, in addition to being useful for chemical
identification purposes, pH titration can also be used for the
conversion and preparation of desired salt forms of vardenafil.
Example 2
Intrinsic Stability Assessment of Vardenafil Compounds
[0134] The intrinsic stability of vardenifil compounds can be
assessed to aid in identification of suitable conditions for
preparation of pharmaceutically acceptable formulations.
Characterization of the degradation pathways for vardenafil
compounds provides information useful to the development of
pharmaceutically acceptable formulations for long term storage.
Described below are exemplary experiments relating to
characterization of VarHCl.3H.sub.2O.
[0135] Materials:
[0136] VarHCl.3H.sub.2O, HPLC grade water, 36.5% HCl, NaOH pellets,
6% H.sub.2O.sub.2 were all purchased. 1N HCl and 1N NaOH were
prepared in house.
[0137] Method:
[0138] VarHCl.3H.sub.2O, HPLC grade water, 36.5% HCl, NaOH pellets,
6% H.sub.2O.sub.2 were all purchased, and 1N HCl and 1N NaOH were
prepared in house. Intrinsic stability testing was performed
according to International Conference on Harmonization (ICH)
Guidance for Industry Q1A(R2) Stability Testing of New Drug
Substances and Products (November 2003, Rev. 2). Briefly, the
compound was tested for acid hydrolysis (1N HCl) and base
hydrolysis (1N NaOH) at r.t. for 48 hr and at 60.degree. C. for 4
hr. Oxidation assessment (6% H.sub.2O.sub.2) was performed at r.t.
for 48 hr. The stability of VarHCl.3H.sub.2O in solution was
assessed using HPLC analysis as described above in Example 1,
Section A.
[0139] Starting Material (Control):
[0140] The HPLC trace for the starting material showed single peak
as expected (R.sub.T=6.050 min; Area %=100). See FIG. 4A.
[0141] Degradation in Acidic Solution:
[0142] In 1N HCl at r.t. after 48 hr, a single degradation peak
(R.sub.T=1.006 min; Area %=2.630) was observed. A similar
degradation peak was observed in 1N HCl at 60.degree. C. for four
hours (R.sub.T=0.998 min; Area %=2.843). The degree of degradation
was comparable in both acidic conditions. The HPLC traces for these
experiments are shown in FIG. 4B (48 hr at r.t.) and FIG. 4C (4 hr
at 60.degree. C.).
[0143] Degradation in Basic Solution:
[0144] In 1N NaOH at r.t. after 48 hr, a major degradation peak
(R.sub.T1=1.000 min; Area %=58.692) was observed and corresponded
with four additional small degradation peaks (R.sub.T2=0.776; Area
%=0.1115; R.sub.T3=1.351; Area %=0.055; R.sub.T4=2.839; Area
%=0.048). When exposed in 1N NaOH 60.degree. C. condition for 4
hrs, a similar degradation pattern was observed: a major
degradation peak (R.sub.T1=0.992 min; Area %=62.652) and
corresponded with four additional small degradation peaks
(R.sub.T2=0.778; Area %=0.193; R.sub.T3=1.342; Area %=0.071;
R.sub.T4=2.774; Area %=0.046). The HPLC traces for these
experiments are shown in FIG. 4D (48 hr at r.t.) and FIG. 4E (4 hr
at 60.degree. C.).
[0145] Degradation in Oxidative Solution:
[0146] In 6% H.sub.2O.sub.2 at r.t. for 48 hr, there were two major
and eight minor degradation peaks. The two major peaks were at
R.sub.T1=1.067 min; Area %=60.270 and R.sub.T2.sup.=4.862 min; Area
%=19.496. The eight minor peaks were at R.sub.T3.sup.=1.339 min;
Area %=0.231; R.sub.T4=1.814 min; Area %=0.454; R.sub.T5=2.469 min;
Area %=0.353; R.sub.T6=3.458 min; Area %=0.523; R.sub.T7.sup.=6.486
min; Area %=1.409; R.sub.T8.sup.=7.197 min; Area %=0.272;
R.sub.T9.sup.=7.594 min; Area %=0.087; R.sub.T10=9.176 min; Area
%=0.574. The HPLC traces for these experiments are shown in FIG.
4F.
[0147] These studies showed that VarHCl.3H.sub.2O demonstrated
degradation in acidic, basic, and oxidative conditions per ICH
Guidance. The extent of degradation was significant in basic and
oxidative conditions, which is understandable because the
sulfonamide group in VarHCl.3H.sub.2O is susceptible to hydrolysis,
particularly in basic condition. The tertiary amine group may
easily form amine oxide in oxidative condition and the amine oxide
may undergo further degradation via a host of chemical reactions.
These observations differ from literature reports on the
degradation of VarHCl.3H.sub.2O (Rao et al, Chromatographia 2008,
68, 829-835, showing less extensive degradation in basic
conditions). Similarly, it is expected that VarBase could also be
oxidized more easily when the free tertiary amine is presented in
the molecule.
[0148] The observed degradation patterns of VarHCl.3H.sub.2O in
aqueous solution suggest that the development of a dry powder
aerosol formulation may be desirable to maintain chemical stability
of the compound. As noted above, no dry powder aerosol formulations
of vardenafil compounds have been developed to date.
Example 3
Excipient Compatability Assessment of Vardenafil Compounds
[0149] Studies were performed to assess the chemical
compatibility/stability of vardenafil compounds with excipients.
The testing of vardenafil compounds with one or more
pharmaceutically acceptable excipients/carriers is an aspect of
developing a pharmaceutically-acceptable, stable, carrier-based
vardenafil formulation. One of the most frequently used excipients
for dry powder aerosol formulation is lactose. However, lactose is
a reducing sugar. Vardenafil contains amine groups that could react
with lactose via the Maillard reaction. In the absence of prior
studies assessing the vardenafil and reducing sugar compatibility,
the following experiments were performed to assess if lactose could
be used to prepare a stable vardenafil blend formulation.
[0150] A. Materials and Methods
[0151] Var(HCl).sub.2.xH.sub.2O and VarBase were purchased, and
VarHCl.3H.sub.2O was prepared in house using
Var(HCl).sub.2.xH.sub.2O. Conversion of Var(HCl).sub.2.xH.sub.2O to
VarHCl.3H.sub.2O was performed by the pH titration described above
in Example 1, Section D. Var(HCl).sub.2.xH.sub.2O was used in
micronized form (prepared using a commercial dry jet-miller) as
described in Example 4. VarBase and VarHCl.3H.sub.2O were not
micronized. Respitose.RTM. ML006 ("ML006") (DMV-Fonterra
Excipients), an inhalation grade lactose, was also purchased.
[0152] Blending ratios were selected based on powder surface area
to ensure sufficient contact between API and excipient. The
following blends were made: Var(HCl).sub.2.xH.sub.2O: ML006 (1:9),
VarBase: ML006 (1:1) and VarHCl.3H.sub.2O: ML006 (1:1). Blends were
prepared by geometric dilution preblending by hand, followed by
mixing using a commercially available laboratory shaker-mixer.
Where enclosed, blends were pouched using foil to prevent moisture
ingress into the powder mixture.
[0153] Saturated NaCl and NaBr salt solutions were added separately
to two desiccators to create equilibrium relative humidity of 75%
at 40.degree. C. and 60% at 25.degree. C. (as described in
Greenspan, J. Res. Natl. Bureau Std.--A, Phy Chem 1977, 81A (1),
89-96). Prior to use, the stability chambers were stored in
incubators at preset temperature for at least 24 hr.
[0154] Samples were (1) pouched and stored at 25.degree. C. and 60%
relative humidity (RH), (2) pouched and stored at 40.degree. C. and
75% RH, and (3) unpouched (exposed to ambient environment) at
40.degree. C. and 75% RH. Samples were assessed for degradation by
HPLC, as described above. Analysis was completed for the following
time points: Var(HCl).sub.2.xH.sub.2O blend at six month, VarBase
blend at three months, and VarHCl.3H.sub.2O blend at one month.
[0155] B. Results
[0156] None of the samples showed chemical degradation products at
any of the time points. Exemplary HPLC traces for the
VarHCl.3H.sub.2O blend at one month are shown in FIG. 5A (25/60
pouched), FIG. 5B (40/75 pouched), FIG. 5C (40/75 open), and FIG.
5D (VarHCl.3H.sub.2O control). These results establish the
stability of vardenafil-lactose blends as vardenafil was found to
not undergo degradation when mixed with lactose under stable or
accelerated conditions. This analysis is the first reporting that
lactose appears to be an acceptable excipient for the preparation
of vardenafil solid dosage forms.
Example 4
Particle Size Distribution of Micronized Vardenafil Compounds
[0157] Particle size of a dry powder aerosol formulation for
administration by inhalation is closely linked to the deposition
profile in the airways. Thus, a narrow size distribution allows
better targeting of the aerosol. The median respirable particle
size range is 0.5 to 5 microns, and more preferably 1-2
microns.
[0158] Var(HCl).sub.2.xH.sub.2O, VarBase, and VarHCl.3H.sub.2O were
purchased and then micronized using a commercial dry jet-miller.
The jet milling was achieved using typical jet milling conditions
and a single milling process. As shown in Example 5, micronization
leads to partial dehydration of VarHCl.3H.sub.2O. As such,
following micronization and absent rehydration, the compound is
designated as VarHCl.xH.sub.2O.
[0159] The APIs were dispersed in mineral spirit, and particle size
analysis was performed by laser diffraction using a Microtrac X100
Particle Size Analyzer. Particle size span was calculated as
span = D v 0.9 - D v 0.1 D v 0.5 ##EQU00003##
where D.sub.v0.1, D.sub.v0.5 and D.sub.v0.9 are 10%, 50% and 90% of
the volume size distributed below the respective values.
[0160] The particle size distributions of the micronized APIs are
shown in FIG. 6A (Var(HCl).sub.2.xH.sub.2O), FIG. 6B (VarBase), and
FIG. 6C (VarHCl.xH.sub.2O) and summarized in the Table 3 below. All
three APIs were easily micronized into respirable size range. The
particle size distributions were surprisingly narrow with spans
less than 1.6 (VarHCl.xH.sub.2O--0.99,
Var(HCl).sub.2.xH.sub.2O--0.27, VarBase--1.557). These experiments
demonstrate that vardenafil compounds can be micronized to achieve
a desirable median respirable particle size range with a narrow
size distribution. Thus, dry powder formulations of vardenafil may
be particularly suited for aerosol administration via
inhalation.
TABLE-US-00003 TABLE 3 Particle Size Distribution Compound
D.sub.V50 Span VarHCl.cndot.xH.sub.2O 1.179 0.99
Var(HCl).sub.2.cndot.xH.sub.2O 1.85 0.267 VarBase 1.557 1.557
[0161] Scanning electron microscopy (SEM) imaging of the micronized
APIs are shown in FIG. 7A (Var(HCl).sub.2.xH.sub.2O), FIG. 7B
(VarBase), and FIG. 7C (VarHCl.xH.sub.2O). The powder was placed on
the SEM stub and sputter coated with Pd--Au. Particle size
distribution shown in SEM matches the laser diffraction data. The
particles form aggregates which are typical for micronized powders
via jet-milling.
Example 5
Physicochemical Characterization of Vardenafil Compounds
[0162] Several additional methods were used to characterize
vardenafil compounds, including differential scanning calorimetry
(DSC), thermogravimetric analysis (TGA), dynamic vapor sorption
(DVS), and x-ray powder diffraction (XRPD). These analytical
methods can be used to confirm identification of the vardenafil
compound and assist with formulation development.
[0163] A. Material and Methods
[0164] APIs:
[0165] Micronized Var(HCl).sub.2.xH.sub.2O, VarBase, and
VarHCl.xH.sub.2O as described in Example 4 were characterized in
these studies.
[0166] DSC Analysis:
[0167] Compounds were deposited in non-hermetic crimped aluminum
pan.
[0168] Thermal properties were assessed using a Q2000 Modulated DSC
(TA Instrument, New Castle, Del.). Method: scanning rate 10.degree.
C./min from 0-350.degree. C.; heating; equilibrate at 0.degree. C.
for 4 min; modulation .+-.0.796.degree. C./min.
[0169] DVS Analysis:
[0170] No DVS results of these APIs have been previously reported.
Moisture sorption and desorption behavior was assessed using a
DVS-Advantage 1 (Surface Measurement Systems, Allentown, Pa.).
Experimental parameters: sample % P/P.sub.0 in a range of 0-80; 5%
P/P.sub.0 increment, equilibrium criteria, both sorption and
desorption. Experiments conducted at 20.degree. C.
[0171] XRPD Analysis:
[0172] XRPD was performed for crystallinity and polymorphic form
identification. Experimental parameters: 2.degree. 2Theta range
from 0-40 degree, 1.degree. 2Theta degree/min. Experiments
conducted at room temperature (ambient).
[0173] TGA Analysis:
[0174] TGA was performed on micronized Var(HCl).sub.2.xH.sub.2O to
assess weight loss on heating. Active agent mass was monitored as
it was exposed to a temperature program in a controlled atmosphere.
Experimental parameters: scanning rate at 10.degree. C./min, and
temperature ranges from 40-280.degree. C.
[0175] B. Results
[0176] The results for each of Var(HCl).sub.2.xH.sub.2O, VarBase,
and VarHCl.xH.sub.2O using each of these methods are described
below.
[0177] 1. Var(HCl).sub.2.xH.sub.2O
[0178] DSC of micronized Var(HCl).sub.2.xH.sub.2O is shown in FIG.
8A. Var(HCl).sub.2.xH.sub.2O exhibited an onset of glass transition
T.sub.g .about.50.degree. C. that ended at .about.110.degree. C.
This suggests that the high energy jet-milling process introduced
amorphous content in the powder. A small endothermic peak was
observed at .about.140.degree. C. that overlapped with the glass
transition. This indicates that some trihydrate form was present
and underwent partial water loss. Two large endothermic peaks were
also observed at 222.degree. C. and at 294.degree. C. The former
was the heat of fusion T.sub.m. The nature of the latter is still
under investigation. The result is similar to the DSC of
Var(HCl).sub.2.3H.sub.2O shown in U.S. Pat. No. 7,977,478 (FIG. 15)
but covered a larger temperature range.
[0179] DVS of micronized Var(HCl).sub.2.xH.sub.2O is shown in FIG.
9A. A critical relative humidity was shown at 70% in sorption and
40% in desorption. In sorption phase, there were two step
inflection points that occurred around 30% RH and 70% RH. The first
may be a glass transition from amorphous to crystalline, and the
second may reflect the formation of trihydrate. The desorption
phase indicated that the trihydrate form is only stable in a short
humidity range of 50% RH-80% RH. It is possible that, when RH is
below 40% RH, loss of bound water may occur. Another desorption
inflection point occurred around 20% RH. This suggests that
Var(HCl).sub.2.xH.sub.2O is unstable in normal ambient condition
and tends to lose bound water. A large hysteresis loop was observed
due to the hydration of Var(HCl).sub.2.
[0180] TGA of micronized Var(HCl).sub.2.xH.sub.2O is shown in FIG.
10. Based on the observed tilted curve, Var(HCl).sub.2.xH.sub.2O
started to continuously lose water above 40.degree. C. There was a
transition at around 220.degree. C. to 240.degree. C. This could be
the melting phase when the TGA result was combined with DSC
thermogram. Another two transitions (inflection points) occurred
around 80.degree. C. and 130.degree. C. The water loss upon heating
profile is comparable to that described in U.S. Pat. No. 7,977,478
(FIG. 16).
[0181] XRPD of micronized Var(HCl).sub.2.xH.sub.2O is shown in FIG.
11A. The XRPD of Var(HCl).sub.2.xH.sub.2O (x=1, 2, or 3) were
previously described in U.S. Pat. No. 7,977,478. The peaks of the
micronized Var(HCl).sub.2 xH.sub.2O preparation were compared to
those illustrated in that reference, which indicates that the
Var(HCl).sub.2 xH.sub.2O preparation is likely a monohydrate and
dihydrate mixture.
[0182] 2. VarBase
[0183] DSC of micronized VarBase is shown in FIG. 8B. The VarBase
preparation showed a sharp endothermic peak indicating heat of
fusion T.sub.m=190.degree. C. The onset temperature was at
.about.177.degree. C. when DSC scanning rate was set at 10.degree.
C./min. When the temperature increased above 250.degree. C.,
decomposition peaks were observed. VarBase has two polymorphic
forms: Form I and Form II. The Form II polymorph was previously
determined to have a heat of fusion T.sub.m=194.degree. C. (U.S.
Pat. No. 7,977,478), which is higher than the T.sub.m determined by
this analysis. Thus, based on T.sub.m, this VarBase preparation
appeared to be the Form I polymorph. The Form I polymorph had
previously been characterized by XRPD (WO/2011/079935). The XRPD
analysis of the VarBase preparation confirmed that it is the Form I
polymorph.
[0184] DVS of micronized VarBase is shown in FIG. 9B. The VarBase
preparation sorption and desorption phases are much simpler as
compared to Var(HCl)2 and VarHCl and their hydration forms, likely
because VarBase cannot form hydrates and, thus, cannot for
pseudopolymorphs. No obvious hysteresis loop was observed
indicating that no hydration occurred. Some minor phase change was
observed. This may be due to a small amount of amorphous content in
the preparation caused by mechanical stress during jet-milling.
[0185] XRPD of micronized VarBase is shown in FIG. 11B. The
comparison of 2.theta. values and % intensity with the crystalline
Form I and Form II of VarBase revealed that the VarBase preparation
is mainly crystalline Form I. The 2.theta. values of the major
intensity peaks are: 9.8, 11.2, 12.4, 14.2, 15.3, 16.2, 17.1, 18.0,
20.1, 21.6, 23.2, 24.6, 27.3 degree. This result is in good
agreement with DSC result.
[0186] 3. VarHCl.xH.sub.2O
[0187] As noted above, VarHCl.3H.sub.2O is thermodynamically
stable. However, under certain conditions (such as micronization),
partial dehydration can occur. This is illustrated in the results
described below.
[0188] DSC of micronized VarHCl.xH.sub.2O is shown in FIG. 8C.
VarHCl.xH.sub.2O had a large endothermic peak at 107.degree. C.
showing the loss of bound water. The onset temperature was about
50.about.60.degree. C. This indicates that VarHCl.xH.sub.2O could
be susceptible to elevated temperature above 50.about.60.degree. C.
The heat of fusion T.sub.m was 199.2.degree. C. Above the heat of
fusion temperature, the material quickly underwent decomposition.
This is the first reporting of DSC analysis of micronized
VarHCl.xH.sub.2O.
[0189] DVS of micronized VarHCl.xH.sub.2O in FIG. 9C and FIG. 9D.
In FIG. 9C, the Y-axis is % w/w H.sub.2O uptake, while in FIG. 9D
the Y-axis is molar ratio. Together, these isotherm plots permit a
clear understanding of stoichiometric water sorption and desorption
of VarHCl.
[0190] In the VarHCl sorption phase, there were two inflection
points. A first water molecule bound to anhydrous VarHCl at a
relative humidity (RH) as low as 5% to form a monohydrate. This
indicated that VarHCl is highly hygroscopic. Between RH 5-40%, a
steady but slower water sorption occurred at increasing RH. This
was followed by a more rapid water uptake between 40-60% RH. The
sorption phase reached a plateau between 60-80% RH when the water
content of the molecule reached the stoichiometric trihydrate form.
This indicated that VarHCl.3H.sub.2O could maintain its integrity
(not reaching deliquescence) up to 80% RH.
[0191] The quick water uptake at RH as low as 5% and preferential
formation of monohydrate is presumably caused by different H-bond
associations among the three water molecules that can bind to
VarHCl. The first water molecule can preferentially form H-bonding
with the acidic proton and the carbonyl group of vardenafil. This
six-membered ring structure could result in stabilized H-bonding
that the following H.sub.2O molecules may not have. See Scheme 1
below.
##STR00003##
[0192] In the VarHCl.3H.sub.2O desorption phase, the trihydrate
form was maintained between 10-80% RH. Water loss only occurred
when RH is lower than 15%, and even more so 10%. These results
indicated that VarHCl.3H.sub.2O is a thermodynamically stable form
and that, once the VarHCl.3H.sub.2O is formed, it is unlikely to
lose bound water in normal RH % when the powder is maintained at
room temperature.
[0193] XRPD of micronized VarHCl.xH.sub.2O is shown in FIG. 11C.
The corresponding 2.theta. values of the major intensity peaks are:
5.1, 8.2, 10.3, 10.9, 15.4, 16.4, 17.3, 19.9, 20.2, 20.8, 22.4,
23.0, 24.5, 25.1, 26.1, 27.0, 27.9, 29.1 degree. The 20 values of
the intensity peaks for the micronized VarHCl.xH.sub.2O were
compared to previously reported values from the XRPD analysis of
VarHCl.3H.sub.2O (see, for example, U.S. Pat. No. 8,273,876). This
comparison indicated that the micronized compound may lose some
crystallinity due to the jet-milling process as the peaks are not
as sharp (possibly due to loss of peak intensity due to the
creation of amorphous content).
Example 6
Preparation of Vardenafil Formulations
[0194] Having established that lactose was a suitable excipient for
vardenafil compound formulations, several lactose blends were
prepared with various vardenafil compounds described in the
previous examples. Mixing conditions were assessed to identify
satisfactory blends.
[0195] The vardenafil compounds used were:
Var(HCl).sub.2.xH.sub.2O, VarBase, micronized VarHCl.xH.sub.2O, and
micronized VarHCl.3H.sub.2O (rehydrated). Formulations were
prepared using two different lactose carriers, a sieved grade of
alpha-monohydrate lactose with an average particle size of about 50
.mu.m (LAC1) and a fine particle lactose having a particle size
distribution D.sub.v50 below about 5 .mu.m (LAC2).
[0196] To break up any large agglomerates and facilitate blending
and blend homogeneity, the micronized APIs and LAC1 were passed
through a 250 .mu.m sieve. The API powders were then accurately
weighed according to the API concentration using a micro balance.
The pre-blend (1-5 g) was achieved by geometric dilution of API
powder into LAC1. Trituration and gentle stirring with a spatula
allowed for a good initial blending condition. The mixtures were
then blended with a Turbula.RTM. T2C Shaker-Mixer. UV analysis was
performed. The API was detected by UV spectrophotometry.
[0197] Various blending speeds were tested to determine what speed
resulted in the best blending uniformity. The rotation speed of the
shaker-mixer was calibrated using a stopwatch to slow (22 rpm),
medium (49 rpm), and high (99 rpm) speeds. Blending was stopped at
5 min, 10 min, 15 min, and 20 min. At each time point, five
accurately weighed samples (0.8-1 mg) from the top (2 samples), the
bottom (2 samples) and the side (1 sample) of the jars were
dissolved in 20 mL HPLC grade H.sub.2O solution (H.sub.2O:
H.sub.3PO.sub.4=1 L: 0.2 mL) and measured by UV spectrophotometry.
The average concentration was analyzed and the relative standard
deviation (% RSD) (also referred to as coefficient of variation (%
CV) was used to evaluate the accuracy of blend concentration and
blending uniformity, respectively. A % CV less than 5% was
considered to be good blend uniformity.
[0198] An exemplary blending example using 5%
Var(HCl).sub.2.xH.sub.2O and LAC1 is shown in FIG. 12. Blending at
high speed (99 rpm) gave the best blending uniformity. The % CV
results were consistently within the range of 5% in 5-20 min. In
contrast, blending at slow and medium speeds showed a pattern of
mixing and de-mixing that is not suitable to reproducibly obtain a
homogenous mixture.
[0199] Blending at high speed for 20 min generally resulted in an
overall good blending uniformity for all API formulations. If UV
analysis indicated that % CV was greater than 5% in any instances,
formulations were mixed for an additional 10-20 min high speed to
reduce the % CV to less than 5%.
[0200] Using the conditions outlined above, the formulation blends
listed in Table 4 were prepared with satisfactory blend
concentration and blend uniformity
TABLE-US-00004 TABLE 4 Formulation Blends
Var(HCl).sub.2.cndot.xH.sub.2O + LAC1 API Concentration: 5% w/w 13%
w/w 20% w/w 40% w/w 60% w/w 80% w/w Var(HCl).sub.2.cndot.xH.sub.2O
+ LAC1 + LAC2 Weight Ratio: 20:77:3 20:20:60 VarBase + LAC1 API
Concentration: 5% w/w 20% w/w VarHCl.cndot.xH.sub.2O + LAC1 API
Concentration: 5% w/w (micronized API) 20% w/w
VarHCl.cndot.3H.sub.2O + LAC1 API Concentration: 20% w/w
(micronized API)
Example 7
Aerosol Performance of Vardenafil Formulations
[0201] One consideration when formulating a dry powder for
inhalation is that its size should be small enough to permit
aerosolization and the deposition at the appropriate site of the
respiratory tract. A failure in deposition may result in a failure
of efficacy.
[0202] There are several inertia sampling apparatuses that can be
used to assess aerosol performance of dry powder formulations.
(<601> Aerosols, Nasal Sprays, Metered-Dose Inhalers, and Dry
Powder Inhalers Monograph, in USP 29-NF 24 The United States
Pharmacopoeia and The National Formulary: The Official Compendia of
Standards. 2006, The United States Pharmacopeial Convention, Inc.:
Rockville, Md. p. 2617-2636 ("USP <601>").) These apparatus
classify aerosol particles on the basis of the particles'
aerodynamic diameter. Each stage of the impactor includes a single
or series of nozzles with specific cutoff size. Particles are
entrained into the apparatus. Those having sufficient inertia will
impact on that particular stage collection plate, while smaller
particles with insufficient inertia will remain entrained in the
airstream and pass to the next stage where the process is repeated.
The aerodynamic size distribution of API can be assessed by
collecting the deposited API mass and the ED %, RF %, FPF % and
MMAD (.mu.m) can be calculated from the API deposition pattern. The
emitted dose fraction (ED (%); Eq. 4) is determined as the
percentage powder mass emitted from the initial dosing
chamber/capsule relative to the total dose in capsules (nominal
dose) (TD). Emitted dose (ED) includes the sum of the API mass left
on inhaler device and deposited on the device stages. Fine particle
fraction (FPF (%); Eq. 5) is expressed as a percentage of fine
particle dose (FPD) below a certain aerodynamic cutoff size to ED.
Respirable fraction (RF (%); Eq. 6) is defined as the percentage of
FPD to total dose (TD).
Emitted dose function ( ED ( % ) ) = ( ED TD ) .times. 100 % ( Eq .
4 ) Fine particle fraction ( FPF ( % ) ) = ( FPD ED ) .times. 100 %
( Eq . 5 ) Respirable function ( RF ( % ) ) = ( FPD TD ) .times.
100 % ( Eq . 6 ) ##EQU00004##
[0203] A. Materials and Methods
[0204] Formulation aerosol performance tests were carried out using
a powder deaggregator modified from that described in U.S. Patent
Publication Nos. 2013/0340754 and 2013/0340747 combined with an
off-the-shelf RS01 dry powder inhaler capsule piercing mechanism
(Plastiape, IT) feeding method. The powder deaggregator had a 2.72
mm inlet diameter, a 10 mm oscillation chamber length, 5.89 mm
oscillation chamber diameter, 4 mm polypropylene bead (density=0.90
mg/mm.sup.3), 2 of 6 bypass channel open, and cross grid. With this
capsule piercing mechanism, the delivery system had a resistance
(R.sub.D) of 0.104 (cmH.sub.2O).degree. *.sup.5/L/min. The
experiments were conducted at an airflow rate that gave a system
pressure drop of 2 kPa (about 40 L/min, 4 L inhalation volume
duration: 5.5 sec) or 4 kPa (about 60 L/min, 4 L inhalation volume
duration: 3.9 sec).
[0205] Formulations:
[0206] Pure drug formulations (no excipient) of micronized VarBase,
micronized VarHCl.xH.sub.2O, micronized Var(HCl).sub.2.xH.sub.2O
(rehydrated), and micronized VarHCl.xH.sub.2O were prepared as
described in Examples 4 and 5. Vardenafil blends (5% API and 20%
API) with LAC1 were prepared as described in Example 6 using
micronized Var(HCl).sub.2.xH.sub.2O, micronized VarBase, micronized
VarHCl.xH.sub.2O, and micronized VarHCl.3H.sub.2O.
[0207] Packaging:
[0208] The blends were packaged into size 3 HPMC capsules. Nominal
dose amounts of 3 mg were prepared for each formulation; 10 mg
nominal doses were also prepared for pure drug VarBase and
Var(HCl).sub.2.xH.sub.2O formulations.
[0209] Methods:
[0210] Two inertial sampling systems were used to assess aerosol
performance: (1) a Next Generation Impactor.RTM. ("NGI") (Copley
Scientific, Shoreview, Minn.), and (2) a Twin Stage Liquid Impinge
("TSLI") (Copley Scientific, Shoreview, Minn.). Aerosol performance
of the VarHCl.xH.sub.2O formulation was assessed using the TSLI
device, while the other formulations were all assessed using the
NGI device. The NGI experiments were carried out using methods in
general agreement with the USP <601>, and the TSLI
experiments were carried using methods in general agreement with
the British Pharmacopoeia, 2007, Vol. IV, Appendix XIIF. A291
Aerodynamic assessment of fine particles, fine particle dose and
particle size distribution. The NGI experiments were run at a
controlled airflow rate that gave a pressure drop of either 2 or 4
kPa across the device. Specifically, at Q=61.4 L/min with a delay
time of 3.9 sec; and at Q=43.4 L/min with a delay time of 5.5 sec.
Before the aerosol testing, the NGI collection plates were coated
with suitable coating. Mass median aerodynamic diameter (MMAD) of
aerosol particles distribution was determined based on a
log-probability distribution (API particle size versus API
deposition percentage) obtained from the NGI data. The TSLI
experiments were run at Q=60 L/min, 4 sec to achieve
.DELTA.P.apprxeq.4 kPa, with a cutoff size of 6.4 .mu.m.
[0211] B. Pure Drug Formulations Aerosol Performance
[0212] Micronized pure drug formulations (100% API, no excipient)
were found to generally have an emitted dose (ED) fraction in the
range of 24-82% and an RF fraction in the range of 21-46%, as shown
in Table 5. This was mainly due to poor powder flow with the
delivery system described in Section A. However, the FPF(ED) was
generally quite high, except for the 10 mg VarBase formulation. The
micronized Var(HCl).sub.2.xH.sub.2O resulted in the highest
FPF(ED), followed by the VarHCl.xH.sub.2O formulation, the
VarHCl.3H.sub.2O formulation, and the 3 mg VarBase formulation,
each of which was well over 50%. Higher dose did not increase the
aerosol performance but did negatively impact FPF(ED) for the
VarBase formulation. Rehydration of Var(HCl).sub.2.xH.sub.2O
increased ED and RF markedly but decreased FPF(ED). The aerosol
performance of the pure drug formulations is comparable to many
currently marketed dry powder formulations. However, the way that
the capsule piercing mechanism used in these experiments works
results in a large amount of powder deposition within the mechanism
itself, which reduces the ED %. Increasing the powder flow
properties of the active agent, such as by adding a suitable dry
powder base (carrier/diluent/excipient) may increase the ED % by
facilitating powder fluidization during aerosolization. Thus, for
use with the deaggregator-capsule piercing mechanism combination in
these studies, improved aerosol performance may be obtained if the
vardenafil compounds are blended with an excipient like
lactose.
TABLE-US-00005 TABLE 5 Pure Drug Formulation Aerosol Performance
Dose MMAD Test API (mg) ED(%) RF(%) FPF(ED)(%) % Recvy (.mu.m) 1
VarBase 3 81.8 45.8 56.0 -- 1.32 2 VarBase 10 64.2 23.9 37.2 115.2
1.51 3 Var(HCl).sub.2 xH.sub.2O 3 26.6 23.5 88.5 -- 0.76 4
Var(HCl).sub.2 xH.sub.2O 10 24.5 21.2 86.5 114.0 0.82 5
Var(HCl).sub.2 xH.sub.2O 3 71.4 45.4 63.6 100.1 1.37 (rehydrated)
6* VarHCl xH.sub.2O 3 40.7 28.1 68.9 112.0 -- *TSLI data cannot be
used to determine MMAD.
[0213] C. API-Lactose Formulation Aerosol Performance
[0214] In a first experiment, aerosol performance of the 5%
Var(HCl).sub.2.xH.sub.2O formulation was assessed. In addition to
assessing impact of added lactose as an excipient, the impact of
nominal load (or payload) on aerosol performance of this
formulation was also assessed. Capsules were loaded with either 10
mg of formulation or 20 mg of formulation and assessed using the
NGI device at 4 kPa airflow rate. The results are shown in Table 6
below (Mean.+-.SD, n=3).
TABLE-US-00006 TABLE 6 5% Var(HCl)2.cndot.xH2O Formulation at 10 mg
or 20 mg Nominal Load Nominal Load ED (%) RF (%) FPF(ED) (%) MMAD
(.mu.m) 10 mg 75.1 .+-. 4.2 51.1 .+-. 4.4 68.0 .+-. 2.9 0.81 .+-.
0.01 20 mg 80.5 .+-. 1.4 53.0 .+-. 1.4 65.8 .+-. 0.7 0.84 .+-.
0.02
[0215] The ED and RF of the 5% Var(HCl).sub.2.xH.sub.2O formulation
was found to be much higher than that of the pure drug
Var(HCl).sub.2.xH.sub.2O formulation, though the FPF(ED) was
reduced. The aerosol performance of the formulation was found to be
independent of the nominal dose at 10 mg or 20 mg as the
performance metrics [ED, RF, FPF(ED)] for each nominal dose were
very similar. These results suggest that lactose-based formulations
may improve aerosol performance of dry powder vardenafil
formulations, at least when used with the delivery system described
above in Example 7, Section A.
[0216] In a second study, the influence of API concentration on the
aerosol performance of lactose-based Var(HCl).sub.2.xH.sub.2O
formulations was evaluated. Capsules were loaded with 20 mg of
either the 5% or 20% API formulation and assessed using the NGI
device at 4 kPa airflow rate. The results are shown in Table 7
below (Mean.+-.SD, n=3).
TABLE-US-00007 TABLE 7 5% + 20% Var(HCl)2.cndot.xH2O Formulation at
20 mg Nominal Load API conc (%) ED (%) RF (%) FPF(ED) (%) MMAD
(.mu.m) 5 80.5 .+-. 1.4 53.0 .+-. 1.4 65.8 .+-. 0.7 0.84 .+-. 0.02
20 80.1 .+-. 7.8 60.8 .+-. 4.8 76.9 .+-. 1.4 0.92 .+-. 0.04
[0217] The results indicated that the RF can be improved by
increasing the API concentration from 5% to 20% for this
formulation. FPF(ED) also improved with increased concentration.
These findings suggested that this delivery system may be
particularly suitable for delivery of lactose-based formulation
with high API concentration.
[0218] In order to evaluate if the other VarBase and
VarHCl.xH.sub.2O formulations have the same trend, a TSLI device
experiment was designed to assess whether 20% API formulations for
VarBase and VarHCl.xH.sub.2O have better aerosol performance than
5% formulations when the deaggregator device-capsule piercing
mechanism are used at 4 kPa airflow condition. For each active
agent, the 20 mg payload of the 20% formulation includes 4 mg of
the API, while the 5% formulation includes 1 g of the API. The
results are shown in Table 8 below. The results for the 5% and 20%
VarBase+LAC1 formulations are averaged data (Mean.+-.SD, n=3).
TABLE-US-00008 TABLE 8 5% and 20% VarBase and
VarHCl.cndot.xH.sub.2O Formulation at 60 L/min Test Formulation ED
(%) RF (%) FPF(ED)(%) 1 5% VarBase + LAC1 67.2 .+-. 3.9 26.6 .+-.
1.0 39.7 .+-. 0.9 2 20% VarBase + LAC1 76.4 .+-. 2.8 42.1 .+-. 2.7
55.0 .+-. 1.8 3 5% VarHCl.cndot.xH.sub.2O + 71.7 37.2 51.9 LAC1 4
20% VarHCl.cndot.xH.sub.2O + 70.8 48.4 68.4 LAC1
[0219] The results show that the 20% VarBase and VarHCl.xH.sub.2O
also have better aerosol performance than the corresponding 5%
formulations. For the VarBase-LAC1 formulation, the increase of API
concentration from 5% to 20% resulted in a RF increase from 26.6%
to 42.1% and a FPF(ED) increase from 39.7% to 55%. For the
VarHCl.xH.sub.2O-LAC1 formulation, the same trend held, with the RF
increasing from 37.2% to 48.4% and the FPF(ED) increasing from
51.9% to 68.4%.
Example 8
Very High Dose Formulation Assessment of Aerosol Performance
[0220] As the 20% API-lactose blend formulations performed so well,
an experiment was designed to assess the aerosol performance of
very high concentration formulations. High concentration
formulations may be desirable if ED is not reduced as a result. A
Dose Unit Sampling Apparatus ("DUSA") (Copley Scientific,
Shoreview, Minn.) was used to assess emitted dose of four
Var(HCl).sub.2.xH.sub.2O-LAC1 formulations were prepared as
described in the preceding examples at an API concentration of 20%,
40%, 60%, and 80%. The DUSA experiments were carried out using
methods in general agreement with the USP <601>. The same
delivery device as described above in Example 7, Section A was
used. As shown in FIG. 15A, a linear relationship (R.sup.2=0.9718)
was observed between ED and the API concentration of the
formulation.
[0221] To investigate the reason for the observed decrease in
emitted dose as seen in FIG. 15A, deposition of the API on the
deaggregator and the capsule piercing mechanism were evaluated
separately. These results show that the amount of the API that was
retained in the device was mainly in the capsule piercing portion
of the device, as the amount of deposition in this portion and the
formulation concentration were positively correlated
(R.sup.2=0.9563) as shown in FIG. 15B. In contrast, the deposition
of API on the deaggregator did not change as API concentration
increased (data not shown; y=0.0052x+0.0873; R.sup.2=0.9563). Thus,
the 5-20% concentration range may result in about 80% ED for the
Var(HCl).sub.2.xH.sub.2O-LAC1 formulations when used with this
delivery system at an airflow of 4 kPa. However, higher
concentration formulations may be used with a different device
capsule piercing mechanism that disperses the drug along the axis
of the air flow and not toward the device internal walls like the
capsule piercing mechanism used in these experiments. In such
cases, it can be expected that less loss of drug to the internal
surfaces will be achieved.
Example 9
Influence of Device Pressure Drop on Aerosol Performance
[0222] Having aerosol performance of a formulation be independent
of airflow conditions is preferable because there is greater
reproducibility in administration where airflow rate may be
variable (for example, based on the user). The NGI device was used
to assess the aerosol performance of the 20%
Var(HCl).sub.2.xH2O+LAC1 formulation as described above in Example
7, Section A except at an airflow pressure of 4 kPa and 2 kPa
(corresponding to about 60 and about 40 L/min airflow rate,
respectively). Using the NGI stage cutoffs identified in the USP
<601>, the aerosol performance data at the 2 kPa pressure
drop was based on NGI cutoff stage 3 and below, and the aerosol
performance data at the 4 kPa pressure drop was based on NGI cutoff
stage 2 and below. The results are shown in Table 9 below
(Mean.+-.SD, n=3).
TABLE-US-00009 TABLE 9 20% Var(HCl).sub.2.cndot.xH.sub.2O
Formulation actuated at 2 kPa vs. 4 kPa Airflow ED (%) RF (%)
FPF(ED) (%) MMAD (.mu.m) 2 kPa 75.9 .+-. 7.5 51.6 .+-. 2.5 69.1
.+-. 2.2 1.15 .+-. 0.06 4 kPa 80.1 .+-. 7.8 60.8 .+-. 4.8 76.9 .+-.
1.4 0.92 .+-. 0.04
[0223] The ED, RF, and FPF(ED) were decreased slightly at 2 kPa as
compared to 4 kPa. However, the effective aerodynamic cutoff
diameter (D.sub.a50) for each impactor stage of the NGI device is
different at different flow rates. At 4 kPa, the impactor stage
cutoff is 4.41 .mu.m (stage 2 and below). In contrast, at 2 kPa the
impactor stage cutoff is 3.32 .mu.m (stage 3 and below). As a
result, at the faster airflow rate, larger size particles passed
the cutoff and contributed to the aerosol performance. This
suggests that the RF and FPF(ED) could be slightly underestimated
at an airflow rate of 2 kPa. As such, the aerosol performance at 2
kPa did not appear to cause a substantial change in aerosol
performance when compared at 4 kPa.
* * * * *