U.S. patent application number 10/550471 was filed with the patent office on 2007-02-22 for trospium containing compositions.
This patent application is currently assigned to ADVANCED INHALATION RESEARCH, INC.. Invention is credited to Robert Clarke, Daniel Deaver, Elliot Ehrich, Michael M. Lipp.
Application Number | 20070041912 10/550471 |
Document ID | / |
Family ID | 33309426 |
Filed Date | 2007-02-22 |
United States Patent
Application |
20070041912 |
Kind Code |
A1 |
Ehrich; Elliot ; et
al. |
February 22, 2007 |
Trospium containing compositions
Abstract
The invention relates to a method for treating a disease
characterized by a constrictive airway comprising administering to
a patient in need thereof via inhalation a pharmaceutical
composition comprising trospium, wherein said patient achieves an
effective therapy for at least 10 hours. The trospium composition
is preferably a particulate formulation useful for administration
via a dry powder inhaler. In a preferred embodiment, the
composition further comprises a second active agent, such as a
beta-2 agonist. A particularly preferred second active agent is
formoterol, wherein the trospium, formoterol composition is
manufactured by spray drying a mixture comprising trospium and
formoterol.
Inventors: |
Ehrich; Elliot; (Lincoln,
MA) ; Deaver; Daniel; (Franklin, MA) ; Clarke;
Robert; (Canton, MA) ; Lipp; Michael M.;
(Framingham, MA) |
Correspondence
Address: |
ELMORE PATENT LAW GROUP, PC
209 MAIN STREET
N. CHELMSFORD
MA
01863
US
|
Assignee: |
ADVANCED INHALATION RESEARCH,
INC.
Cambridge
MA
02139
|
Family ID: |
33309426 |
Appl. No.: |
10/550471 |
Filed: |
September 4, 2003 |
PCT Filed: |
September 4, 2003 |
PCT NO: |
PCT/US03/27618 |
371 Date: |
September 1, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10392333 |
Mar 19, 2003 |
|
|
|
10550471 |
Sep 1, 2006 |
|
|
|
Current U.S.
Class: |
424/46 ;
514/278 |
Current CPC
Class: |
A61K 9/1617 20130101;
A61K 9/0078 20130101; A61K 31/46 20130101; A61K 45/06 20130101;
A61P 11/06 20180101; A61K 9/0075 20130101; A61K 31/40 20130101;
A61K 31/438 20130101; A61P 11/00 20180101 |
Class at
Publication: |
424/046 ;
514/278 |
International
Class: |
A61K 31/4747 20070101
A61K031/4747; A61L 9/04 20060101 A61L009/04 |
Claims
1. A method for treating a disease characterized by a constrictive
airway comprising administering to a patient in need thereof via
inhalation a pharmaceutical composition comprising trospium,
wherein said patient achieves an effective therapy for at least 10
hours.
2. The method of claim 1 wherein said disease is chronic
obstructive pulmonary disease.
3. The method of claim 1 wherein said composition comprises a dose
of trospium of between about 50 to 1200 micrograms.
4. The method of claim 1 wherein said composition comprises a dose
of trospium of between about 200 to 800 mcg.
5. The method of claim 1 wherein said composition comprises an
aqueous solution of trospium hydrochloride.
6. The method of claim 1 wherein said composition comprises a
particulate formulation comprising trospium.
7. The method of claim 1 wherein said composition comprises a dry
particulate formulation of trospium wherein said formulation is
administered with a dry powder inhaler.
8. The method of claim 1 wherein said composition comprises a dry
particulate formulation of trospium characterized by a fine
particle fraction of at least 50% and wherein said formulation is
administered with a dry powder inhaler.
9. The method of claim 8 wherein said trospium formulation
comprises micronized trospium.
10. The method of claim 8 wherein said trospium formulation
comprises spray dried trospium.
11. The method of claim 10 wherein said trospium formulation has a
tap density of less than 0.4 g/cm.sup.3.
12. The method of claim 11 wherein said trospium formulation has a
mass mean aerodynamic diameter of less than 5 microns.
13. The method of claim 12 wherein said trospium formulation
further comprises leucine, a phospholipid or combinations
thereof.
14. The method of claim 13 wherein said formulation comprises at
least about 70% by weight of leucine.
15. The method of claim 14 wherein said formulation contains less
than about 10% by weight of trospium.
16. The method of claim 14 wherein said formulation comprises about
5% by weight trospium hydrochloride; between about 5 and 10% by
weight of phospholipid and between about 85 and 90% by weight of
leucine.
17. The method of claim 16 wherein the dose of trospium
administered is about 50 to 1200 mcg.
18. The method of claim 16 wherein the dose of trospium
administered is about 200 to 800 mcg.
19. The method of claim 17 wherein the patient achieves an
effective therapy for at least about 15 hours.
20. The method of claim 17 wherein the patient achieves an
effective therapy for at least about 24 hours.
21. The method of claim 8 wherein the formulation is administered
once per day.
22. The method of claim 1 further comprising the administration of
a second active agent.
23. The method of claim 22 wherein the second active agent is a
beta-2 agonist.
24. The method of claim 23 wherein the second active agent is
formoterol.
25. The method of claim 23 wherein the second active agent is
administered separately from the trospium formulation.
26. The method of claim 24 wherein the second active agent is
incorporated into the trospium formulation.
27. The method of claim 24 wherein the composition comprises a
spray dried formulation comprising trospium, formoterol, leucine
and, optionally, a phospholipid.
28. A pharmaceutical composition for inhalation comprising trospium
and formoterol.
Description
RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S.
application Ser. No. 10/392,333, filed Mar. 19, 2003, which claims
the benefit of U.S. Provisional Application Nos. 60/366,479,
60/366,449, 60/354,354, 60/366,487 and 60/366,440, filed on Mar.
20, 2002. The entire teachings of the above application(s) are
incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] It is known from the prior art that .beta.-mimetics and
anticholinergics can successfully be used as bronchospasmolytics
for the treatment of obstructive respiratory ailments, such as,
e.g., asthma. Substances with ..beta..-sympathomimetic
effectiveness, such as, e.g., the active substance formoterol, also
known from the prior art, can, however, be associated with
undesirable side-effects when administered to humans. There remains
a need for formulations and methods for administering combinations
of beta-mimetics and anticholingerics in a formulation that
provides long lasting broncoprotection in a patient while
minimizing undesireable side effects.
SUMMARY OF THE INVENTION
[0003] The invention relates to a method for treating a disease
characterized by a constrictive airway comprising administering to
a patient in need thereof via inhalation a pharmaceutical
composition comprising trospium (spiro [8 azaniabicyclo[3.2.1]
octane-8,1'-pyrrolidinium], 3-4[hydroxydiphenylacetyl)oxy]-chloride
(1.alpha., 3.beta., 5.alpha.)) wherein said patient achieves an
effective therapy for at least 10 hours. The trospium composition
is preferably a particulate formulation useful for administration
via a dry powder inhaler. In a preferred embodiment, the
composition further comprises a second active agent, such as a
beta-2 agonist. A particularly preferred second active agent is
formoterol, wherein the trospium, formoterol composition is
manufactured by spray drying a mixture comprising trospium and
formoterol.
BRIEF DESCRIPTION OF THE DRAWINGS
[0004] FIGS. 1a and 1b show the percent (%) baseline PenH over time
following treatment at varying doses of aqueous Ipatropium bromide
(IpBr) (FIG. 1a) and aqueous Trospium Chloride (TRCl) (FIG.
1b).
[0005] FIG. 2 shows the percent (%) baseline PenH over time
following treatment at equal nominal doses of aqueous IpBr or
aqueous TrCl.
[0006] FIG. 3 shows the percent (%) baseline PenH over time
following treatment with aqueous TrCl or particle formulations TrCl
at a nominal dose of 1 mcg for each formulation.
DETAILED DESCRIPTION OF THE INVENTION
[0007] The invention is based upon the discovery that trospium,
when administered via inhalation results in surprisingly long
acting formulation. Thus, a single daily administration, or twice
daily administration, of trospium can be used to achieve and
maintain relief of such diseases as chronic pulmonary disorder.
[0008] Thus, in one embodiment, the invention relates to a method
for treating a disease characterized by a constrictive airway
comprising administering to a patient in need thereof via
inhalation a pharmaceutical composition comprising trospium,
wherein said patient achieves an effective therapy for at least
about 10 hours, preferably at least about 15 hours, more preferably
at least about 24 hours.
[0009] Diseases that can be treated by the present invention
include diseases indicated for trospium. For example, patients
suffering from asthma, chronic obstructive pulmonary disease
(COPD), restriction of the bronchial airways, or bladder diseases,
such as urinary incontinence, can be treated by practicing the
invention
[0010] The invention further relates to pharmaceutical compositions
for use in the present methods. The compositions comprise a
therapeutically effective amount of trospium. A therapeutically
effective amount includes an amount which, alone or in combination
with one or more other active agents, can control, decrease,
inhibit, ameliorate, prevent or otherwise affect one or more
symptoms of the disease(s) or condition(s) to be treated.
[0011] Typically, the dose of the active agent to be delivered is
related to the efficiency of the inhalation device to deliver the
active agent to the patient and the bioavailability of the active
agent upon delivery. The preferred human dose of trospium is about
50 to 1200 micrograms per inhalation nominal dose delivered to
lung, and even more preferably about 200-800 micrograms per
inhalation nominal dose delivered to lung.
[0012] The composition can be administered via a number of
different pulmonary routes, which can impact the form of the
composition. In one embodiment, the composition comprises an
aqueous solution or suspension of trospium or a trospium salt, such
as a hydrochloride. In another embodiment, the composition
comprises a particulate formulation comprising trospium, such as a
dry particulate formulation of trospium to be administered with a
dry powder inhaler. In this context, a "dry powder" contains less
than about 5% by weight of water, based on the total solids of the
composition.
[0013] The trospium formulations can, in one embodiment, comprises
micronized trospium. However, it is preferred to administer
formulations that comprise spray-dried trospium. Preferred
formulations are described in, for example, U.S. Ser. No.
10/392,333, which is incorporated herein by reference. Such
formulations have superior deposition properties. That is,
preferred formulations are characterized by a tap density of less
than 0.4 g/cm.sup.3, preferably less than 0.3 g/cm.sup.3, more
preferably less than about 0.2 g/cm.sup.3, more preferably less
than about 0.1 g/cm.sup.3, or even less than about 0.05 g/cm.sup.3.
Further the formulation has a mass mean aerodynamic diameter of
less than 5 microns. A preferred dry particulate formulation is
characterized by a fine particle fraction of at least about 50%,
wherein the fine particle fraction is defined as the mass of the
composition that possesses an aerodynamic diameter of less than 3.4
microns as determined with an 8 Stage Anderson Cascade Impactor,
used according to manufacturer's instructions.
[0014] Preferred compositions further comprise an amino acid.
Preferred amino acids are hydrophobic amino acids, such as leucine,
isoleucine, alanine, valine and phenylalanine, for example. The
preferred amino acid is leucine. The amino acid can advantageously
be added in amount of at least about 10% by weight of the total
composition. In one embodiment, the amino acid is at least about
40%, preferably at least about 50%, more preferably at least about
70% by weight of total composition.
[0015] The compositions can further advantageously contain or
comprise one or more phospholipids or combinations thereof.
Suitable phospholipids include phosphatidylcholines,
phosphatidylethanolamines, phosphatidylglycerols,
phosphatidylserines, phosphatidylinositols and combinations
thereof. A particularly preferred phospholipid is
dipalmitoylphosphatidylcholine (DPPC). The phospholipid can be
advantageously added in an amount between about 1% and 90%,
preferably between about 1 and 70%, more preferably between about
1% and 30%, such as between about 5 and 10% by weight of the total
composition. The weight of the composition, as defined herein is,
of course, non-inclusive of water and residula solvents or
volatiles.
[0016] The composition can comprise additional optional excipients,
such as sugars, polysaccharides, lactose, salts, buffers, lipids,
cholesterol, fatty acids, and combinations thereof.
[0017] As described above, the formulation contains trospium. The
formulation can consist of or consist essentially of trospium or a
salt thereof. In another embodiment, the formulations can contain
less than about 90%, 80%, 70%, 60%, 50%, 40%, 30% or 20% by weight
trospium. In a preferred embodiment, the formulation contains less
than about 10% by weight of trospium. In another preferred
embodiment, the formulations contain about 1% to 25% by weight
trospium and even more preferably about 4% to 16% by weight
tropsium.
[0018] A preferred composition consists essentially of a
formulation having about 5% by weight trospium hydrochloride;
between about 5 and 10% by weight of phospholipid and between about
85 and 90% by weight of leucine.
[0019] In one embodiment, the method further comprises the
administration of a second active agent. Preferred drugs for
coadministration are described in more detail in U.S. Ser. No.
10/392,333 incorporated herein by reference. A preferred active
agent is a beta-2 agonist, with formoterol and salneterol being
preferred.
[0020] The second active agent can be administered simultaneously
or separately from the trospium formulation. Where the second agent
is administered separately, it can be administered via inhalation
or other route, including without limitation enteral, such as oral,
and parenteral administrations, such as by injection.
[0021] Simultaneous administration via inhalation is, however,
preferred. The second active agent is advantageously incorporated
into the trospium formulation. This can be advantageously
accomplished by spray drying for example, a trospium and formoterol
containing mixture. These combination formulations can be those
described above wherein preferred doses of formoterol are in the
range of 1 to 15 micrograms per inhalation nominal dose delivered
to lung, and more preferably 2.5 to 5 micrograms per inhalation
nominal dose delivered to the lung. Loads of formoterol in spray
dried particles are preferably from 0.01% to 2% and more preferably
from about 0.05% to 0.4%. Ratios of trospium to formoterol in a
formulation are preferably in the range from about 10/1 to 1000/1
and more preferably from about 40/1 to 320/1.
[0022] In a preferred embodiment, the composition comprises a spray
dried formulation comprising trospium, formoterol, leucine and,
optionally, at least one phospholipid, the formulation having a low
tap density, as described herein, and a mean aerodynamic diameter
of between about 1 and 3 microns, and/or with a fine particle
fraction of at least about 50%.
[0023] The formulation is administered in an amount to provide the
desired dose of the active agent. Inherent in pulmonary delivery is
loss of some portion of the drug due to loss of some powder in the
inhaler, expiration of the drug by the patient, and other losses.
Thus, the amount of formulation loaded into the inhaler device can
depend upon the efficiency of the device for the formulation. This
amount can be calculated using methods known to the person of
ordinary skill in the art.
[0024] In accordance with the above, the invention also provides a
pharmaceutical kit comprising one or more compositions or
formulations in separate unit dosage forms, said forms being
suitable for administration of the drugs in effective amounts. Such
a kit can comprise one or more inhalation devices. For example, the
kit may comprise one or more dry powder inhalation (DPI) devices
adapted to deliver dry powder from a capsule, together with
capsules containing a dry powder. In another example, the kit may
comprise a multidose dry powder inhalation device containing in the
reservoir thereof formulations described herein. In a further
example, the kit may comprise a metered dose inhaler (MDI)
containing an aerosol in a propellant. In yet another example, the
kit may comprise a nebulizer inhalation device for delivering
aerosolized compositions described herein.
[0025] Dry powder formulations as described herein may be delivered
using any suitable dry powder inhaler (DPI), i.e., an inhaler
device that utilizes the patient's inhaled breath as a vehicle to
transport the dry powder drug to the lungs. Examples of suitable
inhalers include those of United States Patent Publication No.
2003/0150453, and in PCT publication WO 02/083220 which is hereby
incorporated by reference. Other examples include Inhale
Therapeutic Systems' dry powder inhalation devices as described in
Patton, J. S., et al., U.S. Pat. No. 5,458,135, Oct. 17, 1995;
Smith, A. E., et al., U.S. Pat. No. 5,740,794, Apr. 21, 1998; and
in Smith, A. E., et. al., U.S. Pat. No. 5,785,049, Jul. 28, 1998,
herein incorporated by reference. When administered using a device
of this type, the powdered medicament is contained in a receptacle
having a puncturable lid or other access surface, preferably a
blister package or cartridge, where the receptacle may contain a
single dosage unit or multiple dosage units. Convenient methods for
filling large numbers of cavities (i.e., unit dose packages) with
metered doses of dry powder medicament are described, e.g., in
Parks, D. J., et al., International Patent Publication WO 97/41031,
Nov. 6, 1997, incorporated herein by reference.
[0026] Other dry powder dispersion devices for pulmonary
administration of dry powders include those described, for example,
in Newell, R. E., et al, European Patent No. EP 129985, Sep. 7,
1988; in Hodson, P. D., et al., European Patent No. EP472598, Jul.
3, 1996; in Cocozza, S., et al., European Patent No. EP 467172,
Apr. 6, 1994, and in Lloyd, L. J. et al., U.S. Pat. No. 5,522,385,
Jun. 4, 1996, incorporated herein by reference. Also suitable for
delivering dry powder formulations described herein are inhalation
devices such as the Astra-Draco "TURBUHALER". This type of device
is described in detail in Virtanen, R., U.S. Pat. No. 4,668,218,
May 26, 1987; in Wetterlin, K., et al., U.S. Pat. No. 4,667,668,
May 26, 1987; and in Wetterlin, K., et al., U.S. Pat. No.
4,805,811, Feb. 21, 1989, all of which are incorporated herein by
reference. Other suitable devices include dry powder inhalers such
as Rotahaler.RTM..TM. (Glaxo), Discus.RTM..TM. (Glaxo), Spiros.TM.
inhaler (Dura Pharmaceuticals), and the Spinhaler.RTM..TM.
(Fisons). Also suitable are devices which employ the use of a
piston to provide air for either entraining powdered medicament,
lifting medicament from a carrier screen by passing air through the
screen, or mixing air with powder medicament in a mixing chamber
with subsequent introduction of the powder to the patient through
the mouthpiece of the device, such as described in Mulhauser, P.,
et al, U.S. Pat. No. 5,388,572, Sep. 30, 1997, incorporated herein
by reference.
[0027] Formulations described herein may also be delivered using a
pressurized, metered dose inhaler (MDI), e.g., the
Ventolin.RTM..TM. metered dose inhaler, containing a solution or
suspension of drug in a pharmaceutically inert liquid propellant,
e.g., a chlorofluorocarbon or fluorocarbon, as described in Laube,
et al., U.S. Pat. No. 5,320,094, Jun. 14, 1994, and in Rubsamen, R.
M., et al, U.S. Pat. No. 5,672,581 (1994), both incorporated herein
by reference.
[0028] Alternatively, the formulations described herein may be
dissolved or suspended in a solvent, e.g., water or saline, and
administered by nebulization. Nebulizers for delivering an
aerosolized solution include the AERx.TM. (Aradigm), the
Ultravent.RTM..TM. (Mallinkrodt), the Pari LC Plus.TM. or the Pari
LC Star.TM. (Pari GmbH, Germany), the DeVilbiss Pulmo-Aide, and the
Acorn II (Marquest Medical Products).
[0029] Treatment of inflammatory or obstructive airways diseases in
accordance with the invention may be symptomatic or prophylactic
treatment. Inflammatory or obstructive airways diseases to which
the present invention is applicable include asthma of whatever type
or genesis including both intrinsic (non-allergic) asthma and
extrinsic (allergic) asthma. Treatment of asthma is also to be
understood as embracing treatment of subjects, e.g. of less than 4
or 5 years of age, exhibiting wheezing symptoms and diagnosed or
diagnosable as "wheezy infants", an established patient category of
major medical concern and now often identified as incipient or
early-phase asthmatics. (For convenience this particular asthmatic
condition is referred to as "wheezy-infant syndrome".)
[0030] Prophylactic efficacy in the treatment of asthma will be
evidenced by reduced frequency or severity of symptomatic attack,
e.g. of acute asthmatic or bronchoconstrictor attack, improvement
in lung function or improved airways hyperreactivity. It may
further be evidenced by reduced requirement for other, symptomatic
therapy, i.e. therapy for or intended to restrict or abort
symptomatic attack when it occurs, for example anti-inflammatory
(e.g. corticosteroid) or bronchodilatory. Prophylactic benefit in
asthma may in particular be apparent in subjects prone to "morning
dipping". "Morning dipping" is a recognised asthmatic syndrome,
common to a substantial percentage of asthmatics and characterised
by asthma attack, e.g. between the hours of about 4 to 6 am, i.e.
at a time normally substantially distant form any previously
administered symptomatic asthma therapy.
[0031] Other inflammatory or obstructive airways diseases and
conditions to which the present invention is applicable include
acute lung injury (ALI), acute respiratory distress syndrome
(ARDS), chronic obstructive pulmonary, airways or lung disease
(COPD, COAD or COLD), including chronic bronchitis and emphysema,
bronchiectasis and exacerbation of airways hyperreactivity
consequent to other drug therapy, in particular other inhaled drug
therapy. Further inflammatory or obstructive airways diseases to
which the present invention is applicable include pneumoconiosis
(an inflammatory, commonly occupational, disease of the lungs,
frequently accompanied by airways obstruction, whether chronic or
acute, and occasioned by repeated inhalation of dusts) of whatever
type or genesis, including, for example, aluminosis, anthracosis,
asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis
and byssinosis
EXAMPLES
Example 1
Preparation of Trospium Chloride (TrCl) Particle Formulations
[0032] Particle formulations, as listed in Table 1, where prepared
by spray drying. Pre-spray drying solutions were prepared as
follows. Particle components were dissolved in appropriate solvents
to assure solubility. Table 2 lists the mass of each particle
component dissolved in each respective solvent. Leucine was
dissolved in 300 mL of water. TrCl was subsequently dissolved in
the aqueous solution. DPPC and/or DSPC were dissolved in 700 mL of
ethanol, to form an organic phase. Both solutions were then heated
separately to 50.degree. C.
[0033] Phospholipids (dipalmitoyl phosphatidylcholine (DPPC) and
distearoyl phosphatidylcholine (DSPC)) were obtained from Avanti
Polar Lipids, Inc. (Alabaster, Ala.). TrCl was obtained from
Boeringer Ingelheim and leucine was obtained from Spectrum Quality
Products, Inc. (Gardena, Calif.).
[0034] The aqueous phase was then static mixed with the organic
phase and then spray dried to produce dry powders. A Niro Size 1
Spray Dryer (Niro, Inc., Columbus, Md.) was used with two-fluid
atomization using nitrogen as the atomization gas at 15 gr/min.
Liquid feed at a rate of 60 mL/min was pumped continuously by a
peristaltic pump to the atomizer. Dry nitrogen gas (100 kg/hr) was
used as the drying medium. Both the inlet and outlet temperatures
were measured. The inlet temperature was controlled manually and
was established at approximately 115.degree. C. Outlet temperature
is determined by such factors as the input temperature and the gas
and liquid feed rates, among others. The outlet temperature was
about 54.degree. C. A container was tightly attached to a cyclone
for collecting the powder product. Yield was determined by
comparing final total powder produced and dividing by the total
starting solids of 1 gram. Yields for formulations A, B and C were
50%, 64% and 50%, respectively. TABLE-US-00001 TABLE 1 Formulations
Formulation Composition (weight percent) A Leucine (90%); DPPC
(5%); Trospium (5%) B Leucine (85%); DPPC (10%); Trospium (5%) C
Leucine (855); DPPC (5%); DSPC (5%); Trospium (5%)
[0035] TABLE-US-00002 TABLE 2 Pre-Spray Drying Solution Composition
Ethanol Solution Aqueous Solution Components Components 700 ml 300
ml Formulation DPPC DSPC Leucine TrCl A 50 mg -- 900 mg 50 mg B 100
mg -- 850 mg 50 mg C 50 mg 50 mg 850 mg 50 mg
Example 2
[0036] The Fine Particle Fraction (FPF), volumetric median
geometric diameter, and actual trospium content of the particles
produced in Example 1 were determined.
[0037] The content of trospium chloride in the AIR-Trospium
formulations was determined via HPLC using a Waters HPLC system
equipped with a PDA detector as shown in Table 3. AIR-Trospium
formulations were targeted to have a content of 5% trospium
chloride. TABLE-US-00003 TABLE 3 AIR-Trospium content analysis
parameters. Column Alltech Alltima C18 (250-4.6 mm) Dissolving
Solvent 90% MeOH, 10% 0.01 N HCl Detection Wavelength 265 nm
Injection Volume 10 uL Flow Rate 1 mL/min Mobile Phase 60/40 (0.05%
TFA in Water/ 0.05% TFA in ACN) Run Time 10 min. Relative Retention
Time 6.0 min.
[0038] The volumetric median geometric diameter (VMGD) of the
particles was measured using a RODOS dry powder disperser
(Sympatec, Princeton, N.J.) in conjunction with a HELOS laser
diffractometer (Sympatec). Powder was introduced into the RODOS
inlet and aerosolized by shear forces generated by a compressed air
stream regulated at 1 bar. The aerosol cloud was subsequently drawn
into the measuring zone of the HELOS, where it scattered light from
a laser beam and produced a Fraunhofer diffraction pattern used to
infer the particle size distribution and determine the median
value.
[0039] Fine Particle Fractions (FPF) below 5.6 and 3.4 microns were
obtained via cascade impaction (2-stage system utilizing
gravimetric analysis). Capsule loadings of approximately 5 mg were
utilized. The AIR-1 inhaler was used for these experiments. A flow
rate of 60.+-.1.0 LPM was run for 2 seconds to obtain an overall
air volume of 2 L.
[0040] Volumetric median geometric diameter, FPF<3.4,
FPF<5.6, and actual TrCl content for each of the formulations
produced in Example 1 are shown in Table 3 below. The powders
produced are respirable, as indicated by the physical
characteristics of the powders shown in Table 4. TABLE-US-00004
TABLE 4 Particle Characterization Data FPF Actual TrCl VGMD <3.4
microns FPF <5.6 Content Formulation (microns) (%) microns (%)
(%) A 8.64 58.7 78.6 4.6 B 8.23 55.6 79.9 4.8 C 7.07 53.4 75.4
4.6
Evaluation of Broncoprotection Over Time in a Guinea Pig Model of
Airway Bronchoconstriction
[0041] The purpose of this study was to establish a dose-response
curve for the anti-cholinergic Trospium chloride (TrCl) in a guinea
pig model of airway hyperresponsiveness. Ipratropium bromide
(IpBr), a similar acting anticholinergic drug currently
commercially available for use in the treatment of asthma and COPD,
was used as a comparator. Guinea pigs were intratracheally
instilled with either dry powder or aqueous TrCl or acqueous IpBr
at varying concentrations (1-50 .mu.g for TrCl; 0.1-5.0 .mu.g for
IpBr). Changes in airway responsiveness to nebulized methacholine
(Mch) (1,000 .mu.g/mL) were measured using a BUXCO non-invasive
plethysmography system. Assessment of airway resistance to
methacholine was performed prior to treatment (baseline) and at 2,
6, 10, 14, 24 and 42 hours post-treatment with either IpBr or TrCl.
The enhanced pause (PenH), a surrogate measure of
bronchoconstriction in the BUXCO system, was used as the biomarker
of response in this study. An increase in this value indicates
increased airway resistance; prevention of this increase in
response to methacholine is indicative of bronchoprotection. The
Guinea Pig (GP) Mch-induced bronchoconstriction provides a useful
model that can differentiate between short- and long-acting
bronchodilatory molecules. In addition, this model is a valuable
screening tool for formulation comparisons including dry powders
and aqueous solutions containing TrCl.
[0042] Animals were administered the test compound in a dry powder
formulation (or liquid formulation) using an intratracheal
insufflation technique with a Penn Century (Philadelphia, Pa.)
insufflation device. Briefly, animals were anesthetized prior to
treatment and the tip of the insufflation device is placed into the
trachea about 1 cm above the carina. Actuation of the insufflation
device delivers an aerosol bolus of the test formulation that
deposits throughout the airways and lung parenchyma while avoiding
deposition losses in the oropharyngeal region. Respirable liquid
aerosols containing bronchodilatory API were delivered using a
liquid insuffiation device (Penn Century).
[0043] The degree and duration of bronchoprotection is evaluated at
discrete timepoints in individual animals using a non-invasive
BUXCO Whole Body Plethysmography system (BUXCO Electronics, Inc.
Sharon, Conn.). Briefly, a flow transducer detects pressure/volume
changes within a whole-body plethysmography chamber, which the
BUXCO software subsequently translates into pulmonary function
parameters including a surrogate measure of airway resistance
referred to as PenH, or "enhanced pause". The lower the PenH value
at a given timepoint, the greater the bronchoprotection offered by
the API.
[0044] Bronchoprotection in individual animals was assessed
following challenge with Mch aerosol at discrete timepoints
following API treatment compared to a pre-treatment baseline Mch
challenge. The Mch challenge protocol at each timepoint consists of
three parts: 1) 10 minutes of acclimatization in the whole-body
plethysmograph; during this time, the animals typically develop a
quiescent breathing pattern and a comfortable posture; 2) A
nebulized aerosol of saline (vehicle control) is delivered for 30
seconds and pulmonary function is assessed for 15 minutes; and 3) A
nebulized Mch aerosol is delivered for 30 seconds and pulmonary
function is assessed for 15 minutes. The 15 minute assessment
period following Mch challenge allows observation of the complete
timecourse of the baseline bronchoconstrictive response; following
Mch challenge, peak PenH values occur between 4 and 9 minutes with
a subsequent return to pre-challenge PenH levels by 15 minutes
post-challenge. At each individual timepoint, the degree of
bronchoprotection was measured as the mean peak PenH values (4-9
minutes).
[0045] Data from any individual test animal was excluded if any of
the following conditions are met: 1) Rarely, during insufflation,
the insufflation needle damages the trachea causing an injury that
causes PenH to be elevated ("IJ"); 2) if an animal never exhibits
any bronchoprotection from bronchoprovocative challenge, it is
assumed dosing was missed (DM); 3) At any point during the study
prior to recovery (.gtoreq.24 hours), the animal expires ("EX"); 4)
Following treatment, the animal has a response to methacholine much
greater than that measured prior to treatment at any timepoint
(>200% of the Pre-Treatment bronchoconstrictive response;
"Hyperresponder, HR"); 5) At a timepoint where no further
bronchoprotective effects would be expected (>>24 hours), an
animal exhibits little or no response to methacholine (<40% of
original response; "Non-Responder (NR)"). In addition, animals that
provide little or no initial response to nebulized methacholine
during baseline assessment are excluded from the study.
Trospium Chloride Dose-Response Assessment
[0046] Guinea pigs were delivered aqueous trospium chloride at
increasing doses (range
[0047] =1.0-50.0 pg TrCl) using the Penn Century liquid
insuffiation device. Bronchoprotection from Mch-induced
bronchoconstriction was assessed at 2, 6, 10, 14, and 24 hours
following TrCl treatment and compared to the pre-TrCl treatment
baseline Mch response. Aqueous ipratropium bromide (IpBr) was used
as a control comparator at multiple doses (range=0.1-5.0 mcg).
Doses of each compound are shown in Table 5. TABLE-US-00005 TABLE 5
Dose (mcg) IpBr TrCl 0.1 X 0.5 X 1.0 X X 2.0 X 3.5 X 5.0 X X 10.0 X
50.0 X
[0048] FIGS. 1a and 1b show the percent (%) baseline PenH over time
following treatment at varying doses of aqueous IpBr (FIG. 1a) and
aqueous TrCl (FIG. 1b). Each line represents a group of animals
treated with a single dose of IpBr or TrCl. Each data point within
the line represents the mean % baseline PenH of the treatment group
(assessed as the peak PenH response from minutes 4-9 following Mch
challenge at each timepoint).
[0049] FIG. 2 shows the percent (%) baseline PenH over time
following treatment at equal nominal 5 mg doses of aqueous IpBr or
aqueous TrCl. Each data point within the line represents the mean %
baseline PenH of the treatment group (assessed as the peak PenH
response from minutes 4-9 following Mch challenge at each
timepoint). As shown in FIG. 2, the aqueous TrCl provided
significantly more broncoprotection as compared to aqueous
IpBr.
AIR Trospium Chloride Formulations Compared to Aqueous TrCl at
Equal Doses (1 gmc)
[0050] Three powder TrCl formulations were produced for in vivo
study as described in Examples 1 and 2. The three powder TrCl
formulations were: 1) TrCl/Leu/DPPC (5/90/5); 2) TrCl/Leu/DPPC
(5/85/10); and 3) TrCl/Leu/DSPC/DPPC (5/85/5/5). Guinea pigs were
insufflated with aqueous TrCl or one of three powder TrCl
formulations at an equal nominal dose of 1 mcg API.
Bronchoprotection from Mch-induced bronchoconstriction was assessed
at 2, 12, 16, 20, and 24 hours following TrCl treatment and
compared to the pre-TrCl treatment baseline Mch response.
[0051] FIG. 3 shows the percent (%) baseline PenH over time
following treatment with aqueous TrCl or AIR-TrCl at a nominal dose
of 1 mcg API. Each line represents a group of animals treated with
a single dose of TrCl. Each data point within the line represents
the mean % baseline PenH of the entire treatment group (assessed as
the peak PenH response from minutes 4-9 following Mch challenge at
each timepoint. As shown in FIG. 3, while all formulations provided
broncoprotection, the dry powder TrCl formulations provided even
greater protection as compared to the aqueous TrCl formulation.
[0052] While this invention has been particularly shown and
described with references to preferred embodiments thereof, it will
be understood by those skilled in the art that various changes in
form and details may be made therein without departing from the
scope of the invention encompassed by the appended claims.
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