U.S. patent application number 12/921892 was filed with the patent office on 2011-01-27 for novel dosage and formulation.
Invention is credited to Rosa LAMARCA CASADO.
Application Number | 20110020454 12/921892 |
Document ID | / |
Family ID | 39581534 |
Filed Date | 2011-01-27 |
United States Patent
Application |
20110020454 |
Kind Code |
A1 |
LAMARCA CASADO; Rosa |
January 27, 2011 |
NOVEL DOSAGE AND FORMULATION
Abstract
The present disclosure relates to pharmaceutical compositions
for inhalation comprising aclidinium in the form of a dry powder of
a pharmaceutically acceptable salt in admixture with a
pharmaceutically acceptable dry powder carrier, providing a metered
nominal dose of aclidinium equivalent to about 200 micrograms
aclidinium bromide.
Inventors: |
LAMARCA CASADO; Rosa;
(Barcelona, ES) |
Correspondence
Address: |
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER;LLP
901 NEW YORK AVENUE, NW
WASHINGTON
DC
20001-4413
US
|
Family ID: |
39581534 |
Appl. No.: |
12/921892 |
Filed: |
March 13, 2009 |
PCT Filed: |
March 13, 2009 |
PCT NO: |
PCT/EP09/01831 |
371 Date: |
September 10, 2010 |
Current U.S.
Class: |
424/489 ;
128/203.15; 514/171; 514/305 |
Current CPC
Class: |
A61K 31/58 20130101;
A61K 31/58 20130101; A61K 31/439 20130101; A61K 9/0073 20130101;
A61P 11/08 20180101; A61K 31/439 20130101; A61K 45/06 20130101;
A61K 9/0075 20130101; A61K 31/167 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61P 43/00 20180101;
A61P 11/06 20180101; A61P 11/00 20180101; A61K 31/46 20130101; A61K
31/167 20130101; A61M 15/0065 20130101 |
Class at
Publication: |
424/489 ;
514/305; 514/171; 128/203.15 |
International
Class: |
A61K 9/14 20060101
A61K009/14; A61K 31/439 20060101 A61K031/439; A61K 31/56 20060101
A61K031/56; A61K 31/58 20060101 A61K031/58; A61P 11/06 20060101
A61P011/06; A61P 11/00 20060101 A61P011/00; A61M 15/00 20060101
A61M015/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 13, 2008 |
EP |
08382009.2 |
Claims
1. A pharmaceutical composition comprising aclidinium in the form
of a dry powder of a pharmaceutically acceptable salt in admixture
with a pharmaceutically acceptable dry powder carrier, wherein the
pharmaceutical composition is capable of providing a metered
nominal dose of aclidinium equivalent to about 200 micrograms
aclidinium bromide, wherein the pharmaceutical composition is for
inhalation.
2. The pharmaceutical composition according to claim 1, in the form
of a single-dose dry powder formulation comprising a single metered
nominal dose of aclidinium equivalent to about 200 micrograms
aclidinium bromide.
3. The pharmaceutical composition according to claim 1, in the form
of a multi-dose dry powder formulation for administration in a
multidose dry powder inhaler device calibrated to provide a metered
nominal dose of aclidinium equivalent to about 200 micrograms
aclidinium bromide.
4. The pharmaceutical composition according to claim 1, wherein the
pharmaceutically acceptable salt of aclidinium is aclidinium
bromide.
5. The pharmaceutical composition according to claim 1, wherein the
pharmaceutically acceptable carrier is lactose particles.
6. The pharmaceutical composition according to claim 1, wherein the
ratio aclidinium to carrier ranges from 1:50 to 1:150 by
weight.
7. The pharmaceutical composition according to claim 6, wherein the
ratio of aclidinium to carrier ranges from 1:100 to 1:150 by
weight.
8. The pharmaceutical composition according to claim 1, wherein the
average particle diameter of aclidinium ranges from 2 .mu.m to 5
.mu.m.
9. The pharmaceutical composition according to claim 1, wherein the
carrier comprises particles having a d10 ranging from 90 .mu.m to
160 .mu.m, a d50 ranging from 170 .mu.m to 270 .mu.m, and d90
ranging from 290 .mu.m to 400 .mu.m.
10. The pharmaceutical composition according to claim 1, further
comprising an effective amount of at least one additional active
agent chosen from .beta.2-agonists, PDE IV inhibitors, and
corticosteroids.
11. The pharmaceutical composition according to claim 10, wherein
the at least one additional active agent is chosen from formoterol,
salmeterol, budesonide, and mometasone, wherein the at least one
additional active agent is in free or pharmaceutically acceptable
salt form.
12. The pharmaceutical composition according to claim 11, wherein
the at least one additional active agent is formoterol fumarate in
an amount ranging from about 5 micrograms to 25 micrograms per
metered nominal dose.
13. The pharmaceutical composition according to claim 11, wherein
the at least one additional active agent is mometasone furoate in
an amount ranging from about 100 micrograms to 900 micrograms per
metered nominal dose.
14. A method of treating a respiratory condition chosen from asthma
and chronic obstructive pulmonary disease, comprising administering
a dose of aclidinium equivalent to about 200 micrograms metered
nominal dose of aclidinium bromide by inhalation to a patient in
need of such treatment.
15. (canceled)
16. The method of claim 14, comprising administering a
pharmaceutical composition-comprising aclidinium in the form of a
dry powder of a pharmaceutically acceptable salt in admixture with
a pharmaceutically acceptable dry powder carrier, wherein the
pharmaceutical composition is administered in a metered nominal
dose of aclidinium equivalent to about 200 micrograms aclidinium
bromide.
17. The method of claim 16, further comprising administering an
effective amount of at least one additional active agent chosen
from .beta.2-agonists, PDE IV inhibitors, and corticosteroids.
18. The method of claim 17, wherein the at least one additional
active agent is chosen from formoterol, salmeterol, budesonide, and
mometasone in free or pharmaceutically acceptable salt form.
19. The method according to claim 18, wherein the at least one
additional active agent is formoterol fumarate in an amount ranging
from about 5 micrograms to 25 micrograms per metered nominal
dose.
20. The method according to claim 18, wherein the at least one
additional active agent is mometasone furoate in an amount ranging
from about 100 micrograms to 900 micrograms per metered nominal
dose.
21-25. (canceled)
26. A multidose dry powder inhaler device calibrated to deliver,
upon actuation, a metered nominal dose of aclidinium equivalent to
about 200 micrograms of aclidinium bromide.
27. The method of claim 14, wherein the dose is chosen from a
single-daily dose and a twice-daily dose of aclidinium equivalent
to about 200 micrograms metered nominal dose of aclidinium
bromide.
28. The method of claim 27, wherein the dose is chosen from a
single-daily dose of aclidinium equivalent to about 200 micrograms
metered nominal dose of aclidinium bromide.
Description
[0001] This invention relates to a novel dosage for aclidinium and
to novel methods and formulations for the treatment of respiratory
diseases, especially asthma and chronic obstructive pulmonary
disease (COPD), using aclidinium.
BACKGROUND
[0002] Aclidinium bromide is
3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicy-
clo [2.2.2]octane bromide, described in, e.g., WO 0104118. Although
this compound is known to be a long-acting anticholinergic useful
in the treatment of respiratory diseases, the optimal dosage is not
disclosed.
SUMMARY OF THE INVENTION
[0003] It is now surprisingly found that, for treatment of
respiratory disorders, particularly asthma and COPD, in an adult
human, aclidinium is most effective upon administration by
inhalation in a dosage of about 200 micrograms per metered nominal
dose, typically a single dosage of about 200 micrograms per day
metered nominal dose, (e.g., about 180 micrograms emitted dose, and
about 60 micrograms Fine Particle dose) (weight corresponding to
aclidinium bromide).
[0004] The invention thus provides in a first embodiment a
pharmaceutical composition for inhalation comprising aclidinium in
the form of a dry powder of a pharmaceutically acceptable salt,
e.g., aclidinium bromide, in admixture with a pharmaceutically
acceptable dry powder carrier, e.g., lactose particles, (i)
comprising a single metered nominal dose of aclidinium equivalent
to about 200 micrograms aclidinium bromide, or (ii) in a multidose
dry powder inhaler device calibrated to provide a metered nominal
dose of aclidinium equivalent to about 200 micrograms aclidinium
bromide. This composition can be administered one or more times per
day. Preferably once or twice a day.
[0005] In a second embodiment, the invention provides a method of
treating a respiratory condition, e.g., selected from asthma and
chronic obstructive pulmonary disease, in a patient in need of such
treatment, comprising administering a dose, typically a single
daily dose or twice daily dose, of aclidinium, e.g., aclidinium
bromide, equivalent to about 200 micrograms metered nominal dose
aclidinium bromide, e.g., comprising administering a pharmaceutical
composition according to the previous paragraph. The invention
further provides the use of aclidinium in the manufacture of a
medicament, e.g., as described in the preceding paragraph, for use
in such a method.
[0006] The aclidinium may be administered as monotherapy, or in
combination with one or more additional anti-inflammatory and/or
bronchodilating agents, e.g., corticosteroids, PDE IV inhibitors
and .beta.2-agonists, e.g., formoterol, salmeterol, budesonide, and
mometasone, and the invention thus further provides methods as
described above further comprising administration of an effective
amount of such an agent, as well as pharmaceutical compositions as
described above, further comprising such additional agent(s).
DETAILED DESCRIPTION OF THE INVENTION
[0007] Typically, the aclidinium is administered in the form of a
salt with an anion X, wherein X is a pharmaceutically acceptable
anion of a mono or polyvalent acid. More typically, X is an anion
derived from an inorganic acid, such as hydrochloric acid,
hydrobromic acid, sulphuric acid and phosphoric acid, or an organic
acid such as methanesulphonic acid, acetic acid, fumaric acid,
succinic acid, lactic acid, citric acid or maleic acid. Preferably
the aclidinium is in the form of aclidinium bromide.
[0008] The aclidinium is preferably administered in the form of a
dry powder, in admixture with a suitable carrier, e.g., lactose
powder, suitable for inhalation.
[0009] For example, in one embodiment, the aclidinium is aclidinium
bromide in admixture with lactose powder.
[0010] The respiratory disease or condition to be treated with the
formulations and methods of the present invention is typically
asthma, acute or chronic bronchitis, emphysema, chronic obstructive
pulmonary disease (COPD), bronchial hyperreactivity or rhinitis, in
particular asthma or chronic obstructive pulmonary disease (COPD),
especially COPD.
[0011] In the context of dosage of an active agent, "about" as used
herein means within the normal limits of acceptable variations as
defined by the European and US Pharmacopeia of plus/minus 35% or
preferably acceptable variations as defined by the current most
stringent requirement, the US FDA draft guidance for inhaler of
plus/minus 25% or especially within the metered dosing accuracy for
the dispensing system e.g. +/-10% Thus a metered nominal dose of
"about 200 micrograms" is meant a target dose of 200 micrograms
subject to variation within the normal limits of acceptance for the
dispensing system, e.g. plus/minus 35% (acceptable variations as
defined by the European and US Pharmacopeia) or preferably 150-250
micrograms (or acceptable variations as defined by the current most
stringent requirement, the US FDA draft guidance for inhaler) or
especially 170-230 micrograms (or within the metered dosing
accuracy of the inhaler).
[0012] The emitted dose and the fine particle dose (fine particle
dose=micrograms aclidinium bromide in the emitted dose below a cut
off aerodynamic threshold of 5 micrometer) are subjected to the
same variation and proportional to the metered dose and are
therefore for the emitted dose e.g. a metered nominal dose of about
200 micrograms (plus/minus 35%) corresponds to about 180 micrograms
emitted dose (plus/minus 35%), and about 60 micrograms Fine
Particle dose (plus/minus 35%)
[0013] Packaging of the formulation may be suitable for unit dose
or multi-dose delivery. In the case of multi-dose delivery, the
formulation can be pre-metered or metered in use. Dry powder
inhalers are thus classified into three groups: (a) single dose,
(b) multiple unit dose and (c) multi dose devices.
[0014] Formulations generally contain a powder mix for inhalation
of the compounds of the invention and a suitable powder base
(carrier substance) such as lactose or starch. Use of lactose is
preferred. Each capsule or cartridge may generally contain between
2 .mu.g and 400 .mu.g of each therapeutically active ingredient.
Alternatively, the active ingredient (s) may be presented without
excipients.
[0015] For single dose inhalers of the first type, single doses
have been weighed by the manufacturer into small containers, which
are mostly hard gelatine capsules. A capsule has to be taken from a
separate box or container and inserted into a receptacle area of
the inhaler. Next, the capsule has to be opened or perforated with
pins or cutting blades in order to allow part of the inspiratory
air stream to pass through the capsule for powder entrainment or to
discharge the powder from the capsule through these perforations by
means of centrifugal force during inhalation. After inhalation, the
emptied capsule has to be removed from the inhaler again. Mostly,
disassembling of the inhaler is necessary for inserting and
removing the capsule, which is an operation that can be difficult
and burdensome for some patients. Other drawbacks related to the
use of hard gelatine capsules for inhalation powders are (a) poor
protection against moisture uptake from the ambient air, (b)
problems with opening or perforation after the capsules have been
exposed previously to extreme relative humidity, which causes
fragmentation or indenture, and (c) possible inhalation of capsule
fragments. Moreover, for a number of capsule inhalers, incomplete
expulsion has been reported.
[0016] Some capsule inhalers have a magazine from which individual
capsules can be transferred to a receiving chamber, in which
perforation and emptying takes place, as described in WO 92/03175.
Other capsule inhalers have revolving magazines with capsule
chambers that can be brought in line with the air conduit for dose
discharge (e. g. W091/02558 and GB 2242134). They comprise the type
of multiple unit dose inhalers together with blister inhalers,
which have a limited number of unit doses in supply on a disk or on
a strip.
[0017] Blister inhalers provide better moisture protection of the
medicament than capsule inhalers. Access to the powder is obtained
by perforating the cover as well as the blister foil, or by peeling
off the cover foil. When a blister strip is used instead of a disk,
the number of doses can be increased, but it is inconvenient for
the patient to replace an empty strip. Therefore, such devices are
often disposable with the incorporated dose system, including the
technique used to transport the strip and open the blister
pockets.
[0018] Multi-dose inhalers do not contain pre-measured quantities
of the powder formulation. They consist of a relatively large
container and a dose measuring principle that has to be operated by
the patient. The container bears multiple doses that are isolated
individually from the bulk of powder by volumetric displacement.
Various dose measuring principles exist, including rotatable
membranes (e. g. EP0069715) or disks (e. g. GB 2041763; EP 0424790;
DE 4239402 and EP 0674533), rotatable cylinders (e. g. EP 0166294;
GB 2165159 and WO 92/09322) and rotatable frustums (e. g. WO
92/00771), all having cavities which have to be filled with powder
from the container. Other multi dose devices have measuring slides
(e.g. US 5201308 and WO 97/00703) or measuring plungers with a
local or circumferential recess to displace a certain volume of
powder from the container to a delivery chamber or an air conduit
e. g. EP 0505321, WO 92/04068 and WO 92/04928.
[0019] Reproducible dose measuring is one of the major concerns for
multi dose inhaler devices. The powder formulation has to exhibit
good and stable flow properties, because filling of the dose
measuring cups or cavities is mostly under the influence of the
force of gravity. For reloaded single dose and multiple unit dose
inhalers, the dose measuring accuracy and reproducibility can be
guaranteed by the manufacturer. Multi dose inhalers on the other
hand, can contain a much higher number of doses, whereas the number
of handlings to prime a dose is generally lower.
[0020] Because the inspiratory air stream in multi-dose devices is
often straight across the dose measuring cavity, and because the
massive and rigid dose measuring systems of multi dose inhalers can
not be agitated by this inspiratory air stream, the powder mass is
simply entrained from the cavity and little de-agglomeration is
obtained during discharge.
[0021] Consequently, separate disintegration means are necessary.
However in practice, they are not always part of the inhaler
design. Because of the high number of doses in multi-dose devices,
powder adhesion onto the inner walls of the air conduits and the
de-agglomeration means must be minimized and/or regular cleaning of
these parts must be possible, without affecting the residual doses
in the device. Some multi dose inhalers have disposable drug
containers that can be replaced after the prescribed number of
doses has been taken (e. g. WO 97/000703). For such semi-permanent
multi dose inhalers with disposable drug containers, the
requirements to prevent drug accumulation are even stricter.
[0022] In a preferred embodiment, the aclidinium is administered
via a breath-activated, multidose, dry powder inhaler, calibrated
to permit daily dosing of 200 micrograms metered nominal dose of
aclidinium. An especially preferred inhaler device for this purpose
is Genuair.RTM., (formerly known as Novolizer SD2FL), or as
described in WO 97/000703, WO 03/000325, or WO 03/061742, the
contents of which applications are incorporated herein by
reference.
[0023] Apart from applications through dry powder inhalers the
compositions of the invention can be administered in aerosols which
operate via propellant gases or by means of so-called atomisers or
nebulizers, via which solutions or suspensions of
pharmacologically-active substances can be sprayed under high
pressure so that a mist of inhalable particles results.
[0024] Medicaments for administration by inhalation desirably have
a controlled particle size. The optimum particle size for
inhalation into the bronchial system is usually 1-10 .mu.m,
preferably 2-5 .mu.m. Particles having a size above 20.mu. are
generally too large when inhaled to reach the small airways. To
achieve these particle sizes the particles of the active ingredient
as produced may be size reduced by conventional means eg by
micronisation or supercritical fluid techniques. The desired
fraction may be separated out by air classification or sieving.
Preferably, the particles will be crystalline.
[0025] Achieving a high dose reproducibility with micronised
powders is difficult because of their poor flowability and extreme
agglomeration tendency. To improve the efficiency of dry powder
compositions, the particles should be large while in the inhaler,
but small when discharged into the respiratory tract. Thus, an
excipient, for example a mono-, di- or polysaccharide or sugar
alcohol, e.g., such as lactose, mannitol or glucose is generally
employed. The particle size of the excipient will usually be much
greater than the inhaled medicament within the present invention.
When the excipient is lactose it will typically be present as
lactose particles, preferably crystalline alpha lactose
monohydrate, e.g., having an average particle size range of 20-1000
.mu.m, preferably in the range of 90-150 .mu.m. The median particle
size approximately corresponds to the average and is the diameter
where 50 mass-% of the particles have a larger equivalent diameter,
and the other 50 mass-% have a smaller equivalent diameter. Hence
the average particle size is generally referred to in the art as
equivalent d50. The distribution of particle size around may affect
flow properties, bulk density, etc. Hence to characterize a
particle size diameter, other equivalent diameters can be used in
addition to d50, such as d10 and d90. d10 is the equivalent
diameter where 10 mass-% of the particles have a smaller diameter
(and hence the remaining 90% is coarser). d90 is the equivalent
diameter where 90 mass-% of the particles have a smaller diameter.
In one embodiment, the lactose particles for use in formulations of
the invention have a d10 of 90-160 .mu.m, a d50 of 170-270 .mu.m,
and d90 of 290-400 .mu.m.
[0026] Suitable lactose materials for use in the present invention
are commercially available, e.g., from DMW Internacional (Respitose
GR-001, Respitose SV-001, Respitose SV-003); Meggle (Capsulac 60,
Inhalac 70, Capsulac 60 INH); and Borculo Domo (Lactohale 100-200,
Lactohale 200-300, and Lactohale 100-300).
[0027] The ratio between the lactose particles and the aclidinium
by weight will depend on the inhaler device used, but is typically,
e.g., 5:1 to 200:1, for example 50:1 to 150:1, e.g., 60-70:1.
[0028] In a preferred embodiment, the aclidinium is administered in
the form of a dry powder formulation of aclidinium bromide in
admixture with lactose, in a ratio by weight of aclidinium to
lactose of 1:100 to 1:150, suitable for administration via a dry
powder inhaler, wherein the aclidinium particles have an average
particle size of from 2 to 5 .mu.m in diameter, e.g., less than 3
.mu.m in diameter, and the lactose particles have have a d10 of
90-160 .mu.m, a d50 of 170-270 .mu.m, and d90 of 290-400 .mu.m.
[0029] Additional active agents such as .beta.2-agonists, PDE IV
inhibitors, corticosteroids, leukotriene D4 antagonists, inhibitors
of egfr-kinase, p38 kinase inhibitors or NK1 receptor agonists may
be utilized in the methods and formulations of the inventions. For
example, the invention provides aclidinium formulations as
described herein further comprising an effective amount of one or
more such additional active agents, e.g. further comprising an
effective amount of a .beta.2-agonist and/or a PDE IV inhibitor
and/or a corticosteroid. The invention also provides methods for
treating respiratory conditions as herein before described, e.g.,
asthma or COPD, comprising administering an aclidinium formulation
as described herein and further comprising administering
simultaneously effective amount of one or more such additional
active agents, e.g.
[0030] further comprising an effective amount of a .beta.2-agonist
and/or a PDE IV inhibitor and/or a corticosteroid.
[0031] .beta.2-agonists suitable for use with the aclidinium in the
present invention include, e.g., arformoterol, bambuterol,
bitolterol, broxaterol, carbuterol, clenbuterol, dopexamine,
fenoterol, formoterol, hexoprenaline, ibuterol, isoetharine,
isoprenaline, levosalbutamol, mabuterol, meluadrine,
metaprotenerol, nolomirole, orciprenaline, pirbuterol, procaterol,
reproterol, ritodrine, rimoterol, salbutamol, salmefamol,
salmeterol, sibenadet, sotenerot, sulfonterol, terbutaline,
tiaramide, tulobuterol, GSK-597901, milveterol, GSK-678007,
GSK-642444, GSK-159802, LAS100977
(5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)-hydroxyethyl)-8--
hydroxyquinolin-2(1H)-one), HOKU-81, KUL-1248, carmoterol,
indacaterol and
5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-
-one, 4-hydroxy-7[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}
ethyl]amino}ethyl]-2(3H)-benzothiazolone,
1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamin-
o]ethanol,
1-[3-(4-methoxybenzylamino)-4-hydroxyphenyl]-2-[4-(1-benzimidaz-
olyl)-2-methyl-2-butylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N
-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-me-
thyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-
-methyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1-
,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,
5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-on-
e, 1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert
-butylamino)ethanol and
1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)e-
thanol optionally in the form of their racemates, their
enantiomers, their diastereomers, and mixtures thereof, and
optionally their pharmacologically-compatible acid addition
salts.
[0032] The preferred .beta.2-agonists to be used in the
combinations of the invention are: arformoterol, bambuterol,
bitolterol, broxaterol, carbuterol, clenbuterol, dopexamine,
fenoterol, formoterol, hexoprenaline, ibuterol, isoprenaline,
levosalbutamol, mabuterol, meluadrine, nolomirole, orciprenaline,
pirbuterol, procaterol, (R,R)-formoterol, reproterol, ritodrine,
rimoterol, salbutamol, salmeterol, sibenadet, sulfonterol,
terbutaline, tulobuterol, GSK-597901, milveterol, LAS100977
(5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)
-hydroxyethyl)-8-hydroxyquinolin-2(1 H)-one) , KUL-1248, carmoterol
and indacaterol optionally in the form of their racemates, their
enantiomers, their diastereomers, and mixtures thereof, and
optionally their pharmacologically-compatible acid addition
salts.
[0033] Since the M3 antagonists of the invention have a long
duration of action, it is preferred that they are combined with
long-acting .beta.2-agonists (also known as LABAs). The combined
drugs could thus be administered once or twice a day.
[0034] Particularly preferred LABAs are formoterol, salmeterol and
GSK-597901, milveterol, LAS100977
(5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)-hydroxyethyl)-8--
hydroxyquinolin-2(1H)-one), KUL-1248, carmoterol and indacaterol
optionally in the form of their racemates, their enantiomers, their
diastereomers and mixtures thereof, and optionally their
pharmacologically-compatible acid addition salts. More preferred
are salmeterol, formoterol, LAS 100977
(5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)
-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one), and QAB-149. Still
more preferred are salmeterol, formoterol and LAS100977
(5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)-hydroxyethyl)-8--
hydroxyquinolin-2(1H)-one), in particular salmeterol xinafoate and
formoterol fumarate and LAS100977
(5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)-hydroxyethyl)-8--
hydroxyquinolin-2(1H)-one).
[0035] For example, the invention provides a pharmaceutical
composition for inhalation comprising aclidinium in the form of a
dry powder of a pharmaceutically acceptable salt, e.g., bromide, in
admixture with a pharmaceutically acceptable carrier, e.g., lactose
particles, together with formoterol fumarate, (i) comprising a
single metered nominal dose of aclidinium equivalent to about 200
micrograms aclidinium bromide together with a single metered
nominal dose of about 5-25 micrograms (e.g. 6, 8.5, 12, 18 or 24
micrograms, for example 12 micrograms) formoterol fumarate or (ii)
in a multidose dry powder inhaler device calibrated to provide a
metered nominal dose of aclidinium equivalent to about 200
micrograms aclidinium bromide together with a metered nominal dose
of about 5-25 micrograms (e.g. 6, 8.5, 12, 18 or 24 micrograms, for
example 12 micrograms) formoterol fumarate.
[0036] The pharmaceutical composition for inhalation comprising
aclidinium and a .beta.2-agonist, for example, formoterol or
LAS100977
(5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)-hydroxyethyl)-8--
hydroxyquinolin-2(1H)-one), can be administered one or more times
per day. Preferably once or twice a day.
[0037] Examples of suitable PDE4 inhibitors that can be combined
with aclidinium in the present invention are benafentrine
dimaleate, etazolate, denbufylline, rolipram, cipamfylline,
zardaverine, arofylline, filaminast, tipelukast, tofimilast
piclamilast, tolafentrine, mesopram, drotaverine hydrochloride,
lirimilast, roflumilast, cilomilast, oglemilast, apremilast,
6-[2-(3,4-Diethoxyphenyl)thiazol-4-yl]pyridine-2-carboxylic acid
(tetomilast),
(R)-(+)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine
(CDP-840),
N-(3,5-Dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-y-
l]-2-oxoacetamide (GSK-842470),
9-(2-Fluorobenzyl)-N6-methyl-2-(trifluoromethyl)adenine (NCS-613),
N-(3,5-Dichloro-4-pyridinyl)-8-methoxyquinoline-5-carboxamide
(D-4418),
N-[9-Methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzod-
iazepin-3(R)-yl]pyridine-4-carboxamide,
3-[3-(Cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-puri-
ne hydrochloride (V-11294A),
6-[3-(N,N-Dimethylcarbamoyl)phenylsulfonyl]-4-(3-methoxyphenylamino)-8-me-
thylquinoline-3-carboxamide hydrochloride (GSK-256066),
4-[6,7-Diethoxy-2,3-bis(hydroxymethyl)naphthalen-1-yl]-1-(2-methoxyethyl)-
pyridin-2(1H)-one (T-440),
(-)-trans-2-[3'[3-(N-Cyclopropylcarbamoyl)-4-oxo-1,4-dihydro-1,8-naphthyr-
idin-1-yl]-3-fluorobiphenyl-4-yl]cyclopropanecarboxylic acid
(MK-0873), CDC-801, UK-500001, BLX-914, 2-carbomethoxy
-4-cyano-4-(3-cyclopropylmethoxy-4-difluroromethoxyphenyl)cyclohexan1-one-
, cis
[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan--
1-ol,
5(S)-[3-(Cyclopentyloxy)-4-methoxyphenyl]-3(S)-(3-methylbenzyl)piper-
idin-2-one (IPL-455903), ONO-6126 (Eur Respir J 2003, 22(Suppl.
45): Abst 2557) and the compounds claimed in the PCT patent
applications number W003/097613, W02004/058729, WO 2005/049581, WO
2005/123693 and WO 2005/123692.
[0038] Examples of suitable corticosteroids and glucocorticoids
that can be combined with aclidinium in the present invention are
prednisolone, methylprednisolone, dexamethasone, dexamethasone
cipecilate, naflocort, deflazacort, halopredone acetate,
budesonide, beclomethasone dipropionate, hydrocortisone,
triamcinolone acetonide, fluocinolone acetonide, fluocinonide,
clocortolone pivalate, methylprednisolone aceponate, dexamethasone
palmitoate, tipredane, hydrocortisone aceponate, prednicarbate,
alclometasone dipropionate, Butixocort propionate, RPR-106541,
halometasone, methylprednisolone suleptanate, mometasone furoate,
rimexolone, prednisolone famesylate, ciclesonide, deprodone
propionate, fluticasone propionate, fluticasone furoate,
halobetasol propionate, loteprednol etabonate, betamethasone
butyrate propionate, flunisolide, prednisone, dexamethasone sodium
phosphate, triamcinolone, betamethasone 17-valerate, betamethasone,
betamethasone dipropionate,
21-Chloro-11beta-hydroxy-17alpha-[2-(methylsulfanypacetoxy]-4-pregnene-3,-
20-dione, Desisobutyrylciclesonide, hydrocortisone acetate,
hydrocortisone sodium succinate, NS-126, prednisolone sodium
phosphate, hydrocortisone probutate prednisolone sodium
metasulfobenzoate and clobetasol propionate, especially budesonide
or mometasone.
[0039] For example, the invention provides a pharmaceutical
composition for inhalation comprising aclidinium in the form of a
dry powder of a pharmaceutically acceptable salt, e.g., bromide, in
admixture with a pharmaceutically acceptable carrier, e.g., lactose
particles, together with mometasone furoate, (i) comprising a
single metered nominal dose of aclidinium equivalent to about 200
micrograms aclidinium bromide together with a single metered
nominal dose of about 100-900 .mu.g (e.g. 100, 110, 200, 220, 300,
330, 400, 440, 800 or 880 .mu.g, for example 200-450 .mu.g, e.g.
220 or 440 .mu.g) mometasone furoate, or (ii) in a multidose dry
powder inhaler device calibrated to provide a metered nominal dose
of aclidinium equivalent to about 200 micrograms aclidinium bromide
together with a metered nominal dose of about 100-900 .mu.g (e.g.
100, 110, 200, 220, 300, 330, 400, 440, 800 or 880 .mu.g, for
example 200-450 .mu.g, e.g. 220 or 440 .mu.g) mometasone
furoate.
[0040] The pharmaceutical composition for inhalation comprising
aclidinium and a corticosteroid, for example mometasone furoate,
can be administered one or more times per a day. Preferably once or
twice a day.
[0041] The invention also provides a pharmaceutical composition
comprising aclidinium, a .beta.2-agonist as defined above and a
corticosteroid, as defined above. Most preferred .beta.2-agonists
are selected from LAS100977
((5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)-hydro-
xyethyl)-8-hydroxyquinolin-2(1H)-one) and formoterol. Most
preferred corticosteroid is a mometasone furoate. These triple
combinations are suitable for administration once or twice a
day.
EXAMPLE 1
[0042] Methods: Patients with moderate to severe stable COPD were
randomized to receive double-blind, once-daily treatment with
aclidinium (25, 50, 100, 200, or 400 .mu.g), placebo, or open-label
tiotropium 18 .mu.g for 4 weeks. Spirometric measurements were
performed at 22-24 h after the first dose and then at weekly
intervals, and from 0.5-6 h post-administration on Day 1 and at
Week 4 (Day 29).
[0043] Results: The ITT population included 460 patients.
Aclidinium dose-dependently increased trough FEV.sub.1 on Day 29
(table).
Mean change from baseline in trough FEV.sub.1 on Day 29
TABLE-US-00001 Aclidinium Tiotropium (double-blind) (open-label) 25
.mu.g 50 .mu.g 100 .mu.g 200 .mu.g 400 .mu.g 18 .mu.g n 65 65 69 66
67 64 Mean .DELTA., ml 39 36 83 148* 128* 161* *p < 0.05 vs
placebo
[0044] Unlike tiotropium, the bronchodilatory effect of aclidinium
during the first 6 h post-dose on Day 29 was comparable to that on
Day 1 (all doses). Time to peak FEV.sub.1 was achieved at 3 h
post-dose for aclidinium 100-400 .mu.g. Aclidinium was well
tolerated, with no dose-dependent effect on ECG, laboratory
parameters or adverse events.
[0045] Conclusion: Aclidinium produced sustained bronchodilation
over 24 h and was well tolerated. Aclidinium 200 and 400 .mu.g had
comparable bronchodilatory effects to open-label tiotropium 18
.mu.g. Based on the efficacy and tolerability data, aclidinium 200
.mu.g was selected as the investigational dose for a future
long-term clinical trial in COPD.
* * * * *