U.S. patent application number 16/781587 was filed with the patent office on 2020-06-04 for combinations of a muscarinic receptor antagonist and a beta-2 adrenoreceptor agonist.
This patent application is currently assigned to Glaxo Group Limited. The applicant listed for this patent is Glaxo Group Limited. Invention is credited to Darrell BAKER, Mark BRUCE, Glenn CRATER, Brian NOGA, Marian THOMAS, Patrick WIRE.
Application Number | 20200171009 16/781587 |
Document ID | / |
Family ID | 41573013 |
Filed Date | 2020-06-04 |
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United States Patent
Application |
20200171009 |
Kind Code |
A1 |
BAKER; Darrell ; et
al. |
June 4, 2020 |
COMBINATIONS OF A MUSCARINIC RECEPTOR ANTAGONIST AND A BETA-2
ADRENORECEPTOR AGONIST
Abstract
Combinations of a muscarinic acetylcholine receptor antagonist
and a beta 2 agonist for inhaled administration via the nose or
mouth, and methods of using them are provided.
Inventors: |
BAKER; Darrell; (Uxbridge,
GB) ; BRUCE; Mark; (Stevenage, GB) ; CRATER;
Glenn; (Mississauga, CA) ; NOGA; Brian;
(Durham, NC) ; THOMAS; Marian; (Ware, GB) ;
WIRE; Patrick; (Durham, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Glaxo Group Limited |
Brentford |
|
GB |
|
|
Assignee: |
Glaxo Group Limited
Brentford
GB
|
Family ID: |
41573013 |
Appl. No.: |
16/781587 |
Filed: |
February 4, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
15678246 |
Aug 16, 2017 |
|
|
|
16781587 |
|
|
|
|
14970945 |
Dec 16, 2015 |
9750726 |
|
|
15678246 |
|
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|
13510962 |
Aug 20, 2012 |
|
|
|
PCT/EP2010/068429 |
Nov 29, 2010 |
|
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|
14970945 |
|
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
B65D 75/36 20130101;
A61K 45/06 20130101; A61K 9/0075 20130101; A61K 31/138 20130101;
A61P 11/06 20180101; A61P 43/00 20180101; A61P 11/00 20180101; A61P
11/02 20180101; A61P 29/00 20180101; A61K 31/439 20130101; A61P
11/08 20180101; A61P 37/08 20180101; A61K 31/138 20130101; A61K
2300/00 20130101; A61K 31/439 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/439 20060101
A61K031/439; B65D 75/36 20060101 B65D075/36; A61K 9/00 20060101
A61K009/00; A61K 45/06 20060101 A61K045/06; A61K 31/138 20060101
A61K031/138 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 1, 2009 |
GB |
0921075.8 |
Claims
1. A pharmaceutical combination product comprising a) a compound of
the formula: ##STR00007## wherein X.sup.- is a pharmaceutically
acceptable anion; and b) a compound of the formula: ##STR00008## or
a pharmaceutically acceptable salt thereof (Compound (II)).
2. A product according to claim 1 wherein for Compound (I) the
pharmaceutically acceptable anion is selected from the group
consisting of chloride, bromide, iodide, hydroxide, sulfate,
nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate,
tartrate, oxalate, succinate, mandelate, methanesulfonate or
p-toluenesulfonate.
3. A product according to claim 1 or claim 2 wherein Compound (I)
is
4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicycl-
o[2.2.2]octane bromide.
4. A product according to any of claims 1 to 3 wherein Compound
(II) is
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet-
hyl}-2-(hydroxymethyl)phenol .alpha.-phenylcinnamate.
5. A product according to any of claims 1 to 3 wherein Compound
(II) is
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet-
hyl}-2-(hydroxymethyl)phenol triphenylacetate.
6. A product according to any of claims 1 to 5 wherein Compound (I)
and Compound (II) are presented in a form adapted for separate
administration.
7. A product according to any of claims 1 to 5 wherein Compound (I)
and Compound (II) are presented in a form adapted for sequential
administration.
8. A product according to any of claims 1 to 5 wherein Compound (I)
and Compound (II) are presented in a form adapted for simultaneous
administration.
9. A product according to claim 8 wherein Compound (I) and Compound
(II) are in admixture with each other.
10. A product according to any of claims 1 to 9 wherein at least
one of Compound (I) and Compound (II) is formulated with a
pharmaceutically acceptable carrier or excipient.
11. A product according to any of claims 1 to 9 in a form suitable
for administration by oral or nasal inhalation.
12. A product according to claim 11 wherein the form is suitable
for administration by inhalation via a medicament dispenser
selected from a reservoir dry powder inhaler, a unit-dose dry
powder inhaler, a pre-metered multi-dose dry powder inhaler, a
nasal inhaler or a pressurized metered dose inhaler.
13. A product as claimed in claim 12 wherein each of Compound (I)
and Compound (II) is presented in the form of a dry powder
composition.
14. A product as claimed in claim 13 wherein Compound (I) and
Compound (II) are presented as separate compositions.
15. A product as claimed in claim 13 wherein Compound (I) and
Compound (II) are presented as admixed compositions.
16. A product as claimed in claim 14 or 15 wherein at least one of
said compositions of Compound (I) or Compound (II) contains a
carrier.
17. A product as claimed in claim 14 or 15 wherein both
compositions of Compound (I) and Compound (II) contain a
carrier.
18. A product as claimed in claim 16 or 17 wherein the carrier is
lactose.
19. A product as claimed in any of claims 13 to 18 wherein at least
one of said compositions contains a ternary agent.
20. A product as claimed in any of claims 13 to 18 wherein both
compositions contain a ternary agent.
21. A product as claimed in claim 19 wherein the ternary agent is
magnesium stearate.
22. A product as claimed in claim 20, wherein the ternary agent in
both compositions is magnesium stearate.
23. A product as claimed in claim 22, wherein magnesium stearate is
present in an amount of about 0.6% w/w in a composition of Compound
(I), and/or an amount of about 1.0% w/w in a composition of
Compound (II).
24. A product as claimed in any one of claims 13 to 23 wherein said
separate or admixed compositions are in unit dose form.
25. A product as claimed in claim 24 wherein the unit dose form is
in a capsule, cartridge or blister pack.
26. A product as claimed in any of claims 13 to 25 wherein the
composition is administered via a dry powder inhaler.
27. A product as claimed in claim 26 wherein said inhaler permits
separate containment of the active ingredients.
28. A product as claimed in any one of claims 1 to 27 wherein
Compound (I) is present in an amount of about 1 to 1000
mcg/dose.
29. A product as claimed in any one of claims 1 to 27 wherein
Compound (I) is present in an amount of 125 mcg/dose.
30. A product as claimed in any one of claims 1 to 27 wherein
Compound (I) is present in an amount of 62.5 mcg/dose.
31. A product according to any one of claims 1 to 30 wherein
Compound (II) is present in an amount of 1 to 100 mcg/dose.
32. A product according to any one of claims 1 to 30 wherein
Compound (II) is present in an amount of 25 mcg/dose.
33. A dry powder inhaler containing a product as defined in any of
claims 1 to 32.
34. A product according to claim 11 wherein each of Compound (I)
and Compound (II) is presented in the form of a spray composition
for inhalation.
35. A product according to claim 34 wherein Compound (I) and
Compound (II) are presented as separate or admixed
compositions.
36. A product according to claim 34 or claim 35 wherein the spray
composition is an aqueous solution or suspension.
37. A product according to claim 34 or 35 wherein the spray
composition is an aerosol composition.
38. A product according to claim 37 comprising as propellant a
fluorocarbon or hydrogen-containing chlorofluorocarbon.
39. A product according to claim 38 wherein the propellant is a
hydrofluoroalkane.
40. A product according to claim 39 wherein the propellant is
1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or a
mixture thereof.
41. A product according to any of claims 34 to 40 further
comprising a co-solvent.
42. A product according to any of claims 34 to 41 further
comprising a surface-active agent.
43. A product according to any of claims 1 to 42 further comprising
an inhaled corticosteroid selected from the group consisting of
fluticasone propionate, mometasone furoate, budesonide and
6.alpha.,9.alpha.-difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11.beta.-hy-
droxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic
acid S-fluoromethyl ester (fluticasone furoate).
44. A product according to claim 43 wherein the inhaled
corticosteroid is
6.alpha.,9.alpha.-difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11.beta.-hy-
droxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic
acid S-fluoromethyl ester (fluticasone furoate).
45. A product according to claim 44, wherein
6.alpha.,9.alpha.-difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11.beta.-hy-
droxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic
acid S-fluoromethyl ester (fluticasone furoate) is present in an
amount of 100 mcg/dose.
46. A pressurised metered dose inhaler containing a product as
defined in any of claims 1 to 11 and 34 to 45.
47. Use of the product as defined in any of claims 1 to 32 and 34
to 45 in the manufacture of a medicament for the prophylaxis or
treatment of conditions for which administration of one or more of
Compound (I) and Compound (II) is indicated.
48. The use according to claim 47, for the treatment of
inflammatory or respiratory tract diseases, by simultaneous or
sequential administration, in any order, of Compound (I) and
Compound (II).
49. The use according to claim 47 or 48, for the manufacture of a
medicament for the treatment of chronic obstructive pulmonary
disease (COPD) and/or asthma by simultaneous or sequential
administration of Compound (I) and Compound (II).
50. A method for the prophylaxis or treatment of inflammatory or
respiratory tract diseases, comprising administering to a patient
in need thereof, a product as defined in to any of claims 1 to 32
and 34 to 45.
51. A method according to claim 50 wherein the active ingredients
of said product are administered either sequentially or
simultaneously.
52. A method according to claim 50 or 51 wherein the disease is
selected from the group consisting of chronic obstructive lung
disease, chronic bronchitis, asthma, chronic respiratory
obstruction, pulmonary fibrosis, pulmonary emphysema, allergic
rhinitis, small airways disease, bronchiectasis and cystic
fibrosis.
53. A method according to claim 52 wherein the disease is chronic
obstructive lung disease (COPD).
54. A method according to claim 53 for the treatment of chronic
obstructive pulmonary disease (COPD), by simultaneous or sequential
administration of the active ingredients of a product as defined in
any of claims 1 to 32 and 34 to 45.
55. A method according to any of claims 50 to 54 wherein
administration is via inhalation by the mouth or nose.
56. A method according to claim 55 wherein administration is via a
medicament dispenser selected from a reservoir dry powder inhaler,
a pre-metered multi-dose dry powder inhaler, a nasal inhaler or a
pressurized metered dose inhaler.
57. The method according to any of claims 50 to 56 wherein the
product is administered once per day.
58. A product as defined in any of claims 1 to 32 and 34 to 45 for
use in the treatment of inflammatory or respiratory tract diseases,
by simultaneous or sequential administration, in any order, of
Compound (I) and Compound (II).
59. A product according to claim 58 for use in the treatment of
chronic obstructive pulmonary disease (COPD) and/or asthma by
simultaneous or successive administration of Compound (I) and
Compound (II).
60. A dry powder inhaler comprising two compositions presented
separately, wherein the first composition comprises i.
4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicycl-
o[2.2.2]octane bromide, and ii. lactose, and iii. magnesium
stearate at an amount of about 0.6% w/w based on the total weight
of the first composition; and the second composition comprises iv.
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet-
hyl}-2-(hydroxymethyl)phenol triphenylacetate, and v. lactose, and
vi. magnesium stearate at an amount of about 1.0% w/w based on the
total weight of the second composition.
61. A dry powder inhaler according to claim 60, wherein each
composition is in unit dose form.
62. A dry powder inhaler according to claim 61, wherein the unit
dose form is a capsule, cartridge or blister.
63. A dry powder inhaler according to claim 61 or 62 wherein
4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicycl-
o[2.2.2]octane bromide is present in an amount of about 125
mcg/dose.
64. A dry powder inhaler according to claim 61 or 62 wherein
4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicycl-
o[2.2.2]octane bromide is present in an amount of about 62.5
mcg/dose.
65. A dry powder inhaler according to any of claims 61 to 64
wherein
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet-
hyl}-2-(hydroxymethyl)phenol triphenylacetate is present in an
amount of about 25 mcg/dose.
66. A dry powder inhaler according to claim 60 wherein the second
composition further comprises
6.alpha.,9.alpha.-difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11.beta.-hy-
droxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic
acid S-fluoromethyl ester (fluticasone furoate).
67. A dry powder inhaler according to claim 61 to 65 wherein the
second composition further comprises
6.alpha.,9.alpha.-difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11.beta.-hy-
droxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic
acid S-fluoromethyl ester (fluticasone furoate).
68. A dry powder inhaler according to claim 67 wherein
6.alpha.,9.alpha.-difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11.beta.-hy-
droxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic
acid S-fluoromethyl ester (fluticasone furoate) is present in an
amount of about 100 mcg/dose.
Description
FIELD OF THE INVENTION
[0001] This invention relates to pharmaceutical products and
compositions for use in the treatment of chronic obstructive
pulmonary disease (COPD), asthma and related diseases.
[0002] More particularly this invention relates to the combination
of a muscarinic receptor antagonist and a beta-2 adrenoreceptor
agonist, and the use of said combination in treating diseases
mediated via the M.sub.3 muscarinic acetylcholine receptor and/or
the beta-2 adrenoreceptor.
[0003] More particularly this invention is concerned with novel
pharmaceutical combination products comprising
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet-
hyl}-2-(hydroxymethyl)phenol triphenylacetate and
4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicycl-
o[2.2.2]octane bromide and the use of said combination products in
medicine, particularly in treating diseases mediated via the
M.sub.3 muscarinic acetylcholine receptor and/or the beta-2
adrenoreceptor, for example in the prophylaxis and treatment of
inflammatory or respiratory tract diseases.
BACKGROUND OF THE INVENTION
[0004] Selective .beta..sub.2-adrenoreceptor agonists have been
used in the prophylaxis and treatment of clinical conditions for
which a bronchodilating agent has been indicated. Such conditions
include diseases associated with airflow obstruction such as
chronic obstructive pulmonary diseases (COPD) (e.g. chronic and
wheezy bronchitis, emphysema), asthma, respiratory tract infection
and upper respiratory tract disease (e.g. rhinitis, including
seasonal and allergic rhinitis).
[0005] In particular, asthma and other related disorders are
typically treated with beta-2 adrenergic receptor agonists (beta-2
agonists) as they provide a bronchodilator effect to the patient,
resulting in relief from the symptoms of breathlessness. Within the
beta-2 agonist class there are presently available short acting
compounds for immediate relief, such as salbutamol, biltolterol,
pirbuterol and terbutaline. There are also longer acting compounds
commercially available, such as salmeterol and formoterol.
Salmeterol is available by prescription for use twice daily in the
treatment of asthma.
[0006] Over the last two decades, inhaled anticholinergic agents
have become well established as well-tolerated and effective
bronchodilators for the treatment of COPD. Treatment with
anticholinergics significantly improves FEV.sub.1, (forced
expiratory volume in 1 second) resting and dynamic lung
hyperinflation, symptoms and exercise capacity, and reduces COPD
exacerbations. Currently, only a few inhaled anticholinergic
bronchodilators are available: the short-acting ipratroplum bromide
(ipratropium; dosed four-times-a-day) and oxitropium bromide, and
the long-acting tiotropium bromide (tiotropium; dosed
once-daily).
[0007] WO 03/024439 describes compounds of the general formula:
##STR00001##
and salts, solvates, and physiologically functional derivatives
thereof.
[0008] The compound
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet-
hyl}-2-(hydroxymethyl)phenol is specifically described in
WO03/024439, as are pharmaceutically acceptable salts thereof, in
particular the acetate, triphenylacetate, .alpha.-phenylcinnamate,
1-naphthoate and (R)-mandelate salts. WO2005/104745 describes
compounds of the formulae:
##STR00002##
[0009] WO2005/104745 specifically describes the compound
4-[hydroxy(diphenyl)methyl]-1
{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane
bromide.
SUMMARY OF THE INVENTION
[0010] In a first aspect the present invention provides a novel
pharmaceutical combination product comprising the therapeutic
agents:
a) a compound of the formula:
##STR00003##
wherein X.sup.- is a pharmaceutically acceptable anion; and b) a
compound of the formula:
##STR00004##
or a pharmaceutically acceptable salt thereof.
[0011] Hereinafter, Compound (II) may refer to the free base
depicted above, and/or one or more salts thereof, as dictated by
the context.
[0012] In one embodiment the pharmaceutical combination product
comprises
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet-
hyl}-2-(hydroxymethyl)phenol triphenylacetate and
4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicycl-
o[2.2.2]octane bromide.
[0013] In one embodiment
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet-
hyl}-2-(hydroxymethyl)phenol triphenylacetate and
4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicycl-
o[2.2.2]octane bromide are the sole active ingredients in said
pharmaceutical combination product.
[0014] In another embodiment the pharmaceutical combination product
of Compound (I) and Compound (II) additionally comprises an inhaled
corticosteroid.
[0015] This invention also provides for use of the pharmaceutical
combination product in the manufacture of a medicament for the
treatment of conditions for which administration of one or more of
the therapeutic compounds is indicated.
[0016] In one embodiment the use is for the manufacture of a
medicament for the treatment of inflammatory or respiratory tract
diseases, by simultaneous or sequential administration of Compound
(I) and Compound (II).
[0017] In another embodiment the use is for the manufacture of a
medicament for the treatment of chronic obstructive pulmonary
disease (COPD) and/or asthma, by simultaneous or sequential
administration of Compound (I) and Compound (II).
[0018] The invention also provides said pharmaceutical combination
product for use in the treatment of inflammatory or respiratory
tract diseases, such as chronic obstructive pulmonary disease
(COPD) and/or asthma.
[0019] Another embodiment of the invention is a method for the
treatment of inflammatory or respiratory tract diseases, comprising
administering either sequentially or simultaneously, to a patient
in need thereof, a pharmaceutical combination product comprising
Compound (I) and Compound (II).
[0020] In one embodiment of the invention the inflammatory or
respiratory tract disease is selected from the group consisting of
chronic obstructive pulmonary disease, chronic bronchitis, asthma,
chronic respiratory obstruction, pulmonary fibrosis, pulmonary
emphysema, allergic rhinitis, small airways disease, bronchiectasis
and cystic fibrosis.
[0021] In another embodiment of the invention the pharmaceutical
combination product may be used for the treatment of inflammatory
or respiratory tract diseases, and more specifically the treatment
of chronic obstructive pulmonary disease (COPD) and/or asthma by
simultaneous or sequential administration of Compound (I) and
Compound (II).
DETAILED DESCRIPTION OF THE INVENTION
[0022] The present invention is directed to a pharmaceutical
combination product comprising
a) a compound of formula:
##STR00005##
wherein X.sup.- is a pharmaceutically acceptable anion; and b) a
compound of formula:
##STR00006##
or a pharmaceutically acceptable salt thereof.
[0023] The pharmaceutically acceptable anion depicted by X.sup.-
may be selected from chloride, bromide, iodide, hydroxide, sulfate,
nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate,
tartrate, oxalate, succinate, mandelate, methanesulfonate or
p-toluenesulfonate. In one embodiment the pharmaceutically
acceptable anion X.sup.- is bromide.
[0024] For purposes herein, the structural formula for the
quaternary moiety (cation) of Compound (1) is also referred to as
4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicycl-
o[2.2.2]octane.
[0025] In one embodiment of the invention Compound (I) is
4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicycl-
o[2.2.2]octane bromide (also referred to herein as Compound (I)
bromide).
[0026] Pharmaceutically acceptable acid addition salts of Compound
(II) include those formed from hydrochloric, hydrobromic,
sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic,
trifluoroacetic, triphenylacetic, phenylacetic, substituted phenyl
acetic eg. methoxyphenyl acetic, sulphamic, suiphanilic, succinic,
oxalic, fumaric, maleic, malic, glutamic, aspartic, oxaloacetic,
methanesuiphonic, ethanesulphonic, arylsulponic (for example
p-toluenesulphonic, benzenesulphonic, naphthalenesulphonic or
naphthalenedisulphonic), salicylic, glutaric, gluconic,
tricarballylic, mandelic, cinnamic, substituted cinnamic (for
example, methyl, methoxy, halo or phenyl substituted cinnamic,
including 4-methyl and 4-methoxycinnamic acid and .alpha.-phenyl
cinnamic acid), ascorbic, oleic, naphthoic, hydroxynaphthoic (for
example 1- or 3-hydroxy-2-naphthoic), naphthaleneacrylic (for
example naphthalene-2-acrylic), benzoic, 4-methoxybenzoic, 2- or
4-hydroxybenzoic, 4-chlorobenzoic, 4-phenylbenzoic, bezeneacrylic
(for example 1,4-benzenediacrylic) and isethionic acids.
[0027] In one embodiment the pharmaceutically acceptable salt of
Compound (II) is selected from the acetate, 1-naphthoate and
(R)-mandelate salts.
[0028] In another embodiment the pharmaceutically acceptable salt
of Compound (II) is the .alpha.-phenylcinnamate salt.
[0029] In another embodiment the pharmaceutically acceptable salt
of Compound (II) is the triphenylacetate salt.
[0030] The structural formula shown above for Compound (II) may be
named as
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydrox-
yethyl}-2-(hydroxymethyl)phenol.
[0031] In one embodiment of the invention Compound (II) is
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet-
hyl}-2-(hydroxymethyl)phenol triphenylacetate (also referred to as
Compound (II) triphenylacetate).
[0032] In one embodiment the pharmaceutical combination product of
the invention comprises
4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicycl-
o[2.2.2]octane bromide and
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet-
hyl}-2-(hydroxymethyl)phenol triphenylacetate.
[0033] In another embodiment the pharmaceutical combination product
of Compound (I) and Compound (II) additionally comprises an inhaled
corticosteroid, e.g. fluticasone propionate, mometasone furoate,
budesonide or
6.alpha.,9.alpha.-difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11.beta.-hy-
droxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic
acid S-fluoromethyl ester (fluticasone furoate).
[0034] In one embodiment said pharmaceutical combination product
comprises
4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicycl-
o[2.2.2]octane bromide,
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet-
hyl}-2-(hydroxymethyl)phenol triphenylacetate and
6.alpha.,9.alpha.-difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11.beta.-hy-
droxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic
acid S-fluoromethyl ester (fluticasone furoate).
[0035] In one embodiment, the pharmaceutical combination product of
the invention comprises
4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicycl-
o[2.2.2]octane bromide and
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet-
hyl}-2-(hydroxymethyl)phenol triphenylacetate as the sole active
ingredients.
[0036] Compound (I), specifically
4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicycl-
o[2.2.2]octane bromide has been the subject of studies in animal
models, and in humans, and has been found to be a long acting
high-affinity pan-active muscarinic receptor antagonist which has
potential for once-daily administration.
[0037] Compound (II), specifically
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet-
hyl}-2-(hydroxymethyl)phenol and its salts has been extensively
tested in animal and human studies and has been found to
demonstrate sustained bronchodilation over a 24 hour period in
conjunction with a favourable safety profile and thus has the
potential for once-daily administration.
[0038] Compound (I) and Compound (II), and the combination thereof,
are considered to have potential in the treatment of inflammatory
or respiratory tract diseases such as chronic obstructive pulmonary
disease, chronic bronchitis, asthma, chronic respiratory
obstruction, pulmonary fibrosis, pulmonary emphysema, allergic
rhinitis, small airways disease, bronchiectasis and cystic
fibrosis.
[0039] COPD is a chronic disease characterised by airways
obstruction and reduced maximum expiratory flow from the lungs that
manifests as persistent daily symptoms, such as shortness of breath
(dyspnoea), and limitation of the ability to perform daily
activities or exertion. Furthermore, there are periodic
exacerbations of the condition that result in worsening of the
day-to-day symptoms and activity limitation, and can also lead to
hospitalisation of the patient because of the severity of the
worsening symptoms/limitation. In addition, there is a progressive
decline in lung function (disease progression) over several
years.
[0040] Bronchodilator treatment in COPD includes but is not
necessarily limited to reducing symptoms, particularly dyspnoea, to
allow a patient to undertake more daily activities and other
activities that require exertion, and preventing exacerbations.
[0041] Asthma is a chronic condition, which is characterised by
widespread, variable and reversible airflow obstruction. Symptoms
include coughing, wheezing, breathlessness and/or a tight feeling
in the chest. Asthma attacks are generally caused by exposure to a
trigger, such as pollen, dust or other allergens, which causes
constriction of the airways (bronchoconstriction). It will be
appreciated that a subject suffering from a condition such as
asthma, may variously from time to time display no overt symptoms
of the condition, or may suffer from periodic attacks during which
symptoms are displayed or may experience exacerbations or worsening
of the condition. In this context the term `treatment` is intended
to encompass prevention of such periodic attacks or exacerbations
of the existing condition. Such treatment may be referred to as
`maintenance treatment` or `maintenance therapy`.
[0042] The amounts of Compound (I) and Compound (II), and in one
embodiment of the invention,
4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicycl-
o[2.2.2]octane bromide and
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet-
hyl}-2-(hydroxymethyl)phenol triphenylacetate, required to achieve
a therapeutic effect will, of course, vary with the route of
administration, the subject under treatment, the particular
disorder or disease being treated, and the severity of the disease.
In one embodiment, the route of administration is by inhalation via
the mouth or nose. In a further embodiment, the route of
administration is by inhalation via the mouth.
[0043] In one embodiment Compound (I), and specifically
(4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyc-
lo[2.2.2]octane bromide, may be administered by inhalation at a
dose of from about 1 mcg to about 1000 mcg/daily, e.g. 100, 250 or
500 mcg per day. In a further embodiment, Compound (I) and
specifically
(4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyc-
lo[2.2.2]octane bromide may be administered by inhalation at a dose
of 62.5 mcg or 125 mcg per day. In general Compound (I) will be
administered as a once-daily dose.
[0044] In a further embodiment, Compound (I), and specifically
(4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyc-
lo[2.2.2]octane bromide, may be administered by inhalation,
once-daily, at a dose of 62.5 mcg per day.
[0045] In a further embodiment, Compound (I), and specifically
(4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyc-
lo[2.2.2]octane bromide, may be administered by inhalation,
once-daily, at a dose of 125 mcg per day.
[0046] Compound (II) may for example be administered by inhalation
at a dose of from about 1 mcg to about 400 mcg/day (calculated as
the free base). In one embodiment Compound (II), and specifically
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet-
hyl}-2-(hydroxymethyl)phenol triphenylacetate, may be administered
by inhalation at a dose of from about 1 mcg to 100 mcg/day, for
example 3, 6.25, 12.5, 25, 50 or 100 mcg/day (calculated as the
free base). In general Compound (II) will be administered as a
once-daily dose. In one embodiment Compound (II) may be
administered by inhalation at a dose of 12.5 mcg/day. In another
embodiment Compound (II) may be administered by inhalation at a
dose of 25 mcg/day. In another embodiment Compound (II) may be
administered by inhalation at a dose of 50 mcg/day.
[0047] In a further embodiment,
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet-
hyl}-2-(hydroxymethyl)phenol triphenylacetate, may be administered
by inhalation, once-daily, at a dose of 25 mcg per day.
[0048] In a further embodiment, the present invention provides a
pharmaceutical combination product for once-daily administration by
inhalation, comprising
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet-
hyl}-2-(hydroxymethyl)phenol triphenylacetate at a dose of 25 mcg
per day, and
(4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniab-
icyclo[2.2.2]octane bromide at a dose of 125 mcg per day.
[0049] In a further embodiment, the present invention provides a
pharmaceutical combination product for once-daily administration by
inhalation, comprising
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet-
hyl}-2-(hydroxymethyl)phenol triphenylacetate at a dose of 25 mcg
per day, and
(4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniab-
icyclo[2.2.2]octane bromide at a dose of 62.5 mcg per day.
[0050] When the combination additionally includes an inhaled
corticosteroid, this may be used at doses compatible with those
known for monotherapy. When the inhaled corticosteroid is
fluticasone furoate this may be administered by inhalation at a
dose of from about 25 mcg to about 800 mcg daily, and if necessary
in divided doses. Thus, the daily dose of fluticasone furoate may
be for example 25, 50, 100, 200, 300, 400, 600 or 800 mcg, in
general as a once-daily dose. In one embodiment, the daily dose of
fluticasone furoate is 100 mcg. In a further embodiment, the daily
dose of fluticasone furoate is 50 mcg.
[0051] The individual compounds of the pharmaceutical combination
product as described herein may be administered either sequentially
or simultaneously in separate or combined pharmaceutical
formulations/compositions. Thus Compound (I) and Compound (II) may
for example, be formulated separately and presented in separate
packs or devices, or said individually formulated components may be
presented in a single pack or device. Where appropriate, the
individual compounds may be admixed within the same formulation,
and presented as a fixed pharmaceutical combination. In general
such formulations will include pharmaceutical carriers or
excipients as described hereinafter, but combinations of the
compounds without any excipients are also within the ambit of this
invention. In one embodiment, the individual compounds of the
pharmaceutical combination product may be administered
simultaneously in a combined pharmaceutical formulation or
composition.
[0052] When the pharmaceutical combination product additionally
includes an inhaled corticosteroid, eg
6.alpha.,9.alpha.-difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11.beta.-hy-
droxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic
acid S-fluoromethyl ester (fluticasone furoate) this may likewise
be formulated separately, either with or without one or more
pharmaceutical carriers or excipients, and presented for either
sequential or simultaneous administration, or the inhaled
corticosteroid may be admixed with either Compound (I) and/or
Compound (II).
6.alpha.,9.alpha.-Difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11.beta.-hy-
droxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic
acid S-fluoromethyl ester may be formulated for example as
described in WO02/12265, or as described hereinafter.
[0053] In further aspects the invention therefore provides:
A pharmaceutical combination product comprising Compound (I) and
Compound (II) presented separately for sequential or simultaneous
administration; A pharmaceutical combination product comprising
Compound (I) and Compound (II) presented separately but held in the
same pack or device, for sequential or simultaneous administration;
and A pharmaceutical combination product comprising Compound (I)
and Compound (II) in admixture with each other for simultaneous
administration.
[0054] In each case, each of Compound (I) and/or Compound (II) may
be formulated with or without pharmaceutical carriers or
excipients.
[0055] The present invention further provides a pharmaceutical
combination product comprising Compound (I) and Compound (II)
wherein at least one of Compound (I) and Compound (II) is
formulated with a pharmaceutically acceptable carrier or
excipient.
[0056] The present invention further provides a pharmaceutical
combination product comprising Compound (I) and Compound (II)
wherein each of Compound (I) and Compound (II) is formulated with a
pharmaceutically acceptable carrier or excipient.
[0057] In one embodiment of this invention compositions of
Compounds (I) and (II) include those suitable for inhalation,
including fine particle powders, or mists which may be generated
and administered by means of various types of inhalers for example,
reservoir dry powder inhalers, unit-dose dry powder inhalers,
pre-metered multi-dose dry powder inhalers, nasal inhalers or
pressurized metered dose inhalers, nebulisers or insufflators.
[0058] The compositions may be prepared by any of the methods well
known in the art of pharmacy. In general, said methods include the
step of bringing the active ingredient(s) into association with the
carrier which constitutes one or more accessory ingredients. In
general the compositions are prepared by uniformly and intimately
bringing into association the active ingredient with liquid
carriers or finely divided solid carriers or both and then, if
necessary, shaping the product into the desired composition.
[0059] Powder compositions generally contain a powder mix for
inhalation of the active ingredient and a suitable powder base
(carrier/diluent/excipient substance) such as mono-, di or
poly-saccharides (e.g. lactose or starch). Use of lactose is
preferred. The lactose may be for example anhydrous lactose or
.alpha.-lactose monohydrate. In one embodiment, the carrier is
.alpha.-lactose monohydrate. Dry powder compositions may also
include, in addition to the active ingredient and carrier, a
further excipient (eg a ternary agent) such as a sugar ester,
calcium stearate or magnesium stearate.
[0060] Alternatively, the active ingredient may be presented
without excipients. For the avoidance of doubt use of the term
`composition` or `formulation` herein refers to the active
ingredients either with or without excipients or carriers.
[0061] The present invention further provides a pharmaceutical
combination product comprising Compound (I) and Compound (II)
wherein at least one of Compound (I) and Compound (II) is
formulated with a pharmaceutically acceptable carrier and a ternary
agent.
[0062] The present invention further provides a pharmaceutical
combination product comprising Compound (I) and Compound (II)
wherein Compound (II) is formulated with a pharmaceutically
acceptable carrier and a ternary agent.
[0063] In another embodiment the present invention further provides
a pharmaceutical formulation comprising a combination of Compound
(I) and Compound (II) wherein both Compounds are formulated with a
pharmaceutically acceptable carrier and a ternary agent.
[0064] The present invention further provides a pharmaceutical
combination product for inhaled administration comprising
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet-
hyl}-2-(hydroxymethyl)phenol triphenylacetate and
(4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyc-
lo[2.2.2]octane bromide each formulated separately with a
pharmaceutically acceptable carrier and a ternary agent, but held
in the same pack or device, for sequential or simultaneous
administration.
[0065] In one embodiment said ternary agent is magnesium
stearate.
[0066] The present invention further provides a pharmaceutical
combination product for inhaled administration comprising
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet-
hyl}-2-(hydroxymethyl)phenol triphenylacetate and
(4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyc-
lo[2.2.2]octane bromide each formulated separately with lactose, as
a pharmaceutically acceptable carrier, and magnesium stearate, as a
ternary agent, but held in the same pack or device, for sequential
or simultaneous administration.
[0067] The compositions may be presented in unit dosage form. Dry
powder compositions for topical delivery to the lung by inhalation
may, for example, be presented in capsules and cartridges of for
example gelatine, or blisters of for example laminated aluminium
foil, for use in an inhaler or insufflator.
[0068] Each capsule, cartridge or blister may generally contain
between 1 mcg-1000 mcg, e.g. 100 to 500 mcg of Compound (I) and/or
between 1 mcg-400 mcg, e.g 1 to 100 mcg of Compound (II). Packaging
of the formulation may be suitable for unit dose or multi-dose
delivery. As indicated above Compound (I) and Compound (II) may be
formulated independently or in admixture. Said compounds may thus
be incorporated in separate unit doses or may be combined in a
single unit dose with or without additional excipients as deemed
necessary.
[0069] In a further embodiment, each capsule, cartridge or blister
may contain 125 mcg or 62.5 mcg of Compound (I) and/or 25 mcg of
Compound (II).
[0070] In yet a further embodiment, each capsule, cartridge or
blister may contain 125 mcg or 62.5 mcg of
(4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyc-
lo[2.2.2]octane bromide and/or 25 mcg of
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet-
hyl}-2-(hydroxymethyl)phenol triphenylacetate.
[0071] In one embodiment, a composition suitable for inhaled
administration may be incorporated into a plurality of sealed dose
containers provided on medicament pack(s) mounted inside a suitable
inhalation device. The containers may be rupturable, peelable or
otherwise openable one-at-a-time and the doses of the dry powder
composition administered by inhalation on a mouthpiece of the
inhalation device, as known in the art. The medicament pack may
take a number of different forms, for instance a disk-shape or an
elongate strip. Representative inhalation devices are the
DISKHALER.TM. and DISKUS.TM. devices, marketed by GlaxoSmithKline.
The DISKUS.TM. inhalation device is, for example, described in GB
2242134A.
[0072] A dry powder inhalable composition, may also be provided as
a bulk reservoir in an inhalation device, the device then being
provided with a metering mechanism for metering a dose of the
composition from the reservoir to an inhalation channel where the
metered dose is able to be inhaled by a patient inhaling at a
mouthpiece of the device. Exemplary marketed devices of this type
are TURBUHALER.TM. of AstraZeneca, TWISTHALER.TM. of Schering and
CLICKHALER.TM. of Innovata.
[0073] A further delivery method for a dry powder inhalable
composition is for metered doses of the composition to be provided
in capsules (one dose per capsule) which are then loaded into an
inhalation device, typically by the patient on demand. The device
has means to rupture, pierce or otherwise open the capsule so that
the dose is able to be entrained into the patient's lung when they
inhale at the device mouthpiece. As marketed examples of such
devices there may be mentioned ROTAHALER.TM. of GlaxoSmithKline and
HANDIHALER.TM. of Boehringer Ingelheim.
[0074] A dry powder composition may also be presented in a delivery
device which permits separate containment of Compound (I) and
Compound (II) optionally in admixture with one or more excipients.
Thus, for example, the individual compounds of the combination are
administrable simultaneously but are stored separately, e.g. in
separate pharmaceutical compositions, for example as described in
WO 2003/061743 A1, WO 2007/012871 A1 and/or WO2007/068896. In one
embodiment a delivery device permitting separate containment of
actives is an inhaler device having two medicament packs in
peelable blister strip form, each pack containing pre-metered doses
in blister pockets arranged along its length. Said device has an
internal indexing mechanism which, each time the device is
actuated, peels opens a pocket of each strip and positions the
packs so that each newly exposed dose of each pack is adjacent a
manifold which communicates with a mouthpiece of the device. When
the patient inhales at the mouthpiece, each dose is simultaneously
drawn out of its associated pocket into the manifold and entrained
via the mouthpiece into the patient's respiratory tract. Thus, each
time the device is used, the patient is administered a combination
therapy consisting of a dose from each medicament pack. A further
device that permits separate containment of different compounds is
DUOHALER.TM. of Innovata.
[0075] In a further embodiment, the present invention provides a
dry powder inhaler (Inhaler 1) comprising two compositions
presented separately, wherein a first composition comprises [0076]
i.
4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicycl-
o[2.2.2]octane bromide, and [0077] ii. lactose, and [0078] iii.
magnesium stearate at an amount of about 0.6% w/w based on the
total weight of the first composition; and a second composition
comprises [0079] i.
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet-
hyl}-2-(hydroxymethyl)phenol triphenylacetate, and [0080] ii.
lactose, and [0081] iii. magnesium stearate at an amount of about
1.0% w/w based on the total weight of the second composition.
[0082] In a further embodiment, the present invention provides
Inhaler 1 wherein each composition is in unit dose form.
[0083] In a further embodiment, the present invention provides
Inhaler 1 wherein the unit dose form is a capsule, cartridge or
blister.
[0084] In a further embodiment, the present invention provides
Inhaler 1 wherein
4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azon-
iabicyclo[2.2.2]octane bromide is present in an amount of about 125
mcg/dose.
[0085] In a further embodiment, the present invention provides
Inhaler 1 wherein
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-h-
ydroxyethyl}-2-(hydroxymethyl)phenol triphenylacetate is present in
an amount of about 25 mcg/dose.
[0086] In a further embodiment, the present invention provides
Inhaler 1 wherein the second composition further comprises
6.alpha.,9.alpha.-difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11.beta.-hy-
droxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic
acid S-fluoromethyl ester (fluticasone furoate).
[0087] In a further embodiment, the present invention provides
Inhaler 1 wherein
6.alpha.,9.alpha.-difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11.-
beta.-hydroxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothio-
ic acid S-fluoromethyl ester (fluticasone furoate) is present in an
amount of about 100 mcg/dose.
[0088] Spray compositions for inhalation may for example be
formulated as aqueous solutions or suspensions or as aerosols
delivered from pressurised packs, such as a metered dose inhaler,
with the use of a suitable liquefied propellant. Aerosol
compositions suitable for inhalation can be either a suspension or
a solution and generally contain the pharmaceutical product and a
suitable propellant such as a fluorocarbon or hydrogen-containing
chlorofluorocarbon or mixtures thereof, particularly
hydrofluoroalkanes, especially 1,1,1,2-tetrafluoroethane,
1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof. The
aerosol composition may optionally contain additional formulation
excipients well known in the art such as surfactants e.g. oleic
acid, lecithin or an oligolactic acid derivative e.g. as described
in WO94/21229 and WO98/34596 and/or cosolvents e.g. ethanol.
Pressurised formulations will generally be retained in a canister
(e.g. an aluminium canister) closed with a valve (e.g. a metering
valve) and fitted into an actuator provided with a mouthpiece.
[0089] There is thus provided as a further aspect of the invention
a pharmaceutical combination product comprising Compound (I) and
Compound (II) formulated individually or in admixture, with a
fluorocarbon or hydrogen-containing chlorofluorocarbon as
propellant, optionally in combination with a surface-active agent
and/or a co-solvent. According to another aspect of the invention,
the propellant is selected from 1,1,1,2-tetrafluoroethane,
1,1,1,2,3,3,3-heptafluoro-n-propane and mixtures thereof.
[0090] Another aspect of the invention is a pharmaceutical
combination product consisting of Compound (I) and Compound (II)
formulated individually or in admixture, with a fluorocarbon or
hydrogen-containing chlorofluorocarbon as propellant, optionally in
combination with a surface-active agent and/or a cosolvent. In
another embodiment of the invention the propellant is selected from
1,1,1,2-tetrafluoroethane, or 1,1,1,2,3,3,3-heptafluoro-n-propane
and mixtures thereof.
[0091] Where appropriate compositions according to the invention
may be buffered by the addition of suitable buffering agents.
[0092] Active ingredients for administration by inhalation
desirably have a controlled particle size. The optimum particle
size for inhalation into the bronchial system is usually 1-.mu.m,
preferably 2-5 .mu.m. Particles having a size above 20 .mu.m 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 e.g. by
micronization. The desired fraction may be separated out by air
classification or sieving. Preferably, the particles will be
crystalline.
[0093] Dry powder compositions according to the invention may
comprise a carrier. The carrier when it is lactose e.g.
.alpha.-lactose monohydrate, may form from about 91 to about 99%,
e.g. 97.7-99.0% or 91.0-99.2% by weight of the formulation. In
general, the particle size of the carrier, for example lactose,
will be much greater than the inhaled medicament within the present
invention. When the carrier is lactose it will typically be present
as milled lactose, having a MMD (mass median diameter) of 60-90
.mu.m.
[0094] The lactose component 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 10% by weight of
the total lactose component, such as 3 to 6% by weight fine
lactose, for example 4.5% by weight fine lactose.
[0095] Magnesium stearate, if present in the composition, is
generally used in an amount of about 0.2 to 2%, e.g. 0.6 to 2% or
0.5 to 1.75%, e.g. 0.6%, 0.75%, 1%, 1.25% or 1.5% w/w, based on the
total weight of the composition. The magnesium stearate will
typically have a particle size in the range 1 to 50 .mu.m, and more
particularly 1-20 .mu.m, e.g. 1-10 .mu.m. Commercial sources of
magnesium stearate include Peter Greven, Covidien/Mallinckodt and
FACI.
[0096] In a further embodiment there is provided a pharmaceutical
combination product comprising Compound (I) and Compound (II)
wherein Compound (I) is
(4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyc-
lo[2.2.2]octane bromide and is presented as a dry powder
composition containing magnesium stearate at an amount of 0.6% w/w
based on the total weight of the composition.
[0097] In yet a further embodiment, there is provided a
pharmaceutical combination product comprising Compound (I) and
Compound (II) wherein Compound (II) is
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet-
hyl}-2-(hydroxymethyl)phenol triphenylacetate and is presented as a
dry powder composition containing magnesium stearate at an amount
of 1.0% w/w based on the total weight of the composition.
[0098] Intranasal sprays may be formulated with aqueous or
non-aqueous vehicles with the addition of agents such as thickening
agents, buffer salts or acid or alkali to adjust the pH,
isotonicity adjusting agents or anti-oxidants.
[0099] Solutions for inhalation by nebulization may be formulated
with an aqueous vehicle with the addition of agents such as acid or
alkali, buffer salts, isotonicity adjusting agents or
antimicrobials. They may be sterilized by filtration or heating in
an autoclave, or presented as a non-sterile product.
[0100] The invention also provides a method of preparing a
pharmaceutical combination product as defined herein, the method
comprising either:
(a) preparing a separate pharmaceutical composition for
administration of the individual compounds of the combination
either sequentially or simultaneously, or (b) preparing a combined
pharmaceutical composition for administration of the individual
compounds together in the combination for simultaneous use, wherein
the pharmaceutical composition comprises the combination together
with one or more pharmaceutically acceptable carriers and/or
excipients.
[0101]
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hyd-
roxyethyl}-2-(hydroxymethyl)phenol, and its salts, including
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyet-
hyl}-2-(hydroxymethyl)phenol triphenylacetate may be prepared as
described in WO03/024439 (Example 78(i)), which is incorporated by
reference herein.
[0102]
4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azonia-
bicyclo[2.2.2]octane bromide is described as Example 84, in
WO2005/104745 which is incorporated by reference herein.
Clinical Studies
4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl)}-1-azoniabicycl-
o[2.2.2]octane bromide
[0103]
4-[hydroxy(diphenyl)methyl]-1-2-[(phenylmethyl)oxy]ethyl)-1-azoniab-
icyclo[2.2.2]octane bromide has been found to be an effective
long-acting potent, pan-active anti-muscarinic bronchodilator which
demonstrates slow reversibility at the human M3 receptor in vitro
and long duration of action in vivo when administered directly to
the lungs in pre-clinical models. The long duration of action of
this compound identified using in vitro models, when administered
via inhalation in animals, and subsequently in early phase studies
in healthy volunteers and COPD subjects supports the potential for
use of this compound as a once daily bronchodilator for COPD.
[0104] Several clinical pharmacology studies have been conducted
using
4-[hydroxy(diphenyl)methyl]-1-(2-[(phenylmethyl)oxy]ethyl)-1-azoniabicycl-
o[2.2.2]octane bromide in both healthy volunteers and COPD patients
to investigate the safety, tolerability, pharmacokinetics and
pharmacodynamics of this compound. The bronchodilatory effects and
duration of action of single inhaled doses of this compound as
measured by plethysmography (sG.sub.aw, R.sub.aw) and spirometry
(FEV.sub.1) were assessed in some of the above noted studies. These
studies showed clinically relevant bronchodilation and 24 h
duration of action for the compound.
[0105] In one such study, designed to evaluate the safety, efficacy
and pharmacokinetics of
4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicycl-
o[2.2.2]octane bromide in subjects with COPD, five once-daily doses
(62.5 mcg, 125 mcg, 250 mcg, 500 mcg and 1000 mcg), taken over a
14-day treatment period, produced statistically significant
improvements in pulmonary function compared to placebo. All
once-daily doses showed numerically greater improvement in trough
FEV.sub.1 than the open label tiotropium active control (18 mcg
once-daily). In addition, this study confirmed that
4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicycl-
o[2.2.2]octane bromide has a once-daily profile.
[0106] A further study evaluated the efficacy and safety of three
doses (125 mcg, 250 mcg and 500 mcg) of
4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicycl-
o[2.2.2]octane bromide administered once-daily via a dry powder
inhaler over a 28 day period in subjects with COPD. This study
confirmed that
4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicycl-
o[2.2.2]octane bromide appears to be safe and efficacious,
maintaining significant bronchodilation over twenty four hours.
Compound (II) (as the .alpha.-phenylcinnamate Salt or the
Triphenylacetate Salt)
[0107] Compound (II) as the .alpha.-phenylcinnamate salt and the
triphenylacetate salt has been studied in a number of clinical
pharmacology studies, including single- and repeat-dose studies. In
addition, these studies have evaluated Compound (II) formulated
with lactose and either cellobiose octaacetate or magnesium
stearate.
[0108] In asthmatic patients, a statistically and clinically
significant improvement in trough (24-hour) FEV1 was observed for
all doses of Compound (II) tested, compared to placebo. Single
doses of 25 .mu.g to 100 .mu.g of Compound (II) triphenylacetate
(containing lactose and magnesium stearate) demonstrated 24 hour
duration of action as assessed by a 200 mL or greater increase in
mean 23 to 24 hour post-dose FEV1 versus placebo.
[0109] In COPD patients, treatment with 100 mcg and 400 mcg
Compound (II) alpha-phenylcinnamate (with lactose alone) achieved a
clinically relevant adjusted mean difference from placebo in
weighted mean trough FEV.sub.1 (22 to 24 hrs) of >100 mL. Single
doses of 25 .mu.g to 100 .mu.g of Compound (II) triphenylacetate
(containing lactose and magnesium stearate) demonstrated 24 hour
duration of action as assessed by a 190 mL or greater increase in
mean 23 to 24 hour post-dose FEV1 versus placebo).
Combination Therapy
[0110] A combination of Compound (I) bromide and Compound (II)
triphenylacetate has been administered to sixteen healthy Japanese
volunteers, aged 20 to 65, as part of a clinical trial to assess
the safety, tolerability, pharmacokinetics and pharmacodynamics of
single inhaled doses of Compound (I) bromide and Compound (II)
triphenylacetate as monotherapies and in combination. This study
was a randomised, double blind, placebo-controlled, four-way
crossover study wherein subjects received a single dose of: [0111]
Compound (I) bromide (500 mcg dose), [0112] Compound (II)
triphenylacetate (50 mcg dose), [0113] Compound (1) bromide (500
mcg dose) and Compound (II) triphenylacetate (50 mcg dose)
concurrently, or [0114] placebo at each of the four treatment
periods. On enrolment into the study subjects were assigned to one
of four treatment sequences based on a Williams design.
[0115] This clinical study in healthy Japanese volunteers,
evaluated the effect of Compound (I) bromide (500 mcg dose) and
Compound (II) triphenylacetate (50 mcg dose) administered as single
inhaled doses and concurrently (Compound (I) bromide (500 mcg dose)
and Compound (II) triphenylacetate (50 mcg dose)) on lung function
parameters. Single inhaled doses and the combination administered
using dry powder inhalers were found to be well tolerated. In this
study FEV.sub.1 values were recorded. FEV.sub.1 values were higher
for all treatment groups compared with placebo. The group dosed
with Compound (I) bromide (500 mcg dose) and Compound (II)
triphenylacetate (50 mcg dose) concurrently showing the largest
difference relative to placebo.
Pharmaceutical Formulations
Preparation of Blends
Compound (I) Bromide
[0116] Pharmaceutical grade .alpha.-lactose monohydrate, sourced
from DMV Fronterra Excipients, complying with the requirements of
Ph.Eur/USNF may be used. Before use, the .alpha.-lactose
monohydrate may be sieved through a coarse screen (for example with
a mesh size 500 or 800 microns). The level of fines in the
.alpha.-lactose monohydrate, which can be measured by Sympatec, may
be 4.5% w/w less than 4.5 micron.
[0117] Compound (I) bromide is micronised before use in an APTM
microniser to give a mass median diameter of 1 to 5 microns, such
as 2 to 5 microns.
[0118] Pharmaceutical grade magnesium stearate, sourced from Peter
Greven, complying with the requirements of Ph.Eur/USNF may be used
as supplied with a mass median particle size of 8 to 12
microns.
Blend A
[0119] Lactose monohydrate may be passed through a sieve and then
combined with magnesium stearate and blended using either a high
shear mixer (a QMM, PMA or TRV series mixer, such as TRV25 or
TRV65) or a low shear tumbling blender (a Turbula mixer) to provide
a magnesium stearate/lactose premix, hereinafter referred to as
blend A.
Blend B
[0120] Final blend B may be obtained as follows. An quantity of
blend A and compound (I) bromide may be screened, for example using
a COMIL.TM., and then blended with the remaining blend A using
either a high shear mixer (a QMM, PMA or TRV series mixer, such as
TRV25 or TRV65) or a low shear tumbling blender (a Turbula
mixer).
Representative Batch Formula for Compound (I) Bromide Powder Blend
(62.5 Microgram Per Blister)
TABLE-US-00001 [0121] Ingredient Quantity Micronised Compound (I)
Bromide 74.1 g Magnesium Stearate 75 g Lactose Monohydrate To 12.5
kg Note: 74.1 g of Compound (I) Bromide is equivalent to 62.5 g of
the free cation. The quantity of Compound (I) Bromide added may be
adjusted to reflect the assigned purity of the input drug
substance.
Representative Batch Formula for Compound (1) Bromide Powder Blend
(125 Microgram Per Blister)
TABLE-US-00002 [0122] ingredient Quantity Micronised Compound (I)
Bromide 148.3 g Magnesium Stearate 75 g Lactose Monohydrate To 12.5
kg Note: 148.3 g of Compound (I) Bromide is equivalent to 125 g of
the free cation. The quantity of Compound (I) Bromide added may be
adjusted to reflect the assigned purity of the input drug
substance.
Blending Parameters (Using a TRV25, 12.5 kg Scale)
TABLE-US-00003 [0123] Blend Time (mins) Approximate Speed (fpm) A 6
460 B 10 590
Blister Strip Preparation
[0124] The blended composition may then be transferred into blister
strips (typical nominal mean quantity of blend per blister is
12.5-13.5 mg) of the type generally used for the supply of dry
powder for inhalation and the blister strips were sealed in the
customary fashion.
Compound (II) Triphenylacetate
[0125] Pharmaceutical grade .alpha.-lactose monohydrate, which can
be sourced from DMV Fronterra Excipients, complying with the
requirements of Ph.Eur/USNF may be used. Before use, the
.alpha.-lactose monohydrate may be sieved through a coarse screen
(typical mesh size 500 microns). The level of fines in the
.alpha.-lactose monohydrate, which can be measured by Sympatec, may
be 4.5% w/w less than 4.5 micron.
[0126] Compound (II) triphenylacetate is micronised before use in
an APTM microniser to give a MMD (mass median diameter) of from 1
to 5 microns, such as 2 to 5 microns, for example 1.8 microns.
[0127] Pharmaceutical grade Magnesium stearate, which can be
sourced from Peter Greven, complying with the requirements of
Ph.Eur/USNF may be used as supplied with a mass median particle
size 8 to 12 microns.
Blend A
[0128] Lactose monohydrate may be passed through a sieve and then
combined with magnesium stearate (typically 130 g) and blended
using either a high shear mixer (a QMM, PMA or TRV series mixer,
such as TRV25 or TRV65) or a low shear tumbling blender (a Turbula
mixer) to provide a magnesium stearate/lactose premix, hereinafter
referred to as blend A.
Blend B
[0129] Final blend B may be obtained as follows. An appropriate
quantity of blend A and compound (II) triphenylacetate (typically
5-165 g) may be screened, for example using a COMIL.TM., and then
blended with the remaining blend A using either a high shear mixer
(a QMM, PMA or TRV series mixer) or a low shear tumbling blender (a
Turbula mixer). The final concentration of compound (II)
triphenylacetate in the blends is typically in the range 0.02%
w/w-0.8% w/w free base equivalent.
Blister Strip Preparation
[0130] The blended composition is transferred into blister strips
(typical nominal mean quantity of blend B per blister is 12.5-13.5
mg) or the type generally used for the supply of dry powder for
inhalation and the blister strips are then sealed in the customary
fashion.
EXAMPLE PREPARATIONS
[0131] Using the above-described procedure the following exemplary
formulations may be prepared:
TABLE-US-00004 Mass of Mass of compound (II) Blend Magnesium
triphenylacetate Mass of Quantity per No stearate (micronised) |
lactose blister 1 130 g 5.0 g To 13 kg 13 mg 2 130 g 10.3 g To 13
kg 13 mg 3 130 g 20.7 g To 13 kg 13 mg 4 130 g 41.3 g To 13 kg 13
mg 5 130 g 82.7 g To 13 kg 13 mg 6 130 g 165.4 g To 13 kg 13 mg
Note: The quantity of compound (II) triphenylacetate used is based
on a base to salt conversion factor of 1.59. For example, 41 g of
Compound (II) triphenylacetate is equivalent to 25g of the free
base.
Example Blending Parameters (Using a TRV25, 13 kg Scale, Compound
(II) Triphenylacetate Powder Blend (25 Microgram Blister))
TABLE-US-00005 [0132] Blend Time (mins) Approximate Speed (rpm) A 9
550 B 8.5 550
Example Dry Powder Inhaler Devices
[0133] Compound (I) bromide and Compound (II) triphenylacetate as
an inhalation powder may be administered in a DPI device containing
two blister strips. One strip contains a blend of micronised
Compound (I) bromide (approximately 500 micrograms per blister),
magnesium stearate and lactose monohydrate. The second strip
contains a blend of micronised Compound (II) triphenylacetate
(approximately 25 micrograms per blister), magnesium stearate and
lactose monohydrate. The DPI device will deliver, when actuated,
the contents of a single blister simultaneously from each of the
two blister strips. Each blister strip is a double foil laminate
containing 30 blisters per strip.
[0134] In a further embodiment, Compound (I) bromide and Compound
(II) triphenylacetate as an inhalation powder may be administered
in a dry powder inhaler device containing two blister strips,
wherein one strip contains a blend of micronised Compound (I)
bromide (approximately 125 or 62.5 micrograms per blister),
magnesium stearate (at an amount of 0.6% w/w of the total powder
weight per blister) and lactose monohydrate. The second strip
contains a blend of micronised Compound (II) triphenylacetate
(approximately 25 micrograms per blister), magnesium stearate and
lactose monohydrate. The second strip optionally further comprises
6.alpha.,9.alpha.-difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-1-
1.beta.-hydroxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carboth-
ioic acid S-fluoromethyl ester (fluticasone furoate) at an amount
of approximately 100 micrograms per blister. The DPI device will
deliver, when actuated, the contents of a single blister
simultaneously from each of the two blister strips. Each blister
strip is a double foil laminate containing 7, 14 or filled blisters
per strip.
[0135] In a further embodiment, Compound (I) bromide and Compound
(II) triphenylacetate as an inhalation powder may be administered
in a dry powder inhaler device containing two blister strips,
wherein one strip contains a blend of micronised Compound (I)
bromide (approximately 125 or 62.5 micrograms per blister),
Compound (II) triphenylacetate (approximately 25 micrograms per
blister), magnesium stearate and lactose monohydrate. The second
strip contains a blend of
6.alpha.,9.alpha.-difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11.beta.-hy-
droxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic
acid S-fluoromethyl ester (fluticasone furoate) at an amount of
approximately 100 micrograms per blister, and lactose monohydrate.
The DPI device will deliver, when actuated, the contents of a
single blister simultaneously from each of the two blister strips.
Each blister strip is a double foil laminate containing 7, 14 or 30
filled blisters per strip.
[0136] All publications, including but not limited to patents and
patent applications, cited in this specification are herein
incorporated by reference as if each individual publication were
specifically and individually indicated to be incorporated by
reference herein as though fully set forth.
[0137] The above description fully discloses the invention
including preferred embodiments thereof. Modifications and
improvements of the embodiments specifically disclosed herein are
within the scope of the following claims. Without further
elaboration, it is believed that one skilled in the art can, using
the preceding description, utilize the present invention to its
fullest extent. Therefore, the Examples herein are to be construed
as merely illustrative and not a limitation of the scope of the
present invention in any way. The embodiments of the invention in
which an exclusive property or privilege is claimed are defined as
follows.
* * * * *