U.S. patent application number 11/286391 was filed with the patent office on 2006-04-13 for synergistic combination.
This patent application is currently assigned to ALTANA PHARMA AG. Invention is credited to Ulrich Kilian, Christian Schudt.
Application Number | 20060079539 11/286391 |
Document ID | / |
Family ID | 8238828 |
Filed Date | 2006-04-13 |
United States Patent
Application |
20060079539 |
Kind Code |
A1 |
Kilian; Ulrich ; et
al. |
April 13, 2006 |
Synergistic combination
Abstract
The invention relates to the combined administration of PDE
inhibitors and .beta.2 adrenoceptor agonists for the treatment of
respiratory disorders.
Inventors: |
Kilian; Ulrich; (Reichenau,
DE) ; Schudt; Christian; (Konstanz, DE) |
Correspondence
Address: |
Gary M. Nath;NATH & ASSOCIATES PLLC
6th Fl.
1030 15th St.
Washington
DC
20005
US
|
Assignee: |
ALTANA PHARMA AG
|
Family ID: |
8238828 |
Appl. No.: |
11/286391 |
Filed: |
November 25, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10437005 |
May 14, 2003 |
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11286391 |
Nov 25, 2005 |
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10049999 |
Feb 20, 2002 |
6624181 |
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PCT/EP00/07852 |
Aug 11, 2000 |
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10437005 |
May 14, 2003 |
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09367850 |
Aug 27, 1999 |
6333354 |
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PCT/EP98/01047 |
Feb 24, 1998 |
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10049999 |
Feb 20, 2002 |
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Current U.S.
Class: |
514/263.31 ;
514/424; 514/651 |
Current CPC
Class: |
A61K 31/44 20130101;
A61K 31/52 20130101; A61K 31/4015 20130101; A61P 43/00 20180101;
A61K 31/44 20130101; A61K 31/4015 20130101; A61K 31/52 20130101;
A61K 31/44 20130101; A61K 31/138 20130101; A61K 2300/00 20130101;
A61K 31/44 20130101; A61K 31/44 20130101; A61K 2300/00 20130101;
A61K 31/27 20130101; A61K 31/135 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61P 11/08 20180101; A61K 2300/00 20130101;
A61P 11/00 20180101; A61K 31/138 20130101; A61P 11/06 20180101;
A61K 31/522 20130101; A61K 45/06 20130101; A61K 31/522 20130101;
A61K 31/52 20130101 |
Class at
Publication: |
514/263.31 ;
514/651; 514/424 |
International
Class: |
A61K 31/522 20060101
A61K031/522; A61K 31/4015 20060101 A61K031/4015; A61K 31/138
20060101 A61K031/138 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 21, 1999 |
AT |
EP 99116447.6 |
Claims
1-12. (canceled)
13. A pharmaceutical composition comprising a PDE inhibitor, which
is to be administered orally, from the PDE4 or PDE3/4 inhibitors
group combined with a .beta..sub.2 adrenoceptor agonist in fixed or
free combination, wherein said PDE inhibitor is selected from the
group consisting of roflumilast; AWD-12-281; SB-207499; arofylline;
ibudilast; a pharmacologically tolerable hydrate, solvate, salt,
hydrate of a salt, or solvate of a salt thereof; and an N-oxide of
roflumilast, and wherein said .beta..sub.2 adrenoceptor agonist is
selected from the group consisting of
4-hydroxy-3-hydroxymethyl-.alpha.-[(tert-butylamino)methyl]benzyl
alcohol (salbutamol);
(R)-4-hydroxy-3-hydroxymethyl-.alpha.-[(tert-butylamino)methyl]benzyl
alcohol (levosalbutamol);
1-(3,5-dihydroxyphenyl)-2-(tert-butylamino)-ethanol (terbutaline);
2-hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-tert-butylaminoethyl)pyridine
(pirbuterol);
(R*,R*)-(.+-.)-N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methyl-
ethyl]amino]ethyl]phenyl]formamide (formoterol);
(.+-.)-4-hydroxy-.alpha..sup.1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1-
,3-benzenedimethanol (salmeterol); and a pharmacologically
tolerable hydrate, solvate, salt, hydrate of a salt or solvate of a
salt thereof.
14. The pharmaceutical composition as claimed in claim 13, which is
a fixed oral combination.
15. The pharmaceutical composition as claimed in claim 13, wherein
the PDE inhibitor is a compound selected from the group consisting
of arofylline; ibudilast; SB-207499; and a pharmacologically
tolerable hydrate, solvate, salt, hydrate of a salt or solvate of a
salt thereof.
16. The pharmaceutical composition as claimed in claim 13, wherein
the PDE inhibitor is roflumilast or a pharmacologically tolerable
hydrate, solvate, salt, hydrate of a salt or solvate of a salt
thereof, or an N-oxide of roflumilast.
17. The pharmaceutical composition as claimed in claim 13, wherein
the PDE inhibitor is roflumilast or a pharmacologically tolerable
hydrate, solvate, salt, hydrate of a salt or solvate of a salt
thereof, or an N-oxide of roflumilast, and the .beta..sub.2
adrenoceptor agonist is
(.+-.)-4-hydroxy-.alpha..sup.1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1-
,3-benzenedimethanol (salmeterol) or a pharmacologically tolerable
hydrate, solvate, salt, hydrate of a salt or solvate of a salt
thereof.
18. The pharmaceutical composition as claimed in claim 13, wherein
the .beta..sub.2 adrenoceptor agonist is selected from the group
consisting of
4-hydroxy-3-hydroxymethyl-.alpha.-[(tert-butylamino)methyl]benzyl
alcohol (salbutamol); 1-(3,5-dihydroxyphenyl)-2-(tert-butylamino)
ethanol (terbutaline); and a pharmacologically tolerable hydrate,
solvate, salt, hydrate of a salt or solvate of a salt thereof.
19. The pharmaceutical composition as claimed in claim 13, wherein
the PDE inhibitor is selected from the group consisting of
arofylline; ibudilast; SB-207499; and a pharmacologically tolerable
hydrate, solvate, salt, hydrate of a salt or solvate of a salt
thereof, and the .beta..sub.2 adrenoceptor agonist is selected from
the group consisting of
4-hydroxy-3-hydroxymethyl-.alpha.-[(tert-butylamino)methyl]benzyl
alcohol (salbutamol);
1-(3,5-dihydroxyphenyl)-2-(tert-butylamino)ethanol (terbutaline);
and a pharmacologically tolerable hydrate, solvate, salt, hydrate
of a salt or solvate of a salt thereof.
20. The pharmaceutical composition as claimed in claim 13, wherein
the PDE inhibitor is roflumilast or a pharmacologically tolerable
hydrate, solvate, salt, hydrate of a salt or solvate of a salt
thereof, or an N-oxide of roflumilast, and the .beta..sub.2
adrenoceptor agonist is selected from the group consisting of
4-hydroxy-3-hydroxymethyl-.alpha.-[(tert-butylamino)methyl]benzyl
alcohol (salbutamol);
1-(3,5-dihydroxyphenyl)-2-(tert-butylamino)ethanol (terbutaline);
and a pharmacologically tolerable hydrate, solvate, salt, hydrate
of a salt or solvate of a salt thereof.
21. A method of treating a respiratory tract disorder in a patient,
comprising administering a therapeutically effective amount of a
PDE inhibitor from the PDE4- or PDE3/4 inhibitors group in
combination with a .beta..sub.2 adrenoceptor agonist to said
patient, wherein said PDE inhibitor is administered orally, wherein
said PDE inhibitor is selected from the group consisting of
roflumilast; AWD-12-281; SB-207499; arofylline; ibudilast; a
pharmacologically tolerable hydrate, solvate, salt, hydrate of a
salt, or solvate of a salt thereof; and an N-oxide of roflumilast,
and wherein said .beta..sub.2 adrenoceptor agonist is selected from
the group consisting of
4-hydroxy-3-hydroxymethyl-.alpha.-[(tert-butylamino)methyl]benzyl
alcohol (salbutamol);
(R)-4-hydroxy-3-hydroxymethyl-.alpha.-[(tert-butylamino)methyl]benzyl
alcohol (levosalbutamol);
1-(3,5-dihydroxyphenyl)-2-(tert-butylamino)-ethanol (terbutaline);
2-hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-tert-butylaminoethyl)pyridine
(pirbuterol);
(R*,R*)-(.+-.)-N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methyl-
ethyl]amino]ethyl]phenyl]formamide (formoterol);
(.+-.)-4-hydroxy-.alpha..sup.1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1-
,3-benzenedimethanol (salmeterol); and a pharmacologically
tolerable hydrate, solvate, salt, hydrate of a salt or solvate of a
salt thereof.
22. The pharmaceutical composition as claimed in claim 13, wherein
the PDE inhibitor is roflumilast or a pharmacologically tolerable
hydrate, solvate, salt, hydrate of a salt or solvate of a salt
thereof, or an N-oxide of roflumilast, and the .beta..sub.2
adrenoceptor agonist is
(R*,R*)-(.+-.)-N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methyl-
ethyl]amino]ethyl]phenyl]formamide (formoterol) or a
pharmacologically tolerable hydrate, solvate, salt, hydrate of a
salt or solvate of a salt thereof.
23. The pharmaceutical composition as claimed in claim 13, which
additionally contains an excipient selected from the group
consisting of propellants, surface-active substances, emulsifiers,
stabilizers, preservatives, flavorings, fillers, solvents,
gel-forming agents, tablet excipients, antioxidants, dispersants,
antifoams, flavor corrigents, solubilizers, colorants or permeation
promoters, and complexing agents.
24. The method of claim 21, wherein the respiratory tract disorder
is an allergen-induced or inflammation-induced bronchial
disorder.
25. The method of claim 24, wherein the allergen-induced or
inflammation-induced bronchial disorder is selected from the group
consisting of bronchitis, obstructive bronchitis, spastic
bronchitis, allergic bronchitis, allergic asthma, bronchial asthma,
and COPD.
26. The method of claim 21, wherein the PDE inhibitor and the
.beta..sub.2 adrenoceptor agonist are administered
simultaneously.
27. The method of claim 21, wherein the PDE inhibitor and the
.beta..sub.2 adrenoceptor agonist are administered more or less
simultaneously.
28. The method of claim 21, wherein the PDE inhibitor and the
.beta..sub.2 adrenoceptor agonist are administered in
succession.
29. A method of treating a respiratory tract disorder in a patient,
comprising administering to said patient a therapeutically
effective amount of the pharmaceutical composition as claimed in
claim 17.
30. The method of claim 29, wherein the respiratory tract disorder
is an allergen-induced or inflammation-induced bronchial
disorder.
31. The method of claim 30, wherein the allergen-induced or
inflammation-induced bronchial disorder is selected from the group
consisting of bronchitis, obstructive bronchitis, spastic
bronchitis, allergic bronchitis, allergic asthma, bronchial asthma,
and COPD.
32. The method of claim 29, wherein the PDE inhibitor and the
.beta..sub.2 adrenoceptor agonist are administered
simultaneously.
33. The method of claim 29, wherein the PDE inhibitor and the
.beta..sub.2 adrenoceptor agonist are administered more or less
simultaneously.
34. The method of claim 29, wherein the PDE inhibitor and the
.beta..sub.2 adrenoceptor agonist are administered in
succession.
35. A method of treating a respiratory tract disorder in a patient,
comprising administering to said patient a therapeutically
effective amount of the pharmaceutical composition as claimed in
claim 20.
36. The method of claim 35, wherein the respiratory tract disorder
is an allergen-induced or inflammation-induced bronchial
disorder.
37. The method of claim 36, wherein the allergen-induced or
inflammation-induced bronchial disorder is selected from the group
consisting of bronchitis, obstructive bronchitis, spastic
bronchitis, allergic bronchitis, allergic asthma, bronchial asthma,
and COPD.
38. The method of claim 35, wherein the PDE inhibitor and the
.beta..sub.2 adrenoceptor agonist are administered
simultaneously.
39. The method of claim 35, wherein the PDE inhibitor and the
.beta..sub.2 adrenoceptor agonist are administered more or less
simultaneously.
40. The method of claim 35, wherein the PDE inhibitor and the
.beta..sub.2 adrenoceptor agonist are administered in
succession.
41. A method of treating a respiratory tract disorder in a patient,
comprising administering to said patient a therapeutically
effective amount of the pharmaceutical composition as claimed in
claim 22.
42. The method of claim 41, wherein the respiratory tract disorder
is an allergen-induced or inflammation-induced bronchial
disorder.
43. The method of claim 42, wherein the allergen-induced or
inflammation-induced bronchial disorder is selected from the group
consisting of bronchitis, obstructive bronchitis, spastic
bronchitis, allergic bronchitis, allergic asthma, bronchial asthma,
and COPD.
44. The method of claim 41, wherein the PDE inhibitor and the
.beta..sub.2 adrenoceptor agonist are administered
simultaneously.
45. The method of claim 41, wherein the PDE inhibitor and the
.beta..sub.2 adrenoceptor agonist are administered more or less
simultaneously.
46. The method of claim 41, wherein the PDE inhibitor and the
.beta..sub.2 adrenoceptor agonist are administered in succession.
Description
FIELD OF APPLICATION OF THE INVENTION
[0001] The invention relates to the combination of certain known
active compounds for therapeutic purposes.
[0002] The substances used in the combination according to the
invention are known active compounds from the PDE inhibitors class
and active compounds from the .beta..sub.2 adrenoceptor agonists
class. Their combined use in the sense according to the invention
for therapeutic purposes has not yet been described in the prior
art.
DESCRIPTION OF THE INVENTION
[0003] It is the object of the present invention to make available
respiratory tract therapeutics which fulfill the following
conditions: [0004] Good antiinflammatory action [0005] Marked
bronchorelaxation and -dilatation [0006] Good oral availability, at
least with respect to the PDE inhibitor [0007] Minor side effects
[0008] Good suitability for long-term therapy [0009] Favorable
influence on bronchial hyperreactivity.
[0010] It has now been found that the combined use of a PDE
inhibitor which can be used as a respiratory tract therapeutic and
of a .beta..sub.2 adrenoceptor agonist outstandingly fulfills the
abovementioned conditions.
[0011] The invention thus relates to the combined use of a PDE
inhibitor which can be used as a respiratory tract therapeutic and
a .beta..sub.2 adrenoceptor agonist in the treatment of respiratory
tract disorders.
[0012] PDE inhibitors which can be used as respiratory tract
therapeutics in the sense of the present invention are those
compounds which slow the breakdown of cyclic AMP (cAMP) or cyclic
GMP (cGMP) by inhibition of the phosphodiesterases, which can lead
to a relative increase in the intracellular concentration of cAMP
or cGMP.
[0013] Possible PDE inhibitors within the meaning of the present
invention are primarily those substances which are to be considered
part of the PDE4 inhibitor class and those substances which can be
designated as mixed types of PDE3/4 inhibitors. By way of example,
those PDE inhibitors may be mentioned which are described or
claimed in the following patent applications and patents: DE
1545687, DE 2028869, DE 2123328, DE 2315801, DE 2402908, DE
2413935, DE 3900233, EP 0103497, EP 0139464, EP 0158380, EP
0163965, EP 0335386, EP 0389282, EP 0428302, EP 0435811, EP
0459505, EP 0470805, EP 0490823, EP 0506194, EP 0511865, EP
0527117, EP 0557016, EP 0626939, EP 0664289, EP 0671389, EP
0685474, EP 0685475, EP 0685479, EP 0736532, EP 0738715, EP
0748805, EP 0763534, EP 0816357, EP 0819688, EP 0819689, EP
0832886, EP 0834508, EP 0848000, JP 92234389, JP 94329652, JP
95010875, JP 98072415, JP 98147585, U.S. Pat. No. 5703098, U.S.
Pat. No. 5739144, WO 9117991, WO 9200968, WO 9212961, WO 9307146,
WO 9315044, WO 9315045, WO 9318024, WO 9319068, WO 9319720, WO
9319747, WO 9319749, WO 9319751, WO 9325517, WO 9402465, WO
9412461, WO 9420455, WO 9422852, WO 9427947, WO 9501338, WO
9501980, WO 9503794, WO 9504045, WO 9504046, WO 9505386, WO
9508534, WO 9509623, WO 9509624, WO 9509627, WO 9509836, WO
9514667, WO 9514680, WO 9514681, WO 9517392, WO 9517399, WO
9519362, WO 9520578, WO 9522520, WO 9524381, WO 9527692, WO
9535281, WO 9535283, WO 9535284, WO 9600218, WO 9601825, WO
9606843, WO 9611690, WO 9611917, WO 9612720, WO 9631486, WO
9631487, WO 9635683, WO 9636595, WO 9636596, WO 9636611, WO
9636625, WO 9636638, WO 9638150, WO 9639408, WO 9640636, WO
9703967, WO 9704779, WO 9705105, WO 9708143, WO 9709345, WO
9712895, WO 9718208, WO 9719078, WO 9720833, WO 9722585, WO
9722586, WO 9723457, WO 9723460, WO 9723461, WO 9724117, WO
9724355, WO 9725312, WO 9728131, WO 9730999, WO 9731000, WO
9732853, WO 9735854, WO 9736905, WO 9743288, WO 9744036, WO
9744322, WO 9747604, WO 9748697, WO 9804534, WO 9805327, WO
9806692, WO 9806704, WO 9807715, WO 9808828, WO 9808830, WO
9808841, WO 9808844, WO 9809946, WO 9809961, WO 9811113, WO
9814448, WO 9818796, WO 9821208, WO 9822453, WO 9845268, WO
9855481, WO 9856756, WO 9905111, WO 9905112, WO 9505113, WO 9906404
and WO 9918095. Those PDE inhibitors are to be emphasized which are
claimed in the patent applications or patents EP 0393500, EP
0510562, EP 0553174, WO 9501338, WO 9603399, WO 9636625, WO
9636626, WO 9735854, WO 9821208, WO 9831674, WO 9840382, WO
9855481, WO 9905111, WO 9905112, WO 9905113, WO 9931071 and WO
9931090. Substances having good oral availability are preferred
here.
[0014] Exemplary PDE inhibitors are shown on the following pages
with the aid of their formulae: ##STR1## ##STR2## ##STR3## ##STR4##
##STR5## ##STR6## ##STR7## ##STR8## ##STR9## ##STR10## ##STR11##
##STR12## ##STR13## ##STR14## ##STR15## ##STR16## ##STR17##
##STR18## ##STR19## ##STR20## ##STR21## ##STR22## ##STR23##
##STR24## ##STR25## ##STR26## ##STR27## ##STR28## ##STR29##
##STR30## ##STR31## ##STR32## ##STR33## ##STR34## ##STR35##
##STR36## ##STR37## ##STR38## ##STR39## ##STR40## ##STR41##
##STR42## ##STR43## ##STR44## ##STR45## ##STR46## ##STR47##
##STR48## ##STR49## ##STR50## ##STR51## ##STR52## ##STR53##
[0015] No hydrogen atoms are indicated in the above formulae. --O
is accordingly-OH, --N is NH.sub.2. Methyl groups, e.g. on the
oxygen atoms, are indicated by lines.
[0016] PDE inhibitors to be emphasized which are selected from the
abovementioned compounds and which may be mentioned are the active
compounds arofylline, atizoram, AWD-12-281, BAY-19-8004,
benafentrine, BYK-33043, CC-3052, CDP-840, CI-1018, cipamfylline,
CP-220629, CP-293121, D-22888, D-4396, D-4418, denbufylline,
filaminast, GW-3600, ibudilast, KF-17625, KS-506-G, laprafylline,
NA-0226A, NA-23063A, ORG-20241, ORG-30029, PDB-093, pentoxifylline,
piclamilast, roflumilast, rolipram, RPR-117658, RPR-122818,
RPR-132294, RPR-132703, RS-17597, RS-25344-000, SB-207499,
SB-210667, SB-211572, SB-211600, SB-212066, SB-212179, SDZ-ISQ-844,
SDZ-MNS-949, SKF-107806, SQ-20006, T-2585, T-440, tibenelast,
tolafentrine, UCB-29646, V-11294A, YM-58997, YM-976 and
zardaverine.
[0017] The compounds preferred from the group of the abovementioned
PDE inhibitors are arofylline, cipamfylline, D-4418, filaminast,
ibudilast, laprafylline, ORG-20241, piclamilast, rolipram,
SB-207499, tibenelast and V-11294A. The compounds particularly
preferred are BYK-33043 and in particular roflumilast.
[0018] .beta..sub.2 adrenoceptor agonists which may particularly be
mentioned are those selectively acting substances which only have a
slight cardiac action and therefore are also employed in therapy,
in particular in the oral therapy of respiratory tract disorders.
.beta..sub.2 adrenoceptor agonists which may be mentioned are, for
example: AR-C68397AA, broxaterol, CHF-1035, HOKU-81, ibuterol,
KUL-1248, soterenol, meluadrine, TA-2005, tiaramide, salbutamol,
levosalbutamol, tulobuterol, terbutaline, carbuterol, pirbuterol,
reproterol, clenbuterol, fenoterol, hexoprenaline, orciprenaline,
isoprenaline, formoterol, salmeterol, rimiterol, procaterol,
bambuterol, bitolterol and mabuterol. The orally readily available
.beta..sub.2 adrenoceptor agonists such as clenbuterol,
orciprenaline, salbutamol, terbutaline, tulobuterol, bambuterol and
reproterol are preferred. Particularly preferred are the so-called
long acting .beta..sub.2 adrenoceptor agonists, such as
salmeterol.
[0019] The PDE inhibitors and the .beta..sub.2 adrenoceptor
agonists can be present as such or in chemically bonded form. It is
understood hereby that the active compounds mentioned can also be
present, for example, in the form of their pharmacologically
tolerable salts and/or as solvates (e.g. hydrates), and/or in the
form of their N-oxides etc. Suitable pharmacologically tolerable
salts here are in particular water-soluble and water-insoluble acid
addition salts with acids such as, for example, hydrochloric acid,
hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid,
acetic acid, citric acid, D-gluconic acid, benzoic acid,
2-(4-hydroxybenzoyl)-benzoic acid, butyric acid, sulfosalicylic
acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic
acid, oxalic acid, tartaric acid, embonic acid, stearic acid,
toluenesulfonic acid, methanesulfonic acid or 1-hydroxy-2-naphthoic
acid, the acids being employed in salt preparation--depending on
whether it is a mono- or polybasic acid and depending on which salt
is desired--in an equimolar quantitative ratio or one differing
therefrom. Furthermore, the active compounds mentioned can also be
present as pure enantiomers or as enantiomer mixtures in any mixing
ratio.
[0020] Respiratory tract disorders which may be mentioned are in
particular allergen- and inflammation-induced bronchial disorders
(bronchitis, obstructive bronchitis, spastic bronchitis, allergic
bronchitis, allergic asthma, bronchial asthma, COPD), which can be
treated by the combination according to the invention also in the
sense of a long-term therapy (if desired with appropriate
adjustment of the dose of the individual components to the needs at
the time, for example needs subject to seasonally related
variations).
[0021] "Combined use" or "combination" within the meaning of the
present invention is to be understood as meaning that the
individual components can be administered simultaneously (in the
form of a combination medicament), more or less simultaneously
(from separate pack units) or in succession (directly in succession
or else alternatively at a relatively large time interval) in a
manner which is known per se and customary.
[0022] Within the meaning of the present invention, "use" is
preferably understood as meaning the oral administration of both
active compounds. If only the PDE inhibitor is administered orally,
"use" with respect to the .beta..sub.2 adrenoceptor agonist is
understood in particular as meaning topical application in
inhalatory form. For this, the .beta..sub.2 adrenoceptor agonist is
preferably administered by inhalation in the form of an aerosol,
the aerosol particles of solid, liquid or mixed composition having
a diameter of 0.5 to 10 .mu.m, advantageously of 2 to 6 .mu.m.
[0023] Aerosol generation can be carried out, for example, by
pressure-driven jet atomizers or ultrasonic atomizers, but
advantageously by propellant-driven metered aerosols or
propellant-free administration of micronized active compounds from
inhalation capsules.
[0024] The active compounds are dosed in an order of magnitude
customary for the individual dose, it more likely being possible,
on account of the individual actions, which are mutually positively
influencing and reinforcing, to reduce the respective doses on the
combined administration of the active compounds compared with the
norm. Customarily, the .beta..sub.2 adrenoceptor agonist (depending
on potency) is administered in a dose of, for example, 0.002 to 2.0
mg per day on administration by inhalation.
[0025] Depending on the inhaler system used, in addition to the
active compounds the administration forms additionally contain the
required excipients, such as, for example, propellants (e.g. Frigen
in the case of metered aerosols), surface-active substances,
emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g.
lactose in the case of powder inhalers) or, if appropriate, further
active compounds.
[0026] For the purposes of inhalation, a large number of
apparatuses are available with which aerosols of optimum particle
size can be generated and administered, using an inhalation
technique which is as right as possible for the patient. In
addition to the use of adaptors (spacers, expanders) and
pear-shaped containers (e.g. Nebulator.RTM., Volumatic.RTM.)), and
automatic devices emitting a puffer spray (Autohaler.RTM.), for
metered aerosols, in particular in the case of powder inhalers, a
number of technical solutions are available (e.g. Diskhaler.RTM.,
Rotadisk.RTM., Turbohaler.RTM. or the inhaler described in European
Patent Application EP 0 505 321), using which an optimal
administration of active compound can be achieved.
[0027] In the case of the oral administration of the .beta..sub.2
adrenoceptor agonists together with the PDE inhibitor, which is the
preferred administration form, the .beta..sub.2 adrenoceptor
agonist is administered in a daily dose of, for example, 0.05 to 60
mg. For the PDE inhibitors, it is possible in the case of oral
administration to vary the doses--depending on the active
compound--within a wide range, it being possible, as bounds, to
start from a dose of 1-2000 .mu.g/kg of body weight. In the case of
the administration of the preferred PDE inhibitor roflumilast, the
dose is in the range from 2-20 .mu.g/kg of body weight.
[0028] The PDE inhibitors to be administered orally are
formulated--if appropriate together with the .beta..sub.2
adrenoceptor agonists--to give medicaments according to processes
known per se and familiar to the person skilled in the art. The
pharmacologically active compounds are employed as medicaments,
preferably in combination with suitable pharmaceutical excipients
or vehicles, in the form of tablets, coated tablets, capsules,
emulsions, suspensions or solutions, the active compound content
advantageously being between 0.1 and 95% and, by the appropriate
choice of the excipients and vehicles, it being possible to achieve
a pharmaceutical administration form precisely tailored to the
active compound(s) and/or to the desired onset of action (e.g. a
sustained-release form or an enteric form). Particularly worthy of
mention within the meaning of the combined, oral administration of
both active compounds according to the invention are oral
administration forms, e.g. tablets or capsules, in which one part
of the .beta..sub.2 adrenoceptor agonist and the PDE inhibitor is
present in non sustained-release form and a further, preferably
larger part, of the .beta..sub.2 adrenoceptor agonist is present in
sustained-release form.
[0029] The person skilled in the art is familiar on the basis of
his/her expert knowledge with which excipients or vehicles are
suitable for the desired pharmaceutical formulations. In addition
to solvents, gel-forming agents, tablet excipients and other active
compound carriers, it is possible to use, for example,
antioxidants, dispersants, emulsifiers, antifoams, flavor
corrigents, preservatives, solubilizers, colorants or permeation
promoters and complexing agents (e.g. cyclodextrins).
Pharmacology
Model
[0030] Late Inflammatory Airway Reaction in the
Ovalbumin-sensitized/-challenged Brown-Norway Rat
[0031] Anti-inflammatory activity of Roflumilast, Pumafentrine
(BYK-33043), and Salmeterol was determined in ovalbumin
(OVA)-sensitized and OVA-challenged Brown Norway rats.
Sensitization was done by simultaneous injection of Bordetella
pertussis suspension i.p. and OVA/AHG suspension s.c. on day 1, 14
and 21. 28 days after start of sensitization, conscious
Brown-Norway rats were challenged by inhalation of the aerosolized
OVA solution for 1 h (.about.20 ml/h). Non-challenged, only
sensitized animals were used as baseline control. The drugs
(thoroughly mixed with lactose) or the placebo control (lactose)
were administered intratracheally (i.t.) as dry powders 1 h before
OVA-challenge. 48 h later, OVA-challenged or non-challenged animals
were anaesthetized and bronchoalveolar lavage (BAL) was performed
using 3.times.4 ml BAL buffer per animal. The number of total cells
and eosinophils in the BAL fluid, and the concentration of protein
in the cell-free BAL fluid were determined. Drug-induced relative
changes were calculated and statistically analyzed by the
Jonckheere Terpstra test.
[0032] Results TABLE-US-00001 Dose % Inhibition of Infiltration/
PDE3/4 [.mu.mol/ Appl. Accumulation [Median/Mean .+-. SEM] Compound
IC50[.mu.mol] kg] Route N Total cells EOS Protein Roflumilast
>10/0.0007 0.3 it 8 -25 -15 -8 -37.6 .+-. 26.7 -22 .+-. 25.7
-22.3 .+-. 25.5 Pumafentrine 0.028/0.007 3 it 8 -19 -26 17 -39.1
.+-. 30.5 -28.5 .+-. 30.1 23.5 .+-. 10.6 Salmeterol 3 it 8 19 39 44
6.3 .+-. 17.9 31 .+-. 14.8 37.5 .+-. 16.2 Salmeterol/ 3/0.3 it 8 50
67 ** 59 ** Roflumilast 34.5 .+-. 21.1 61.1 .+-. 7.9 ** 50.8 .+-.
13.6 ** Salmeterol/ 3/3 it 8 56 * 85 ** 75 ** Pumafentrine 58.1
.+-. 12.3 * 83 .+-. 3.7 ** 67.1 .+-. 11.1 ** * p < 0.05, ** p
< 0.01 v.s. untreated, OVA-challenged control groups
Summary
[0033] The PDE inhibitors Roflumilast (PDE4 inhibitor) and
Pumafentrine (PDE3>4 inhibitor) administered at doses of 0.3
.mu.mol/kg and 3 .mu.mol/kg i.t., respectively, did not show any
significant effects on cell infiltration and protein accumulation.
The negative values obtained (trend: amplification of inflammation)
fall into the range of biological variability of the model and
therefore, no significance must be attached to these data.
[0034] In contrast, the long-acting .beta.2-adrenergic receptor
agonist Salmeterol given at a dose of 3 .mu.mol/kg i.t exhibited
inhibitory effects on total cell and eosinophil influx into
alveolar space and protein levels in BAL fluid. However, the data
failed to reach significance.
[0035] Co-administration of the PDE inhibitor Roflumilast or
Pumafentrine with Salmeterol resulted in synergistic effects
compared to administration of every compound alone, i.e. both PDE
inhibitors combined with the .beta.2 agonist displayed a
significant inhibition of eosinophilia and reduction of protein
concentration in the BAL fluid. The combination of the PDE3/4
inhibitor Pumafentrine and Salmeterol was more efficacious on all
parameters measured (difference was not significant), and
additionally, showed a significant effect on inhibition of total
cell influx into the alveolar space.
* * * * *