U.S. patent application number 11/759763 was filed with the patent office on 2008-03-13 for pharmaceutical compositions for inhalation containing an anticholinergic, corticosteroid, and betamimetic.
This patent application is currently assigned to Boehringer Ingelheim Pharma GmbH & Co. KG. Invention is credited to Christopher John Montague Meade, Michel Pairet, Michael Paul Pieper.
Application Number | 20080063608 11/759763 |
Document ID | / |
Family ID | 33424349 |
Filed Date | 2008-03-13 |
United States Patent
Application |
20080063608 |
Kind Code |
A1 |
Pieper; Michael Paul ; et
al. |
March 13, 2008 |
Pharmaceutical Compositions for Inhalation Containing an
Anticholinergic, Corticosteroid, and Betamimetic
Abstract
A pharmaceutical composition comprising: (a) an anticholinergic
of formula 1 ##STR1## wherein X.sup.- is an anion with a single
negative charge; (b) a corticosteroid; and (c) a betamimetic,
wherein each component (a), (b), and (c) are optionally in the form
of the solvates or hydrates thereof, processes for preparing them,
and their use in the treatment of respiratory diseases.
Inventors: |
Pieper; Michael Paul;
(Biberach, DE) ; Meade; Christopher John Montague;
(Bingen, DE) ; Pairet; Michel; (Biberach,
DE) |
Correspondence
Address: |
MICHAEL P. MORRIS;BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY ROAD
P. O. BOX 368
RIDGEFIELD
CT
06877-0368
US
|
Assignee: |
Boehringer Ingelheim Pharma GmbH
& Co. KG
Ingelheim
DE
|
Family ID: |
33424349 |
Appl. No.: |
11/759763 |
Filed: |
June 7, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10625129 |
Jul 23, 2003 |
7244742 |
|
|
11759763 |
Jun 7, 2007 |
|
|
|
60413177 |
Sep 24, 2002 |
|
|
|
Current U.S.
Class: |
424/46 ; 514/171;
514/291 |
Current CPC
Class: |
A61K 9/008 20130101;
A61K 45/06 20130101; A61K 9/0075 20130101 |
Class at
Publication: |
424/046 ;
514/171; 514/291 |
International
Class: |
A61K 9/14 20060101
A61K009/14; A61K 31/4745 20060101 A61K031/4745; A61K 31/56 20060101
A61K031/56 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 17, 2002 |
DE |
102 37 739 |
Claims
1-21. (canceled)
22. A pharmaceutical composition comprising: (a) an anticholinergic
of formula 1 ##STR4## wherein X.sup.- is an anion with a single
negative charge; (b) a corticosteroid; and (c) a betamimetic,
wherein each component (a), (b), and (c) is optionally in the form
of a solvate or hydrate thereof, and wherein the pharmaceutical
composition is suitable for inhalation and a propellant-containing
aerosol composition containing the anticholinergic, the
corticosteroid, and the betamimetic in dissolved or dispersed
form.
23. The propellant-containing aerosol composition according to
claim 22, wherein the propellant gas is a hydrocarbon or
halohydrocarbon or a mixture thereof.
24. The propellant-containing aerosol composition according to
claim 23, wherein the propellant gas is selected from n-propane,
n-butane, isobutane, or the chlorinated and/or fluorinated
derivatives of methane, ethane, propane, butane, cyclopropane, or
cyclobutane, or a mixture thereof.
25. The propellant-containing aerosol composition according to
claim 22, wherein the propellant gas is TG134a, TG227, or a mixture
thereof
26. The propellant-containing aerosol composition according to one
of claims 22 to 25, further comprising a cosolvent, stabilizer,
surfactant, antioxidant, lubricant, or means for adjusting the pH,
or mixture thereof.
27. The propellant-containing aerosol composition according to one
of claims 22 to 25, wherein the total amount of the
anticholinergic, the corticosteroid, and the betamimetic is up to 5
wt.-% of the composition.
Description
RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 10/625,129, filed Jul. 23, 2003, which claims priority to
U.S. Ser. No. 60/413,177, filed Sep. 24, 2002, and German
Application No. 102 37 739.1, filed Aug. 17, 2002, each of which is
hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to novel pharmaceutical
compositions based on a new anticholinergic, and corticosteroids
and betamimetics, processes for preparing them, and their use in
the treatment of respiratory diseases.
BRIEF DESCRIPTION OF THE DRAWINGS
[0003] FIG. 1a: shows an inhaler for use in pharmaceutical
compositions according this invention.
[0004] FIG. 2a: shows a longitudinal section through the atomizer
with the spring under tension.
[0005] FIG. 2b: shows a longitudinal section through the atomizer
with the spring released.
DESCRIPTION OF THE INVENTION
[0006] The present invention relates to novel pharmaceutical
compositions for inhalation based on a new anticholinergic, and
corticosteroids and betamimetics, processes for preparing them, and
their use in the treatment of respiratory diseases.
[0007] Surprisingly, an unexpectedly beneficial therapeutic effect,
particularly a synergistic effect can be observed in the treatment
of inflammatory or obstructive diseases of the respiratory tract if
a new anticholinergic is used with one or more corticosteroids and
with one or more betamimetics. In view of this synergistic effect,
the pharmaceutical combinations according to the invention can be
used in smaller doses than would be the case with the individual
compounds used in monotherapy in the usual way. This reduces
unwanted side effects such as may occur when, for example,
corticosteroids and betamimetics are administered.
[0008] The effects mentioned above may be observed both when the
three active substances are administered simultaneously in a single
active substance formulation and when they are administered
successively in separate formulations. According to the invention,
it is preferable to administer the active substance ingredients
simultaneously in a single formulation. The pharmaceutical
compositions according to the invention are preferably administered
by inhalation according to the invention.
[0009] Within the scope of the present invention the
anticholinergics used are the salts of formula 1 ##STR2##
[0010] wherein: [0011] X.sup.- denotes an anion with a single
negative charge, preferably an anion selected from the group
consisting of chloride, bromide, iodide, sulfate, phosphate,
methanesulfonate, nitrate, maleate, acetate, citrate, fumarate,
tartrate, oxalate, succinate, benzoate, and p-toluenesulfonate.
[0012] Preferably, the salts of formula 1 are used wherein: [0013]
X.sup.- denotes an anion with a single negative charge selected
from the group consisting of chloride, bromide, 4-toluenesulfonate,
and methanesulfonate, preferably bromide.
[0014] Most preferably, the salts of formula 1 are used wherein:
[0015] X.sup.- denotes an anion with a single negative charge
selected from the group consisting of chloride, bromide, and
methanesulfonate, preferably bromide.
[0016] Particularly preferred according to the invention is the
salt of formula 1 wherein X.sup.- denotes bromide.
[0017] The salts of formula 1 are known from International Patent
Application WO 02/32899. Any reference to the salts of formula 1
includes a reference to any hydrates and solvates thereof which may
be obtained.
[0018] Within the scope of the present patent application, an
explicit reference to the pharmacologically active cation of
formula ##STR3## can be recognized by the use of the designation
1'. Any reference to compounds 1 naturally includes a reference to
the cation 1'.
[0019] Within the scope of the present invention, the word
corticosteroids (hereinafter 2) denotes compounds selected from
among flunisolide, beclomethasone, triamcinolone, budesonide,
fluticasone, mometasone, ciclesonide, rofleponide, GW 215864, KSR
592, ST-126, and dexamethasone. Preferably, compound 2 is selected
from among flunisolide, beclomethasone, triamcinolone, budesonide,
fluticasone, mometasone, ciclesonide, and dexamethasone. Most
preferably, compound 2 is selected from among budesonide,
fluticasone, mometasone, and ciclesonide. In some cases, within the
scope of the present patent application, the term steroids 2 may
also be used on its own instead of the word corticosteroids 2.
[0020] Any reference to steroids 2 within the scope of the present
invention includes a reference to salts or derivatives 2' which may
be formed from the steroids. Examples of possible salts or
derivatives 2' include: sodium salts, sulfobenzoates, phosphates,
isonicotinates, acetates, propionates, dihydrogen phosphates,
palmitates, pivalates, or furoates. In some cases, the compounds of
formula 2 may also occur in the form of their hydrates.
[0021] Examples of betamimetics 3 which may be used according to
the invention include bambuterol, bitolterol, carbuterol,
clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol,
pirbuterol, procaterol, reproterol, salmeterol, sulfonterol,
terbutaline, tolubuterol,
4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}ethyl]amino}ethyl]-
-2(3H)-benzothiazolone,
1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamin-
o]ethanol,
1-[3-(4-methoxybenzylamino)-4-hydroxyphenyl]-2-[4-(1-benzimidaz-
olyl)-2-methyl-2-butylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminoph-
enyl)-2-methyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-me-
thyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-
-methyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1-
,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,
5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-on-
e,
1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert-butylamino)ethanol,
or
1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)et-
hanol.
[0022] According to the invention, the following betamimetics 3 are
preferably used in the active substance combination: formoterol,
salmeterol,
4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}ethyl]amino}ethyl]-
-2(3H)-benzothiazolone,
1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamin-
o]ethanol,
1-[3-(4-methoxybenzylamino)-4-hydroxyphenyl]-2-[4-(1-benzimidaz-
olyl)-2-methyl-2-butylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminoph-
enyl)-2-methyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-me-
thyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-
-methyl-2-propylamino]ethanol, or
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1-
,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol.
[0023] Salmeterol salts or formoterol salts are preferably used as
the long-acting betamimetics 3 according to the invention. Any
reference to the term betamimetics 3 also includes a reference to
the relevant enantiomers or mixtures thereof. For example, any
reference to the preferred compounds 3 according to the invention,
the salts of salmeterol and formoterol, also includes the relevant
enantiomeric salts of R-salmeterol, S-salmeterol, R,R-formoterol,
S,S-formoterol, R,S-formoterol, S,R-formoterol, and the mixtures
thereof, while the enantiomeric salts of R-salmeterol and
R,R-formoterol are of particular importance. The compounds 3 may
also be present according to the invention in the form of the
hydrates or solvates thereof.
[0024] Within the scope of the present invention, any reference to
compounds 3 is to be understood as being a reference to
physiologically acceptable acid addition salts. By physiologically
acceptable acid addition salts of the betamimetics 3 are meant
according to the invention pharmaceutically acceptable salts which
are selected from the salts of hydrochloric acid, hydrobromic acid,
sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid,
fumaric acid, succinic acid, lactic acid, citric acid, tartaric
acid, 1-hydroxy-2-naphthalenecarboxylic acid, or maleic acid. If
desired, mixtures of the abovementioned acids may be used to
prepare the salts 3.
[0025] According to the invention, the salts of the betamimetics 3
selected from among the hydrochloride, hydrobromide, sulfate,
phosphate, fumarate, methanesulfonate, and xinafoate are preferred.
Particularly preferably, in the case of salmeterol, the salts of 3
are selected from those salts which have a solubility in water of
0.1 mg/mL or less, preferably 0.05 mg/mL or less, most preferably
0.04 mg/mL or less. In this context, xinafoate, 4-phenylcinnamate,
and diflunisal are mentioned as particularly preferred salts of
salmeterol. Particularly preferred salts 3 of salmeterol have a
solubility in water of 0.035 mg/mL or less, such as, for example,
4-phenylcinnamate or diflunisal.
[0026] Particularly preferably, in the case of formoterol, the
salts of 3 are selected from the hydrochloride, sulfate, and
fumarate, of which the hydrochloride and fumarate are particularly
preferred. Of exceptional importance according to the invention is
formoterol fumarate.
[0027] If, within the scope of the present invention, there is a
reference to betamimetics which are not in the salt form, this can
be taken to mean a reference to compounds 3'. For example, the
preferred betamimetics 3' according to the invention which are not
in salt form are the free base of formoterol or salmeterol, whereas
the particularly preferred compounds 3 according to the invention
are, for example, salmeterol xinafoate, salmeterol
4-phenylcinnamate, or formoterol fumarate.
[0028] Within the scope of the present invention, the betamimetics
3 are optionally also referred to as sympathomimetics or
beta.sub.2-receptor agonists (.beta..sub.2-agonists). All these
names can be regarded as equivalent within the scope of the present
invention.
[0029] The pharmaceutical combinations of 1, 2, and 3 according to
the invention are preferably administered by inhalation. Suitable
inhalable powders packed into suitable capsules (inhalettes) may be
administered using suitable powder inhalers.
[0030] Accordingly, in one aspect, the present invention relates to
a pharmaceutical composition which contains a combination of 1, 2,
and 3.
[0031] In another aspect, the present invention relates to a
pharmaceutical composition which contains one or more salts 1, one
or more compounds 2 and one or more compounds 3, optionally in the
form of their solvates or hydrates. The active substances may be
combined in a single preparation or contained in two or three
separate formulations. Pharmaceutical compositions which contain
the active substances 1, 2, and 3 in a single preparation are
preferred according to the invention.
[0032] In another aspect, the present invention relates to a
pharmaceutical composition which contains, in addition to
therapeutically effective quantities of 1, 2, and 3, a
pharmaceutically acceptable excipient. In another aspect, the
present invention relates to a pharmaceutical composition which
does not contain any pharmaceutically acceptable excipient in
addition to therapeutically effective quantities of 1, 2, and
3.
[0033] The present invention also relates to the use of 1, 2, and 3
for preparing a pharmaceutical composition containing
therapeutically effective quantities of 1, 2, and 3 for treating
inflammatory and/or obstructive diseases of the respiratory tract,
particularly asthma and/or chronic obstructive pulmonary disease
(COPD), by simultaneous or successive administration. In addition,
the pharmaceutical combinations according to the invention may be
used to prepare a drug for treating cystic fibrosis or allergic
alveolitis (farmer's lung), for example, by simultaneous or
successive administration. The combinations of active substances
according to the invention will not be used only if treatment with
one of the pharmaceutically active ingredients is
contraindicated.
[0034] The present invention also relates to the simultaneous or
successive use of therapeutically effective doses of the
combination of the above pharmaceutical compositions 1, 2, and 3
for treating inflammatory or obstructive diseases of the
respiratory tract, particularly asthma and/or chronic obstructive
pulmonary disease (COPD), provided that treatment with steroids or
betamimetics is not contraindicated from a therapeutic point of
view, by simultaneous or successive administration. The invention
further relates to the simultaneous or successive use of
therapeutically effective doses of the combination of the above
pharmaceutical compositions 1, 2, and 3 for treating cystic
fibrosis or allergic alveolitis (farmer's lung).
[0035] In the active substance combinations of 1, 2, and 3
according to the invention, ingredients 1, 2, and 3 may be present
in the form of their enantiomers, mixtures of enantiomers or in the
form of racemates. For example, the pharmaceutical compositions
according to the invention contain the active substances 1, 2, and
3 according to the invention in amounts such that a single
administration corresponds to a dosage of the combination of active
substances 1, 2, and 3 of 1 .mu.g to 10000 .mu.g, preferably from
10 .mu.g to 2000 .mu.g.
[0036] The proportions in which the active substances 1, 2, and 3
may be used in the active substance combinations according to the
invention are variable. Active substances 1, 2 and 3 may possibly
be present in the form of their solvates or hydrates. Depending on
the choice of the compounds 1, 2, and 3, the weight ratios which
may be used within the scope of the present invention vary on the
basis of the different molecular weights of the various compounds
and their different potencies. As a rule, the pharmaceutical
combinations according to the invention may contain compounds 1'
and 2 in ratios by weight ranging from 1:250 to 250:1, and
preferably from 1:150 to 150:1. In the particularly preferred
pharmaceutical combinations which contain in addition to 1' a
compound selected from among budesonide, fluticasone, mometasone,
and ciclesonide as steroid 2, the weight ratios of 1' to 2 are most
preferably in a range from about 1:40 to 40:1, and more preferably
in the range from 1:30 to 30:1.
[0037] For example, without restricting the scope of the invention
thereto, preferred combinations of 1 and 2 according to the
invention may contain the cation 1' and one of the abovementioned
preferred steroids 2 in the following proportions by weight: 1:20;
1:19; 1:18; 1:17; 1:16; 1:15; 1:14; 1:13; 1:12; 1:11; 1:10; 1:9;
1:8; 1:7; 1:6; 1:5; 1:4; 1:3; 1:2; 1:1; 2:1; 3:1; 4:1; 5:1; 6:1;
7:1; 8:1; 9:1; 10:1; 11:1; 12:1; 13:1; 14:1; 15:1; 16:1; 17:1;
18:1; 19:1; or 20:1.
[0038] The pharmaceutical compositions according to the invention
containing the combinations of 1 and 2 are normally administered so
that 1' and 2 are present together in doses of 5 .mu.g to 5000
.mu.g, preferably from 10 .mu.g to 2000 .mu.g, more preferably from
15 to 1000 .mu.g, even more preferably from 20 .mu.g to 800 .mu.g,
preferably according to the invention from 30 .mu.g to 700 .mu.g,
preferably from 40 .mu.g to 600 .mu.g, preferably from 50 .mu.g to
500 .mu.g, preferably from 40 .mu.g to 500 .mu.g, more preferably
from 50 .mu.g to 400 .mu.g per single dose. For example,
combinations of 1 and 2 according to the invention contain a
quantity of 1' and steroid 2 such that the total dosage per single
dose is about 35 .mu.g, 45 .mu.g, 50 .mu.g, 55 .mu.g, 60 .mu.g, 65
.mu.g, 70 .mu.g, 75 .mu.g, 80 .mu.g, 85 .mu.g, 90 .mu.g, 95 .mu.g,
100 .mu.g, 105 .mu.g, 110 .mu.g, 115 .mu.g, 120 .mu.g, 125 .mu.g,
130 .mu.g, 135 .mu.g, 140 .mu.g, 145 .mu.g, 150 .mu.g, 155 .mu.g,
160 .mu.g, 165 .mu.g, 170 .mu.g, 175 .mu.g, 180 .mu.g, 185 .mu.g,
190 .mu.g, 195 .mu.g, 200 .mu.g, 205 .mu.g, 210 .mu.g, 215 .mu.g,
220 .mu.g, 225 .mu.g, 230 .mu.g, 235 .mu.g, 240 .mu.g, 245 .mu.g,
250 .mu.g, 255 .mu.g, 260 .mu.g, 265 .mu.g, 270 .mu.g, 275 .mu.g,
280 .mu.g, 285 .mu.g, 290 .mu.g, 295 .mu.g, 300 .mu.g, 305 .mu.g,
310 .mu.g, 315 .mu.g, 320 .mu.g, 325 .mu.g, 330 .mu.g, 335 .mu.g,
340 .mu.g, 345 .mu.g, 350 .mu.g, 355 .mu.g, 360 .mu.g, 365 .mu.g,
370 .mu.g, 375 .mu.g, 380 .mu.g, 385 .mu.g, 390 .mu.g, 395 .mu.g,
400 .mu.g, 405 .mu.g, 410 .mu.g, 415 .mu.g, 420 .mu.g, 425 .mu.g,
430 .mu.g, 435 .mu.g, 440 .mu.g, 445 .mu.g, 450 .mu.g, 455 .mu.g,
460 .mu.g, 465 .mu.g, 470 .mu.g, 475 .mu.g, 480 .mu.g, 485 .mu.g,
490 .mu.g, 495 .mu.g, 500 .mu.g, 505 .mu.g, 510 .mu.g, 515 .mu.g,
520 .mu.g, 525 .mu.g, 530 .mu.g, 535 .mu.g, 540 .mu.g, 545 .mu.g,
550 .mu.g, 555 .mu.g, 560 .mu.g, 565 .mu.g, 570 .mu.g, 575 .mu.g,
580 .mu.g, 585 .mu.g, 590 .mu.g, 595 .mu.g, 600 .mu.g, 605 .mu.g,
610 .mu.g, or the like. It is clear to the skilled man that these
proposed dosages per single dose are not to be regarded as being
restricted to the numerical values explicitly mentioned.
Fluctuations of around .+-.2.5 .mu.g, particularly fluctuations in
the decimal range, are also covered as will be apparent to anyone
skilled in the art. In these dosage ranges the active substances 1'
and 2 may be present in the weight ratios described above.
[0039] For example, and without restricting the scope of the
invention thereto, the combinations of 1 and 2 according to the
invention may contain an amount of cation 1' and steroid 2 such
that each single dose contains 16.5 .mu.g of 1' and 25 .mu.g of 2,
16.5 .mu.g of 1' and 25 .mu.g of 2, 16.5 .mu.g of 1' and 50 .mu.g
of 2, 16.5 .mu.g of 1' and 100 .mu.g of 2, 16.5 .mu.g of 1' and 150
.mu.g of 2, 16.5 .mu.g of 1' and 200 .mu.g of 2, 16.5 .mu.g of 1'
and 250 .mu.g of 2, 33.0 .mu.g of 1' and 25 .mu.g of 2, 33.0 .mu.g
of 1' and 50 .mu.g of 2, 33.0 .mu.g of 1' and 100 .mu.g of 2, 33.0
.mu.g of 1' and 150 .mu.g of 2, 33.0 .mu.g of 1' and 200 .mu.g of
2, 33.0 .mu.g of 1' and 250 .mu.g of 2, 49.5 .mu.g of 1' and 25
.mu.g of 2, 49.5 .mu.g of 1' and 50 .mu.g of 2, 49.5 .mu.g of 1'
and 100 .mu.g of 2, 49.5 .mu.g of 1' and 150 .mu.g of 2, 49.5 .mu.g
of 1' and 200 .mu.g of 2, 49.5 .mu.g of 1' and 250 .mu.g of 2, 82.6
.mu.g of 1' and 25 .mu.g of 2, 82.6 .mu.g of 1' and 50 .mu.g of 2,
82.6 .mu.g of 1' and 100 .mu.g of 2, 82.6 .mu.g of 1' and 150 .mu.g
of 2, 82.6 .mu.g of 1' and 200 .mu.g of 2, 82.6 .mu.g of 1' and 250
.mu.g of 2, 165.1 .mu.g of 1' and 25 .mu.g of 2, 165.1 .mu.g of 1'
and 50 .mu.g of 2, 165.1 .mu.g of 1' and 50 .mu.g of 2, 165.1 .mu.g
of 1' and 100 .mu.g of 2, 165.1 .mu.g of 1' and 150 .mu.g of 2,
165.1 .mu.g of 1.mu. and 200 .mu.g of 2, 165.1 .mu.g of 1' and 250
.mu.g of 2, 206.4 .mu.g of 1' and 25 .mu.g of 2, 206.4 .mu.g of 1'
and 50 .mu.g of 2, 206.4 .mu.g of 1' and 100 .mu.g of 2, 206.4
.mu.g of 1' and 150 .mu.g of 2, 206.4 .mu.g of 1' and 200 .mu.g of
2, 206.4 .mu.g of 1' and 250 .mu.g of 2, 412.8 .mu.g of 1' and 25
.mu.g of 2, 412.8 .mu.g of 1' and 50 .mu.g of 2, 412.8 .mu.g of 1'
and 100 .mu.g of 2, 412.8 .mu.g of 1' and 150 .mu.g of 2, 412.8
.mu.g of 1' and 200 .mu.g of 2, and 412.8 .mu.g of 1' and 250 .mu.g
of 2.
[0040] If the active substance combination wherein the bromide is
used as the salt 1 and 2 denotes one of the preferred steroids
disclosed hereinbefore is used as a preferred combination of 1 and
2 according to the invention, the quantities of active substances
1' and 2 administered per single dose as specified by way of
example correspond to the following quantities of 1 and 2
administered per single dose: 20 .mu.g of 1 and 25 .mu.g of 2, 20
.mu.g of 1 and 50 .mu.g of 2, 20 .mu.g of 1 and 100 .mu.g of 2, 20
.mu.g of 1 and 150 .mu.g of 2, 20 .mu.g of 1 and 200 .mu.g of 2, 20
.mu.g of 1 and 250 .mu.g of 2, 40 .mu.g of 1 and 25 .mu.g of 2, 40
.mu.g of 1 and 25 .mu.g of 2, 40 .mu.g of 1 and 50 .mu.g of 2, 40
.mu.g of 1 and 100 .mu.g of 2, 40 .mu.g of 1 and 150 .mu.g of 2, 40
.mu.g of 1 and 200 .mu.g of 2, 40 .mu.g of 1 and 250 .mu.g of 2, 60
.mu.g of 1 and 25 .mu.g of 2, 60 .mu.g of 1 and 50 .mu.g of 2, 60
.mu.g of 1 and 100 .mu.g of 2, 60 .mu.g of 1 and 150 .mu.g of 2, 60
.mu.g of 1 and 200 .mu.g of 2, 60 .mu.g of 1 and 250 .mu.g of 2,
100 .mu.g of 1 and 25 .mu.g of 2, 100 .mu.g of 1 and 50 .mu.g of 2,
100 .mu.g of 1 and 100 .mu.g of 2, 100 .mu.g of 1 and 150 .mu.g of
2, 100 .mu.g of 1 and 200 .mu.g of 2, 100 .mu.g of 1 and 250 .mu.g
of 2, 200 .mu.g of 1 and 25 .mu.g of 2, 200 .mu.g of 1 and 50 .mu.g
of 2, 200 .mu.g of 1 and 100 .mu.g of 2, 200 .mu.g of 1 and 150
.mu.g of 2, 200 .mu.g of 1 and 200 .mu.g of 2, 200 .mu.g of 1 and
250 .mu.g of 2, 250 .mu.g of 1 and 25 .mu.g of 2, 250 .mu.g of 1
and 50 .mu.g of 2, 250 .mu.g of 1 and 100 .mu.g of 2, 250 .mu.g of
1 and 150 .mu.g of 2, 250 .mu.g of 1 and 200 .mu.g of 2, 250 .mu.g
of 1 and 250 .mu.g of 2, 500 .mu.g of 1 and 25 .mu.g of 2, 500
.mu.g of 1 and 50 .mu.g of 2, 500 .mu.g of 1 and 100 .mu.g of 2,
500 .mu.g of 1 and 150 .mu.g of 2, 500 .mu.g of 1 and 200 .mu.g of
2, and 500 .mu.g of 1 and 250 .mu.g of 2.
[0041] At the same time, the ratio of 1 to 3 may be 1:300 to 30:1,
preferably from 1:230 to 20:1, more preferably from 1:150 to 10:1,
still more preferably from 1:50 to 5:1, and more preferably from
1:35 to 2:1.
[0042] In the case of formoterol, for example, the active substance
combinations according to the invention may contain 1' and 3' in
ratios by weight which are, for example, in the range from about
1:10 to 300:1, preferably 1:5 to 200:1, preferably 1:3 to 150:1,
and more preferably from 1:2 to 100:1.
[0043] For example and without restricting the scope of the
invention thereto, preferred combinations of 1 and 3 according to
the invention contain the pharmacologically active cation 1' and
formoterol 3' in the following ratios by weight: 1:5, 1:4, 1:3,
1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1,
13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1,
24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1,
35:1, 36:1, 37:1, 38:1, 39:1, 40:1, 41:1, 42:1, 43:1, 44:1, 45:1,
46:1, 47:1, 48:1, 49:1, 50:1, 51:1, 52:1, 53:1, 54:1, 55:1, 56:1,
57:1, 58:1, 59:1, 60:1, 61:1, 62:1, 63:1, 64:1, 65:1, 66:1, 67:1,
68:1, 69:1, 70:1, 71:1, 72:1, 73:1, 74:1, 75:1, 76:1, 77:1, 78:1,
79:1, 80:1, 81:1, 82:1, 83:1, 84:1, 85:1, 86:1, 87:1, 88:1, 89:1,
90:1, 91:1, 92:1, 93:1, 94:1, 95:1, 96:1, 97:1, 98:1, 99:1, or
100:1.
[0044] The pharmaceutical compositions according to the invention
containing the combinations of 1 and 3 are normally used so that
the pharmacologically active cation 1' and formoterol 3' are
present together in doses from 5 .mu.g to 5000 .mu.g, preferably
from 10 .mu.g to 2000 .mu.g, more preferably from 15 .mu.g to 1000
.mu.g, still more preferably from 20 .mu.g to 800 .mu.g, preferably
according to the invention from 30 .mu.g to 600 .mu.g, preferably
from 40 .mu.g to 500 .mu.g.
[0045] For example, the combinations of 1 and 3 according to the
invention contain an amount of cation 1' and formoterol 3' such
that the total dosage per single dose is about 10 .mu.g, 15 .mu.g,
20 .mu.g, 25 .mu.g, 30 .mu.g, 35 .mu.g, 45 .mu.g, 50 .mu.g, 55
.mu.g, 60 .mu.g, 65 .mu.g, 70 .mu.g, 75 .mu.g, 80 .mu.g, 85 .mu.g,
90 .mu.g, 95 .mu.g, 100 .mu.g, 105 .mu.g, 110 .mu.g, 115 .mu.g, 120
.mu.g, 125 .mu.g, 130 .mu.g, 135 .mu.g, 140 .mu.g, 145 .mu.g, 150
.mu.g, 155 .mu.g, 160 .mu.g, 165 .mu.g, 170 .mu.g, 175 .mu.g, 180
.mu.g, 185 .mu.g, 190 .mu.g, 195 .mu.g, 200 .mu.g, 205 .mu.g, 210
.mu.g, 215 .mu.g, 220 .mu.g, 225 .mu.g, 230 .mu.g, 235 .mu.g, 240
.mu.g, 245 .mu.g, 250 .mu.g, 255 .mu.g, 260 .mu.g, 265 .mu.g, 270
.mu.g, 275 .mu.g, 280 .mu.g, 285 .mu.g, 290 .mu.g, 295 .mu.g, 300
.mu.g, 305 .mu.g, 310 .mu.g, 315 .mu.g, 320 .mu.g, 325 .mu.g, 330
.mu.g, 335 .mu.g, 340 .mu.g, 345 .mu.g, 350 .mu.g, 355 .mu.g, 360
.mu.g, 365 .mu.g, 370 .mu.g, 375 .mu.g, 380 .mu.g, 385 .mu.g, 390
.mu.g, 395 .mu.g, 400 .mu.g, 405 .mu.g, 410 .mu.g, 415 .mu.g, 420
.mu.g, 425 .mu.g, 430 .mu.g, 435 .mu.g, 440 .mu.g, 445 .mu.g, 450
.mu.g, 455 .mu.g, 460 .mu.g, 465 .mu.g, 470 .mu.g. 475 .mu.g, 480
.mu.g, 485 .mu.g, 490 .mu.g, 495 .mu.g, 500 .mu.g, 505 .mu.g, 510
.mu.g, 515 .mu.g, 520 .mu.g, 525 .mu.g, 530 .mu.g, 535 .mu.g, 540
.mu.g, 545 .mu.g, 550 .mu.g, 555 .mu.g, 560 .mu.g, 565 .mu.g, 570
.mu.g, 575 .mu.g, 580 .mu.g, 585 .mu.g, 590 .mu.g, 595 .mu.g, 600
.mu.g, or similar. It is clear to the skilled man that these
proposed dosages per single dose are not to be regarded as being
restricted to the numerical values explicitly mentioned.
Fluctuations of around .+-.2.5 .mu.g, particularly fluctuations in
the decimal range, are also covered as will be apparent to anyone
skilled in the art. In these dosage ranges the active substances 1'
and 3' are present in the weight ratios described above.
[0046] For example and without restricting the scope of the
invention thereto, the combinations of 1 and 3 according to the
invention contain an amount of cation 1' and formoterol 3' such
that they contain, per single dose, for example 8.3 .mu.g of 1' and
2.5 .mu.g of 3', 8.3 .mu.g of 1' and 4.9 .mu.g of 3', 8.3 .mu.g of
1' and 9.8 .mu.g of 3', 8.3 .mu.g of 1' and 14.7 .mu.g of 3', 8.3
.mu.g of 1' and 19.6 .mu.g of 3', 8.3 .mu.g of 1' and 24.4 .mu.g of
3', 16.5 .mu.g of 1' and 2.5 .mu.g of 3', 16.5 .mu.g of 1' and 4.9
.mu.g of 3', 16.5 .mu.g of 1' and 9.8 .mu.g of 3', 16.5 .mu.g of 1'
and 14.7 .mu.g of 3', 16.5 .mu.g, of 1' and 19.6 .mu.g of 3', 16.5
.mu.g of 1' and 24.4 .mu.g of 3', 33.0 .mu.g of 1' and 2.5 .mu.g
3', 33.0 .mu.g of 1' and 4.9 .mu.g of 3', 33.0 .mu.g of 1' and 9.8
.mu.g of 3', 33.0 .mu.g of 1' and 14.7 .mu.g of 3', 33.0 .mu.g of
1' and 19.6 .mu.g of 3', 33.0 .mu.g of 1' and 24.4 .mu.g of 3',
49.5 .mu.g of 1' and 2.5 .mu.g of 3', 49.5 .mu.g of 1' and 4.9
.mu.g of 3', 49.5 .mu.g of 1' and 9.8 .mu.g of 3', 49.5 .mu.g of 1'
and 14.7 .mu.g of 3', 49.5 .mu.g of 1' and 19.6 .mu.g of 3', 49.5
.mu.g of 1' and 24.4 .mu.g of 3', 82.6 .mu.g of 1' and 2.5 .mu.g of
3', 82.6 .mu.g of 1' and 4.9 .mu.g of 3', 82.6 .mu.g of 1' and 9.8
.mu.g of 3', 82.6 .mu.g of 1' and 14.7 .mu.g of 3', 82.6 .mu.g of
1' and 19.6 .mu.g of 3', 82.6 .mu.g of 1' and 24.4 .mu.g of 3',
165.1 .mu.g of 1' and 2.5 .mu.g of 3', 165.1 .mu.g of 1' and 4.9
.mu.g of 3', 165.1 .mu.g of 1' and 9.8 .mu.g of 3', 165.1 .mu.g of
1' and 14.7 .mu.g of 3', 165.1 .mu.g of 1' and 19.6 .mu.g of 3',
165.1 .mu.g of 1' and 24.4 .mu.g of 3', 206.4 .mu.g of 1' and 2.5
.mu.g of 3', 206.4 .mu.g of 1' and 4.9 .mu.g of 3', 206.4 .mu.g of
1' and 9.8 .mu.g of 3', 206.4 .mu.g of 1' and 14.7 .mu.g of 3',
206.4 .mu.g of 1' and 19.6 .mu.g of 3', 206.4 .mu.g of 1' and 24.4
.mu.g of 3', 412.8 .mu.g of 1' and 2.5 .mu.g of 3', 412.8 .mu.g of
1' and 4.9 .mu.g of 3', 412.8 .mu.g of 1' and 9.8 .mu.g of 3',
412.8 .mu.g of 1' and 14.7 .mu.g of 3', 412.8 .mu.g of 1' and 19.6
.mu.g of 3', and 412.8 .mu.g of 1' and 24.4 .mu.g of 3'.
[0047] If the active substance combination wherein the salt 1 is
the bromide and 3 denotes formoterol fumarate is used as a
preferred combination of 1 and 3 according to the invention, the
quantities of active substances 1' and 3 administered per single
dose as specified by way of example correspond to the following
quantities of 1 and 3 administered per single dose: 10 .mu.g of 1
and 2.9 .mu.g of 3, 10 .mu.g of 1 and 5.7 .mu.g of 3, 10 .mu.g of 1
and 11.5 .mu.g of 3, 10 .mu.g of 1 and 17.2 .mu.g of 3, 10 .mu.g of
1 and 22.9 .mu.g of 3, 10 .mu.g of 1 and 28.5 .mu.g of 3, 20 .mu.g
of 1 and 2.9 .mu.g of 3, 20 .mu.g of 1 and 5.7 .mu.g of 3, 20 .mu.g
of 1 and 11.5 .mu.g of 3, 20 .mu.g of 1 and 17.2 .mu.g of 3, 20
.mu.g of 1 and 22.9 .mu.g of 3, 20 .mu.g of 1 and 28.5 .mu.g of 3,
40 .mu.g of 1 and 2.9 .mu.g of 3, 40 .mu.g of 1 and 5.7 .mu.g of 3,
40 .mu.g of 1 and 11.5 .mu.g of 3, 40 .mu.g of 1 and 17.2 .mu.g of
3, 40 .mu.g of 1 and 22.9 .mu.g of 3, 40 .mu.g of 1 and 28.5 .mu.g
of 3, 60 .mu.g of 1 and 2.9 .mu.g of 3, 60 .mu.g of 1 and 5.7 .mu.g
of 3, 60 .mu.g of 1 and 11.5 .mu.g of 3, 60 .mu.g of 1 and 17.2
.mu.g of 3, 60 .mu.g of 1 and 22.9 .mu.g of 3, 60 .mu.g of 1 and
28.5 .mu.g of 3, 100 .mu.g of 1 and 2.9 .mu.g of 3, 100 .mu.g of 1
and 5.7 .mu.g of 3, 100 .mu.g of 1 and 11.5 .mu.g of 3, 100 .mu.g
of 1 and 17.2 .mu.g of 3, 100 .mu.g of 1 and 22.9 .mu.g of 3, 100
.mu.g of 1 and 28.5 .mu.g of 3, 200 .mu.g of 1 and 2.9 .mu.g of 3,
200 .mu.g of 1 and 5.7 .mu.g of 3, 200 .mu.g of 1 and 11.5 .mu.g of
3, 200 .mu.g of 1 and 17.2 .mu.g of 3, 200 .mu.g of 1 and 22.9
.mu.g of 3, 200 .mu.g of 1 and 28.5 .mu.g of 3, 250 .mu.g of 1 and
2.9 .mu.g of 3, 250 .mu.g of 1 and 5.7 .mu.g of 3, 250 .mu.g of 1
and 11.5 .mu.g of 3, 250 .mu.g of 1 and 17.2 .mu.g of 3, 250 .mu.g
of 1 and 22.9 .mu.g of 3, 250 .mu.g of 1 and 28.5 .mu.g of 3, 500
.mu.g of 1 and 2.9 .mu.g of 3, 500 .mu.g of 1 and 5.7 .mu.g of 3,
500 .mu.g of 1 and 11.5 .mu.g of 3, 500 .mu.g of 1 and 17.2 .mu.g
of 3, 500 .mu.g of 1 and 22.9 .mu.g of 3, and 500 .mu.g of 1 and
28.5 .mu.g of 3.
[0048] If the active substance combination wherein 3 denotes
formoterol fumarate dihydrate and the salt 1 is the bromide is used
as a preferred combination of 1 and 3 according to the invention,
the quantities of active substances 1' and 3' administered per
single dose as specified by way of example correspond to the
following quantities of 1 and 3 administered per single dose: 10
.mu.g of 1 and 3 .mu.g of 3, 10 .mu.g of 1 and 6 .mu.g of 3, 10
.mu.g of 1 and 12 .mu.g of 3, 10 .mu.g of 1 and 18 .mu.g of 3, 10
.mu.g of 1 and 24 .mu.g of 3, 10 .mu.g of 1 and 30 .mu.g of 3, 20
.mu.g of 1 and 3 .mu.g of 3, 20 .mu.g of 1 and 6 .mu.g of 3, 20
.mu.g of 1 and 12 .mu.g of 3, 20 .mu.g of 1 and 18 .mu.g of 3, 20
.mu.g of 1 and 24 .mu.g of 3, 20 .mu.g of 1 and 30 .mu.g of 3, 40
.mu.g of 1 and 3 .mu.g of 3, 40 .mu.g of 1 and 6 .mu.g of 3, 40
.mu.g of 1 and 12 .mu.g of 3, 40 .mu.g of 1 and 18 .mu.g of 3, 40
.mu.g of 1 and 24 .mu.g of 3, 40 .mu.g of 1 and 30 .mu.g of 3, 60
.mu.g of 1 and 3 .mu.g of 3, 60 .mu.g of 1 and 6 .mu.g of 3, 60
.mu.g of 1 and 12 .mu.g of 3, 60 .mu.g of 1 and 18 .mu.g of 3, 60
.mu.g of 1 and 24 .mu.g of 3, 60 .mu.g of 1 and 30 .mu.g of 3, 100
.mu.g of 1 and 3 .mu.g of 3, 100 .mu.g of 1 and 6 .mu.g of 3, 100 g
of 1 and 12 .mu.g of 3, 100 .mu.g of 1 and 18 .mu.g of 3, 100 .mu.g
of 1 and 24 .mu.g of 3, 100 .mu.g of 1 and 30 .mu.g of 3, 200 .mu.g
of 1 and 3 .mu.g of 3, 200 .mu.g of 1 and 6 .mu.g of 3, 200 .mu.g
of 1 and 12 .mu.g of 3, 200 .mu.g of 1 and 18 .mu.g of 3, 200 .mu.g
of 1 and 24 .mu.g of 3, 200 .mu.g of 1 and 30 .mu.g of 3, 250 .mu.g
of 1 and 3 .mu.g of 3, 250 .mu.g of 1 and 6 .mu.g of 3, 250 .mu.g
of 1 and 12 .mu.g of 3, 250 .mu.g of 1 and 18 .mu.g of 3, 250 .mu.g
of 1 and 24 .mu.g of 3, 250 .mu.g of 1 and 30 .mu.g of 3, 500 .mu.g
of 1 and 3 .mu.g of 3, 500 .mu.g of 1 and 6 .mu.g of 3, 500 .mu.g
of 1 and 12 .mu.g of 3, 500 .mu.g of 1 and 18 .mu.g of 3, 500 .mu.g
of 1 and 24 .mu.g of 3, and 500 .mu.g of 1 and 30 .mu.g of 3.
[0049] In the case of salmeterol, for example, the active substance
combinations according to the invention may contain 1' and 3' in
ratios by weight which are in the range from about 1:30 to 400:1,
preferably 1:25 to 200:1, preferably 1:20 to 100:1, more preferably
from 1:15 to 50:1, for example.
[0050] For example, and without restricting the scope of the
invention thereto, the preferred combinations of 1 and 3 according
to the invention may contain the cation 1' and salmeterol 3' in the
following ratios by weight: 1:15, 1:14, 1:13, 1:12, 1:11, 1:10,
1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1,
6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1,
18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1,
29:1, 30:1, 31:1, 32:1, 33:1, 34:1, or35:1.
[0051] The pharmaceutical compositions according to the invention
containing the combinations of 1 and 3 are normally used so that
the cation 1' and salmeterol 3' are present together in doses from
5 .mu.g to 5000 .mu.g, preferably from 10 .mu.g to 2000 .mu.g, more
preferably from 15 .mu.g to 1000 .mu.g, still more preferably from
20 .mu.g to 800 .mu.g, preferably according to the invention from
30 .mu.g to 750 .mu.g, preferably from 40 .mu.g to 700 .mu.g.
[0052] For example, the combinations of 1 and 3 according to the
invention contain an amount of 1' and salmeterol 3' such that the
total dosage per single dose is about 15 .mu.g, 20 .mu.g, 25 .mu.g,
30 .mu.g, 35 .mu.g, 45 .mu.g, 50 .mu.g, 55 .mu.g, 60 .mu.g, 65
.mu.g, 70 .mu.g, 75 .mu.g, 80 .mu.g, 85 .mu.g, 90 .mu.g, 95 .mu.g,
100 .mu.g, 105 .mu.g, 110 .mu.g, 115 .mu.g, 120 .mu.g, 125 .mu.g,
130 .mu.g, 135 .mu.g, 140 .mu.g, 145 .mu.g, 150 .mu.g, 155 .mu.g,
160 .mu.g, 165 .mu.g, 170 .mu.g, 175 .mu.g, 180 .mu.g, 185 .mu.g,
190 .mu.g, 195 .mu.g, 200 .mu.g, 205 .mu.g, 210 .mu.g, 215 .mu.g,
220 .mu.g, 225 .mu.g, 230 .mu.g, 235 .mu.g, 240 .mu.g, 245 .mu.g,
250 .mu.g, 255 .mu.g, 260 .mu.g, 265 .mu.g, 270 .mu.g, 275 .mu.g,
280 .mu.g, 285 .mu.g, 290 .mu.g, 295 .mu.g, 300 .mu.g, 305 .mu.g,
310 .mu.g, 315 .mu.g, 320 .mu.g, 325 .mu.g, 330 .mu.g, 335 .mu.g,
340 .mu.g, 345 .mu.g, 350 .mu.g, 355 .mu.g, 360 .mu.g, 365 .mu.g,
370 .mu.g, 375 .mu.g, 380 .mu.g, 385 .mu.g, 390 .mu.g, 395 .mu.g,
400 .mu.g, 405 .mu.g, 410 .mu.g, 415 .mu.g, 420 .mu.g, 425 .mu.g,
430 .mu.g, 435 .mu.g, 440 .mu.g, 445 .mu.g, 450 .mu.g, 455 .mu.g,
460 .mu.g, 465 .mu.g, 470 .mu.g, 475 .mu.g, 480 .mu.g, 485 .mu.g,
490 .mu.g, 495 .mu.g, 500 .mu.g, 505 .mu.g, 510 .mu.g, 515 .mu.g,
520 .mu.g, 525 .mu.g, 530 .mu.g, 535 .mu.g, 540 .mu.g, 545 .mu.g,
550 .mu.g, 555 .mu.g, 560 .mu.g, 565 .mu.g, 570 .mu.g, 575 .mu.g,
580 .mu.g, 585 .mu.g, 590 .mu.g, 595 .mu.g, 600 .mu.g, 605 .mu.g,
610 .mu.g, 615 .mu.g, 620 .mu.g, 625 .mu.g, 630 .mu.g, 635 .mu.g,
640 .mu.g, 645 .mu.g, 650 .mu.g, 655 .mu.g, 660 .mu.g, 665 .mu.g,
670 .mu.g, 675 .mu.g, 680 .mu.g, 685 .mu.g, 690 .mu.g, 695 .mu.g,
700 .mu.g, or the like. It is clear to the skilled man that these
proposed dosages per single dose are not to be regarded as being
restricted to the numerical values explicitly mentioned.
Fluctuations of around .+-.2.5 .mu.g, particularly fluctuations in
the decimal range, are also covered as will be apparent to anyone
skilled in the art. In these dosage ranges the active substances 1'
and 3' are present in the weight ratios described above.
[0053] For example and without restricting the scope of the
invention thereto, the combinations of 1 and 3 according to the
invention contain an amount of cation 1' and salmeterol 3' such
that they contain, per single dose, for example 8.3 .mu.g of 1' and
12.5 .mu.g of 3', 8.3 .mu.g of 1' and 25 .mu.g of 3', 8.3 .mu.g of
1' and 50 .mu.g of 3', 8.3 .mu.g of 1' and 75 .mu.g of 3', 8.3
.mu.g of 1' and 100 .mu.g of 3', 8.3 .mu.g of 1' and 200 .mu.g of
3', 16.5 .mu.g of 1' and 12.5 .mu.g of 3', 16.5 .mu.g of 1' and 25
.mu.g of 3', 16.5 .mu.g of 1' and 50 .mu.g of 3', 16.5 .mu.g of 1'
and 75 .mu.g of 3', 16.5 .mu.g of 1' and 100 .mu.g of 3', 16.5
.mu.g of 1' and 200 .mu.g of 3', 33.0 .mu.g of 1' and 12.5 .mu.g of
3', 33.0 .mu.g of 1' and 25 .mu.g of 3', 33.0 .mu.g of 1' and 50
.mu.g of 3', 33.0 .mu.g of 1' and 75 .mu.g of 3', 33.0 .mu.g of 1'
and 100 .mu.g of 3', 33.0 .mu.g of 1' and 200 .mu.g of 3', 49.5
.mu.g of 1' and 12.5 .mu.g of 3', 49.5 .mu.g of 1' and 25 .mu.g of
3', 49.5 .mu.g of 1' and 50 .mu.g of 3', 49.5 .mu.g of 1' and 75
.mu.g of 3', 49.5 .mu.g of 1' and 100 .mu.g of 3', 49.5 .mu.g of 1'
and 200 .mu.g of 3', 82.6 .mu.g of 1' and 12.5 .mu.g of 3', 82.6
.mu.g of 1' and 25 .mu.g of 3', 82.6 g of 1' and 50 .mu.g of 3',
82.6 .mu.g of 1' and 75 .mu.g of 3', 82.6 .mu.g of 1' and 100 .mu.g
of 3', 82.6 .mu.g of 1' and 200 .mu.g of 3', 165.1 .mu.g of 1' and
12.5 .mu.g of 3', 165.1 .mu.g of 1' and 25 .mu.g of 3', 165.1 .mu.g
of 1' and 50 .mu.g of 3', 165.1 .mu.g of 1' and 75 .mu.g of 3',
165.1 .mu.g of 1' and 100 .mu.g of 3', 165.1 .mu.g of 1' and 200
.mu.g of 3', 206.4 .mu.g of 1' and 12.5 .mu.g of 3', 206.4 .mu.g of
1' and 25 .mu.g of 3', 206.4 .mu.g of 1' and 50 .mu.g of 3', 206.4
.mu.g of 1' and 75 .mu.g of 3', 206.4 .mu.g of 1' and 100 .mu.g of
3', 206.4 .mu.g of 1' and 200 .mu.g of 3', 412.8 .mu.g of 1' and
12.5 .mu.g of 3', 412.8 .mu.g of 1' and 25 .mu.g of 3', 412.8 .mu.g
of 1' and 50 .mu.g of 3', 412.8 .mu.g of 1' and 75 .mu.g of 3',
412.8 .mu.g of 1' and 100 .mu.g of 3', and 412.8 .mu.g of 1' and
200 .mu.g of 3'.
[0054] If the active substance combination wherein the bromide is
used as the salt 1 and 3 denotes salmeterol xinafoate is used as a
preferred combination of 1 and 3 according to the invention, the
quantities of active substances 1' and 3' administered per single
dose as specified by way of example correspond to the following
quantities of 1 and 3 administered per single dose: 10 .mu.g of 1
and 18.2 .mu.g of 3, 10 .mu.g of 1 and 36.3 .mu.g of 3, 10 .mu.g of
1 and 72.6 .mu.g of 3, 10 .mu.g of 1 and 108.9 .mu.g of 3, 10 .mu.g
of 1 and 145.2 .mu.g of 3, 10 .mu.g of 1 and 290.4 .mu.g of 3, 20
.mu.g of 1 and 18.2 .mu.g of 3, 20 .mu.g of 1 and 36.3 .mu.g of 3,
20 .mu.g of 1 and 72.6 .mu.g of 3, 20 .mu.g of 1 and 108.9 .mu.g of
3, 20 .mu.g of 1 and 145.2 .mu.g of 3, 20 .mu.g of 1 and 290.4
.mu.g of 3, 40 .mu.g of 1 and 18.2 .mu.g of 3, 40 .mu.g of 1 and
36.3 .mu.g of 3, 40 .mu.g of 1 and 72.6 .mu.g of 3, 40 .mu.g of 1
and 108.9 .mu.g of 3, 40 .mu.g of 1 and 145.2 .mu.g of 3, 40 .mu.g
of 1 and 290.4 .mu.g of 3, 60 .mu.g of 1 and 18.2 .mu.g of 3, 60
.mu.g of 1 and 36.3 .mu.g of 3, 60 .mu.g of 1 and 72.6 .mu.g of 3,
60 .mu.g of 1 and 108.9 .mu.g of 3, 60 .mu.g of 1 and 145.2 .mu.g
of 3, 60 .mu.g of 1 and 290.4 .mu.g of 3, 100 .mu.g of 1 and 18.2
.mu.g of 3, 100 .mu.g of 1 and 36.3 .mu.g of 3, 100 .mu.g of 1 and
72.6 .mu.g of 3, 100 .mu.g of 1 and 108.9 .mu.g of 3, 100 .mu.g of
1 and 145.2 .mu.g of 3, 100 .mu.g of 1 and 290.4 .mu.g of 3, 200
.mu.g of 1 and 18.2 .mu.g of 3, 200 .mu.g of 1 and 36.3 .mu.g of 3,
200 .mu.g of 1 and 72.6 .mu.g of 3, 200 .mu.g of 1 and 108.9 .mu.g
of 3, 200 .mu.g of 1 and 145.2 .mu.g of 3, 200 .mu.g of 1 and 290.4
.mu.g of 3, 250 .mu.g of 1 and 18.2 .mu.g of 3, 250 .mu.g of 1 and
36.3 .mu.g of 3, 250 .mu.g of 1 and 72.6 .mu.g of 3, 250 .mu.g of 1
and 108.9 .mu.g of 3, 250 .mu.g of 1 and 145.2 .mu.g of 3, 250
.mu.g of 1 and 290.4 .mu.g of 3, 500 .mu.g of 1 and 18.2 .mu.g of
3, 500 .mu.g of 1 and 36.3 .mu.g of 3, 500 .mu.g of 1 and 72.6
.mu.g of 3, 500 .mu.g of 1 and 108.9 .mu.g of 3, 500 .mu.g of 1 and
145.2 .mu.g of 3, and 500 .mu.g of 1 and 290.4 .mu.g of 3.
[0055] The quantities of active substance in the pharmaceutical
combinations according to the invention can be calculated
analogously if instead of salmeterol xinafoate the compounds 3
salmeterol-4-phenylcinnamic acid salt (4-phenylcinnamate) and
salmeterol-5-(2,4-difluorophenyl)salicylic acid salt
(5-(2,4-difluorophenyl)salicylate; diflunisal) are used, which are
equally preferred according to the invention.
[0056] The active substance combinations of 1, 2, and 3 according
to the invention are preferably administered by inhalation. For
this purpose, ingredients 1, 2, and 3 have to be made available in
forms suitable for inhalation. Inhalable preparations include
inhalable powders, propellant-containing metering aerosols or
propellant-free inhalable solutions. Inhalable powders according to
the invention containing the combination of active substances 1, 2,
and 3 may consist of the active substances on their own or of a
mixture of the active substances with physiologically acceptable
excipients. Within the scope of the present invention the term
carrier may optionally be used instead of the term excipient.
Within the scope of the present invention, the term propellant-free
inhalable solutions also includes concentrates or sterile inhalable
solutions ready for use. The preparations according to the
invention may contain the combination of active substances 1, 2,
and 3 either together in one formulation or in two or three
separate formulations. These formulations which may be used within
the scope of the present invention are described in more detail in
the next part of the specification.
[0057] A. Inhalable Powder Containing the Combinations of Active
Substances 1, 2, and 3 According to the Invention
[0058] The inhalable powders according to the invention may contain
1, 2, and 3 either on their own or in admixture with suitable
physiologically acceptable excipients.
[0059] If the active substances 1, 2, and 3 are present in
admixture with physiologically acceptable excipients, the following
physiologically acceptable excipients may be used to prepare these
inhalable powders according to the invention: monosaccharides
(e.g., glucose or arabinose), disaccharides (e.g., lactose,
saccharose, or maltose), oligo- and polysaccharides (e.g.,
dextran), polyalcohols (e.g., sorbitol, mannitol, or xylitol),
salts (e.g., sodium chloride or calcium carbonate) or mixtures of
these excipients. Preferably, mono- or disaccharides are used,
while the use of lactose or glucose is preferred, particularly, but
not exclusively, in the form of their hydrates. For the purposes of
the invention, lactose is the particularly preferred excipient,
while lactose monohydrate is most particularly preferred.
[0060] Within the scope of the inhalable powders according to the
invention the excipients have a maximum average particle size of up
to 250 .mu.m, preferably between 10 .mu.m and 150 .mu.m, most
preferably between 15 .mu.m and 80 .mu.m. It may sometimes seem
appropriate to add finer excipient fractions with an average
particle size of 1 .mu.m to 9 .mu.m to the excipients mentioned
above. These finer excipients are also selected from the group of
possible excipients listed hereinbefore. Finally, in order to
prepare the inhalable powders according to the invention,
micronised active substance 1, 2, and 3, preferably with an average
particle size of 0.5 .mu.m to 10 .mu.m, more preferably from 1
.mu.m to 5 .mu.m, is added to the excipient mixture. Processes for
producing the inhalable powders according to the invention by
grinding and micronizing and lastly mixing the ingredients together
are known from the prior art. The inhalable powders according to
the invention may be prepared and administered either in the form
of a single powder mixture which contains 1, 2, and 3 or in the
form of separate inhalable powders which contain only 1, 2, or
3.
[0061] The inhalable powders according to the invention may be
administered using inhalers known from the prior art. Inhalable
powders according to the invention which contain a physiologically
acceptable excipient in addition to 1, 2, and 3 may be
administered, for example, by means of inhalers which deliver a
single dose from a supply using a measuring chamber as described in
U.S. Pat. No. 4,570,630, or by other means as described in DE 36 25
685 A. Preferably, the inhalable powders according to the invention
which contain physiologically acceptable excipients in addition to
1, 2, and 3 are packed into capsules (to produce so-called
inhalettes) which are used in inhalers as described, for example,
in WO 94/28958, which is equivalent to U.S. Pat. No. 5,947,118,
both of which are hereby incorporated by reference in their
entireties.
[0062] A particularly preferred inhaler for using the
pharmaceutical combination according to the invention in inhalettes
is shown in FIG. 1.
[0063] This HANDIHALER.RTM. inhaler for inhaling powdered
pharmaceutical compositions from capsules is characterized by a
housing 1 containing two windows 2, a deck 3 in which there are air
inlet ports and which is provided with a screen 5 secured via a
screen housing 4, an inhalation chamber 6 connected to the deck 3
on which there is a push button 9 provided with two sharpened pins
7 and movable counter to a spring 8, and a mouthpiece 12 which is
connected to the housing 1, the deck 3 and a cover 11 via a spindle
10 to enable it to be flipped open or shut and air holes 13 for
adjusting the flow resistance.
[0064] If the inhalable powders according to the invention are to
be packed into capsules (inhalettes) for the preferred use
described above, the quantities packed into each capsule should be
1 mg to 30 mg, preferably 3 mg to 20 mg, more particularly 5 mg to
10 mg of inhalable powder per capsule. These capsules contain,
according to the invention, either together or separately, the
doses of 1, 2, and 3 mentioned hereinbefore for each single
dose.
[0065] B. Propellant Gas-Driven Inhalation Aerosols Containing the
Combinations of Active Substances 1, 2, and 3 According to the
Invention
[0066] Inhalation aerosols containing propellant gas according to
the invention may contain substances 1, 2, and 3 dissolved in the
propellant gas or in dispersed form. 1, 2, and 3 may be present in
separate formulations or in a single preparation, in which 1, 2,
and 3 are either each dissolved, dispersed or only one or two of
the components is or are dissolved and the other or others is or
are dispersed. The propellant gases which may be used to prepare
the inhalation aerosols according to the invention are known from
the prior art. Suitable propellant gases are selected from among
hydrocarbons such as n-propane, n-butane, or isobutane and
halohydrocarbons such as fluorinated derivatives of methane,
ethane, propane, butane, cyclopropane, or cyclobutane. The
propellant gases mentioned above may be used on their own or in
mixtures thereof. Particularly preferred propellant gases are
halogenated alkane derivatives selected from TG134a, TG227, and
mixtures thereof.
[0067] The propellant-driven inhalation aerosols according to the
invention may also contain other ingredients such as co-solvents,
stabilizers, surfactants, antioxidants, lubricants, preservatives,
and pH adjusters. All these ingredients are known in the art.
[0068] The inhalation aerosols containing propellant gas according
to the invention may contain up to 5 wt.-% of active substance 1,
2, and/or 3. Aerosols according to the invention contain, for
example, 0.002 to 5 wt.-%, 0.01 to 3 wt.-%, 0.015 to 2 wt.-%, 0.1
to 2 wt.-%, 0.5 to 2 wt.-%, or 0.5 to 1 wt.-% of active substance
1, 2, and/or 3.
[0069] If the active substances 1, 2 and/or 3 are present in
dispersed form, the particles of active substance preferably have
an average particle size of up to 10 .mu.m, preferably from 0.1
.mu.m to 5 .mu.m, more preferably from 1 .mu.m to 5 .mu.m.
[0070] The propellant-driven inhalation aerosols according to the
invention mentioned above may be administered using metered dose
inhalers (MDI) known in the art. Accordingly, in another aspect,
the present invention relates to pharmaceutical compositions in the
form of propellant-driven aerosols as hereinbefore described
combined with one or more inhalers suitable for administering these
aerosols. In addition, the present invention relates to inhalers
which are characterized in that they contain the propellant
gas-containing aerosols described above according to the invention.
The present invention also relates to cartridges which are fitted
with a suitable valve and can be used in a suitable inhaler and
which contain one of the above-mentioned propellant gas-containing
inhalation aerosols according to the invention. Suitable cartridges
and methods of filling these cartridges with the inhalable aerosols
containing propellant gas according to the invention are known from
the prior art.
[0071] C. Propellant-Free Inhalable Solutions or Suspensions
Containing the Combinations of Active Substances 1, 2, and 3
According to the Invention
[0072] It is particularly preferred to use the active substance
combination according to the invention in the form of
propellant-free inhalable solutions and suspensions. The solvent
used may be an aqueous or alcoholic, preferably an ethanolic
solution. The solvent may be water on its own or a mixture of water
and ethanol. The relative proportion of ethanol compared with water
is not limited but the maximum is up to 70 percent by volume, more
particularly up to 60 percent by volume and most preferably up to
30 percent by volume. The remainder of the volume is made up of
water. The solutions or suspensions containing 1, 2 and 3,
separately or together, are adjusted to a pH of 2 to 7, preferably
2 to 5, using suitable acids. The pH may be adjusted using acids
selected from inorganic or organic acids. Examples of suitable
inorganic acids include hydrochloric acid, hydrobromic acid, nitric
acid, sulfuric acid and/or phosphoric acid. Examples of
particularly suitable organic acids include ascorbic acid, citric
acid, malic acid, tartaric acid, maleic acid, succinic acid,
fumaric acid, acetic acid, formic acid, and/or propionic acid, etc.
Preferred inorganic acids are hydrochloric and sulfuric acids. It
is also possible to use the acids which have already formed an acid
addition salt with one of the active substances. Of the organic
acids, ascorbic acid, fumaric acid, and citric acid are preferred.
If desired, mixtures of the above acids may be used, particularly
in the case of acids which have other properties in addition to
their acidifying qualities, e.g., as flavorings, antioxidants, or
complexing agents, such as citric acid or ascorbic acid, for
example. According to the invention, it is particularly preferred
to use hydrochloric acid to adjust the pH.
[0073] According to the invention, the addition of edetic acid
(EDTA) or one of the known salts thereof, sodium edetate, as
stabilizer or complexing agent is unnecessary in the present
formulation. Other embodiments may contain this compound or these
compounds. In a preferred embodiment the content based on sodium
edetate is less than 100 mg/100 mL, preferably less than 50 mg/100
mL, more preferably less than 20 mg/100 mL. Generally, inhalable
solutions in which the content of sodium edetate is from 0 to 10
mg/100 mL are preferred.
[0074] Co-solvents and/or other excipients may be added to the
propellant-free inhalable solutions according to the invention.
Preferred co-solvents are those which contain hydroxyl groups or
other polar groups, e.g., alcohols, particularly isopropyl alcohol,
glycols, particularly propyleneglycol, polyethyleneglycol,
polypropyleneglycol, glycol ether, glycerol, polyoxyethylene
alcohols, and polyoxyethylene fatty acid esters. The terms
excipients and additives in this context denote any
pharmacologically acceptable substance which is not an active
substance but which can be formulated with the active substance or
substances in the physiologically suitable solvent in order to
improve the qualitative properties of the active substance
formulation. Preferably, these substances have no pharmacological
effect or, in connection with the desired therapy, no appreciable
or at least no undesirable pharmacological effect. The excipients
and additives include, for example, surfactants such as soya
lecithin, oleic acid, sorbitan esters, such as polysorbates,
polyvinylpyrrolidone, other stabilizers, complexing agents,
antioxidants, and/or preservatives which guarantee or prolong the
shelf life of the finished pharmaceutical formulation, flavorings,
vitamins and/or other additives known in the art. The additives
also include physiologically acceptable salts such as sodium
chloride as isotonic agents. The preferred excipients include
antioxidants such as ascorbic acid, for example, provided that it
has not already been used to adjust the pH, vitamin A, vitamin E,
tocopherols, and similar vitamins and provitamins occurring in the
human body.
[0075] Preservatives may be used to protect the formulation from
contamination with pathogens. Suitable preservatives are those
which are known in the art, particularly cetyl pyridinium chloride,
benzalkonium chloride or benzoic acid or benzoates such as sodium
benzoate in the concentration known from the prior art. The
preservatives mentioned above are preferably present in
concentrations of up to 50 mg/100 mL, more preferably between 5 and
20 mg/100 mL.
[0076] Preferred formulations contain, in addition to the solvent
water and the combination of active substances 1, 2, and 3, only
benzalkonium chloride and sodium edetate. In another preferred
embodiment, no sodium edetate is present.
[0077] The propellant-free inhalable solutions according to the
invention are administered in particular using inhalers of the kind
which are capable of nebulizing a small amount of a liquid
formulation in the required therapeutic dose within a few seconds
to produce an aerosol suitable for therapeutic inhalation. Within
the scope of the present invention, preferred nebulizers are those
in which a quantity of less than 100 .mu.L, preferably less than 50
.mu.L, more preferably between 20 .mu.L and 30 .mu.L of active
substance solution can be nebulized in preferably one spray action
to form an aerosol with an average particle size of less than 20
.mu.m, preferably less than 10 .mu.m, in such a way that the
inhalable part of the aerosol corresponds to the therapeutically
effective quantity.
[0078] An apparatus of this kind for propellant-free delivery of a
metered quantity of a liquid pharmaceutical composition for
inhalation is described for example in International Patent
Application WO 91/14468 and also in WO 97/12687 (cf, in particular,
FIGS. 6a and 6b). The nebulizers (devices) described therein are
known by the name RESPIMAT.RTM.. WO 91/14468 is equivalent to U.S.
Pat. Nos. 5,457,944 and 5,662,271; and WO 97/12687 is equivalent to
U.S. Pat. Nos. 5,964,416, 6,402,055, and 6,497,373, all of which
are hereby incorporated by reference in their entireties.
[0079] This RESPIMAT.RTM. nebulizer can advantageously be used to
produce the inhalable aerosols according to the invention
containing the combination of active substances 1, 2, and 3.
Because of its cylindrical shape and handy size of less than 9 cm
to 15 cm long and 2 cm to 4 cm wide, this device can be carried at
all times by the patient. The nebulizer sprays a defined volume of
pharmaceutical formulation using high pressures through small
nozzles so as to produce inhalable aerosols.
[0080] The preferred atomizer essentially consists of an upper
housing part, a pump housing, a nozzle, a locking mechanism, a
spring housing, a spring, and a storage container, characterized
by: [0081] a pump housing which is secured in the upper housing
part and which comprises at one end a nozzle body with the nozzle
or nozzle arrangement, [0082] a hollow plunger with valve body,
[0083] a power takeoff flange in which the hollow plunger is
secured and which is located in the upper housing part, [0084] a
locking mechanism situated in the upper housing part, [0085] a
spring housing with the spring contained therein, which is
rotatably mounted on the upper housing part by means of a rotary
bearing, and [0086] a lower housing part which is fitted onto the
spring housing in the axial direction.
[0087] The hollow plunger with valve body corresponds to a device
disclosed in WO 97/12687. It projects partially into the cylinder
of the pump housing and is axially movable within the cylinder.
Reference is made in particular to FIGS. 1 to 4, especially FIG. 3,
and the relevant parts of the description. The hollow plunger with
valve body exerts a pressure of 5 MPa to 60 MPa (about 50 bar to
600 bar), preferably 10 MPa to 60 MPa (about 100 bar to 600 bar) on
the fluid, the measured amount of active substance solution, at its
high pressure end at the moment when the spring is actuated.
Volumes of 10 to 50 microliters are preferred, while volumes of 10
to 20 microliters are particularly preferred and a volume of 15
microliters per spray is most particularly preferred.
[0088] The valve body is preferably mounted at the end of the
hollow plunger facing the nozzle body.
[0089] The nozzle in the nozzle body is preferably microstructured,
i.e., produced by microtechnology. Microstructured nozzle bodies
are disclosed, for example, in WO 94/07607, particularly FIG. 1
therein and the associated description. WO 94/07607 is equivalent
to U.S. Pat. Nos. 5,911,851; 6,007,676; and 6,503,362, all of which
are hereby incorporated by reference in their entireties.
[0090] The nozzle body consists for example of two sheets of glass
and/or silicon firmly joined together, at least one of which has
one or more microstructured channels which connect the nozzle inlet
end to the nozzle outlet end. At the nozzle outlet end there is at
least one round or non-round opening 2 to 10 microns deep and 5 to
15 microns wide, the depth preferably being 4.5 to 6.5 microns
while the length is preferably 7 to 9 microns.
[0091] In the case of a plurality of nozzle openings, preferably
two, the directions of spraying of the nozzles in the nozzle body
may extend parallel to one another or may be inclined relative to
one another in the direction of the nozzle opening. In a nozzle
body with at least two nozzle openings at the outlet end the
directions of spraying may be at an angle of 20.degree. to
160.degree. to one another, preferably 60.degree. to 150.degree.,
most preferably 80.degree. to 100.degree.. The nozzle openings are
preferably arranged at a spacing of 10 to 200 microns, more
preferably at a spacing of 10 to 100 microns, most preferably 30 to
70 microns. Spacings of 50 microns are most preferred. The
directions of spraying will therefore meet in the vicinity of the
nozzle openings.
[0092] The liquid pharmaceutical preparation strikes the nozzle
body with an entry pressure of up to 600 bar, preferably 200 bar to
300 bar, and is atomized into an inhalable aerosol through the
nozzle openings. The preferred particle or droplet sizes of the
aerosol are up to 20 microns, preferably 3 to 10 microns.
[0093] The locking mechanism contains a spring, preferably a
cylindrical helical compression spring, as a store for the
mechanical energy. The spring acts on the power takeoff flange as
an actuating member the movement of which is determined by the
position of a locking member. The travel of the power takeoff
flange is precisely limited by an upper and lower stop. The spring
is preferably biased, via a power step-up gear, e.g., a helical
thrust gear, by an external torque which is produced when the upper
housing part is rotated counter to the spring housing in the lower
housing part. In this case, the upper housing part and the power
takeoff flange have a single or multiple V-shaped gear.
[0094] The locking member with engaging locking surfaces is
arranged in a ring around the power takeoff flange. It consists,
for example, of a ring of plastic or metal which is inherently
radially elastically deformable. The ring is arranged in a plane at
right angles to the atomizer axis. After the biasing of the spring,
the locking surfaces of the locking member move into the path of
the power takeoff flange and prevent the spring from relaxing. The
locking member is actuated by means of a button. The actuating
button is connected or coupled to the locking member. In order to
actuate the locking mechanism, the actuating button is moved
parallel to the annular plane, preferably into the atomizer; this
causes the deformable ring to deform in the annular plane. Details
of the construction of the locking mechanism are given in WO
97/20590.
[0095] The lower housing part is pushed axially over the spring
housing and covers the mounting, the drive of the spindle and the
storage container for the fluid.
[0096] When the atomizer is actuated the upper housing part is
rotated relative to the lower housing part, the lower housing part
taking the spring housing with it. The spring is thereby compressed
and biased by means of the helical thrust gear and the locking
mechanism engages automatically. The angle of rotation is
preferably a whole-number fraction of 360.degree., e.g.,
180.degree.. At the same time as the spring is biased, the power
takeoff part in the upper housing part is moved along by a given
distance, the hollow plunger is withdrawn inside the cylinder in
the pump housing, as a result of which some of the fluid is sucked
out of the storage container and into the high pressure chamber in
front of the nozzle.
[0097] If desired, a number of exchangeable storage containers
which contain the fluid to be atomized may be pushed into the
atomizer one after another and used in succession. The storage
container contains the aqueous aerosol preparation according to the
invention.
[0098] The atomizing process is initiated by pressing gently on the
actuating button. As a result, the locking mechanism opens up the
path for the power takeoff member. The biased spring pushes the
plunger into the cylinder of the pump housing. The fluid leaves the
nozzle of the atomizer in atomized form.
[0099] Further details of construction are disclosed in PCT
Applications WO 97/12683 and WO 97/20590, to which reference is
hereby made. WO 97/12683 is equivalent to U.S. Pat. No. 6,176,442;
and WO 97/20590 is equivalent to U.S. Pat. No. 6,453,795, all of
which are hereby incorporated by reference in their entireties.
[0100] The components of the atomizer (nebulizer) are made of a
material which is suitable for its purpose. The housing of the
atomizer and, if its operation permits, other parts as well, are
preferably made of plastics, e.g., by injection molding. For
medicinal purposes, physiologically safe materials are used.
[0101] FIGS. 2a/b attached hereto, which are identical to FIGS.
6a/b of WO 97/12687, show the RESPIMAT.RTM. nebulizer which can
advantageously be used for inhaling the aqueous aerosol
preparations according to the invention.
[0102] FIG. 2a shows a longitudinal section through the atomizer
with the spring biased while FIG. 2b shows a longitudinal section
through the atomizer with the spring relaxed.
[0103] The upper housing part (51) contains the pump housing (52)
on the end of which is mounted the holder (53) for the atomizer
nozzle. In the holder is the nozzle body (54) and a filter (55).
The hollow plunger (57) fixed in the power takeoff flange (56) of
the locking mechanism projects partially into the cylinder of the
pump housing. At its end the hollow plunger carries the valve body
(58). The hollow plunger is sealed off by means of the seal (59).
Inside the upper housing part is the stop (60) on which the power
takeoff flange abuts when the spring is relaxed. On the power
takeoff flange is the stop (61) on which the power takeoff flange
abuts when the spring is biased. After the biasing of the spring
the locking member (62) moves between the stop (61) and a support
(63) in the upper housing part. The actuating button (64) is
connected to the locking member. The upper housing part ends in the
mouthpiece (65) and is sealed off by means of the protective cover
(66) which can be placed thereon.
[0104] The spring housing (67) with compression spring (68) is
rotatably mounted on the upper housing part by means of the snap-in
lugs (69) and rotary bearing. The lower housing part (70) is pushed
over the spring housing. Inside the spring housing is the
exchangeable storage container (71) for the fluid (72) which is to
be atomized. The storage container is sealed off by the stopper
(73) through which the hollow plunger projects into the storage
container and is immersed at its end in the fluid (supply of active
substance solution). The spindle (74) for the mechanical counter is
mounted in the covering of the spring housing. At the end of the
spindle facing the upper housing part is the drive pinion (75). The
slider (76) sits on the spindle.
[0105] The nebulizer described above is suitable for nebulizing the
aerosol preparations according to the invention to produce an
aerosol suitable for inhalation.
[0106] If the formulation according to the invention is nebulized
using the method described above (with the RESPIMAT.RTM. nebulizer)
the quantity delivered should correspond to a defined quantity with
a tolerance of not more than 25%, preferably 20% of this amount in
at least 97%, preferably at least 98% of all operations of the
inhaler (spray actuations). Preferably, between 5 mg and 30 mg of
formulation, most preferably between 5 mg and 20 mg of formulation
are delivered as a defined mass on each actuation.
[0107] However, the formulation according to the invention may also
be nebulized by means of inhalers other than those described above,
e.g., jet stream inhalers.
[0108] Accordingly, in a further aspect, the invention relates to
pharmaceutical formulations in the form of propellant-free
inhalable solutions or suspensions as described above combined with
a device suitable for administering these formulations, preferably
in conjunction with the RESPIMAT.RTM. nebulizer. Preferably, the
invention relates to propellant-free inhalable solutions or
suspensions characterized by the combination of active substances
1, 2, and 3 according to the invention in conjunction with the
RESPIMAT.RTM. nebulizer. In addition, the present invention relates
to the above-mentioned devices for inhalation, preferably the
RESPIMAT.RTM. nebulizer, characterized in that they contain the
propellant-free inhalable solutions or suspensions according to the
invention as described hereinbefore.
[0109] The propellant-free inhalable solutions or suspensions
according to the invention may take the form of concentrates or
sterile inhalable solutions or suspensions ready for use, as well
as the above-mentioned solutions and suspensions designed for use
in a RESPIMAT.RTM. nebulizer. Formulations ready for use may be
produced from the concentrates, for example, by the addition of
isotonic saline solutions. Sterile formulations ready for use may
be administered using energy-operated fixed or portable nebulizers
which produce inhalable aerosols by means of ultrasound or
compressed air by the Venturi principle or other principles.
[0110] Accordingly, in another aspect, the present invention
relates to pharmaceutical compositions in the form of
propellant-free inhalable solutions or suspensions as described
hereinbefore which take the form of concentrates or sterile
formulations ready for use, combined with a device suitable for
administering these solutions, characterized in that the device is
an energy-operated free-standing or portable nebulizer which
produces inhalable aerosols by means of ultrasound or compressed
air by the Venturi principle or other methods.
[0111] The Examples which follow serve to illustrate the present
invention in more detail without restricting the scope of the
invention to the following embodiments by way of example.
EXAMPLES OF FORMULATIONS
[0112] TABLE-US-00001 1. Inhalable Powder Ingredients .mu.g per
capsule 1'-bromide 100 budesonide 200 salmeterol xinafoate 55.9
lactose 4644.1 Total 5000
[0113] TABLE-US-00002 2. Inhalable Powder Ingredients .mu.g per
capsule 1'-bromide 75 fluticasone propionate 125
salmeterol-4-phenylcinnamate 50 lactose 4650 Total 5000
[0114] TABLE-US-00003 3. Inhalable Powder Ingredients .mu.g per
capsule 1'-bromide 75 mometasone furoate 250 formoterol fumarate
dihydrate 12 lactose 4663 Total 5000
[0115] TABLE-US-00004 4. Inhalable Powder Ingredients .mu.g per
capsule 1'-bromide 100 fluticasone propionate 250 formoterol
fumarate dihydrate 12 lactose 4638 Total 5000
[0116] TABLE-US-00005 5. Inhalable Powder Ingredients .mu.g per
capsule 1'-bromide 200 formoterol fumarate dihydrate 12 fluticasone
propionate 250 lactose 24538 Total 25000
[0117] TABLE-US-00006 6. Inhalable Powder Ingredients .mu.g per
capsule 1'-bromide 75 fluticasone propionate 125
salmeterol-diflunisal 50 lactose 24750 Total 25000
[0118] TABLE-US-00007 7. Suspension Aerosol Containing Propellant
Gas Ingredients wt.-% 1'-bromide 0.035 budesonide 0.4 formoterol
fumarate dihydrate 0.066 soya lecithin 0.2 TG 134a:TG227 (2:3) to
100
[0119] TABLE-US-00008 8. Suspension Aerosol Containing Propellant
Gas Ingredients wt.-% 1'-bromide 0.039 fluticasone propionate 0.3
salmeterol xinafoate 0.033 isopropyl myristate 0.1 TG 227 to
100
[0120] TABLE-US-00009 9. Suspension Aerosol Containing Propellant
Gas Ingredients wt.-% 1'-bromide 0.039 mometasone furoate 0.6
salmeterol-diflunisal 0.066 isopropyl myristate 0.1 TG 227 to
100
[0121] TABLE-US-00010 10. Suspension Aerosol Containing Propellant
Gas Ingredients wt.-% 1'-bromide 0.035 fluticasone propionate 0.3
salmeterol 4-phenylcinnamate 0.066 soya lecithin 0.2 TG 11:TG12
(2:3) to 100
[0122] TABLE-US-00011 11. Suspension Aerosol Containing Propellant
Gas Ingredients wt.-% 1'-bromide 0.039 salmeterol xinafoate 0.033
budesonide 0.4 absolute ethanol 0.5 isopropyl myristate 0.1 TG 227
to 100
* * * * *