WO2004004704A1

WO2004004704A1 - Novel pharmaceutical compositions comprising novel anticholinergic agents and pde-iv inhibitors

Info

Publication number: WO2004004704A1
Application number: PCT/EP2003/006668
Authority: WO
Inventors: Michel Pairet; Christopher John Montague Meade; Michael P. Pieper
Original assignee: Boehringer Ingelheim Pharma Gmbh & Co. Kg
Priority date: 2002-07-09
Filing date: 2003-06-25
Publication date: 2004-01-15
Also published as: JP2005532379A; EP1521576A1; DE10230769A1; AU2003242755A1; CA2492026A1

Abstract

The invention relates to novel pharmaceutical compositions comprising novel anticholinergic agents and PDE-IV inhibitors, method for production and use thereof in the treatment of respiratory diseases.

Description

New drug compositions based on new anticholinergics and

PDE-IV inhibitors

The present invention relates to novel pharmaceutical compositions based on new anticholinergics and PDE-IV inhibitors, processes for their preparation and their use in the therapy of respiratory diseases.

DESCRIPTION OF THE INVENTION The present invention relates to novel pharmaceutical compositions based on new anticholinergics and PDE-IV inhibitors, processes for their preparation and their use in the therapy of respiratory diseases.

Surprisingly, an unexpectedly advantageous therapeutic effect, in particular a synergistic effect in the treatment of inflammatory and / or obstructive respiratory diseases, can be observed if one or more, preferably a new anticholinergic of formula 1 together with one or more, preferably a PDE-IV inhibitor 2 apply. Because of this synergistic effect, the pharmaceutical combinations according to the invention can be used in lower doses than is the case with the otherwise customary monotherapy of the individual compounds. In addition, undesirable side effects, which can occur when PDE IV inhibitors are applied, can thereby be reduced.

The above-mentioned effects are observed both with simultaneous application within a single active substance formulation and with successive application of the two active substances in separate formulations. According to the invention, the simultaneous application of the two active ingredient components in a single formulation is preferred.

In the context of the present invention, the salts of

formula 1

wherein

X ^{_ is} a single negatively charged anion, 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 means to use.

The salts of formula 1 are preferably used, in which X ^{■ is} a single negatively charged anion selected from the group consisting of chloride, bromide, 4-toluenesulfonate and methanesulfonate, preferably bromide.

The salts of the formula ± are particularly preferably used, in which X "denotes a simply negatively charged anion selected from the group consisting of chloride, bromide and methanesulfonate, preferably bromide.

According to the invention, the salt of formula 1 in which X "represents bromide is particularly preferred.

The salts of Fromel J are known from international patent application WO 02/32899.

Within the scope of the present patent application there is an explicit reference to the pharmacologically active cation of the formula

recognized by using the designation V. A reference to

Compounds 1 naturally include a reference to the cation V.

A reference made within the scope of the present invention to the salts 1 which can be used according to the invention includes optionally available hydrates and solvates of these compounds. In the context of the present invention, PDE-IV inhibitors (hereinafter 2) are understood to mean compounds which are selected from the group consisting of enprofylline, theophylline, roflumilast, ariflo (cilomilast), Bay-198004, CP-325,366, BY343, D. -4396 (Sch-351591), V-11294A, AWD-12-281, N- (3,5-dichloro-1-oxo-pyridin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide and the tricyclic nitrogen heterocycles of general formula 2a

in which

R ^{1 is} C- | -C5-alkyl, Cs-Cß-cycloalkyl, phenyl, benzyl or a 5- or 6-membered, saturated or unsaturated heterocyclic ring which can contain one or two heteroatoms selected from the group consisting of oxygen and nitrogen; R ² C- | -C5-alkyl or C2-C4-alkenyl;

R ^{3 is} C 5 -C 5 -alkyl, which is optionally substituted by C-] -C 4 -alkoxy,

Cδ-Cß-cycloalkyl, phenoxy or by a 5- or 6-membered, saturated or unsaturated heterocyclic ring which can contain one or two heteroatoms selected from the group consisting of oxygen and nitrogen,

Cs-Cß-cycloalkyl or phenyl or benzyl optionally substituted by C -C4-alkoxy, can mean, optionally in the form of their racemates, their enantiomers, in the form of their diastereomers and their mixtures, optionally in the form of their tautomers and, if appropriate, their pharmacologically acceptable

Acid addition salts.

Of the abovementioned compounds of the formula 2a, those compounds of the formula 2a are preferably used in those within the scope of the present invention

R ¹ C ¹ -C 4 -alkyl, Cs-Cß-cycloalkyl, tetrahydrofuranyi, tetrahydropyranyl,

Piperazinyl, morpholinyl or phenyl; R ² Ci -C4 alkyl or C ₂ -C alkenyl;

R ^{3 is} C 1 -C 4 -alkyl, which may be by C 1 -C 4 -alkoxy, C-δ-Cß-cycloalkyl, phenoxy, (C- | -C-4-alkoxy) phenyloxy, piperazine or pyrrole can be substituted, Cs-Cß-cycloalkyl or phenyl or benzyl optionally substituted by Cι-C-4-alkoxy, can mean, if appropriate, in the form of their racemates, their enantiomers, in the form of their diastereomers and their mixtures, if appropriate in the form of their tautomers and, if appropriate, their pharmacologically acceptable acid addition salts.

Of the compounds of the formula 2a, those compounds of the formula 2a are particularly preferably used in the context of the present invention

Application in those

R ^{1 is} ethyl, propyl, butyl, cyclopentyl, tetrahydrofuranyl, tetrahydropyranyl,

N-morpholinyl or phenyl;

R ^{2 is} ethyl, propyl, allyl or butenyl; R ^{3 is} ethyl, propyl, butyl, cyclopentyl, cyclohexylmethyl, benzyl, phenylethyl,

Phenoxy methyl, methoxybenzyl or N-pyrolylmethyl, can optionally be in the form of their racemates, their enantiomers, in

Form of their diastereomers and their mixtures, optionally in the form of their

Tautomers and, if appropriate, their pharmacologically acceptable acid addition salts.

Particularly preferred components 2 are those of

Formula 2a for use in which

R ^{1 is} ethyl, n-propyl, tert-butyl, cyclopentyl, 3-tetrahydrofuryl, N-morpholinyl or phenyl;

R ^{2 is} ethyl or n-propyl;

R ^{3 is} ethyl, i-propyl, n-propyl, n-butyl, t-butyl, cyclopentyl, cyclohexylmethyl,

Benzyl, phenylethyl, phenoxymethyl, 4-methoxybenzyl or N-pyrollylmethyl, can optionally be in the form of their racemates, their enantiomers, in the form of their diastereomers and their

Mixtures, optionally in the form of their tautomers and optionally their pharmacologically acceptable acid addition salts.

As alkyl groups (also insofar as they are part of other radicals), branched and unbranched alkyl groups with 1 to 5 carbon atoms are considered, for example the following are mentioned: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. Butyl , tert-butyl, n-pentyl, isopentyl or neopentyl. Possibly The abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. are also used for the above-mentioned groups.

Cycloalkyl radicals with 5 or 6 carbon atoms are called cyclopentyl or cyclohexyl. Examples of 5- or 6-membered, saturated or unsaturated heterocyclic rings which may contain one or two heteroatoms selected from the group consisting of oxygen and nitrogen are: furan, tetrahydrofuran, tetrahydrofuranone, γ-butylrolactone, -pyran, γ-pyran , Dioxolane, tetrahydropyran, dioxane, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, morpholine, oxazole, isoxazole, oxazine, pyrazolidine.

Table 1 summarizes those compounds of the general formula 2a which are particularly preferably used in combination with the compounds 1 in the context of the present invention.

Table 1 :

Continuation of table 1:

The preparation of the compounds of the general formula 2a can be carried out analogously to that of the prior art for some representatives of the compounds of the general formula (I) defined above (Tenor et al., Chem. Ber. Vol. 97 (1964) p. 1373) -1382) described procedure, to which reference is made at this point.

Compound 2 is furthermore preferably selected from the group consisting of enprofylline, roflumilast, Ariflo and AWD-12-281, N- (3,5-dichloro-1-oxopyridin-4-yl) -4-difluoromethoxy-3- cyclopropylmethoxybenzamide, Ariflo, roflumilast, AWD-12-281 and the above-mentioned compounds of formula 2a being particularly preferred as compound 2 according to the invention.

In the context of the present invention, a reference to the abovementioned PDE IV inhibitors 2 includes a reference to their pharmacologically acceptable acid addition salts which may exist.

According to the invention, the physiologically compatible acid addition salts which can be formed by 2 are understood to be pharmaceutically compatible 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 or maleic acid , According to the invention, preference is given to the salts of the compounds 2 which are selected from the group consisting of acetate, hydrochloride, hydrobromide, sulfate, phosphate and methanesulfonate.

The pharmaceutical combinations according to the invention from 1_ and 2 are preferably administered by inhalation. Suitable inhalable powders can be filled into suitable capsules (inhalettes) appropriate powder inhalers are applied, are used. As an alternative, inhalative use can also be carried out by applying suitable inhalation aerosols. This also includes inhalation aerosols which contain, for example, HFA134a (also called TG134a), HFA227 (also called TG227) or their mixture as propellant. The inhalation application can also take place by means of suitable solutions of the drug combination consisting of 1 and 2.

One aspect of the present invention accordingly relates to a medicament which contains a combination of 1 and 2.

Another aspect of the present invention relates to a medicament which contains one or more salts 1 and one or more compounds 2, optionally in the form of their solvates or hydrates. Here, too, the active ingredients can either be used together in a single dosage form or in two separate forms

Dosage forms may be included. According to the invention, preference is given to medicaments which contain the active compounds 1 and 2 in a single administration form.

Another aspect of the present invention relates to a medicament which, in addition to therapeutically effective amounts of 1 and 2, contains a pharmaceutically acceptable auxiliary. Another aspect of the present invention relates to a medicament which, in addition to therapeutically effective amounts of ± and 2, contains no pharmaceutically acceptable auxiliary.

The present invention further relates to the use of Λ_ and 2 for the production of a therapeutically effective amount of ± and 2 containing medicament for the treatment of inflammatory and / or obstructive respiratory diseases, in particular asthma or chronic obstructive pulmonary disease (COPD), and their complications such as pulmonary Hypertension, also allergic and non-allergic rhinitis.

The present invention further aims at the simultaneous or successive use of therapeutically effective doses of the combination of the above medicinal products 1 and 2 for the treatment of inflammatory and / or obstructive respiratory diseases, in particular asthma or chronic obstructive pulmonary disease (COPD), and their complications such as, for example, pulmonary hypertension, also allergic and non-allergic rhinitis, through simultaneous or successive application. In the active compound combinations according to the invention from 1 and 2, constituents 1 and 2 can be present in the form of their enantiomers, mixtures of the enantiomers or in the form of the racemates.

The ratios in which the two active substances ± and 2 can be used in the active substance combinations according to the invention are variable. The active ingredients 1 and 2 may optionally be in the form of their solvates or hydrates. Depending on the choice of compounds 1 and 2, the weight ratios which can be used in the context of the present invention vary on account of the different molecular weight of the different compounds and on the basis of their different potency. As a rule, the pharmaceutical combinations according to the invention can contain the compounds 1 and 2 in weight ratios which are in a range from 1: 100 to 100: 1, preferably from 1:80 to 80: 1. In particularly preferred pharmaceutical combinations, the weight ratios of 1 to 2 are particularly preferably in a range in which V and 2 are contained in ratios of 1:50 to 50: 1, further preferably 1:20 to 20: 1.

For example and without restricting the scope of the invention thereto, preferred combinations according to the invention of V and PDE-IV inhibitor 2 can contain the following weight ratios:

1:65; 1:64; 1: 631: 62; 1:61; 1:60; 1:59; 1:58; 1:57; 1:56; 1:55; 1:54; 1:53; 1:52; 1:51;

1:50; 1:49; 1:48; 1:47; 1:46; 1:45; 1:44; 1:43; 1:42; 1:41; 1:40; 1:39; 1:38; 1:37; 1:36;

1:35; 1:34; 1:33; 1:32; 1:31; 1:30; 1:29; 1:28; 1:27; 1:26; 1:25; 1:24; 1:23; 1:22; 1:21; 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; 20: 1.

The pharmaceutical compositions according to the invention containing the combinations of 1 and 2 are usually used in such a way that 1 and 2 together in doses of from 0.01 to 10,000 / g, preferably from 0.1 to 2000 / g, particularly preferably from 1 to 1500 g , further preferably from 50 to 1200μg per single dose are included. For example, combinations of 1. and 2 according to the invention contain such an amount of V and PDE-IV inhibitor 2 that the total dosage per single dose is 100 / g, 105 g, 110 // g, 115 g, 120 / g, 125 g, 130 g, 135 g, 140 g, 145 / g, 150 g, 155 / g, 160 // g, 165 // g, 170 g, 175 g, 180 g, 185 / g, 190 g, 195 g, 200ιg, 205 / g, 210; g, 215 g, 220 g, 225 / g, 230 // g, 235 // g, 240yg, 245 g, 250yi / g, 255 g, 260 g, 265 / yg, 270 g, 275 / g, 280 g, 285y / g, 290 g, 295 // g, 300 g, 305 / g, 310 / g, 315 / g, 320y / g, 325μg, 330 / g, 335y / g, 340 g , 345 / g, 350yt / g, 355 / g, 360jt / g, 365 g, 370 ₎ C / g, 375 / yg, 380 / yg, 385 / g, 390 / yg, 395 / yg, 400 // g, 405 / yg, 410 / g, 415 / yg, 420 / yg, 425 / yg, 430 / yg, 435 / g, 440 / yg, 445 / yg, 450 / g, 455 / tg, 460 / yg, 465 / yg, 470 / yg, 475y / g, 480 // g, 485 / g, 490 / ^y g, 495 / g, 500 / g, 505 // g, 510 / yg, 515 / yg, 520 // g, 525 / yg, 530 / g, 535 / yg, 540 // g, 545 / ^y g, 550 / ^y g, 555 // g, 560 / yg, 565 / yg, 570 / yg, 575 / g, 580 / yg, 585 / yg, 590 / yg, 595 / g, 600 / yg, 605 / yg, 610 / yg , 615 / g, 620 / g, 625 / yg, 630 / yg, 635 / yg, 640 / yg, 645 / g, 650 / yg, 655 / ^y g, 660 / ^y g, 665 / yg, 670 / tg , 675 / yg, 680 / yg, 685 / ^y g, 690 / yg, 695 / yg, 700 / g, 705 / yg, 710 ^y g, 715 / ^y g, 720 / yg, 725 // g, 730 / / g, 735 / yg, 740 / yg, 745 / yg, 750 // g, 755 / yg, 760 // g, 765 / ^y g, 770 / ^y g, 775 / g, 780 / yg, 785 / ^y g, 790 / yg, 795 / yg, 800 / yg, 805 / yg, 810 / yg, 815 / yg, 820 // g, 825 / ^y g, 830 // g, 835 // g, 840 // g , 845 / ^y g, 850 // g, 855 / vg, 860 / yg, 865 / yg, 870 / vg, 875 / yg, 880 / yg, 885 // g, 890 / yg, 895 // g, 900 / yg, 905 / yg, 910 / yg, 915 yg, 920 / g, 925 / g, 930 / g, 935 / ^y g, 940 / vg, 945 / yg, 950 / yg, 955 / yg, 960 // g, 965 / yg, 970 / yg, 975 / yg, 980 g , 985 / yg, 990 / yg, 995 / yg, 1000 // g, 1005 / yg, 1010 vg, 1015 / yg, 1020 / yg, 1025 / g, 1030 / yg, 1035 / yg, 1040 / yg, 1045 / yg, 1050 // g, 1055 / tg, 1060 / g, 1065 / yg, 1070 / vg, 1075 / yg, 1080 // g, 1085 / yg, 1090 / yg, 1095 // g, 1100 / yg or is similar. The above-mentioned dosage suggestions per single dose are not to be regarded as limited to the explicitly stated numerical values, but only serve as dosage examples disclosed. Of course, dosages that fluctuate around the above-mentioned numerical values in a range of approximately +/- 2.5 / vg are also included in the presently explained values. In these dosage ranges, the active ingredients V and 2 can be contained in the weight ratios described above.

For example and without restricting the scope of the invention thereto, the combinations according to the invention from 1 and 2 can contain such an amount of V and PDE-IV inhibitor 2 that 16.5 / yg V and 25 / yg 2, 16, 5 / yg V and 50 / yg 2, 16.5 / ^y g and 100 / yg 2, 16.5 / yg V and 200 / yg 2, 16.5 / yg V and 300 / yg 2, 16.5 / yg r and 400 / ^y g 2, 16.5 / yg r and 500 // g 2, 16.5 / tg and 600 / g 2, 16.5 / yg V and 700 / g 2, 16.5 / ^y g V and 800 / g 2, 16.5 / tg and 900 // g 2, 16.5 / yg V and 1000 / yg 2, 33.1 / yg and 25 / ^y g 2, 33.1 / yg r and 50 // g 2, 33.1 / ^y g and 100 // g 2, 33.1 / yg and 200 // g 2, 33.1 / ^y g and 300 / yg 2, 33.1 / g V and 400 / ^y g 2, 33.1 / yg V and 500 / yg 2, 33.1 / yg and 600 / ^y g 2, 33.1 yg and 700 / g 2, 33.1 / yg V and 800 / yg 2, 33.1 / yg V and 900 / ^y g 2, 33.1 / ^y g and 1000 / yg 2, 49.5 / yg V and 25 / ^y g 2, 49.5 // g V and 50 / g 2, 49.5 / yg and 100 / g 2, 49.5 / vg and 200 / yg 2, 49.5 tg V and 300 / yg 2, 49.5 / yg and 400 // g 2, 49 , 5 tg V and 500 // g 2, 49.5 yg V and 600 // g 2, 49.5 // g and 700 / yg 2, 49.5 // g un d 800 / g 2, 49.5 / g V and 900 // g 2, 49.5 ^y g and 1000 // g 2, 82.6 / yg and 25 / yg 2, 82.6 / ^y g and 50 / yg 2, 82.6 / yg V and 100 / ^y g 2, 82.6 / yg V and 200 / yg 2, 82.6 / yg and 300 / ^y g 2, 82.6 / yg V and 400 yg 2, 82.6 / ^y g V and 500 / yg 2, 82.6 // g and 600 / yg 2, 82.6 / ^y g and 700 / yg 2, 82.6 / g and 800 / ^y g 2 , 82.6 / yg V and 900 / yg 2, 82.6 // g and 1000 ^y g 2, 165.1 / yg r and 25 / yg 2, 165.1 / ^y g and 50 / yg 2, 165 , 1 / yg V and 100 yg 2, 165.1 / yg r and 200 / yg 2, 165.1 / yg V and 300 / yg 2, 165.1 / yg V and 400 // g 2, 165.1 / yg V and 500 / yg 2, 165.1 / yg V and 600 / yg 2, 165.1 / yg r and 700 / yg 2, 165.1 / yg and 800 / yg 2, 165.1 / yg and 900 / yg 2, 165.1 / yg and 1000 / yg 2, 206.4 // g and 25 / yg 2, 206.4 / yg V and 50 // g 2, 206.4 / yg V and 100 yg 2, 206.4 // g V and 200 / yg 2, 206.4 / yg V and 300 / yg 2, 206.4 / yg V and 400 / ^y g 2, 206.4 / yg r and 500 / yg 2 or 206.4 / yg V and 600 / yg 2, 206.4 / yg V and 700 / yg 2, 206.4 / yg r and 800 / yg 2, 206.4 / yg V and 900 / yg 2, 206.4 / yg and 1000 / yg 2, 412.8 / yg and 25 / yg 2, 412.8 / vg and 50 / yg 2, 412.8 / yg V and 100 // g 2, 412.8 / yg and 200 / ^y g 2, 412.8 / yg V and 300 / yg 2, 412.8 / yg and 400 / yg 2, 412.8 yg V and 500 / g 2 or 412.8 // g V and 600 / yg 2, 412.8 yg V and 700 / yg 2, 412.8 / g V and 800 / yg 2, 412.8 / yg r and 900 / yg 2, 412.8 / yg and 1000 / yg 2 can be applied.

If the combination of active ingredients in which 1 represents the bromide is used as the combination of 1 and 2 preferred according to the invention, the amounts of active ingredient V and 2 applied per single administration given above correspond to the subsequent amounts of 1 and 2: 20 / yg 1 and administered per single administration 25 // g 2, 20 / yg 1 and 50 / yg 2, 20 / yg 1 and 100 / yg 2, 20 / yg 1 and 200 / yg 2, 20 yg 1 and 300 yg 2, 20 / yg I and 400 / yg 2, 20 / yg 1 and 500 / yg 2, 20 yg 1 and 600 / yg 2, 20 // g 1 and 700 / yg 2, 20 / yg 1 and 800 yg 2, 20 / yg 1 and 900 / yg 2, 20 / yg 1 and 1000 // g 2, 40 / yg 1 and 25 / g 2, 40 / yg I and 50 / yg 2, 40 / yg I and 100 yg 2, 40 / yg 1 and 200 yg 2, 40 / yg 1 and 300 / yg 2, 40 / yg 1 and 400 / yg 2, 40 / yg 1 and 500 yg 2, 40 / yg I and 600 yg 2, 40 / yg 1 and 700 / yg 2, 40 / yg 1 and 800 / yg 2, 40 / ^y gi and 900 / yg 2, 40 / yg 1 and 1000 / yg 2, 60 / yg 1 and 25 / yg 2, 60 / yg 1 and 50 / yg 2, 60 / ^y g 1 and 100 / yg 2, 60 / yg 1 and 200 / yg 2, 60 yg 1 and 300 / yg 2, 60 / yg i and 400 / yg 2, 60 / yg 1 and 500 / yg 2, 60 / yg 1 and 600 / yg 2, 60 / yg 1 and 700 / yg 2, 60 / yg 1 and 800 / yg 2, 60 / yg 1 and 900 / yg 2, 60 / yg 1 and 1000 yg 2, 100 / yg 1 and 25 / yg 2 , 100 / yg 1 and 50 / yg 2, 100 yg 1 and 100 / yg 2, 100 yg 1 and 200 yg 2, 100 yg 1 and 300 yg 2, 100 / yg 1 and 400 / yg 2, 100 / yg 1 and 500 / yg 2, 100 / yg 1 and 600 / yg 2, 100 / yg 1 and 700 / yg 2, 100 / yg 1 and 800 / yg 2, 100 / yg 1 and 900 / yg 2, 100 / yg 1 and 1000 / yg 2, 200 / yg 1 and 25 / yg 2, 200 yg 1 and 50 / yg 2, 200 / yg 1 and 100 / yg 2, 200 / yg 1 and 200 / ^y g 2, 200 / yg 1 and 300 / yg 2, 200 / yg 1 and 400 / yg 2, 200 / yg 1 and 500 / yg 2, 200 / yg I and 600 / ^y g 2, 200 / yg 1 and 700 / yg 2, 200 // g 1 and 800 / yg 2, 200 / yg I and 900 / yg 2, 200 / ^y g 1 and 1000 / yg 2, 250 / yg 1 and 25 / yg 2, 250 / yg 1 and 50 / yg 2, 250 / yg I and 100 / yg 2, 250 / yg 1 and 200 / yg 2, 250 / yg I and 300 / yg 2, 250 / yg 1 and 400 / yg 2, 250 / yg 1 and 500 / ^y g 2, 250 / yg I and 600 / yg 2, 250 yg 1 and 700 / ^y g 2, 250 yg I and 800 yg 2, 250 / ^y g 1 and 900 / tg 2, 250 / yg 1 and 1000 / yg 2, 500 / ^y g 1 and 25 / yg 2, 500 / yg I and 50 / ^y g 2, 500 / yg 1 and 100 / yg 2, 500 / yg 1 and 200 / yg 2, 500 / ^y g 1 and 300 yg 2, 500 / yg 1 and 400 / ^y g 2, 500 / yg 1 and 500 / yg 2, 500 / yg 1 and 600 / yg 2 , 500 / yg and 700 1 / yg 2 500 / ^y g 1 and 800 / yg 2, 500 / yg and 900 1 or 500 2 yg / yg 1 and 1000 / yg 2, The active ingredient combinations according to the invention from 1 and 2 are preferably administered by inhalation. For this purpose, the components and 2 must be provided in inhalable dosage forms. Inhalable dosage forms, inhalation powders containing propellant gas or propellant-free inhalation solutions come into consideration. Inhalable powders according to the invention containing the combination of active substances 1 and 2 can consist solely of the active substances mentioned or of a mixture of the active substances mentioned with physiologically compatible auxiliaries. In the context of the present invention, the term propellant-free inhalation solutions also includes concentrates or sterile, ready-to-use inhalation solutions. The dosage forms according to the invention can contain the active ingredient combination from 1 and 2 either together in one or in two separate dosage forms. These dosage forms which can be used in the context of the present invention are described in detail in the following part of the description.

A) Inhalable powder containing the active ingredient combinations according to the invention from 1 and 2: The inhalable powders according to the invention can contain 1 and 2 either alone or in a mixture with suitable physiologically acceptable excipients.

If the active ingredients 1 and 2 are contained in a mixture with physiologically acceptable auxiliaries, the following physiologically acceptable auxiliaries can be used to prepare these inhalable powders according to the invention

Applications are: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, maltose, trehalose), oligo- and polysaccharides (e.g. dextrans), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or Mixtures of these auxiliaries with one another. Mono- or disaccharides are preferably used, the use of lactose or glucose being preferred, in particular, but not exclusively, in the form of their hydrates. Lactose, most preferably lactose monohydrate, is used as an auxiliary as particularly preferred in the sense of the invention.

In the context of the inhalable powders according to the invention, the auxiliaries have a maximum average particle size of up to 250 / ym, preferably between 10 and 150 / ym, particularly preferably between 15 and 80 / ym. If appropriate, it may appear sensible to add finer excipient fractions with an average particle size of 1 to 9 / ym to the excipients mentioned above. The latter finer excipients are also selected from the group of excipients that can be used. Finally, to produce the inhalable powders according to the invention, micronized active ingredients I and 2, preferably with an average particle size of 0.5 to 10 / ym, particularly preferably 1 to 5 / ym, are admixed with the excipient mixture. Processes for producing the inhalable powders according to the invention by grinding and micronizing and by finally mixing the constituents are known from the prior art. The inhalable powders according to the invention can be provided and applied either in the form of a single powder mixture which contains both 1 and 2 or in the form of separate inhalable powders which contain only 1 and 2.

The inhalable powders according to the invention can be applied using inhalers known from the prior art. Inhalation powders according to the invention which, in addition to 1 and 2, furthermore contain a physiologically acceptable auxiliary, can be applied, for example, by means of inhalers which take a single dose from a supply by means of a measuring chamber, as described in US 4570630A, or via other apparatus, such as those are described in DE 36 25 685 A, meter. The inhalable powders according to the invention, which in addition to 1 and 2 contain physiologically acceptable excipients, are preferably filled into capsules (for so-called inhalers), which are used in inhalers as described, for example, in WO 94/28958.

An inhaler which is particularly preferred for use of the pharmaceutical combination according to the invention in inhalettes can be seen in FIG. 1. This inhaler (Handihaier) for the inhalation of powdered pharmaceuticals from capsules is characterized by a housing 1, containing two windows 2, a deck 3, in which there are air inlet openings and which is provided with a sieve 5 attached via a sieve housing 4, one with a deck 3 connected

Inhalation chamber 6, on which a pusher 9, provided with two ground needles 7 and movable against a spring 8, is provided, as well as a mouthpiece 12, which is hinged to the housing 1, the deck 3 and a cap 11, and air passage holes 13 for adjustment the flow resistance.

If the inhalable powders according to the invention are to be filled into capsules (inhalettes) in the sense of the preferred use mentioned above, fill quantities of 1 to 30 mg, preferably from 3 to 20 mg, preferably 5 to 10 mg inhalation powder per capsule. According to the invention, these contain either together or in each case the doses per single dose already mentioned above for V and 2.

B) propellant gas inhalation aerosols containing the active ingredient combinations according to the invention from 1 and 2:

Inhalation aerosols containing propellant gas according to the invention can contain 1 and 2 dissolved in the propellant gas or in dispersed form. Here, 1 and 2 can be contained in separate dosage forms or in a common dosage form, where 1 and 2 can either be both dissolved, both dispersed or in each case only one component dissolved and the other dispersed. The propellant gases which can be used to produce the inhalation aerosols according to the invention are known from the prior art. Suitable propellants are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halogenated hydrocarbons such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The above-mentioned propellant gases can be used alone or in mixtures thereof. Particularly preferred propellants are halogenated alkane derivatives selected from TG 134a and TG227 and mixtures thereof.

The inhalation aerosols containing propellant gas according to the invention can furthermore contain further constituents such as cosolvents, stabilizers, surfactants, antioxidants, lubricants and agents for adjusting the pH. All of these components are known in the art.

The inhalation aerosols containing propellant gas according to the invention can contain up to 5% by weight of active ingredient 1 and / or 2. Aerosols according to the invention contain, for example, 0.002 to 5% by weight, 0.01 to 3% by weight, 0.015 to 2% by weight, 0.1 to 2% by weight, 0.5 to 2% by weight or 0.5 to 1 % By weight of active ingredient 1 and / or 2.

If the active ingredients 1 and / or 2 are in dispersed form, the active ingredient particles preferably have an average particle size of up to 10 μm, preferably from 0.1 to 5 μm, particularly preferably from 1 to 5 μm.

The above-mentioned inhalation aerosols containing propellant gas according to the invention can be administered by means of inhalers known in the art (MDIs = metered dose inhalers). Accordingly, a further aspect of the present invention relates to medicaments in the form of propellant-containing aerosols as described above in connection with one or more for Administration of these aerosols suitable inhalers. The present invention further relates to inhalers, characterized in that they contain propellant-containing aerosols according to the invention described above. The present invention further relates to cartridges which can be used with a suitable valve in a suitable inhaler and which contain one of the above-mentioned inhalation aerosols containing propellant gas according to the invention. Suitable cartridges and methods for filling these cartridges with the inhalation aerosols containing propellant gas according to the invention are known from the prior art.

C) Propellant-free inhalation solutions or suspensions containing the active ingredient combinations according to the invention from 1 and 2:

If appropriate, the active compound combination according to the invention is applied in the form of propellant-free inhalation solutions and inhalation suspensions. Suitable solvents for this purpose are aqueous or alcoholic, preferably ethanolic, solutions. The solvent can only be water or it is a mixture of water and ethanol. The relative proportion of ethanol to water is not limited, but the maximum limit is preferably up to 70 percent by volume, in particular up to 60 percent by volume and particularly preferably up to 30 percent by volume. The remaining volume percentages are filled up with water. The solutions and suspensions containing 1 and 2, separately or together, are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. Acids selected from inorganic or organic acids can be used to adjust this pH. Examples of particularly suitable inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid. Examples of particularly suitable organic acids are: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid and others. Preferred inorganic acids are hydrochloric acid, sulfuric acid. It is also possible to use the acids which already form an acid addition salt with one of the active ingredients. Ascorbic acid, fumaric acid and citric acid are preferred among the organic acids. If appropriate, mixtures of the acids mentioned can also be used, in particular in cases of acids which, in addition to their acidifying properties, also have other properties, for example as flavorings, antioxidants or complexing agents, such as, for example, citric acid or ascorbic acid. According to the invention, hydrochloric acid is particularly preferably used to adjust the pH. According to the invention, the addition of editic acid (EDTA) or one of the known salts thereof, sodium edetate, as a stabilizer or complexing agent can be dispensed with in the present formulation. Other embodiments include this connection (s). In such a preferred embodiment, the content based on sodium edetate is below 100 mg / 100 ml, preferably below 50 mg / 100 ml, particularly preferably below 20 mg / 100 ml.

Inhalation solutions in which the sodium edetate content is 0 to 10 mg / 100 ml are generally preferred.

Co-solvents and / or other auxiliaries can be added to the propellant-free inhalation solutions according to the invention.

Preferred co-solvents are those which contain hydroxyl groups or other polar groups, for example alcohols - in particular isopropyl alcohol, glycols - in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. In this context, auxiliaries and additives are understood to mean any pharmacologically compatible substance which is not an active substance, but which can be formulated together with the active substance (s) in the pharmacologically suitable solvent in order to improve the qualitative properties of the

Improve drug formulation. These substances preferably have no or no significant or at least no undesirable pharmacological effect in the context of the desired therapy. The auxiliaries and additives include e.g. surfactants such as Soy lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilizers, complexing agents,

Antioxidants and / or preservatives that guarantee or extend the useful life of the finished pharmaceutical formulation, flavors, vitamins and / or other additives known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents.

The preferred auxiliary substances include antioxidants, such as, for example, ascorbic acid, unless already used for adjusting the pH, vitamin A, vitamin E, tocopherols and similar vitamins or provitamins occurring in the human organism.

Preservatives can be used to protect the formulation from contamination with germs. Suitable preservatives are those known from the prior art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate concentration known from the prior art. The preservatives mentioned above are preferably present in concentrations of up to 50 mg / 100 ml, particularly preferably between 5 and 20 mg / 100 ml.

In addition to the solvent water and the active ingredient combination of 1 and 2, preferred formulations only contain benzalkonium chloride and sodium edetate. In another preferred embodiment, sodium edetate is dispensed with.

For the application of the propellant-free inhalation solutions according to the invention, there are particularly those inhalers which can nebulize a small amount of a liquid formulation in the therapeutically necessary dosage within a few seconds into an aerosol suitable for therapeutic inhalation. For the purposes of the present invention, those nebulizers are preferred in which an amount of less than 100 / yL, preferably less than 50 μL, particularly preferably between 20 and 30 μL of active ingredient solution, preferably with a stroke to an aerosol with an average particle size of less than 20 μm, preferably less than 10 m, can be atomized so that the inhalable portion of the aerosol already corresponds to the therapeutically effective amount.

Such a device for propellant-free administration of a metered amount of a liquid medicament for inhalation use is described in detail, for example, in international patent application WO 91/14468 and also in WO 97/12687 (there in particular FIGS. 6a and 6b). The nebulizers described there are also known under the name Respimat®.

This nebulizer (Respimat®) can advantageously be used to produce the inhalable aerosols according to the invention containing the combination of active substances 1 and 2. Due to its cylinder-like shape and a handy size of less than 9 to 15 cm in length and 2 to 4 cm in width, this device can be carried by the patient at any time. The nebulizer sprays a defined volume of the drug formulation using high pressures through small nozzles, so that inhalable aerosols are formed.

Essentially, the preferred atomizer consists of an upper housing part, a pump housing, a nozzle, a locking mechanism, a spring housing, a spring and a reservoir, characterized by a pump housing which is fastened in the upper housing part and which has a nozzle body with the nozzle at one end or carries the nozzle arrangement, a hollow piston with valve body, an output flange in which the hollow piston is fastened and which is located in the upper housing part, a locking mechanism which is located in the upper housing part, - a spring housing with the spring located therein, which is rotatably mounted on the upper housing part by means of a rotary bearing, a lower housing part, which is attached to the spring housing in the axial direction.

The hollow piston with valve body corresponds to a device disclosed in WO 97/12687. It projects partially into the cylinder of the pump housing and is arranged axially displaceably in the cylinder. In particular, reference is made to FIGS. 1-4 - in particular FIG. 3 - and the associated parts of the description. The hollow piston with valve body exerts a pressure of 5 to 60 Mpa (about 50 to 600 bar), preferably 10 to 60 Mpa (about 100 to 600 bar) on the fluid, the measured active ingredient solution on its high pressure side at the time the spring is triggered. Volumes of 10 to 50 microliters are preferred, volumes of 10 to 20 microliters are particularly preferred, and a volume of 15 microliters per stroke is very particularly preferred.

The valve body is preferably attached to the end of the hollow piston which faces the nozzle body.

The nozzle in the nozzle body is preferably microstructured, i.e. made by microtechnology. Microstructured nozzle bodies are disclosed, for example, in WO-94/07607; reference is hereby made to this document, in particular to FIG. 1 disclosed there and its description.

The nozzle body is e.g. of two firmly connected plates made of glass and / or silicon, of which at least one plate has one or more microstructured channels, which the nozzle inlet side with the

Connect the nozzle outlet side. On the nozzle outlet side there is at least one round or non-round opening of 2 to 10 micrometers deep and 5 to 15 micrometers wide, the depth preferably being 4.5 to 6.5 micrometers and the length being 7 to 9 micrometers. In the case of several nozzle openings, preferably two, the

Jet directions of the nozzles in the nozzle body run parallel to one another or they are inclined towards one another in the direction of the nozzle opening. In the case of a nozzle body with at least two nozzle openings on the outlet side, the jet directions can be changed be inclined towards one another at an angle of 20 degrees to 160 degrees, an angle of 60 to 150 degrees is preferred, particularly preferably 80 to 100 degrees. The nozzle openings are preferably arranged at a distance of 10 to 200 micrometers, more preferably at a distance of 10 to 100 micrometers, particularly preferably 30 to 70 micrometers. Most preferred are 50 microns.

Accordingly, the jet directions meet in the vicinity of the nozzle openings.

The liquid pharmaceutical preparation hits the nozzle body at an inlet pressure of up to 600 bar, preferably 200 to 300 bar, and is atomized into an inhalable aerosol via the nozzle openings. The preferred particles. Droplet sizes of the aerosol are up to 20 micrometers, preferably 3 to 10 micrometers.

The locking mechanism contains a spring, preferably a cylindrical helical compression spring, as a store for the mechanical energy. The spring acts on the output flange as a jumping piece, the movement of which is determined by the position of a locking element. The path of the output flange is precisely limited by an upper and a lower stop. The spring is preferably via a force-transmitting gear, e.g. a screw-type thrust gear, tensioned by an external torque generated when the upper housing part is turned against the spring housing in the lower housing part. In this case, the upper part of the housing and the output flange contain a single or multi-speed wedge gear.

The locking member with engaging locking surfaces is arranged in a ring around the output flange. It consists, for example, of a radially elastically deformable ring made of plastic or metal. The ring is arranged in a plane perpendicular to the atomizer axis. After tensioning the spring, the locking surfaces of the locking member slide into the path of the output flange and prevent the spring from relaxing. The locking element is triggered by a button. The trigger button is connected or coupled to the locking member. To release the locking mechanism, the release button is moved parallel to the ring plane, and preferably into the atomizer; the deformable ring is deformed in the plane of the ring. Structural details of the locking mechanism are described in WO 97/20590. The lower part of the housing is pushed in the axial direction over the spring housing and covers the bearing, the drive of the spindle and the reservoir for the fluid.

When the atomizer is actuated, the upper housing part is against the

Lower housing part rotated, the lower housing part taking the spring housing with it. The spring is compressed and tensioned via the screw-type thrust gear, and the locking mechanism engages automatically. The angle of rotation is preferably an integer fraction of 360 degrees, e.g. 180 degrees. Simultaneously with the tensioning of the spring, the driven part in the upper part of the housing is shifted by a predetermined distance, the hollow piston is withdrawn inside the cylinder in the pump housing, whereby a part of the fluid is sucked out of the reservoir into the high-pressure space in front of the nozzle.

If necessary, a number of interchangeable storage containers containing the fluid to be atomized can be inserted and used in the atomizer. The storage container contains the aqueous aerosol preparation according to the invention.

The atomization process is initiated by gently pressing the trigger button. The barrage clears the way for the stripping section. The tensioned spring pushes the piston into the cylinder of the pump housing. The fluid exits the atomizer nozzle in atomized form.

Further structural details are disclosed in PCT applications WO 97/12683 and WO 97/20590, to which reference is hereby made.

The components of the atomizer (nebulizer) are made of a material that is suitable for their function. The housing of the atomizer and - as far as the function allows - other parts are preferably made of plastic, e.g. manufactured by injection molding. Physiologically harmless materials are used for medical purposes.

FIGS. 6 a / b of WO 97/12687 describe the nebulizer (Respimat®) with which the aqueous aerosol preparations according to the invention can advantageously be inhaled.

Figure 6a of WO 97/12687, to which reference is expressly made here, shows a longitudinal section through the atomizer with the spring under tension. Figure 6b the WO 97/12687, to which reference is explicitly made at this point, shows a longitudinal section through the atomizer with the spring relaxed. The upper housing part (51) contains the pump housing (52), at the end of which the holder (53) for the atomizer nozzle is attached. The nozzle body (54) and a filter (55) are located in the holder. The hollow piston (57) fastened in the output flange (56) of the locking tension mechanism partially projects into the cylinder of the pump housing. The hollow piston carries the valve body (58) at its end. The hollow piston is sealed by means of the seal (59). Inside the upper part of the housing is the stop (60), against which the output flange rests when the spring is relaxed. The stop (61) is located on the output flange, against which the output flange rests when the spring is tensioned. After tensioning the spring, the locking member (62) slides between the stop (61) and a support (63) in the upper part of the housing. The release button (64) is connected to the locking member. The upper housing part ends in the mouthpiece (65) and is closed with the clip-on protective cap (66).

The spring housing (67) with compression spring (68) is rotatably mounted on the upper part of the housing by means of the snap lugs (69) and rotary bearings. The lower housing part (70) is pushed over the spring housing. The exchangeable storage container (71) for the fluid (72) to be atomized is located within the spring housing. The

The storage container is closed with the stopper (73) through which the hollow piston protrudes into the storage container and with its end is immersed in the fluid (supply of active substance solution).

The spindle (74) for the mechanical counter is mounted in the outer surface of the spring housing. The drive pinion (75) is located at the end of the spindle which faces the upper housing part. The rider (76) sits on the spindle.

The nebulizer described above is suitable for nebulizing the aerosol preparations according to the invention into an aerosol suitable for inhalation.

If the formulation according to the invention is atomized using the technique described above (Respimat®), the mass applied should be at least 97%, preferably at least 98%, of all actuations of the inhaler (hub) of a defined amount with a tolerance range of at most 25%, preferably 20% Amount. Between 5 and 30 mg of formulation are preferably applied as a defined mass per stroke, particularly preferably between 5 and 20 mg. However, the formulation according to the invention can also be nebulized using inhalers other than those described above, for example jet stream inhalers.

Accordingly, a further aspect of the present invention relates to medicaments in the form of propellant-free inhalable solutions or suspensions as described above in connection with a device suitable for the administration of these formulations, preferably in connection with the Respimat®. The present invention preferably aims at propellant-free inhalation solutions or suspensions characterized by the combination of active substances according to the invention and 2 in conjunction with the device known under the name Respimat®. Furthermore, the present invention relates to the above-mentioned devices for inhalation, preferably the Respimat®, characterized in that they contain propellant-free inhalable solutions or suspensions according to the invention described above.

The propellant-free inhalation solutions or suspensions according to the invention can, in addition to the solutions and suspensions intended for application in the Respimat, also be present as concentrates or sterile, ready-to-use inhalation solutions or suspensions. Ready-to-use formulations can be generated from the concentrates, for example, by adding isotonic saline solutions. Sterile, ready-to-use formulations can be applied using energy-operated stand-up or portable nebulisers that generate inhalable aerosols using ultrasound or compressed air according to the Venturi principle or other principles.

Accordingly, a further aspect of the present invention relates to medicaments in the form of propellant-free inhalable solutions or suspensions as described above, which are present as concentrates or sterile, ready-to-use formulations, in conjunction with a

Administration of these solutions suitable device, characterized in that it is an energy-operated standing or portable nebulizer that generates inhalable aerosols by means of ultrasound or compressed air according to the Venturi principle or other principles.

The following examples serve to explain the present invention in more detail without, however, restricting the scope of the invention to the following exemplary embodiments. formulation Examples

A) Inhalable powder: 1)

2)

3)

4)

5)

6)

B) Inhalation aerosols containing propellant gas: 1) Suspension aerosol:

w 2)

Claims

claims

1) Medicinal product characterized by a content of one or more

Anticholinergics of Formula 1

wherein

X "is a single negatively charged anion, 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 means in combination with one or more PDE-IV inhibitors (2), optionally in the form of their enantiomers, mixtures of the enantiomers or in the form of the racemates, optionally in the form of the solvates or hydrates and optionally together with a pharmaceutically acceptable auxiliary.

2) Medicament according to claim 1, characterized in that the active ingredients 1 and 2 are either contained together in a single dosage form or in two separate dosage forms.

3) Medicament according to one of claims 1 or 2, characterized in that in the compounds of formula IX ^"means a simply negatively charged anion selected from the group consisting of chloride, bromide, 4-toluenesulfonate and methanesulfonate.

4) Medicament according to one of claims 1 to 3, characterized in that in the compounds of formula 1 X ^" stands for bromide. 5) Medicament according to one of claims 1 to 4, characterized in that 2 is selected from the group consisting of Enprofylline, Theophylline, Roflumilast, Ariflo, Bay-198004, CP-325,366, BY343, D-4396 (Sch-351591), V-11294A, AWD-12-281, N- (3,5-dichloro-1-oxopyridin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide and the tricyclic nitrogen heterocycles of the general formula 2a

wherein R ¹ -C -C-alkyl, C5-C6-cycloalkyl, phenyl, benzyl or a 5- or 6-membered, saturated or unsaturated heterocyclic ring which may contain one or two heteroatoms selected from the group consisting of oxygen and nitrogen; R ² C- | -C-5-alkyl or C-2-C-4-alkenyl; R ^{3 is} C- | -C5-alkyl, which may be replaced by C- | C4-alkoxy,

C5-C6-cycloalkyl, phenoxy or by a 5- or 6-membered, saturated or unsaturated heterocyclic ring which may contain one or two heteroatoms selected from the group consisting of oxygen and nitrogen, Cδ-Ce-cycloalkyl or optionally by C- | -C4-Alkoxy may be substituted phenyl or benzyl, optionally in the form of their racemates, their enantiomers, in the form of their diastereomers and their mixtures, optionally in the form of their tautomers and, if appropriate, their pharmacologically acceptable acid addition salts.

6) Medicament according to one of claims 1 to 5, characterized in that 2 is selected from the group consisting of Enprofylline, Roflumilast, Ariflo, AWD-12-281, N- (3,5-dichloro-1-oxo-pyridine- 4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide and the tricyclic

Nitrogen heterocycles of the general formula 2a. 7) Medicament according to one of claims 1 to 6, characterized in that the weight ratios of 1 to 2 are in a range from 1: 100 to 100: 1, preferably from 1: 80 to 80: 1.

8) Medicament according to one of claims 1 to 7, characterized in that a single application corresponds to a dosage of the active ingredient combination 1 and 2 from 0.01 to 10000μg, preferably from 0.1 to 2000μg.

9) Medicament according to one of claims 1 to 8, characterized in that it is in the form of a dosage form suitable for inhalation.

10) Medicament according to claim 9, characterized in that it is a dosage form selected from the group of inhalation powders, propellant aerosols and propellant-free inhalation solutions or suspensions.

11) Medicament according to claim 10, characterized in that it is an inhalation powder which 1 and 2 in a mixture with suitable physiologically acceptable excipients selected from the group consisting of monosaccharides, disaccharides, oligo- and polysaccharides,

Contains polyalcohols, salts, or mixtures of these auxiliaries.

12) inhalation powder according to claim 11, characterized in that the excipient has a maximum average particle size of up to 250 microns, preferably between 10 and 150 microns.

13) capsules characterized by a content of inhalable powder according to claim 11 or 12.

14) Medicament according to claim 10, characterized in that it is a

Inhalation powder is, which contains only the active ingredients 1 and 2 as components.

15) Medicament according to claim 10, characterized in that it is a propellant-containing inhalation aerosol which contains Λ_ and 2 in dissolved or dispersed form.

6) propellant gas inhalation aerosol according to claim 15, characterized in that it contains hydrocarbons such as n-propane, n- Contains butane or isobutane or halogenated hydrocarbons such as chlorinated and / or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.

17) propellant-containing inhalation aerosol according to claim 16, characterized in that the propellant gas is TG 134a, TG227 or a mixture thereof.

18) propellant gas inhalation aerosol according to claim 15, 16 or 17, characterized in that it is optionally one or more

Contains ingredients selected from the group consisting of cosolvents, stabilizers, surfactants, antioxidants, lubricants and agents for adjusting the pH.

19) propellant gas inhalation aerosol according to one of claims 15 to 18, characterized in that it can contain up to 5% by weight of active ingredient 1 and / or 2.

20) Medicament according to claim 10, characterized in that it is a propellant-free inhalation solution or suspension, which as

Solvent contains water, ethanol or a mixture of water and ethanol.

21) inhalation solution or suspension according to claim 20, characterized in that the pH is 2-7, preferably 2-5.

22) inhalation solution or suspension according to claim 21, characterized in that the pH by means of an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, ascorbic acid, citric acid, malic acid, tartaric acid,

Maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and propionic acid or mixtures thereof.

23) inhalation solution or suspension according to any one of claims 20 to 22, characterized in that it optionally contains further co-solvents and / or auxiliaries. 24) inhalation solution or suspension according to claim 23, characterized in that it contains, as co-solvents, constituents which contain hydroxyl groups or other polar groups, for example

5 alcohols - especially isopropyl alcohol, glycols - especially

Propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters.

25) inhalation solution or suspension according to one of claims 23 or 24, characterized in that it contains surfactants as auxiliary substances

Contains stabilizers, complexing agents, antioxidants and / or preservatives, flavorings, pharmacologically acceptable salts and / or vitamins.

15 26) inhalation solution or suspension according to claim 25, characterized in that it contains, as complexing agent, editic acid or a salt of editic acid, preferably sodium edetate.

27) Inhalable solution or suspension according to Claim 25 or 26, characterized in that it contains, as antioxidants, compounds selected from the group consisting of ascorbic acid, vitamin A, vitamin E and tocopherols.

28) inhalation solution or suspension according to claim 25, 26 or 27, characterized 5, that it contains as a preservative compounds selected from cetylpyridinium chloride, benzalkonium chloride, benzoic acid and benzoates.

29) inhalation solution or suspension according to any one of claims 23 to 28, 0 characterized in that in addition to the active ingredients 1 and 2 and the

Solvent only contains bezalkonium chloride and sodium edetate.

30) inhalation solution or suspension according to one of claims 23 to 28, characterized in that it contains only benzalkonium chloride in addition to the active ingredients 1 and 2 and the 5 solvent.

31) Inhalation solution or suspension according to one of claims 20 to 30, characterized in that it is a concentrate or a sterile, ready-to-use inhalation solution or suspension. 32) Use of a capsule according to claim 13 in an inhaler, preferably in a handihaler.

33) Use of an inhalation solution according to one of claims 20 to 30 for nebulization in an inhaler according to WO 91/14468 or an inhaler as described in Figures 6a and 6b of WO 97/12687.

34) Use of an inhalation solution according to claim 31 for nebulization in an energy-operated standing or portable nebulizer that generates inhalable aerosols by means of ultrasound or compressed air according to the Venturi principle or other principles.

35) Use of a composition according to any one of claims 1 to 31 for the manufacture of a medicament for the treatment of inflammatory or obstructive respiratory diseases.