DE10230769A1 - New drug compositions based on new anticholinergics and PDE-IV inhibitors - Google Patents

Abstract

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

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

Surprisingly can have an unexpectedly beneficial therapeutic effect, in particular a synergistic effect in the treatment of inflammatory and / or obstructive airways disease are observed when one or more, preferably a new anticholinergic of the formula 1 together with one or more, preferably a PDE-IV inhibitor 2 apply. Because of this synergistic effect are the drug combinations according to the invention can be used at a lower dosage than with the usual one Monotherapy of the individual connections is the case. Let also thereby becoming undesirable Side effects as they occur when applying PDE-IV inhibitors can reduce.

The above effects are both with simultaneous application within a single Drug formulation as well as with successive application of the two Active substances observed in separate formulations. Preferred according to the invention is the simultaneous application of the two active ingredients in a single wording.

worin
X– ein einfach negativ geladenes Anion, vorzugsweise ein Anion ausgewählt aus der Gruppe bestehend aus Chlorid, Bromid, lodid, Sulfat, Phosphat, Methansulfonat, Nitrat, Maleat, Acetat, Citrat, Fumarat, Tartrat, Oxalat, Succinat, Benzoat und p-Toluolsulfonat bedeutet zur Anwendung.In the context of the present invention, the salts of formula 1 are used as anticholinergic

wherein
X - 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 - a simply negatively charged anion selected from the group consisting of chloride, bromide, methyl sulfate, 4-toluenesulfonate and methanesulfonate, preferably bromide.

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

According to the invention, that salt of formula 1 in which
X- stands for bromide.

The salts of Fromel 1 are from the international patent application WO 02/32893 known.

durch Verwendung der Bezeichnung 1' zu erkennen. Eine Bezugnahme auf Verbindungen 1 schließt naturgemäß eine Bezugnahme auf das Kation 1' mit ein.Within the scope of the present patent application there is an explicit reference to the pharmacologically active cation of the formula

recognizable by using the designation 1 '. A reference to compounds 1 naturally includes a reference to the cation 1 '.

One within the scope of the present invention reference to the salts 1 which can be used according to the invention optionally closes available Hydrates and solvates of these compounds.

wobei
R¹ C₁-C₅-Alkyl, C₅-C₆-Cycloalkyl, Phenyl, Benzyl oder ein 5- oder 6-gliedriger, gesättigter oder ungesättigter heterocyclischer Ring, der ein oder zwei Heteroatome, ausgewählt aus der Gruppe Sauerstoff und Stickstoff enthalten kann;
R² C₁-C₅-Alkyl oder C₂-C₄-Alkenyl;
R³ C₁-C₅-Alkyl, das gegebenenfalls durch C₁-C₄-Alkoxy, C₅-C₆-Cycloalkyl, Phenoxy oder durch einen 5- oder 6-gliedrigen, gesättigten oder ungesättigten heterocyclischen Ring, der ein oder zwei Heteroatome, ausgewählt aus der Gruppe Sauerstoff und Stickstoff enthalten kann, substituiert sein kann, C₅-C₆-Cycloalkyl oder gegebenenfalls durch C₁-C₄-Alkoxy substituiertes Phenyl oder Benzyl, bedeuten können, gegebenenfalls in Form ihrer Racemate, ihrer Enantiomere, in Form ihrer Diastereomere und ihrer Gemische, gegebenenfalls in Form ihrer Tautomere sowie gegebenenfalls ihrer pharmakologisch unbedenklichen Säureadditionssalze.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, 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-cycfopropylmethoxybenzamide as well as the tricyclic nitrogen heterocycles of the general formula 2a

in which
R ^{1 is} C ₁ -C ₅ alkyl, C ₅ -C ₆ cycloalkyl, phenyl, benzyl or a 5- or 6-membered, saturated or unsaturated heterocyclic ring containing one or two heteroatoms selected from the group consisting of oxygen and nitrogen can;
R ^{2 is} C ₁ -C ₅ alkyl or C ₂ -C ₄ alkenyl;
R ^{3 is} C ₁ -C ₅ alkyl which is optionally substituted by C ₁ -C ₄ alkoxy, C ₅ -C ₆ cycloalkyl, phenoxy or by a 5- or 6-membered, saturated or unsaturated heterocyclic ring which is one or two Heteroatoms selected from the group consisting of oxygen and nitrogen can be substituted, can be C ₅ -C ₆ cycloalkyl or phenyl or benzyl optionally substituted by C ₁ -C ₄ alkoxy, optionally 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 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 is} C ₁ -C ₄ alkyl, C ₅ -C ₆ cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholinyl or phenyl;
R ^{2 is} C ₁ -C ₄ alkyl or C ₂ -C ₄ alkenyl;
R ^{3 is} C ₁ -C ₄ alkyl, which can optionally be substituted by C ₁ -C ₄ alkoxy, C ₅ -C ₆ cycloalkyl, phenoxy, (C ₁ -C ₄ alkoxy) phenyloxy, piperazine or pyrrole, C _5- C ₆ -cycloalkyl or phenyl or benzyl optionally substituted by C ₁ -C ₄ -alkoxy may optionally be 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 those within the scope of the present invention
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, phenoxymethyl, methoxybenzyl or N-pyrolylmethyl,
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 optionally their pharmacologically unbe conceivable acid addition salts.

Compounds 2 of the formula 2a are particularly preferably used 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 can} mean ethyl, i-propyl, n-propyl, n-butyl, t-butyl, cyclopentyl, cyclohexylmethyl, benzyl, phenylethyl, phenoxymethyl, 4-methoxybenzyl or N-pyrollylmethyl, optionally in the form of their racemates, their enantiomers, in 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 as far as they Other residues are) are branched and unbranched Consider alkyl groups with 1 to 5 carbon atoms, for example are mentioned: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec.butyl, tert-butyl, n-pentyl, isopentyl or neopentyl. If necessary for above abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. are used.

As cycloalkyl radicals with 5 or 6 Carbon atoms are called cyclopentyl or cyclohexyl. As Examples 5- or 6-membered, saturated or unsaturated heterocyclic Rings that are one or two heteroatoms selected from the group oxygen and can contain nitrogen, are called: furan, tetrahydrofuran, tetrahydrofuranone, γ-butylrolactone, α-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, together in the context of the present Invention particularly preferably in combination with the compounds 1 are used.

Table 1:

Continuation of table 1:

The making of the connections of the general formula 2a can be analogous to that by the state of the Technology for some representatives of the general compounds defined above Formula (I) (Tenor et al., Chem. Ber. Vol. 97 (1964) pp. 1373-1382) Procedure are carried out on the content related at this point is taken.

The connection is further preferred 2 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, where Ariflo, roflumilast and the above compounds of the formula 2a as compound 2 are particularly preferred according to the invention.

A reference to the above PDE-IV inhibitors 2 includes within the scope of the present Invention a reference to their existing, if any pharmacologically acceptable acid addition salts on.

Among the physiologically tolerable Acid addition salts, which can be formed by 2 are pharmaceutical according to the invention compatible Salts understood that selected from the salts of hydrochloric acid, hydrobromic, Sulfuric acid, Phosphoric acid, methane, Acetic acid, fumaric acid, Succinic acid, Lactic acid, Citric acid, tartaric acid or maleic acid are. Preferred according to the invention are the salts of compounds 2 which are selected from the group consisting of from acetate, hydrochloride, hydrobromide, sulfate, phosphate, and methanesulfonate.

The application of the drug combinations according to the invention 1 and 2 are preferably inhaled. Suitable ones can be used here Inhalable powder, which is filled into suitable capsules (inhalettes) by means of appropriate Powder inhalers are used. alternative In addition, inhalative use can also be done by applying more suitable Inhalation aerosols take place. This also includes inhalation aerosols, for example the HFA134a (also called TG134a), HFA227 (also TG227 called) or contain their mixture as propellant. The inhalative Application can also be carried out using suitable solutions of the drug combination consisting of 1 and 2.

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

Another aspect of the present Invention relates to a medicament containing one or more salts 1 and one or more compounds 2, optionally in the form of their Contains solvates or hydrates. Here too you can the active ingredients either together in a single dosage form or contained in two separate dosage forms. Preferred according to the invention are drugs that contain the active ingredients 1 and 2 in a single Pharmaceutical form included.

further aspect of the present The invention relates to a pharmaceutical which, in addition to being therapeutically active Amounts of 1 and 2 contains a pharmaceutically acceptable excipient. On Another aspect of the present invention relates to a medicament, which besides therapeutically effective amounts of 1 and 2 none pharmaceutically acceptable Contains excipient.

The present invention relates to further the use of 1 and 2 for the preparation of a therapeutic effective amounts of 1 and 2 containing drug for treatment of inflammatory and / or obstructive respiratory diseases, especially asthma or chronic obstructive pulmonary disease (COPD), as well as their Complications such as pulmonary hypertension, besides also allergic and non-allergic rhinitis.

The present extension also aims at the simultaneous or successive use of therapeutically effective doses of the combination of the above drugs 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 pulmonary hypertension, besides all genetic and non-allergic rhinitis, through simultaneous or successive application.

In the active ingredient combinations according to the invention from 1 and 2 can ingredients 1 and 2 in the form of their enantiomers, mixtures of Enantiomers or in the form of racemates may be included.

The relationships in which the two Active substances 1 and 2 in the active substance combinations according to the invention can be used are variable. The active ingredients 1 and 2 may optionally be in the form of their Solvates or hydrates are present. Depending on the choice of connections 1 or 2 vary those that can be used in the context of the present invention weight ratios due to the different molecular weight of the different Connections as well as due to their different potency. In usually can the drug combinations according to the invention contain the compounds 1 and 2 in weight ratios, which in a range from 1: 100 to 100: 1, preferably from 1:80 to 80: 1, lie. Particularly preferred drug combinations are the weight ratios from 1 to 2 particularly preferably in a range in which 1 'and 2 in ratios from 1:50 to 50: 1, further preferably from 1:20 to 20: 1 are.

For example and without the scope to limit the invention to can preferred combinations according to the invention from 1 'and PDE = IV inhibitor 2 in the following weight ratios included: 1:65; 1:64; 1:63 1:62; 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 use of the medicament according to the invention containing the combinations of 1 and 2 is usually done so that 1 and 2 together in doses of 0.01 to 10000μg, preferred from 0.1 to 2000μg, particularly preferably from 1 to 1500μg, further preferably from 50 to 1200μg each Single dose is included. For example, contain combinations according to the invention from 1 and 2 such an amount of 1 'and PDE-IV inhibitor 2 that the total dose 100μg per single dose, 105μg, 110μg, 115μg, 120μg, 125μg, 130μg, 135μg, 140μg, 145μg, 150μg, 155μg, 160μg, 165μg, 170μg, 175μg, 180μg, 185μg, 190μg, 195μg, 200μg, 205μg, 210μg, 215μg, 220μg, 225 230μg, 235μg, 240μg, 245μg, 250μg, 255μg, 260μg, 265μg, 270μg, 275μg, 280μg, 285μg, 290μg, 295μg, 300μg, 305μg, 310μg, 315μg, 320μg, 325μg, 330μg, 335μg, 340μg, 34μμ 355μg, 360μg, 365μg, 370μg, 375μg, 380μg, 385μg, 390μg, 395μg, 400μg, 405μg, 410μg, 415μg, 420μg, 425μg, 430μg, 435μg, 440μg, 445μg, 450μg, 455μg, 460μg, 460μg, 460μg 480μg, 485μg, 490μg, 495μg, 500μg, 505μg, 510μg, 515μg, 520μg, 525μg, 530μg, 535μg, 540μg, 545μg, 550μg, 555μg, 560μg, 565μg, 570μg, 575μg, 5μμ, 580μg, 580μ 605μg, 610μg, 615μg, 620μg, 625μg, 630μg, 635μg, 640μg, 645μg, 650μg, 655μg, 660μg, 665μg, 670μg, 675μg, 680μg, 685μg, 690μg, 695μg, 700μg, 725μg, 705μg 730μg, 735μg, 740μg, 745μg, 750μg, 755μg, 760μg, 765μg, 770μg, 775μg, 780μg, 785μg, 790μg, 795μg, 800μg, 805μg, 810μg, 815μg, 820μg, 825μg, 830μg, $ 35μg, 840μg, 845μg, 850μg , 855μg, 860μg, 865μg, 870μg, 875μg, 880μg, 885μg, 890μg, 895μg, 900μg, 905μg, 910μg, 915μg, 920μg, 925μg, 930μg, 935μg, 940μg, 945μg, 975μg, 950μg, 950μg, 950μg, 950μg, 950μg , 980μg, 985μg, 990μg, 995μg, 1000μg, 1005μg, 1010μg, 1015μg, 1020μg, 1025μg, 1030μg, 1035μg, 1040μg, 1045μg, 1050μg, 1055μg, 1060μg, 1065μg, 1070gg, 1090μg, 1075μg, 1075μg or similar is.

The above suggested doses per single dose are not to be regarded as limited to the explicitly stated numerical values, but only serve as doses disclosed by way of example. Of course for example, doses that are above Numerical values in one Fluctuate in the range of approx. +/- 2.5μg, encompassed by the present exemplary values. at these dosage ranges the active ingredients 1 'and 2 be included 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 1 'and PDE-IV inhibitor 2 that 16.5 μg 1 ′ and 25 μg 2, 16.5 μg 1 per single dose 'and 50μg 2, 16.5μg 1' and 100μg 2, 16.5μg 1 'and 200μg 2, 16.5μg 1' and 300μg 2, 16.5μg 1 'and 400μg 2, 16.5μg 1' and 500μg 2, 16.5μg 1 'and 600μg 2, 16.5μg 1' and 700μg 2, 16.5μg 1 'and 800μg 2, 16.5μg 1' and 900μg 2, 16.5μg 1 'and 1000μg 2, 33.1 μg 1 'and 25μg 2, 33.1 μg 1' and 50μg 2, 33.1 μg 1 'and 100μg 2, 33.1 μg 1' and 200μg 2, 33.1μg 1 'and 300μg 2, 33.1μg 1' and 400μg 2, 33.1μg 1 'and 500μg 2, 33.1 μg 1' and 600μg 2, 33.1 μg 1 'and 700μg 2, 33.1 μg 1' and 800μg 2, 33.1 μg 1 'and 900μg 2, 33.1 μg 1 'and 1000μg 2, 49.5μg 1' and 25μg 2, 49.5μg 1 'and 50μg 2, 49.5μg 1' and 100μg 2, 49.5μg 1 'and 200μg 2, 49, 5μg 1 'and 300μg 2, 49.5μg 1' and 400μg 2, 49.5μg 1 'and 500μg 2, 49.5μg 1' and 600μg 2, 49.5μg 1 'and 700μg 2, 49.5μg 1' and 800μg 2, 49.5μg 1 'and 900μg 2, 49.5μg 1' and 1000μg 2, 82.6μg 1 'and 25μg 2, 82 , 6μg 1 'and 50μg 2, 82.6μg 1' and 100μg 2, 82.6μg 1 'and 200μg 2, 82.6μg 1' and 300μg 2, 82.6μg 1 'and 400μg 2, 82.6μg 1' and 500μg 2, 82.6μg 1 'and 600μg 2, 82.6μg 1' and 700μg 2, 82.6μg 1 'and 800μg 2, 82.6μg 1' and 900μg 2, 82.6μg 1 'and 1000μg 2, 165, 1 μg 1 'and 25μg 2, 165.1 μg 1' and 50μg 2, 165.1 μg 1 'and 100μg 2, 165.1 μg 1' and 200μg 2, 165.1 μg 1 'and 300μg 2, 165, 1 μg 1 'and 400μg 2, 165.1 μg 1' and 500μg 2, 165.1 μg 1 'and 600μg 2, 165.1 μg 1' and 700μg 2, 165.1 μg 1 'and 800μg 2, 165, 1 μg 1 'and 900μg 2, 165.1 μg 1' and 1000μg 2, 206.4μg 1 'and 25μg 2, 206.4μg 1' and 50μg 2, 206.4μg 1 'and 100μg 2, 206.4μg 1' and 200μg 2, 206.4μg 1 'and 300μg 2, 206 , 4μg 1 'and 400μg 2, 206.4μg 1' and 500μg 2 or 206.4μg 1 'and 600μg 2, 206.4μg 1' and 700μg 2, 206.4μg 1 'and 800μg 2, 206.4μg 1' and 900μg 2, 206.4μg 1 'and 1000μg 2, 412.8μg 1' and 25μg 2, 412.8μg 1 'and 50μg 2, 412.8μg 1' and 100μg 2, 412.8μg 1 'and 200μg 2, 412, 8μg 1 'and 300μg 2, 412.8μg 1' and 400μg 2, 412.8μg 1 'and 500μg 2 or 412.8μg 1' and 600μg 2, 412.8μg 1 'and 700μg 2, 412.8μg 1' and 800μg 2, 412.8μg 1 'and 900μg 2, 412.8μg 1' and 1000μg 2 can be applied.

Is preferred as the invention Combination of 1 and 2 used the combination of active ingredients in the 1 for that Bromide stands, correspond to those mentioned above by way of example per single dose of active ingredient applied from 1 'and 2 the following per single dose applied quantities of 1 and 2: 20μg 1 and 25μg 2, 20μg 1 and 50μg 2, 20μg 1 and 100μg 2, 20μg 1 and 200μg 2, 20μg 1 and 300μg 2, 20μg 1 and 400μg 2, 20μg 1 and 500μg 2 , 20μg 1 and 600μg 2, 20μg 1 and 700μg 2, 20μg.1 and 800μg 2, 20μg 1 and 900μg 2, 20μg 1 and. 1000μg 2, 40μg 1 and 25μg 2, 40μg 1 and 50μg 2, 40μg 1 and 100μg 2, 40μg 1 and 200μg 2, 40μg 1 and 300μg 2, 40μg 1 and 400μg 2, 40μg 1 and 500μg 2, 40μg 1 and 600μg 2, 40μg 1 and 700μg 2, 40μg 1 and 800μg 2, 40μg 1 and 900μg 2, 40μg 1 and 1000μg 2, 60μg 1 and 25μg 2, 60μg 1 and 50μg 2, 60μg 1 and 100μg 2, 60μg 1 and 200μg 2, 60μg 1 and 300μg 2, 60μg 1 and 400μg 2, 60μg 1 and 500μg 2, 60μg 1 and 600μg 2, 60μg 1 and 700μg 2, 60μg 1 and 800μg 2, 60μg 1 and 900μg 2, 60μg 1 and 1000μg 2, 100μg 1 and 25μg 2, 100μg 1 and 50μg 2, 100μg 1 and 100μg 2, 100μg 1 and 200μg 2, 100μg 1 and 300μg 2, 100μg 1 and 400μg 2, 100μg 1 and 500μg 2, 100μg 1 and 600μg 2, 100μg 1 and 700μg 2, 100μg 1 and 800μg 2, 100μg 1 and 900μg 2, 100μg 1 and 1000μg 2, 200μg 1 and 25μg 2, 200μg 1 and 50μg 2, 200μg 1 and 100μg 2, 200μg 1 and 200μg 2, 200μg 1 and 300μg 2, 200μg 1 and 400μg 2, 200μg 1 and 500μg 2, 200μg 1 and 600μg 2, 200μg 1 and 700μg 2, 200μg 1 and 800μg 2, 200μg 1 and 900μg 2, 200μg 1 and 1000μg 2, 250μg 1 and 25μg 2, 250μg 1 and 50μg 2, 250μg 1 and 100μg 2, 250μg 1 and 200μg 2, 250μg 1 and 300μg 2, 250μg 1 and 400μg 2, 250μg 1 and 500μg 2, 250μg 1 and 600μg 2, 250μg 1 and 700μg 2, 250μg 1 and 800μg 2, 2 50μg 1 and 900μg 2, 250μg 1 and 1000μg 2, 500μg 1 and 25μg 2, 500μg 1 and 50μg 2, 500μg 1 and 100μg 2, 500μg 1 and 200μg 2, 500μg 1 and 300μg 2, 500μg 1 and 400μg 2, 500μg 1 and 500μg 2, 500μg 1 and 600μg 2, 500μg 1 and 700μg 2, 500μg 1 and 800μg 2, 500μg 1 and 900μg 2 or 500μg 1 and 1000μg 2, the application of the active compound combinations according to the invention 1 and 2 are preferably inhaled. To do this, the Components 1 and 2 provided in inhalable dosage forms become.

As inhalable dosage forms come inhalation powder, propellant aerosols or propellant-free inhalation solutions into consideration.

Containing inhalation powder according to the invention the active ingredient combination of 1 and 2 can be obtained from the above alone Active ingredients or from a mixture of the active ingredients mentioned physiologically acceptable Auxiliary materials exist. Within the scope of the present invention from the term propellant-free inhalation solutions also concentrates or sterile, ready-to-use inhalation solutions. The dosage forms according to the invention can the combination of active ingredients from 1 and 2 either together in one or contained in two separate dosage forms. This in the frame Dosage forms that can be used in the present invention described in detail in the following part of the description.

A) Containing inhalation powder the active ingredient combinations according to the invention from 1 and 2:

The inhalable powders according to the invention can 1 and 2 either alone or in a mixture with suitable physiologically harmless Contain auxiliaries.

Are the active ingredients 1 and 2 in a mixture contain with physiologically safe auxiliaries, can for Representation of this inhalation powder according to the invention the following physiologically acceptable excipients for use get: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, maltose), oligo- and polysaccharides (e.g. Dextrans), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. Sodium chloride, calcium carbonate) or mixtures of these auxiliaries together. Mono- or disaccharides are preferably used, wherein the use of lactose or glucose, in particular, however not exclusively in the form of their hydrates is preferred. As particularly preferred in According to the invention, lactose, most preferably lactose monohydrate as an adjuvant for use.

The excipients show in the frame the inhalable powder according to the invention a maximum average particle size of up to 250 μm, preferred between 10 and 150μm, particularly preferably between 15 and 80 μm. If necessary, it can appear useful, the above-mentioned excipients finer Excipient fractions with an average particle size of 1 up to 9μm to mix.

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 ingredient 1 and 2, preferably with an average particle size of 0.5 to 10 μm, particularly preferably 1 to 5 μm, 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 either be in the form of a single powder mixture that contains both 1 and 2 or in the form of separate inhalation powders that contain only 1 and 2 and are provided and applied.

The inhalable powders according to the invention can be by means of inhalers known from the prior art can be applied.

Inhalation powders according to the invention, which in addition to 1 and 2 also 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 the US 4570630A is described, or via other apparatus, as described in the DE 36 25 685 A be described, dose. The inhalable powders according to the invention, which in addition to 1 and 2 contain physiologically acceptable excipients, are preferably filled into capsules (into what are known as inhalers) which are used in inhalers such as, for example, in WO 94/28958 described, apply.

An inhaler which is particularly preferred for use of the pharmaceutical combination according to the invention in inhalets is 1 refer to.

This inhaler (handihaler) for inhaling 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 one with a screen housing 4 attached strainer 5 is provided, one with deck 3 connected inhalation chamber 6 , on the one with two ground needles 7 provided, against a spring 8th movable pusher 9 is provided, as well as one over an axis 10 foldable with the housing 1 , the deck 3 and a cap 11 connected mouthpiece 12 ,

Are the inhalable powders according to the invention in the sense of the preferred use mentioned above in capsules Bottled fill quantities are available from 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 already mentioned above for 1 'and 2 per single dose.

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

Inhalation aerosols containing propellant gas according to the invention can 1 and 2 dissolved in the propellant or contained in dispersed form. Here 1 and 2 can be separated Dosage forms or contained in a common dosage form be, where 1 and 2 either both dissolved, both dispersed or solved only one component at a time and the others may be dispersed.

Those for the preparation of the inhalation aerosols according to the invention usable propellant gases 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 named propellants can can be used alone or in mixtures thereof. Particularly preferred propellants are halogenated alkane derivatives selected from TG134a and TG227 and mixtures thereof.

The inhalation aerosols containing propellant gas according to the invention can also other components such as cosolvents, stabilizers, surface-active Agents (surfactants), antioxidants, lubricants and agents for Adjustment of the pH value included. 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 up 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.

Are the active ingredients 1 and / or 2 in dispersed form, the active substance particles preferably have one average particle size from to to 10 μm, preferably from 0.1 to 5 μm, particularly preferably from 1 to 5 μm on.

The above-mentioned propellant gas according to the invention Inhaled aerosols can using inhalers known in the prior art (MDIs = metered dose inhalers). Accordingly, another concerns Aspect of the present invention Pharmaceuticals in the form of as above described propellant-containing aerosols in connection with a or several inhalers suitable for the administration of these aerosols. Furthermore, the present invention relates to inhalers, characterized in that they above described propellant gas according to the invention Aerosols included.

The present invention relates to also cartridges equipped with a suitable valve can be used in a suitable inhaler and the one of the above-mentioned propellant-containing inhalation aerosols according to the invention contain. Suitable cartridges and procedures for filling them Cartridges with the propellant gas containing the invention Inhalation aerosols 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 necessary, the application takes place the active ingredient combination according to the invention in the form of propellant-free inhalation solutions and inhalation suspensions. As a solvent come watery 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 compared Water is not limited, but the maximum limit is preferred at 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 by water. The 1 and 2, separately or solutions containing them together or suspensions are adjusted to a pH value with suitable acids 2 to 7, preferably from 2 to 5. To set this pH value can acids selected from inorganic or organic acids are used. Examples for special suitable inorganic acids are hydrochloric acid, hydrobromic, Nitric acid, sulfuric acid and / or phosphoric acid. examples for 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 and other. Preferred inorganic acids are hydrochloric acid, sulfuric acid. It can also the acids can be used with an acid addition salt already with one of the active ingredients form. Among the organic acids are ascorbic acid, fumaric acid and citric acid prefers. If necessary, you can also mixtures of the acids mentioned are used, especially in cases of acids, in addition to their acidifying properties other properties, e.g. as flavors, antioxidants or have complexing agents such as citric acid or Ascorbic acid. According to the invention particularly hydrochloric acid is preferred used to adjust the pH.

According to the present invention Formulation for the addition of editic acid (EDTA) or one of the known Salts thereof, sodium edetate, as a stabilizer or complexing agent to be dispensed with.

Other embodiments include these Links).

In such a preferred embodiment the content based on sodium edetate is less than 100 mg / 100 ml, preferably below 50 mg / 100 ml, particularly preferably below 20 mg / 100ml.

In general, such inhalation solutions are preferred in which the content of sodium edetate is 0 to 10mg / 100ml.

The propellant-free inhalation solutions according to the invention can be co-solvents and / or further auxiliaries are added.

Preferred co-solvents are those which contain hydroxyl groups or other polar groups, for example Alcohols - especially Isopropyl alcohol, glycols - especially Propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, Glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters.

Among auxiliaries and additives in this context, any pharmacologically acceptable substance understood, which is not an active ingredient, but together with the Active ingredients) are formulated in the pharmacologically suitable solvent can to the qualitative properties of the drug formulation improve. These substances preferably do not develop at all or in context with the desired therapy no significant or at least no unwanted pharmacological effect. The auxiliaries and additives include e.g. surfactants Fabrics such as Soy lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilizers, complexing agents, Antioxidants and / or preservatives that extend the useful life ensure or extend the finished pharmaceutical formulation, flavorings, Vitamins and / or other additives known in the art. The additives include also pharmacologically acceptable salts such as sodium chloride as isotonants.

The preferred auxiliaries include antioxidants, such as ascorbic acid, if not already for used the adjustment of 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. As Preservatives are known from the prior art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or Benzoates such as sodium benzoate in the known from the prior art Concentration. The above preservatives are preferably in concentrations of up to 50mg / 100ml, especially preferably contain between 5 and 20 mg / 100ml.

Preferred formulations included except the solvent Water and the active ingredient combination of 1 and 2 only benzalkonium chloride and sodium edetate. In another preferred embodiment dispensed with sodium edetate.

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. As part of the In the present invention, those nebulizers are preferred in which an amount of less than 100 .mu.L, preferably less than 50 .mu.L, particularly preferably between 20 and 30 .mu.L of active ingredient solution, preferably with a stroke to an aerosol with an average particle size of less than 20 .mu.m, is preferred less than 10 microns, 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, for example, in the international patent application WO 91/14468 as well in the WO 97/12687 (there in particular 6a and 6b ) described in detail. The nebulizers described there are also known under the name Respimat ^® .

This nebuliser (Respimat ^®) may be advantageous to produce the inhalable aerosols according to the invention containing the combination of active substances 1 and are used. 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.

• – ein Pumpengehäuse, das im Gehäuseoberteil befestigt ist, und das an seinem einen Ende einen Düsenkörper mit der Düse bzw. Düsenanordnung trägt,
• – einen Hohlkolben mit Ventilkörper,
• – einen Abtriebsflansch, in dem der Hohlkolben befestigt ist, und der sich im Gehäuseoberteil befindet,
• – ein Sperrspannwerk, das sich im Gehäuseoberteil befindet,
• – ein Federgehäuse mit der darin befindlichen Feder, das am Gehäuseoberteil mittels eines Drehlagers drehbar gelagert ist,
• – ein Gehäuseunterteil, das auf das Federgehäuse in axialer Richtung aufgesteckt ist.

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 storage container, characterized by

• A pump housing which is fastened in the upper housing part and which carries at one end a nozzle body with the nozzle or 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 part of the housing,
• - a locking mechanism, which is located in the upper part of the housing,
• 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 one in the WO 97/12687 disclosed device. It projects partially into the cylinder of the pump housing and is arranged axially displaceably in the cylinder. In particular, the 1 - 4 - in particular 3 - And the associated description parts referenced. The hollow piston with valve body exerts a pressure of 5 to 60 Mpa (about 50 to 600 bar) on its high pressure side at the time the spring is triggered, preferably 10 up to 60 Mpa (about 100 to 600 bar) on the fluid, the measured active ingredient solution. 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 at the end attached of the hollow piston, which faces the nozzle body.

The nozzle in the nozzle body is preferably microstructured, that is to say manufactured by micro technology. Microstructured nozzle bodies are for example in the WO-94/07607 disclosed; reference is hereby made to this document, in particular to the one disclosed therein 1 and their description.

The nozzle body is e.g. from two sheets of glass and / or silicon firmly connected to one another, at least one plate has one or more microstructured ones channels having the nozzle inlet side with connect the nozzle outlet side. Is on the nozzle outlet side at least one round or non-round opening of 2 to 10 microns Depth and 5 to 15 microns wide, with the depth preferred at 4, 5 to 6.5 microns and the length at 7 to 9 microns is.

In the event of multiple nozzle openings failing, two are preferred the jet directions of the nozzles in Nozzle body parallel run to each other or they are inclined towards each other in the direction of the nozzle opening. at with a nozzle body at least two nozzle openings on the outlet side can the beam directions with an angle of 20 degrees to 160 degrees to each other be inclined, an angle of 60 to 150 degrees is preferred, in particular preferably 80 to 100 °.

The nozzle openings are preferred in arranged at a distance of 10 to 200 micrometers, more preferred at a distance of 10 to 100 microns, particularly preferred 30 to 70 microns. The strongest 50 micrometers are preferred.

The beam directions meet accordingly in the vicinity of the nozzle openings.

The liquid drug preparation hits with an inlet pressure of up to 600 bar, preferably 200 to 300 bar on the nozzle body and is about the nozzle openings atomized into an inhalable aerosol. The preferred particle or droplet sizes of the Aerosols 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 as a jumping piece on the output flange Movement 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 tensioned via a force-transmitting gear, for example a screw-push gear, by an external torque which is generated when the upper housing part is rotated 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. Construction details of the locking mechanism are in the WO 97/20590 described.

The lower part of the housing is axial Direction over the spring case pushed and covered the bearing, the drive of the spindle and the reservoir for the Fluid.

When you operate the atomizer the upper housing part against the lower part of the housing rotated, the lower housing part the spring case entraining. The spring is over the screw-type thrust gear is compressed and tensioned, and the locking mechanism snaps automatically on. The angle of rotation is preferably an integer fraction of 360 degrees, e.g. 180 degrees. Simultaneously with the tensioning of the spring becomes the driven part in the upper part of the housing moved by a predetermined distance, the hollow piston is inside of the cylinder in the pump housing withdrawn, whereby a subset of the fluid from the reservoir into the High pressure room in front of the nozzle is sucked in.

In the atomizer you can, if necessary, one after the other several that to be atomized Interchangeable reservoir containing fluid inserted and used become. The reservoir contains the aqueous according to the invention Aerosol formulation.

The atomization process is easy push in the release button initiated. The barrage clears the way for the stripping section. The tensioned spring pushes the piston into the cylinder of the pump housing.

The fluid enters from the atomizer nozzle atomized Shape out.

Further design details are in the PCT applications WO 97/12683 and WO 97/20590 to which reference is hereby made.

The components of the nebulizer are made of a material that is suitable for the function. The casing of the atomizer and so as far as the function allows - also other parts are preferably made of plastic, e.g. in the injection molding process, manufactured. For medical purposes become physiologically harmless materials used.

In the attached to this patent application 2a / b that are identical to the 6a / b the WO 97/12687 describes the nebulizer (Respimat ^® ) with which the aqueous aerosol preparations according to the invention can advantageously be inhaled.

2a shows a longitudinal section through the atomizer with the spring under tension, 2 B 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 ) is attached to the atomizer nozzle. The nozzle body is located in the holder ( 54 ) and a filter ( 55 ). The in the output flange ( 56 ) hollow pistons attached to the locking mechanism ( 57 ) partially protrudes into the cylinder of the pump housing. At its end, the hollow piston carries the valve body ( 58 ). The hollow piston is secured by means of the seal ( 59 ) sealed. The stop is located inside the upper part of the housing ( 60 ) on which the output flange rests when the spring is relaxed. The stop is located on the output flange ( 61 ) on which the output flange rests when the spring is tensioned. After the spring has been tensioned, the locking element moves ( 62 ) between the stop ( 61 ) and a support ( 63 ) in the upper part of the housing. The release button ( 64 ) is connected to the locking element. The upper housing part ends in the mouthpiece ( 65 ) and is with the clip-on protective cap ( 66 ) locked.

The spring case ( 67 ) with compression spring ( 68 ) is by means of the snap noses ( 69 ) and pivot bearing on the upper part of the housing rotatably. The lower part of the housing ( 70 ) pushed. The replaceable storage container is located inside the spring housing ( 71 ) for the fluid to be atomized ( 72 ). The reservoir is with the stopper ( 73 ) closed, through which the hollow piston protrudes into the storage container and with its end immerses in the fluid (supply of active substance solution).

In the outer surface of the spring housing, the spindle ( 74 ) attached for the mechanical counter. At the end of the spindle, which faces the upper part of the housing, is the drive pinion ( 75 ). The rider sits on the spindle ( 76 ).

The nebulizer described above is suitable, the aerosol preparations according to the invention to one for nebulize the inhalation of suitable aerosol.

If the formulation according to the invention nebulised using the method described above (Respimat ^®), the mass expelled, in at least 97%, preferably at least 98% of all actuations of the inhaler (spray) a defined quantity with a tolerance of not more than 25%, preferably 20% of these 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 by means of inhalers other than those described above, for example, jet stream inhalers.

Accordingly, another concerns Aspect of the present invention Pharmaceuticals in the form of as above described propellant-free inhalation solutions or suspensions in Compound with one suitable for the administration of these formulations Device, preferably in connection with the Respimat®. Prefers The present invention aims at propellant-free inhalation solutions or Suspensions characterized by the active ingredient combination according to the invention from 1 and 2 in connection with the one known as Respimat® Contraption. The present invention further relates to the above mentioned devices for inhalation, preferably the Respimat®, thereby characterized that they propellant-free inhalable solutions according to the invention described above or Suspensions included.

The propellant-free inhalation solutions according to the invention or Suspensions can. in addition to the solutions provided above for application in the Respimat and Suspensions also as concentrates or sterile ready-to-use inhalation solutions or suspensions are available. For example, from the concentrates Ready-to-use formulations by adding isotonic saline solutions to generate. Sterile ready-to-use formulations can be made using energy-operated standing or portable nebulizer, the inhalable Aerosols using ultrasound or compressed air based on the Venturi principle or generate other principles.

Accordingly, another concerns Aspect of the present invention Pharmaceuticals in the form of as above described propellant-free inhalable solutions or suspensions that are available as concentrates or sterile, ready-to-use formulations, in connection with a suitable for the administration of these solutions Device, characterized in that this device an energy-operated standing or portable nebulizer is the inhalable aerosols using ultrasound or compressed air produced according to the Venturi principle or other principles.

The following examples serve one further explanation of the present invention, but without the scope of the invention to be limited to the following exemplary embodiments.

Formulation examples A) Inhalable powder:

Claims (35)

1 ) Medicaments characterized by a content of one or more anticholinergics of the 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- Toluene sulfonate 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. Medicament according to claim 1, characterized in that the active substances 1 and 2 either together in a single dosage form or are contained in two separate dosage forms. Medicament according to one of claims 1 or 2, characterized in that that in the compounds of formula 1 X– simply negatively charged anion selected from the group chloride, Bromide and methanesulfonate means. Medicament according to one of claims 1 to 3, characterized in that that in the compounds of formula 1 X- for bromide stands. 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-cyc lopropylmethoxybenzamide and the tricyclic nitrogen heterocycles of the general formula 2a

where R ^{1 is} C ₁ -C ₅ alkyl, C ₅ -C ₆ cycloalkyl, phenyl, benzyl or a 5- or 6-membered, saturated or unsaturated heterocyclic ring which contains one or two heteroatoms selected from the group consisting of oxygen and nitrogen may contain; R ^{2 is} C ₁ -C ₅ alkyl or C ₂ -C ₄ alkenyl; R ^{3 is} C ₁ -C ₅ alkyl which is optionally substituted by C ₁ -C ₄ alkoxy, C ₅ -C ₆ cycloalkyl, phenoxy or by a 5- or 6-membered, saturated or unsaturated heterocyclic ring which is one or two Heteroatoms selected from the group consisting of oxygen and nitrogen can be substituted, can be C ₅ -C ₆ cycloalkyl or phenyl or benzyl optionally substituted by C ₁ -C ₄ alkoxy, optionally 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. Medicament according to one of claims 1 to 5, characterized in that that 2nd selected is from the group consisting of Enprofylline, Roflumilast, Ariflo, 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. Medicament according to one of claims 1 to 6, characterized in that that the Weight ratios of 1 to 2 in a range from 1: 100 to 100: 1, preferably from 1:80 up to 80: 1. Medicament according to one of claims 1 to 7, characterized in that that a single application of a dosage of the active ingredient combination 1 and 2 from 0.01 to 10000μg, preferably corresponds to from 0.1 to 2000μg. Medicament according to one of claims 1 to 8, characterized in that that it in the form of a for there is a suitable dosage form for inhalation. Medicament according to claim 9, characterized in that it is selected a dosage form from the group inhalation powder, propellant aerosols and propellant-free inhalation solutions or suspensions. Medicament according to Claim 10, characterized in that it is a Inhalation powder is 1 and 2 mixed with suitable physiologically safe auxiliary substances selected from the group consisting of from monosaccharides, disaccharides, oligo- and polysaccharides, polyalcohols, Contains salts, or mixtures of these auxiliaries. Inhalable powder according to claim 11, characterized in that that the Excipient a maximum average particle size of up to 250 microns, preferred between 10 and 150μm having. Capsules characterized by their inhalation powder content according to claim 11 or 12. Medicament according to Claim 10, characterized in that it is a Inhaled powder is the only active ingredient 1 and 2 contains. Medicament according to Claim 10, characterized in that it is is an inhalation aerosol containing propellant gas, which 1 and 2 in solution or in dispersed form. Inhalation aerosol containing propellant gas according to claim 15, characterized in that it contains hydrocarbons such as n-propane, n-butane or isobutane or halogenated hydrocarbons such as chlorinated as the propellant gas and / or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. Propellant-containing inhalation aerosol according to claim 16, characterized characterized that the Propellant TG134a, TG227 or a mixture thereof. Inhalation aerosol containing propellant gas according to Claim 15, 16 or 17, characterized by the fact that it may be one or more further components selected from the group consisting of from cosolvents, stabilizers, surfactants, Antioxidants, lubricants and pH adjusters contains. Inhalation aerosol containing propellant gas 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. Medicament according to Claim 10, characterized in that it is is a propellant-free inhalation solution or suspension, the as a solvent Contains water, ethanol or a mixture of water and ethanol. Inhaltionslösung or suspension according to claim 20, characterized in that the pH 2-7, preferred Is 2-5. Inhaltionslösung or suspension according to claim 21, characterized in that the pH using 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 or mixtures thereof. inhalation solution or suspension according to one of claims 20 to 22, characterized in that it is optionally contains further co-solvents and / or auxiliary substances. inhalation solution or suspension according to claim 23, characterized in that it as Contains co-solvents components which contain hydroxyl groups or other polar groups, for example Alcohols - especially Isopropyl alcohol, glycols - especially Propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, Glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. inhalation solution or suspension according to one of claims 23 or 24, characterized in that it as Surfactant auxiliaries Substances stabilizers, complexing agents, antioxidants and / or preservatives, Flavors, pharmacologically acceptable salts and / or vitamins contains. inhalation solution or suspension according to claim 25, characterized in that it as Complexing agent editic acid or a salt of editic acid, preferably sodium edetate. inhalation solution or suspension according to Claim 25 or 26, characterized in that that she as antioxidants, compounds selected from the group consisting of from ascorbic acid, Contains vitamin A, vitamin E and tocopherols. inhalation solution or suspension according to claim 25, 26 or 27, characterized in that that they as Preservative compounds selected from cetylpyridinium chloride, Benzalkonium chloride, benzoic acid and contains benzoates. inhalation solution or suspension according to one of claims 23 to 28, characterized in that it in addition the active ingredients 1 and 2 and the solvent only bezalkonium chloride and contains sodium edetate. inhalation solution or suspension according to one of claims 23 to 28, characterized in that it in addition the active ingredients 1 and 2 and the solvent only benzalkonium chloride contains. inhalation solution or suspension according to one of claims 20 to 30, characterized in that it a concentrate or a sterile, ready-to-use inhalation solution, or - suspension deals. Use of a capsule according to claim 13 in an inhaler, preferably in a handihaler. Use of an inhalation solution according to one of claims 20 to 30 for nebulization in an inhaler according to the WO 91/14468 or one like in the 6a and 6b the WO 97/12687 described inhaler. Use of an inhalation solution according to claim 31 for nebulization in an energy-operated standing or portable nebulizer, the inhalable aerosols using ultrasound or compressed air after Venturi principle or other principles generated. 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 airway disease.