DE102004038886A1 - Pharmaceutical formulation useful for treating inflammatory and obstructive respiratory diseases comprises at least one anticholinergic compound, at least one corticosteroid and at least one betamimetic - Google Patents

Abstract

A pharmaceutical formulation (F1) comprises at least one anticholinergic compound, at least one corticosteroid and at least one betamimetic. A pharmaceutical formulation comprises at least one anticholinergic compound of formula (I) and their enantiomers, racemates, solvates, hydrates and/or acid addition salts; at least one corticosteroid (a1); and at least one betamimetic (a2). X->anion with a single negative charge. [Image] ACTIVITY : Respiratory-Gen.; Antiinflammatory. MECHANISM OF ACTION : None given.

Description

The The present invention relates to novel drug compositions based on a new anticholinergic, corticosteroids and Betamimetics, process for their preparation and their use in the treatment of respiratory diseases.

Description of the invention

The The present invention relates to novel drug compositions for the Inhalation based on a new anticholinergic, corticosteroids and betamimetics, processes for their preparation and their use in the treatment of respiratory diseases.

Surprisingly may be an unexpectedly beneficial therapeutic effect, in part a synergistic effect in the treatment of inflammatory or obstructive airway disease will be shown if one new anticholinergic along with one or more corticosteroids and together with one or more betamimetics. Because of this advantageous effect are the drug combinations according to the invention can be used in lower doses than in the usual Monotherapy of the individual compounds is the case. Leave it unwanted Side effects, such as in the application of corticosteroids and betamimetics can occur, Reduce.

The above effects can both with simultaneous administration within a single drug formulation as well as in successive application of the three active ingredient components be observed in separate formulations. According to the invention preferred is the simultaneous application of the active ingredient in one single formulation. The medicaments according to the invention are preferred according to the invention applied by inhalation.

worin
X – ein einfach negativ geladenes Anion, vorzugsweise ein Anion ausgewählt aus der Gruppe bestehend aus Chlorid, Bromid, Iodid, 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 the formula 1 are obtained as the anticholinergic agent

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.

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

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

Particularly according to the invention preferred is that salt of formula 1 in which X - for bromide stands.

The salts of formula 1 are known from international patent application WO 03/064419. Reference to the salts of Formula 1 includes reference to their optionally available Hy drate and solvates.

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

by recognizing the designation 1 '. Reference to compounds 1 naturally includes a reference to cation 1 '.

in the Scope of the present invention are corticosteroids (hereinafter 2) means compounds which are selected from the group consisting of flunisolides, beclomethasone, triamcinolone, Budesonide, fluticasone, mometasone, ciclesonide, rofleponide, GW 215864, KSR 592, ST-126 and Dexametasone. The compound is preferred 2 selected from the group consisting of flunisolides, beclomethasone, triamcinolone, Budesonide, Fluticasone, Mometasone, Ciclesonide and Dexametasone. Particularly preferred compound 2 is selected from budesonide, fluticasone, Mometasone and Ciclesonide.

possibly is used in the context of the present patent application instead of the name Corticosteroids 2 also used only the term Steroids 2.

A Reference to steroids 2 is included in the present Invention a reference to salts or derivatives 2 'derived from the steroids can be formed with a. As possible Salts or derivatives 2 'become for example: sodium salts, sulfobenzoates, phosphates, Isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, Pivalate or furoate. Optionally, the compounds of formula 2 are also present in the form of their hydrates.

According to the invention, bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, salmeterol, sulfonterol, terbutaline, tolubuterol, 4-hydroxy-7- [2 - {[2 - { 3- (2-phenylethoxy) propyl] sulfonyl} ethyl] amino} ethyl] -2 (3H) -benzothiazolone, 1- (2-fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2 -methyl-2-butylamino] ethanol, 1- [3- (4-methoxybenzylamino) -4-hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino] ethanol, 1 - [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino] ethanol, 1- [2H 5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-n-butyloxyphenyl) -2-methyl-2-propylamino] ethanol, 1- [2H- 5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- {4- [3- (4-methoxyphenyl) -1,2,4-triazol-3-yl] -2- methyl-2-butylamino} ethanol, 5-hydroxy-8- (1-hydroxy-2-isopropylaminobutyl) -2H-1,4- benzoxazin-3- (4H) -one,
1- (4-amino-3-chloro-5-trifluoromethylphenyl) -2-tert-butylamino) ethanol or
1- (4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2- (tert -butylamino) ethanol.

Preferably used according to the invention as betamimetics 3 in the combination of active substances according to the invention are formoterol, salmeterol,
4-hydroxy-7- [2 - {[2 - {[3- (2-phenylethoxy) propyl] sulfonyl} ethyl] -amino} ethyl] -2 (3H) -benzothiazolone,
1- (2-Fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [3- (4-methoxybenzylamino) -4-hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol,
1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino] ethanol .
1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino] ethanol,
1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-n-butyloxyphenyl) -2-methyl-2-propylamino] ethanol or
1- [2N-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- {4- [3- (4-methoxyphenyl) -1,2,4-triazol-3- yl] -2-methyl-2-bu tylamino} ethanol.

When Betamimetics 3 according to the invention particularly preferably salmeterol salts or formoterol salts. A reference to the term Betamimetics 3 concludes a reference to the respective enantiomers or mixtures thereof with a. For example, closes a reference to the erfindunsgemäß particularly preferred compounds 3, the salts of salmeterol and formoterol, accordingly the respective enantiomeric salts of R-salmeterol, S-salmeterol, R, R-formoterol, S, S-formoterols, R, S-formoterols, SR-formoterols and mixtures thereof with, wherein the enantiomeric salts of R-salmeterol and R, R-formoterol a special meaning. The compounds 3 can according to the invention furthermore in the form of their hydrates or solvates.

in the The scope of the present invention is with reference to compounds 3 to understand a reference to physiologically acceptable acid addition salts. As physiologically compatible Acid addition salts The betamimetics 3 according to the invention are pharmaceutically acceptable salts understood, the 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, 1-hydroxy-2-naphthoic acid, cinnamic acid, 4-phenylcinnamic acid, diflunisal or maleic acid are. If necessary, you can for the preparation of the salts 3 and mixtures of the aforementioned acids used become.

According to the invention preferred the salts of betamimetics 3 are selected from the group from hydrochloride, hydrobromide, sulfate, phosphate, fumarate, methanesulfonate, 4-phenylcinnamate, diflunisal and xinafoate. Particularly preferred the salts of 3 in the case of salmeterol selected from those salts, the one solubility in water of 0.1 mg / ml or less, preferably 0.05 mg / ml or less, more preferably 0.04 mg / ml or less. In this connection, as particularly preferred salts of Almeterol's xinafoate, 4-phenylcinnamate and diflunisal called. Particularly preferred salts 3 of salmeterol have in Water a solubility of 0.035 mg / ml or less, such as 4-phenylcinnamate or the diflunisal.

Especially Preferably, the salts of 3 are selected in the case of the formoterol Hydrochloride, sulfate and fumarate, of which the hydrochloride and Fumarate are particularly preferred. Of outstanding importance according to the invention is Formoterolfumarat.

He follows in the context of the present invention, a reference to not in The salt form beta-betamimetics present, this is by a reference recognizable on compounds 3 '. For example, among the inventively preferred, not in the Salt form beta-metimimetics 3 'or the formoterol free base salmeterol understood, whereas it is in accordance with the invention especially preferred compounds 3, for example salmeterol xinafoate, Salmeterol 4-phenylcinnamate or formoterol fumarate.

in the In the context of the present invention, the betamimetics 3 are optionally also referred to as sympathomimetics or beta-2 receptor agonists (Β2-agonists). All these Designations are considered equivalent in the context of the present invention to watch.

The Application of the drug combinations according to the invention from 1, 2 and 3 according to the invention by inhalation. in this connection can preferred according to the invention suitable inhalation powders which are placed in suitable capsules (inhalettes) bottled be administered by means of appropriate powder inhalers, for Use come.

One Aspect of the present invention accordingly relates to a pharmaceutical which contains a combination of 1, 2 and 3.

One Another aspect of the present invention relates to a pharmaceutical which one or more salts 1, one or more compounds 2 and one or more compounds 3, optionally in the form of their solvates or hydrates. Here you can the active substances either together in a single dosage form, be contained in two or three separate dosage forms. According to the invention are preferred Medicines containing active substances 1, 2 and 3 in a single dosage form contain.

Another aspect of the present invention relates to a pharmaceutical composition which, besides therapeutic effective amounts of 1, 2 and 3 contains a pharmaceutically acceptable carrier. Another aspect of the present invention relates to a pharmaceutical composition which, in addition to therapeutically effective amounts of 1, 2 and 3, does not contain a pharmaceutically acceptable carrier.

The The present invention further relates to the use of 1, 2 and 3 for the preparation of a therapeutically effective amounts of 1, 2 and 3 containing medicament for the treatment of inflammatory and / or obstructive pulmonary diseases, in particular asthma and / or chronic obstructive pulmonary disease (COPD) by simultaneous or successive application. Furthermore, the drug combinations according to the invention for the manufacture of a medicament for the treatment of fibrotic Pulmonary diseases, such as cystic fibrosis or allergic Alveolitis (Farmers Lung) by simultaneous or successive application Find use. An application of the active compound combinations according to the invention does not take place unless a treatment with one of the pharmaceutical active agents is contraindicated.

The The present invention further seeks to be simultaneous or successive Use of therapeutically effective doses of the combination above Medicines 1, 2 and 3 for the treatment of inflammatory or obstructive Respiratory diseases, in particular of asthma and / or chronic obstructive pulmonary disease (COPD), provided treatment with Steroids or betamimetics are not contraindicated from a therapeutic point of view is, by simultaneous or successive application. The present The invention further aims at simultaneous or successive use therapeutically effective doses of the combination of the above drugs 1, 2 and 3 for the treatment of, for example, cystic fibrosis or allergic alveolitis (Farmers Lung).

In the active compound combinations according to the invention from 1, 2 and 3 can the components 1, 2 and 3 in the form of their enantiomers, mixtures the enantiomers or in the form of racemates. For example contain the medicaments according to the invention the active compounds 1, 2 and 3 in such an amount that a single Application of a dosage of the active ingredient combination 1, 2 and 3 from 1 to 10000μg, preferably from 10 to 2000μg equivalent.

The relationships in which the active compounds 1, 2 and 3 used in the active compound combinations according to the invention can be are variable. The active compounds 1, 2 and 3 may optionally in the form their solvates or hydrates are present. Depending on the choice of connections 1, 2 and 3 vary the usable in the context of the present invention weight ratios due to the different molecular weight of the different ones Compounds as well as due to their different potency. In usually can the drug combinations according to the invention the compounds 1 'and 2 in weight ratios contained in a range of 1: 250 to 250: 1, preferably from 1: 150 to 150: 1, lie. In the most preferred drug compositions, the next 1 'one Connection selected from the group consisting of budesonide, fluticasone, mometasone, ST-126 and Ciclesonide contain as steroid 2, the weight ratios from 1 'to 2 especially preferably in a range of about 1:40 to 40: 1, further preferred from 1:30 to 30: 1.

For example and without limiting the scope of the invention thereto, may be preferred inventive combinations 1 and 2, the cation 1 'and one of the above preferably used Steroids 2 in the following weight ratios: 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 medicaments according to the invention containing the combinations of 1 and 2 is usually carried out so that 1 'and 2 together in dosages of 5 to 5000μg preferably from 10 to 5000μg, more preferably from 15 to 4500μg, further preferably from 20 to 4000μg, according to the invention preferably from 30 to 3500μg, preferably from 40 to 3000μg, preferably from 50 to 2500μg, preferably from 40 to 2250μg, more preferably from 50 to 2000μg are included per single dose. For example, combinations according to the invention of 1 and 2 contain such an amount of 1 'and steroid 2 that the total dosage per single dose is approximately 35 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg. 105μg, 110μg, 115μg, 120μg, 125μg, 130μg, 135μg, 140μg, 145μg, 150μg, 155μg, 160μg, 165μg, 170μg, 175μg, 180μg, 185μg, 190μg, 195μg, 200μg, 205μg, 210μg, 215μg, 220μg, 225μg, 230μg, 235μg, 240μg, 245μg, 250μg, 255μg, 260μg, 265μg, 270μg, 275μg, 280μg, 285μg, 290μg, 295μg, 300μg, 305μg, 310μg, 315μg, 320μg, 325μg, 330μg, 335μg, 340μg, 345μg, 350μg, 355 μg, 360 μg, 365 μg, 370 μg, 375 μg, 380 μg, 385 μg, 390 μg, 395 μg, 400 μg, 405 μg, 410 μg, 415 μg, 420 μg, 425 μg, 430 μg, 435 μg, 440 μg, 445 μg, 450 μg, 455 μg, 460 μg, 465 μg, 470 μg, 475 μg, 480 μg, 485 μg, 490 μg, 495 μg, 500 μg, 505 μg, 510 μg, 515 μg, 520 μg, 525 μg, 530 μg, 535 μg, 540 μg, 545 μg, 550 μg, 580 μg, 585 μg, 590 μg, 595 μg, 600 μg, 605 μg, 610 μg, 610 μg, 615 μg, 620 μg, 625 μg, 630 μg, 635 μg, 640 μg, 645 μg, 650 μg, 655 μg, 660 μg, 665 μg 695 μg, 700 μg, 705 μg, 710 μg, 715 μg, 720 μg, 725 μg, 730 μg, 735 μg, 740 μg, 745 μg, 750 μg, 755 μg, 760 μg, 765 μg, 770 μg, 775 μg, 780 μg, 785 μg, 790 μg, 795 μg, 800 μg, 805 μg, 810 μg, 815 μg 820 μg, 825 μg, 830 μg, 835 μg, 840 μg, 845 μg, 850 μg, 855 μg, 860 μg, 865 μg, 870 μg, 875 μg, 880 μg, 885 μg, 890 μg, 895 μg, 900 μg, 905 μg, 910 μg, 915 μg, 920 μg, 925 μg, 930 μg, 935 μg, 940 μg, 945μg, 950μg, 955μg, 960μg, 965μg, 970μg, 975μg, 980μg, 985μg, 990μg, 995μg, 1000μg, 1005μg, 1010μg, 1015μg, 1020μg, 1025μg, 1030μg, 1035μg, 1040μg, 1045μg, 1050μg, 1055μg, 1060μg, 106 5μg, 1070μg, 1075μg, 1080μg, 1085μg, 1090μg, 1095μg, 1100μg, 1105μg, 1110μg, 1115μg, 1120μg, 1125μg, 1130μg, 1135μg, 1140μg, 1145μg, 1150μg, 1155μg, 1160μg, 1165μg, 1170μg, 1175μg, 1180μg, 1185μg, 1190μg, 1195μg, 1200μg, 1205μg, 1210μg, 1215μg, 1220μg, 1225μg, 1230μg, 1235μg, 1240μg, 1245μg, 1250μg, 1255μg, 1260μg, 1265μg, 1270μg, 1275μg, 1280μg, 1285μg, 1290μg, 1295μg, 1300μg, 1305μg, 1310μg, 1315μg, 1320μg, 1325μg, 1330μg, 1335μg, 1340μg, 1345μg, 1350μg, 1355μg, 1360μg, 1365μg, 1370μg, 1375μg, 1380μg, 1385μg, 1390μg, 1395μg, 1400μg, 1405μg, 1410μg, 1415μg, 1420μg, 1425μg, 1430μg, 1435μg, 1440μg, 1445μg, 1450μg, 1455μg, 1460μg, 1465μg, 1470μg, 1475μg, 1480μg, 1485μg, 1490μg, 1495μg, 1500μg, 1505μg, 1510μg, 1515μg, 1520μg, 1525μg, 1530μg, 1535μg, 1540μg, 1545μg, 1550μg, 1555μg, 1560μg, 1565μg, 1570μg, 1575μg, 1580μg, 1585μg, 1590μg, 1595μg, 1600μg, 1605μg, 1610μg, 1615μg, 1620 μg, 1625μg, 1630μg, 1635μg, 1640μg, 1645μg, 1650μg, 1655μg, 1660μg, 1665μg, 1670μg, 1675μg, 1680μg, 1685μg, 1690μg, 1695μg, 1700μg, 1705μg, 1710μg, 1715μg, 1720μg, 1725μg, 1730μg, 1735μg, 1740μg, 1745μg, 1750μg, 1755μg, 1760μg, 1765μg, 1770μg, 1775μg, 1780μg, 1785μg, 1790μg, 1795μg, 1800μg, 1805μg, 1810μg, 1815μg, 1820μg, 1825μg, 1830μg, 1835μg, 1840μg, 1845μg, 1850μg, 1855μg, 1860μg, 1865μg, 1870μg, 1875μg, 1880μg, 1885μg, 1890μg, 1895μg, 1900μg, 1905μg, 1910μg, 1915μg, 1920μg, 1925μg, 1930μg, 1935μg, 1940μg, 1945μg, 1950μg, 1955μg, 1960μg, 1965μg, 1970μg, 1975μg, 1980μg, 1985μg, 1990μg, 1995μg, 2000μg or similar amounts. It will be apparent to those skilled in the art that the above dosage suggestions per single dose should not be construed as limited to those explicitly indicated. Fluctuations of about ± 2.5μg, especially variations in the decimal range, are also included, as will be apparent to those skilled in the art. In these dosage ranges, the active ingredients 1 'and 2 can be contained in the weight ratios described above.

For example and without limiting the scope of the invention thereto, the combinations according to the invention 1 and 2 contain such an amount of cation 1 'and steroid 2 that per single dose 2, 5μg 1 'and 25μg 2, 2.5μg 1' and 50μg 2, 2.5μg 1 'and 100μg 2, 2.5μg 1' and 150μg 2, 2.5μg 1 'and 200μg 2, 2.5μg 1' and 250μg 2, 2.5μg 1 'and 300μg 2, 2.5μg 1' and 320μg 2, 2.5μg 1 'and 350μg 2, 2.5μg 1' and 400μg 2, 2.5μg 1 'and 500μg 2, 2 , 5μg 1 'and 600μg 2, 2.5μg 1' and 700μg 2, 2.5μg 1 'and 800μg 2, 2.5μg 1' and 1000μg 2, 7.5μg 1 'and 25μg 2, 7.5μg 1' and 50μg 2, 7,5μg 1 'and 100μg 2, 7,5μg 1' and 150μg 2, 7,5μg 1 'and 200μg 2, 7,5μg 1' and 250μg 2, 7,5μg 1 'and 300μg 2, 7, 5μg 1 'and 320μg 2, 7.5μg 1' and 350μg 2, 7.5μg 1 'and 400μg 2, 7.5μg 1' and 500μg 2, 7.5μg 1 'and 600μg 2, 7.5μg 1' and 700μg 2, 7.5μg 1 'and 800μg 2, 7.5μg 1' and 1000μg 2, 15μg 1 'and 25μg 2, 15μg 1' and 50μg 2, 15μg 1 'and 100μg 2, 15μg 1' and 150μg 2, 15μg 1 'and 200μg 2, 15μg 1' and 250μg 2, 15μg 1 'and 300μg 2, 15μg 1' and 320μg 2, 15μg 1 'and 350μg 2, 15μg 1' and 400μg 2, 15μg 1 'and 500μg 2, 15μg 1' and 600μg 2, 15μg 1 'and 700μg 2, 15μg 1' and 800μg 2, 15μg 1 'and 1000μg 2, 30.0μg 1' and 25μg 2, 30.0μg 1 'and 50μg 2, 30.0μg 1' and 100μg 2, 30.0μg 1 'and 150μg 2, 30.0μg 1' and 200μg 2, 30.0μg 1 'and 250μg 2, 30.0μg 1' and 300μg 2, 30.0μg 1 'and 320μg 2, 30.0μg 1' and 350μg 2, 30.0μg 1 'and 400μg 2, 30.0μg 1' and 500μg 2, 30.0μg 1 'and 600μg 2, 30.0μg 1' and 700μg 2, 30.0μg 1 'and 800μg 2, 30.0μg 1' and 1000μg 2, 60.0μg 1 'and 25μg 2, 60.0μg 1' and 50μg 2, 60.0μg 1 'and 100μg 2, 60.0μg 1' and 150μg 2, 60.0μg 1 'and 200μg 2, 60 , 0μg 1 'and 250μg 2, 60.0μg 1' and 300μg 2, 60.0μg 1 'and 320μg 2, 60.0μg 1' and 350μg 2, 60.0μg 1 'and 400μg 2, 60.0μg 1' and 500μg 2, 60.0μg 1 'and 600μg 2, 60.0μg 1' and 700μg 2, 60.0μg 1 'and 800μg 2, 60.0μg 1' and 1000μg 2, 90.0μg 1 'and 25μg 2, 90, 0μg 1 'and 50μg 2, 90.0μg 1' and 100μg 2, 90.0μg 9 'and 150μg 2, 90.0μg 1' and 200μg 2, 90.0μg 1 'and 250μg 2, 90.0μg 1' and 300μg 2, 90.0μg 1 'and 3 20μg 2, 90.0μg 1 'and 350μg 2, 90.0μg 1' and 400μg 2, 90.0μg 1 'and 500μg 2, 90.0μg 1' and 600μg 2, 90.0μg 1 'and 700μg 2, 90, 0μg 1 'and 800μg 2, 90.0μg 1' and 1000μg 2, included are.

simultaneously can the relationship from 1 to 3 1: 500 to 30: 1, preferably from 1: 400 to 20: 1, more preferably from 1: 300 to 10: 1, more preferably from 1: 200 to 5: 1, especially preferably from 1: 100 to 2: 1.

The active compound combinations according to the invention can 1 'and 3' in the case of, for example Formoterol in weight ratios included, for example, in a range of about 1:50 to 300: 1, preferably 1:20 to 200: 1, preferably 1:10 to 150: 1, especially preferably from 1: 5 to 100: 1.

For example and without limiting the scope of the invention thereto, may be preferred inventive combinations from 1 and 3, the pharmacologically active cation 1 'and formoterol 3' in the following weight ratios contain: 1:80, 1:79, 1:78, 1:77, 1:76, 1:75, 1:74, 1:73, 1:72, 1:71, 1:70, 1:69, 1:68, 1:67, 1:66, 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, 1:10, 1: 9, 1: 8, 1: 7, 1: 6, 1: 5, 1: 4, 1: 3, 1: 2, 1: 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, 10: 1, 11: 1, 12: 1, 13: 1, 14: 1, 15: 1, 16: 1, 17: 1, 18: 1, 19: 1, 20: 1, 21: 1, 22: 1, 23: 1, 24: 1, 25: 1, 26: 1, 27: 1, 28: 1, 29: 1, 30: 1, 31: 1, 32: 1, 33: 1, 34: 1, 35: 1, 36: 1, 37: 1, 38: 1, 39: 1, 40: 1, 41: 1, 42: 1, 43: 1, 44: 1, 45: 1, 46: 1, 47: 1, 48: 1, 49: 1, 50: 1, 51: 1, 52: 1, 53: 1, 54: 1, 55: 1, 56: 1, 57: 1, 58: 1, 59: 1, 60: 1, 61: 1, 62: 1, 63: 1, 64: 1, 65: 1, 66: 1, 67: 1, 68: 1, 69: 1, 70: 1, 71: 1, 72: 1, 73: 1, 74: 1, 75: 1, 76: 1, 77: 1, 78: 1, 79: 1, 80: 1.

The Application of the medicaments according to the invention containing the combinations of 1 and 3 is usually carried out so that that pharmacologically active cation 1 'and Formoterol 3 'in common in dosages from 0.05 to 2500μg, preferably from 0.5 to 1250 μg, more preferably from 1.0 to 1000μg, further preferably from 5 to 750μg, according to the invention preferred from 10 to 500μg, preferably from 15 to 250μg are included.

For example contain combinations according to the invention 1 and 3 such an amount of cation 1 'and formoterol 3' that the total dosage per single dose about 0.5μg, 1μg, 5μg, 10μg, 15μg, 20μg, 25μg, 30μg, 35μg, 45μg, 50μg, 55μg, 60μg, 65μg, 70μg, 75μg, 80μg, 85μg, 90μg, 95μg, 100μg, 105μg, 110μg, 115μg, 120μg, 125μg, 130μg, 135μg, 140μg, 145μg, 150μg, 155μg, 160μg, 165μg, 170μg, 175μg, 180μg, 185μg, 190μg, 195μg, 200μg, 205μg, 210μg, 215μg, 220μg, 225μg, 230μg, 235μg, 240μg, 245μg, 250μg, 255μg, 260μg, 265μg, 270μg, 275μg, 280μg, 285μg, 290μg, 295μg, 300μg, 305μg, 310μg, 315μg, 320μg, 325μg, 330μg, 335μg, 340μg, 345μg, 350μg, 355μg, 360μg, 365μg, 370μg, 375μg, 380 μg, 385 μg, 390 μg, 395 μg, 400 μg, 405 μg, 410 μg, 415 μg, 420 μg, 425 μg, 430 μg, 435 μg, 440 μg, 445 μg, 450 μg, or the like is. For the One skilled in the art will recognize that above mentioned dosage suggestions per single input not as to the explicitly specified numerical values limited is to be considered. Fluctuations of about ± 2.5 μg, in particular fluctuations in decimal are, as for the skilled person also includes. For these dosage ranges are the active ingredients 1 'and 3 'in the previous one contain described weight ratios.

For example and without limiting the scope of the invention thereto, the combinations according to the invention 1 and 3 contain such an amount of cation 1 'and formoterol 3' that, for example, for each single dose 2.5μg 1 'and 2.5μg 3', 2.5μg 1 'and 4.9μg 3', 2.5μg 1 'and 9.8μg 3', 2.5μg 1 'and 14.7μg 3', 2, 5μg 1 'and 19.6μg 3', 2.5μg 1 'and 24.4μg 3', 7.5μg 1 'and 2.5μg 3', 7.5μg 1 'and 4.9μg 3', 7.5μg 1 'and 9.8μg 3', 7.5μg 1 'and 14.7μg 3', 7.5μg 1 'and 19.6μg 3', 7.5μg 1 'and 24.4μg 3', 15.0μg 1 'and 2.5μg 3 ', 15,0μg 1' and 4,9μg 3 ', 15,0μg 1' and 9,8μg 3 ', 15,0μg 1' and 14,7μg 3 ', 15,0μg 1' and 19, 6μg 3 ', 15.0μg 1' and 24.4μg 3 ', 30.0μg 1' and 2.5μg 3 ', 30.0μg 1' and 4.9μg 3 ', 30.0μg 1' and 9.8μg 3 ', 30.0μg 1' and 14.7μg 3 ', 30.0μg 1' and 19.6μg 3 ', 30.0μg 1' and 24.4μg 3 ', 60.0μg 1' and 2.5μg 3 ', 60.0μg 1 'and 4.9μg 3', 60.0μg 1 'and 9.8μg 3', 60.0μg 1 'and 14.7μg 3', 60.0μg 1 'and 19.6μg 3', 60, 0μg 1 'and 24.4μg 3', 90.0μg 1 'and 2.5μg 3', 90.0μg 1 'and 4.9μg 3', 90.0μg 1 'and 9.8μg 3', 90.0μg 1 'and 14.7μg 3', 90.0μg 1 'and 19.6μg 3', 90.0μg 1 'and 24.4μg 3' are included.

The active compound combinations according to the invention can 1 'and 3' in the case of, for example Salmeterol in weight ratios included, for example, in a range of about 1:30 to 400: 1, preferably 1:25 to 200: 1, preferably 1:20 to 100: 1, especially preferably from 1:15 to 50: 1.

For example and without limiting the scope of the invention thereto, may be preferred inventive combinations 1 and 3, the cation 1 'and Salmeterol 3 'in the following weight ratios contain: 1:15, 1:14, 1:13, 1:12, 1:11, 1:10, 1: 9, 1: 8, 1: 7, 1: 6, 1: 5, 1: 4, 1: 3, 1: 2, 1: 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, 10: 1, 11: 1, 12: 1, 13: 1, 14: 1, 15: 1, 16: 1, 17: 1, 18: 1, 19: 1, 20: 1, 21: 1, 22: 1, 23: 1, 24: 1, 25: 1, 26: 1, 27: 1, 28: 1, 29: 1, 30: 1, 31: 1, 32: 1, 33: 1, 34: 1, 35: 1.

The Application of the medicaments according to the invention containing the combinations of 1 and 3 is usually carried out so that that Cation 1 'and salmeterol 3 'together in Dosages from 5 to 5000μg, preferably from 10 to 2000μg, especially preferably from 15 to 1000 μg, furthermore preferably from 20 to 800 μg, preferred according to the invention from 30 to 750μg, preferably from 40 to 700μg are included.

For example, combinations of 1 and 3 according to the invention contain such an amount of 1 'and salmeterol 3' that the total dosage per single dose is approximately 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 45 μg, 50 μg. 55μg, 60μg, 65μg, 70μg, 75μg, 80μg, 85μg, 90μg, 95μg, 100μg, 105μg, 110μg, 115μg, 120μg, 125μg, 130μg, 135μg, 140μg, 145μg, 150μg, 155μg, 160μg, 165μg, 170μg, 175μg, 180μg, 185μg, 190μg, 195μg, 200μg, 205μg, 210μg, 215μg, 220μg, 225μg, 230μg, 235μg, 240μg, 245μg, 250μg, 255μg, 260μg, 265μg, 270μg, 275μg, 280μg, 285μg, 290μg, 295μg, 300μg, 305 μg, 310 μg, 315 μg, 320 μg, 325 μg, 330 μg, 335 μg, 340 μg, 345 μg, 350 μg, 355 μg, 360 μg, 365 μg, 370 μg, 375 μg, 380 μg, 385 μg, 390 μg, 395 μg, 400 μg, 405 μg, 410 μg, 415 μg, 420 μg 430μg, 435μg, 440μg, 445μg, 450μg or similar. It will be apparent to those skilled in the art that the above dosage suggestions per single dose should not be construed as limited to those explicitly indicated. Variations of about ± 2.5μg, particularly variations in the decimal range, are also included, as will be apparent to those skilled in the art. In these dosage ranges, the active compounds 1 'and 3' are contained in the weight ratios described above.

For example and without limiting the scope of the invention thereto, the combinations according to the invention 1 and 3 contain such an amount of cation 1 'and salmeterol 3' that, for example, for each single dose 2.5 μg 1 'and 12.5 μg 3', 2.5 μg 1 'and 25 μg 3', 2.5 μg 1 'and 50 μg 3', 2.5 μg 1 'and 75 μg 3', 2.5 μg 1 'and 100 μg 3 ', 2.5μg 1' and 200μg 3 ', 7.5μg 1' and 12.5μg 3 ', 7.5μg 1' and 25μg 3 ', 7.5μg 1' and 50μg 3 ', 7.5μg 1' and 75μg 3 ', 7,5μg 1' and 100μg 3 ', 7,5μg 1' and 200μg 3 ', 15,0μg 1' and 12,5μg 3 ', 15,0μg 1' and 25μg 3 ', 15,0μg 1 'and 50μg 3', 15.0μg 1 'and 75μg 3', 15.0μg 1 'and 100μg 3', 15.0μg 1 'and 200μg 3', 30.0μg 1 'and 12.5μg 3', 30, 0μg 1 'and 25μg 3', 30.0μg 1 'and 50μg 3', 30.0μg 1 'and 75μg 3', 30.0μg 1 'and 100μg 3', 30.0μg 1 'and 200μg 3', 60, 0μg 1 'and 1' 2,5μg 3 ', 60,0μg 1' and 25μg 3 ', 60,0μg 1' and 50μg 3 ', 60,0μg 1' and 75μg 3 ', 60,0μg 1' and 100μg 3 ', 60.0μg 1' and 200μg 3 ', 490.0μg 1' and 12.5μg 3 ', 490.0μg 1' and 25μg 3 ', 490.0μg 1' and 50μg 3 ', 490.0μg 1' and 75μg 3 ', 490.0μg 1' and 100μg 3 ', 490.0μg 1' and 200μg 3 'are included.

From the quantities of 1 'indicated above, the corresponding amounts of the salts of the formula 1 as well as the corresponding amounts of optionally existing hydrates and / or solvates of the salts 1 for the expert, taking into account the mass of the anion X ^- , and optionally taking into account the mass of water of hydration and or solvate molecules easily calculable. Likewise, from the amounts of 2 'or 3' given above, the corresponding amounts of salts 2 or 3 as well as the corresponding amounts of optionally existing hydrates and / or solvates of salts 2 or 3 are readily calculable by a person skilled in the art.

The Application of the active compound combinations according to the invention from 1, 2 and 3 is preferably carried out by inhalation. For this, the Ingredients 1, 2 and 3 provided in inhalable dosage forms become.

When inhalable dosage forms according to the invention come in inhalation powder, propellant-containing metered dose inhalers or propellant-free inhalation solutions in Consideration. Inventive inhalable powders containing the active ingredient combination of 1, 2 and 3 alone from the named active substances or from a mixture of the named Active ingredients with physiologically acceptable excipients exist.

Possibly is used in the context of the present invention instead of the term excipient also the term carrier used. In the context of the present invention are of the term propellant-free inhalation solutions also includes concentrates or sterile, ready-to-use inhalation solutions. The Dosage forms according to the invention can the active ingredient combination of 1, 2 and 3 either together in one, contained in two or three separate presentations. These in the context of the present invention applicable dosage forms are described in detail in the following part of the description.

A) containing inhalation powder the active compound combinations according to the invention from 1, 2 and 3:

The The inhalable powder of the invention can 1, 2 and 3 either alone or in admixture with appropriate physiological safe excipients included.

are the active compounds 1, 2 and 3 in admixture with physiologically acceptable May contain adjuvants to illustrate these inhalable powders of the invention, the following Physiologically acceptable excipients are used: 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 excipients. Mono or disaccharides for use, wherein the use of lactose or glucose, especially but not exclusively in the form of their hydrates, is preferred. As being particularly preferred according to the invention Lactose, highest prefers lactose monohydrate as adjuvant for use.

The Auxiliaries have a maximum in the context of the inhalable powders according to the invention mean particle size from to to 250μm, preferably between 10 and 150 μm, more preferably between 15 and 80μm. If necessary it can make sense, the abovementioned auxiliaries finer Helper fractions with a mean particle size of 1 up to 9μm to mix. The latter finer excipients are also selected from the aforementioned group of usable excipients. Finally, the Production of the inhalable powders according to the invention micronized active ingredient 1, 2 and 3, preferably with a middle Particle size of 0.5 up to 10μm, more preferably from 1 to 5 μm, added to the excipient mixture. Process for the preparation of The inhalable powder of the invention by grinding and micronizing and by final mixing the ingredients are known in the art. The inhalable powders according to the invention can either in the form of a single powder mix containing both 1 and 2 and 3 contains or in the form of separate inhalable powders containing only 1, 2 and 3 contain provided and applied.

The inhalable powder according to the invention can applied by inhalers known from the prior art become.

Inhalable powders according to the invention, which in addition to 1, 2 and 3 also contain one or more physiologically acceptable auxiliaries, can be administered, for example, by means of inhalers which deliver a single dose from a supply by means of a measuring chamber as described in US Pat US 4570630A or other apparatus as described in the DE 36 25 685 A be described, dose. Preferably, the inhalable powders according to the invention, which contain physiologically acceptable excipients in addition to 1, 2 and 3, are, however, filled into capsules (known as inhalers) which are used in inhalers as described, for example, in WO 94/28958.

A particularly preferred inhaler for use of the drug combination according to the invention in inhalants is 1 refer to.

This inhaler (handihaler) for the inhalation of powdered drugs from capsules is characterized by a housing 1 containing two windows 2 , a deck 3 , in which there are air inlet openings and which one with a sieve housing 4 attached sieve 5 is provided, one with deck 3 connected inhalation chamber 6 , at the one with two cut needles 7 provided, against a spring 8th movable pusher 9 is provided, as well as on an axis 10 foldable with the housing 1 the deck 3 and a cap 11 connected mouthpiece 12 as well as air passage holes 13 for adjusting the flow resistance.

Should the inhalable powders according to the invention in the sense of the aforementioned preferred application in capsules (Inhalers) bottled can be filled from 1 to 30 mg, preferably from 3 to 20 mg, preferably from 5 to 10 mg of inhalable powder per capsule. These contain according to the invention either together or in each case already mentioned above for 1, 2 and 3 dosages per single dose.

B) Propellant-containing inhalation aerosols containing the active compound combinations according to the invention from 1, 2 and 3

 Propellant gas-containing according to the invention Inhalation aerosols can 1, 2 and 3 dissolved in the propellant gas or in dispersed form. Here can 1, 2 and 3 in separate Dosage forms or in a common dosage form included be, wherein 1, 2 and 3 either dissolved in each case, in each case dispersed or optionally only one or two of the components are solved and the other respectively the other components may be dispersed.

The can be used for the preparation of inhalation aerosols according to the invention Propellant gases are known from the prior art. Suitable propellant gases are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as fluorinated derivatives of methane, Ethane, propane, butane, cyclopropane or cyclobutane. The above mentioned propellant gases used alone or in mixtures thereof. Particularly preferred propellants are halogenated alkane derivatives selected from TG134a and TG227 and mixtures thereof.

The according to the invention propellant gas Inhalation aerosols can further components such as cosolvents, stabilizers, surface-active Surfactants, antioxidants, lubricants, preservatives and pH adjusting agents. All these ingredients are known in the art.

The propellant gas-containing according to the invention Inhalation aerosols can contain up to 5% by weight of active ingredient 1, 2 and / or 3. 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 to active ingredient 1, 2 and / or 3.

Lie the active compounds 1, 2 and / or 3 in dispersed form before, have the active ingredient particles preferably have a mean particle size of up to to 10 μm, preferably from 0.1 to 5 μm, more preferably from 1 to 5 microns on.

The abovementioned propellant gas-containing content ion aerosols according to the invention can by inhalers known in the art (MDIs = metered dose inhalers). Accordingly, another concerns Aspect of the present invention Drugs in the form of as above described propellant-containing aerosols in conjunction with a or more inhalers suitable for administering these aerosols. Furthermore, the present invention relates to inhalers, characterized in that they are above described propellant gas-containing invention Contain aerosols.

The The present invention further relates to cartridges equipped with a suitable valve in a suitable inhaler for use can reach and the one of the abovementioned propellant gas-containing according to the invention Inhalation aerosols. Suitable cartridges and methods for bottling of these cartridges with the propellant-containing inhalable inhalation aerosols according to the invention are known from the prior art.

C) propellant-free inhalation solutions or Suspensions containing the active compound combinations according to the invention from 1, 2 and 3:

Especially The application of the active ingredient combination according to the invention is preferably carried out in the form of propellant-free inhalable solutions and suspension suspensions. As a solvent come to this aqueous or alcoholic, preferably ethanolic solutions into consideration. The solvent can only Be it water or it is a mixture of water and ethanol. Of the relative proportion of ethanol compared Water is not limited, but the maximum limit is preferred at up to 70% by volume, especially up to 60% by volume and more preferably at up to 30 volume percent. The remaining Volume percentages are filled up with water. The 1, 2 and 3, separated or solutions together or suspensions are treated with appropriate acids to a pH of 2 to 7, preferably set from 2 to 5. To set this pH can acids selected find use of inorganic or organic acids. 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, malic, tartaric, maleic, succinic, fumaric, acetic, formic and / or propionic and other. Preferred inorganic acids are hydrochloric acid, sulfuric acid. It can also the acids Already used with one of the active ingredients an acid addition salt form. Among the organic acids are ascorbic acid, fumaric acid and citric acid prefers. If necessary, you can also mixtures of the acids mentioned be used, in particular in cases of acids, in addition to their Säuerungseigenschaften also other properties, e.g. as flavorings, antioxidants or complexing agents, such as citric acid or Ascorbic acid. Particularly according to the invention hydrochloric acid is preferred used to adjust the pH.

According to the invention, in of the present formulation on the addition of editic acid (EDTA) or one of the known salts thereof, sodium edetate, as a stabilizer or complexing agents are dispensed with.

Other embodiments include this compound (s).

In Such a preferred embodiment the content based on sodium edetate is below 100 mg / 100 ml, preferred below 50mg / 100ml, more preferably below 20mg / 100ml. As a general rule are such content solutions preferred in which the content of sodium edetate at 0 to 10mg / 100ml lies.

The propellant-free according to the invention inhalable can Co-solvents and / or other auxiliaries are added.

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 ethers, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid ter.

Under In this context, auxiliaries and additives will all be physiological compatible Understood substance that is not an active ingredient, but together with the (the) active ingredients) in the physiologically suitable solvent can be formulated to the qualitative properties of the drug formulation to improve. Preferably, these substances do not develop 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 e.g. Soya lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone other stabilizers, complexing agents, Antioxidants and / or preservatives, the duration of use ensure or extend the finished drug formulation, flavors, Vitamins and / or other additives known in the art. Additives include also physiologically acceptable salts such as sodium chloride as isotonic agents.

To counting the preferred excipients Antioxidants, such as ascorbic acid, if not already for the setting of the pH used, vitamin A, vitamin E, tocopherols and the like in the human organism occurring vitamins or provitamins.

preservatives can Be used to the formulation before contamination with germs too protect. Suitable preservatives are those known in the art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or Benzoates such as sodium benzoate in the well-known in the art Concentration. The above-mentioned preservatives are preferably in concentrations of up to 50mg / 100ml, especially preferably between 5 and 20mg / 100ml.

preferred Formulations include except the solvent Water and the drug combination of 1, 2 and 3 only benzalkonium chloride and sodium edetate. In another preferred embodiment is dispensed with sodium edetate.

to Application of propellant-free invention inhalable Especially those inhalers that contain a small amount of a liquid formulation in the therapeutically necessary dosage within a few seconds be able to nebulize in a therapeutic inhalation suitable aerosol. in the Within the scope of the present invention, such nebulizers are preferred. where already an amount of less than 100 μL, preferred less than 50μL, particularly preferably between 20 and 30 .mu.l drug solution with preferably a stroke to an aerosol with an average particle size of less than 20μm, preferably less than 10 μm, be so fogged that the inhalable fraction of the aerosol already the therapeutically effective Quantity corresponds.

Such a device for propellant-free administration of a metered amount of a liquid medicament for inhalation use, for example, in International Patent Application WO 91/14468 as well as in WO 97/12687 (there in particular 6a and 6b ) described in detail. The nebulisers (devices) described therein are also known by the name Respimat ^®.

This nebuliser (Respimat ^®) can be advantageously used for containing produce the inhalable aerosols according to the invention the active substance combination of 1 and 2. 3 Due to its cylindrical shape and a handy size of less than 9 to 15 cm in length and 2 to 4 cm in width, this device can always be carried by the patient. The nebulizer sprays a defined volume of the drug formulation using high pressures through small nozzles to produce inhalable aerosols.

• – 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 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 fixed in the housing upper part and which carries at its 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 a device disclosed in WO 97/12687. It partially protrudes into the cylinder of the pump housing and is arranged axially displaceably in the cylinder. In particular, on the 1 - 4 - especially 3 - and the related parts of the description with reference. The hollow piston with valve body exerts on its high pressure side at the time of release of the spring 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 drug solution. Volumes of from 10 to 50 microliters are preferred, volumes from 10 to 20 microliters are particularly preferred, and a volume of 15 microliters per stroke is very particularly preferred.

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

The nozzle in the nozzle body is preferably microstructured, ie produced by microtechnology. Microstructured nozzle bodies are disclosed, for example, in WO-94/07607; This document is hereby incorporated by reference, in particular to those disclosed therein 1 and their description.

Of the Nozzle body exists e.g. made of two fixed plates of glass and / or Silicon, of which at least one plate microstructured one or more channels having, which the nozzle inlet side with connect the nozzle outlet side. On the nozzle outlet side is at least one round or non-round opening from 2 to 10 microns Depth and 5 to 15 microns wide, with the depth preferably at 4, 5 to 6.5 microns and the length at 7 to 9 microns is.

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

The orifices are preferably arranged at a distance of 10 to 200 micrometers, stronger preferably at a distance of 10 to 100 microns, especially preferably 30 to 70 microns. Most preferred are 50 microns.

The Beam directions meet accordingly in the environment of Nozzle openings.

The liquid Pharmaceutical preparation meets with an inlet pressure of up to 600 bar, preferably 200 to 300 bar on the nozzle body and is on the orifices atomized into an inhalable aerosol. The preferred particle or droplet sizes of Aerosols are up to 20 microns, preferably 3 to 10 microns.

The Locking mechanism contains a spring, preferably a cylindrical helical compression spring, as Memory for the mechanical energy. The spring acts on the output flange as a jump, whose movement is determined by the position of a locking member. The way of the output flange is through an upper and a bottom stop precise limited. The spring is preferably a force translating Transmission, e.g. a screw thrust mechanism, by an external torque curious, when turning the upper housing part against the spring housing in the lower housing part is produced. In this case, the upper housing part and the output flange contain a single or multiple course Spline gear.

The Locking member with engaging Restricted areas is ring-shaped arranged around the output flange. There is e.g. from one in radially elastically deformable ring made of plastic or of Metal. The ring is in a plane perpendicular to the atomizer axis arranged. After tensioning the spring, the blocking surfaces of the Locking member in the path of the output flange and prevent the Relax the spring. The Sprerrglied is triggered by a button. The shutter button is connected or coupled to the blocking member. To trigger the Sperrspannwerkes is the shutter button parallel to the plane of the ring, preferably into the atomizer, postponed; while the deformable ring is deformed in the ring plane. Structural details of the locking mechanism are in WO 97/20590 described.

The Housing bottom becomes over in the axial direction the spring housing pushed and concealed the storage, the drive of the spindle and the reservoir for the Fluid.

When operating the atomizer, the housing upper part is rotated against the housing lower part, wherein the lower housing part takes along the spring housing. The spring is compressed and tensioned via the screw slide, and the lock engages automatically. The angle of rotation is preferably an integer fraction of 360 degrees, for example 180 degrees. Simultaneously with the tensioning of the spring, the driven part is displaced in the upper housing part by a predetermined path, the hollow piston is withdrawn within the cylinder in the pump housing, whereby a subset of the fluid from the reservoir is sucked into the high-pressure chamber in front of the nozzle.

In the atomizer can optionally one after the other several interchangeable containing the fluid to be atomized reservoir be inserted and used. The reservoir contains the aqueous according to the invention Aerosol formulation.

Of the atomizing is by slight impressions the shutter button initiated. The blocking mechanism clears the way for the stripping section. The Tensioned spring pushes the piston into the cylinder of the pump housing.

The Fluid exits the nozzle the atomizer in atomized Shape out.

Further Structural details are disclosed in PCT applications WO 97/12683 and US Pat WO 97/20590, incorporated herein by reference becomes.

The Components of the atomizer (Nebulizer) are suitable for one of the function Material. The housing the atomizer and so far the function allows it - too other parts are preferably made of plastic, e.g. in injection molding, produced. For Medical purposes become physiologically harmless materials used.

In the 6a / b of WO 97/12687, which is incorporated by reference in addition to the associated description components at this Stell, the nebuliser (Respimat ^® ) is described, with which the aqueous aerosol preparations according to the invention can be advantageously inhaled.

6a shows a longitudinal section through the atomizer with cocked spring, 6b shows a longitudinal section through the atomizer with a relaxed spring.

The upper housing part ( 51 ) contains the pump housing ( 52 ), at the end of which the holder ( 53 ) is mounted for the atomizer nozzle. In the holder is the nozzle body ( 54 ) and a filter ( 55 ). The in the output flange ( 56 ) of the locking mechanism mounted hollow piston ( 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 by means of the seal ( 59 ) sealed. Within the housing upper part is the stop ( 60 ), on which the output flange rests with a relaxed spring. At the output flange is the stop ( 61 ), on which the output flange rests when the spring is tensioned. After tensioning the spring, the locking member pushes ( 62 ) between the stop ( 61 ) and a support ( 63 ) in the upper part of the housing. The shutter button ( 64 ) is in communication with the locking member. The housing shell ends in the mouthpiece ( 65 ) and with the attachable protective cap ( 66 ) locked.

The spring housing ( 67 ) with compression spring ( 68 ) is by means of snap-in lugs ( 69 ) and rotary bearing rotatably mounted on the upper housing part. About the spring housing is the housing lower part ( 70 ) pushed. Within the spring housing is the replaceable reservoir ( 71 ) for the fluid to be atomized ( 72 ). The reservoir is filled with the stopper ( 73 ), through which the hollow piston protrudes into the reservoir and with its end immersed in the fluid (stock of drug solution).

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

Of the Nebulizer described above is suitable, the aerosol preparations according to the invention to one for to nebulise 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 correspond. Between 5 and 30 mg of formulation as defined Mas are preferred per stroke se, more preferably between 5 and 20 mg.

The inventive formulation However, it can also be by means other than those described above Inhalators, such as jet stream inhalers, are aerosolized.

Accordingly, a further aspect of the present invention relates to medicaments in the form of above-described propellant-free inhalable solutions or suspensions in combination with a suitable device for administering these formulations, preferably in conjunction with the Respimat ^®. Preferably the present invention to propellant-free inhalable solutions or suspensions characterized by the aims of the invention combination of active substances 1, 2 and 3 in conjunction with the known under the name Respimat ^® device. Furthermore, the present invention relates to the above-mentioned devices for inhalation, preferably the Respimat ^® , characterized in that they contain above-described propellant-free inhalable solutions or suspensions according to the invention.

The propellant-free according to the invention inhalation solutions or suspensions can in addition to the above, provided for application in the Respimat solutions and Suspensions also as concentrates or sterile ready to use inhalation solutions or suspensions are present. From the concentrates can be, for example by the addition of isotonic saline solutions ready-to-use formulations to generate. Sterile ready-to-use formulations can be prepared by means of Energy-powered stand-alone or portable nebulizer, the inhalable Aerosols by means of ultrasound or compressed air according to the venturi principle or other principles are applied.

Accordingly another aspect of the present invention relates to pharmaceuticals in the form of propellant-free inhalable solutions as described above or Suspensions that are ready to use as concentrates or sterile Formulations are present, in conjunction with one for administration suitable for these solutions Device, characterized in that it is in this device an energy-powered stand-alone or transportable nebulizer the inhalable aerosols by means of ultrasound or compressed air produced according to the venturi principle or other principles.

2)

3)

4)

5)

6)

B) Treibgashaltige Inhaltionsaerosole: 1) Suspensionsaerosol:

2) Suspensionsaerosol:

3) Suspensionsaerosol:

4) Suspensionsaerosol:

5) Suspensionsaerosol:

The following examples serve to further illustrate the present invention without, however, limiting the scope of the invention to the following exemplary embodiments. Formulation Examples A) Ingredients: 1)

2)

3)

4)

5)

6)

B) propellant-containing inhalation aerosols: 1) suspension aerosol:

2) suspension aerosol:

3) suspension aerosol:

4) suspension aerosol:

5) suspension aerosol:

Claims (24)

Medicaments for inhalation characterized by a content of at least one anticholinergic of the formula 1,

wherein X ^{- is} a singly 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 sulphonate means at least one corticosteroid ( 2 ) and at least one betamimetic ( 3 ), 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 physiologically acceptable excipient. Medicament according to claim 1, characterized in that the active ingredients 1, 2 and 3 either together in a single dosage form or in two or three separate presentations. Medicament according to one of claims 1 or 2, characterized in that 1 is selected from the group of salts in which X ^- for a single negatively charged anion selected from the group consisting of chloride, bromide, 4-toluenesulfonate and methanesulfonate, preferably bromide stands. Medicament according to one of claims 1 to 3, characterized in that 2 is selected from the group consisting of flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, GW 215864, KSR 592, ST-126 and dexametasone. Medicament according to claim 4, characterized in that 2 is selected from the group consisting of flunisolides, beclomethasone, triamcinolone, Budesonide, Fluticasone, Mometasone, Ciclesonide and Dexametasone. Medicament according to one of claims 1 to 5, characterized that 3 selected is from the group consisting of bambuterol, bitolterol, carbuterol, Clenbuterol, Fenoterol, Formoterol, Hexoprenalin, Ibuterol, Pirbuterol, Procaterol, reproterol, salmeterol, sulfonterol, terbutaline, toluubuterol, 4-hydroxy-7- [2 - {[2 - {[3- (2-phenylethoxy) propyl] sulfonyl} ethyl] -amino} ethyl] -2 (3H) -benzothiazolone, 1- (2-Fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [3- (4-methoxybenzyl-amino) -4-hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [2N-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino] ethanol . 1- [2N-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-n-butyloxyphenyl) -2-methyl-2-propylamino] ethanol . 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- {4- [3- (4-methoxyphenyl) -1,2,4-triazol-3- yl] -2-methyl-2-butylamino} ethanol, 5-Hydroxy-8- (1-hydroxy-2-isopropylaminobutyl) -2H-1,4-benzoxazin-3- (4H) -one, 1- (4-amino-3-chloro-5-trifluoromethylphenyl) -2-tert.-butylamino) ethanol and 1- (4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2- (tert -butylamino) ethanol. Medicament according to claim 6, characterized in that 3 is selected from the group consisting of formoterol, salmeterol, 4-hydroxy-7- [2 - {[2 - {[3- (2-phenylethoxy) propyl] sulfonyl} ethyl] -amino} ethyl] -2 (3H) -benzothiazolone, 1- (2-Fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [3- (4-methoxybenzyl-amino) -4-hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino] ethanol . 1- [2N-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-n-butyloxyphenyl) -2-methyl-2-propylamino] ethanol and 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- {4- [3- (4-methoxyphenyl) -1,2,4-triazol-3- yl] -2-methyl-2-butylamino} ethanol. Medicament according to one of claims 1 to 7, characterized that the Weight ratios of 1 'to 2 in one Range from 1: 250 to 250: 1, preferably from 1: 150 to 150: 1. Medicament according to one of claims 1 to 8, characterized that the Weight ratios of 1 to 3 in a range of 1: 300 to 30: 1, preferably 1: 230 to 20: 1 lie. Medicament according to one of Claims 1 to 9, characterized that one single application of a dosage of the drug combination 1, 2 and 3 from 1 to 10000μg, preferably from 10 to 2000μg equivalent. Medicament according to one of Claims 1 to 10, characterized that it in the form of a for the inhalation suitable dosage form is present. Medicament according to claim 11, characterized in that it is selected for a dosage form from the group inhalation powder, propellant-containing MDIs and propellant-free inhalation solutions or suspensions. Medicament according to Claim 12, characterized in that it contains a Inhalable powder is which 1, 2 and 3 in admixture with suitable Physiologically acceptable excipients selected from the group consisting from monosaccharides, disaccharides, oligo- and polysaccharides, Polyalcohols, salts, or mixtures of these excipients. Inhalable powder according to claim 13, characterized in that the auxiliary agent has a maximum mean Re particle size of up to 250 .mu.m, preferably between 10 and 150 .mu.m. Capsules characterized by a content of inhalation powder according to claim 13 or 14. Medicament according to Claim 12, characterized in that it contains a Inhalation powder is, which as ingredients only the active ingredients 1, 2 and 3 contains. Medicament according to claim 12, characterized in that it is is a propellant-containing inhalation aerosol, which 1, 2 and 3 in dissolved or dispersed form. Propellant-containing inhalation aerosol according to claim 17, characterized characterized in that it as propellant hydrocarbons such as n-propane, n-butane or isobutane or halogenated hydrocarbons such as chlorinated and / or fluorinated derivatives of methane, ethane, Propane, butane, cyclopropane or cyclobutane. Propellant-containing inhalation aerosol according to claim 18, characterized characterized in that Propellant TG134a, TG227 or a mixture thereof represents. Propellant-containing inhalation aerosol according to claim 17, 18 or 19, characterized in that it optionally one or more further constituents selected from the group consisting from cosolvents, stabilizers, surfactants, Antioxidants, lubricants and pH adjusters contains. Propellant-containing inhalation aerosol according to one of claims 17 to 20, characterized in that it may contain up to 5% by weight of active ingredient 1, 2 and / or 3. Use of a capsule according to claim 15 in an inhaler, preferably in Handihaler. Use of a composition according to any one of claims 1 to 21 for the manufacture of a medicament for the treatment of inflammatory and / or obstructive respiratory diseases. Use of a composition according to claim 23 for the preparation a drug for the treatment of asthma or COPD.