DE10111058A1 - New drug compositions based on anticholinergics and NK¶1¶ receptor antagonists - Google Patents

Abstract

The invention relates to novel medicament compositions based on anticholinergics and on NK1 receptor antagonists, to methods for the production thereof, and to their use in the treatment of respiratory tract diseases.

Description

The present invention relates to novel pharmaceutical compositions based on anticholinergics and NK ₁ receptor antagonists, processes for their preparation and their use in the therapy of respiratory diseases.

Description of the invention

The present invention relates to novel pharmaceutical compositions based on anticholinergics and NK ₁ receptor antagonists, processes for their preparation and their use in the therapy of respiratory diseases.

Surprisingly, an unexpectedly advantageous therapeutic effect, in particular a synergistic effect in the treatment of inflammatory and / or obstructive respiratory diseases, can be observed if one or more, preferably an anticholinergic, is used together with one or more, preferably an NK ₁ receptor, antagonist , Because of this synergistic effect, the pharmaceutical combinations according to the invention can be used at lower doses than is the case with the otherwise customary monotherapy of the individual compounds.

The active ingredient combinations according to the invention are surprisingly further both through a rapid onset of action and through a long-lasting Duration of action marked. This is of great importance for the wellbeing of the Patients, because on the one hand, after application of the combination, it His condition improved and on the other hand due to the long Duration of application once a day is sufficient. The above effects are both with simultaneous application within a single active ingredient formulation as well as with successive application of the two active substances observed in separate formulations. According to the invention preference is given to the simultaneous application of the two active ingredient components in one single wording.

In the context of the present invention, anticholinergics 1 are understood to mean salts which are preferably selected from the group consisting of tiotropium salts, oxitropium salts and ipratropium salts, tiotropium salts being particularly preferred. In the above-mentioned salts, the cations tiotropium, oxitropium and ipratropium are the pharmacologically active constituents. In the context of the present patent application, reference is to be made to the above cations by using the designation 1 ' . Reference to compounds 1 naturally includes reference to constituents 1 '(tiotropium, oxitropium or ipratropium).

The salts 1 which can be used in the context of the present invention are to be understood as meaning the compounds which, in addition to tiotropium, oxitropium or ipratropium, contain chloride, bromide, iodide, methanesulfonate, para-toluenesulfonate or methyl sulfate as counterion (anion). Of the salts 1, methanesulfonate, chloride, bromide or iodide are preferred in the context of the present invention, methanesulfonate or bromide being of particular importance. Of outstanding importance according to the invention are salts 1 which are selected from the group consisting of tiotropium bromide, oxitropium bromide and ipratropium bromide. Tiotropium bromide is particularly preferred.

In the context of the present invention, NK ₁ receptor antagonists (hereinafter 2 ) are understood to mean compounds which are selected from the group consisting of BIIF 1149, FK-888, NKP 608C, NKP 608A, CGP 60829, SR 48968 (Saredutant) , SR 140333 (Nolpitantium besilate / chloride), LY 303 870 (Lanepitant), MEN-11420 (Nepadutant), SB 223412, MDL-105172A, MDL-103896, MEN-11149, MEN-11467, DNK 333 A, SR-144190 , YM-49244, YM-44778, ZM-274773, MEN-10930, S-19752, Neuronorm, YM-35375, DA-5018, MK-869, L-754030, CJ-11974, L-758298, DNK-33A , 6b-I, CJ-11974, TAK-637, GR 205171 and the arylglycinamide derivatives of the general formula 3

wherein
R ¹ and R ² together with the N to which they are attached form a ring of the formula

form where r and s are 2 or 3;
R ⁶ H, -C ₁ -C ₅ alkyl, C ₃ -C ₅ alkenyl, propynyl, hydroxy (C ₂ -C ₄ ) alkyl, methoxy (C ₂ -C ₄ ) alkyl, di (C ₁ -C ₃ ) alkylamino (C ₂ -C ₄ ) alkyl, amino (C ₂ - C ₄ ) alkyl, amino, di (C ₁ -C ₃ ) alkylamino, monofluoro- to perfluoro (C ₁ - C ₂ ) alkyl, N-methylpiperidinyl, Means pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl,
R ^{7 has} one of the meanings (a) to (d),

• a) hydroxy
• b) 4-piperidinopiperidyl,
  wherein R ¹⁶ and R ¹⁷ independently of one another are H, (C ₁ -C ₄ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, hydroxy (C ₂ -C ₄ ) alkyl, dihydroxy (C ₂ -C ₄ ) alkyl, (C ₁ -C ₃ ) alkoxy (C ₂ -C ₄ ) alkyl, phenyl (C ₁ - C ₄ ) alkyl or di (C ₁ -C ₃ ) alkylamino (C ₂ -C ₄ ) alkyl,

R ⁸

H means
optionally in the form of their enantiomers and mixtures of the enantiomers, optionally in the form of their racemates.

The abovementioned compounds of the formula 3 are known, for example, from international patent applications WO 96/32386 and WO 97/32865, to which reference is made in full at this point.

Compound 2 is preferably selected from the group consisting of BIIF 1149, CGP 60829, MK-869, CJ-11974, GR 205171 and the arylglycinamide derivatives of the general formula 3 , in which
R ¹ and R ² together with the N to which they are attached form a ring of the formula

form where s is 2 or 3;
R ⁷ for a group

wherein R ¹⁶ and R ¹⁷ independently of one another are H, (C ₁ -C ₄ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, hydroxy (C ₂ -C ₄ ) alkyl, dihydroxy (C ₂ -C ₄ ) alkyl, (C ₁ -C ₃ ) alkoxy (C ₂ -C ₄ ) alkyl, phenyl (C ₁ - C ₄ ) alkyl or di (C ₁ -C ₃ ) alkylamino (C ₂ -C ₄ ) alkyl,
R ⁸ H means
optionally in the form of their enantiomers and mixtures of the enantiomers, and optionally in the form of their racemates.

The compound 2 is particularly preferably selected from BIIF 1149 and the arylglycinamide derivatives of the general formula 3 , in which R ¹ and R ² together with the N to which they are attached form a ring of the formula

form where s is 2 and
R ⁷ for a group

where R ¹⁶ and R ^{17 are} independently H, (C ₁ -C ₄ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, hydroxy (C ₂ -C ₄ ) alkyl or dihydroxy (C ₂ -C ₄ ) alkyl,
R ⁸ denotes H, optionally in the form of their enantiomers and mixtures of the enantiomers, and optionally in the form of their racemates.

As alkyl groups (also insofar as they are part of other radicals), so far not otherwise defined, branched and unbranched alkyl groups with 1 to 5 Considered carbon atoms. Examples include: methyl, ethyl, propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl (tert-butyl), etc. Here are the definitions of propyl, butyl and pentyl respective isomeric residues always included. Hydroxy or dihydroxyalkyl groups represent alkyl groups which are substituted by one or two hydroxyl groups.

As alkenyl groups (also insofar as they are part of other radicals) called branched and unbranched alkenyl groups with 3 to 5 carbon atoms, if they have at least one double bond, such as propenyl, iso-propenyl, butenyl etc.

Cycloalkyl is generally a saturated cyclic Hydrocarbon residue with 3 to 6 carbon atoms. As examples Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, Cylobutylmethyl, Cyclopentylmethyl, Cylopropylethyl, Cyclobutylethyl etc. called.

Alkyloxy, which may also be referred to as alkoxy, stands for a straight-chain or branched alkyl group bonded via an oxygen atom. The methoxy group is particularly preferred.

In the context of the present invention, a reference to the aforementioned NK ₁ receptor antagonists 2 includes a reference to their pharmacologically acceptable acid addition salts which may exist.

According to the invention, the physiologically compatible acid addition salts which can be formed by 2 are understood to be pharmaceutically compatible salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid , According to the invention, preference is given to the salts of the compounds 2 which are selected from the group consisting of acetate, hydrochloride, hydrobromide, sulfate, phosphate and methanesulfonate.

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

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

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

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

The present invention further relates to the use of 1 and 2 for the production of a therapeutically effective amount of medicament containing 1 and 2 for the treatment of inflammatory and / or obstructive respiratory diseases, in particular asthma or chronic obstructive pulmonary disease (COPD), provided treatment with NK ₁ -Receptor antagonists from a therapeutic point of view is not contraindicated, by simultaneous or successive application.

The present invention further 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), provided that treatment with NK ₁ receptor -Antagonists are not contraindicated from a therapeutic point of view, by simultaneous or successive application.

In the active compound combinations according to the invention from 1 and 2 , the constituents 1 and 2 can be present in the form of their enantiomers, mixtures of the enantiomers or in the form of the racemates. The ratios in which the two active ingredients 1 and 2 can be used in the active ingredient combinations according to the invention are variable. Active ingredients 1 and 2 may optionally be in the form of their solvates or hydrates. Depending on the choice of compounds 1 and 2 , the weight ratios which can be used in the context of the present invention vary on account of the different molecular weights of the various compounds and on account of their different potency. As a rule, the pharmaceutical combinations according to the invention can contain the compounds 1 and 2 in weight ratios which are in a range from 1: 300 to 50: 1, preferably from 1: 250 to 40: 1. In the particularly preferred drug combinations, the tiotropium salt as compound 1 and a compound selected from the group consisting of BIIF 1149, CGP 60829, MK-869, CJ-11974, GR 205171 and the arylglycinamide derivatives of the formula 3 as NK ₁ receptor antagonist 2 contained, the weight ratios of 1 to 2 are particularly preferably in a range in which tiotropium 1 ' and 2 are contained in ratios of 1: 150 to 30: 1, further preferably from 1:50 to 20: 1.

For example and without restricting the scope of the invention thereto, preferred combinations according to the invention of 1 and 2 tiotropium 1 ' and NK ₁ - receptor antagonists 2 can contain the following weight ratios: 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: 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 medicaments according to the invention containing the combinations of 1 and 2 are usually used in such a way that 1 and 2 together in doses of from 0.01 to 10000 μg, preferably from 0.1 to 2000 μg, particularly preferably from 1 to 1500 μg, are further preferred from 50 to 1200 µg per single dose are included. For example, combinations of 1 and 2 according to the invention contain such an amount of tiotropium 1 ' and NK ₁ receptor antagonist 2 that the total dosage per single dose is 100 µg, 105 µg, 110 µg, 115 µg, 120 µg, 125 µg, 130 µg, 135 µg, 140 µg, 145 µg, 150 µg, 155 µg, 160 µg, 165 µg, 170 µg, 175 µg, 180 µg, 185 µg, 190 µg, 195 µg, 200 µg, 205 µg, 210 µg, 215 µg , 220 µg, 225 µg, 230 µg, 235 µg, 240 µg, 245 µg, 250 µg, 255 µg, 260 µg, 265 µg, 270 µg, 275 µg, 280 µg, 285 µg, 290 µg, 295 µg, 300 µg, 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, 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, 55 5 ug, 560 ug, 565 ug, 570 ug, 575 ug, 580 ug, 585 ug, 590 ug, 595 ug, 600 ug, 605 ug, 610 ug, 615 ug, 620 ug, 625 ug, 630 ug, 635 ug , 640 µg, 645 µg, 650 µg, 655 µg, 660 µg, 665 µg, 670 µg, 675 µg, 680 µg, 685 µg, 690 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, 945 µg, 950 µg, 955 µg, 960 µg, 965 µg, 970 µg, 975 µg, 980 µg, 985 µg, 990 µg, 995 µg, 1000 µg, 1005 µg, 1010 µg, 1015 µg, 1020 µg, 1025 µg, 1030 µg, 1035 µg, 1040 µg, 1045 µg, 1050 µg, 1055 µg, 1060 µg, 1065 µg, 1070 µg, 1075 µg, 1080 µg, 1085 µg, 1090 µg, 1095 µg, 1 Is 100 µg or the like. The above-mentioned dosage suggestions per single dose are not to be regarded as limited to the explicitly stated numerical values, but only serve as dosage examples disclosed. Of course, dosages that fluctuate around the above numerical values in a range of approximately +/- 2.5 µg are of course also included in the presently explained values. In these dosage ranges, the active ingredients 1 ' and 2 can be contained in the weight ratios described above.

Limiting example, and without limiting the scope of the invention thereto, the combinations according to the invention 1 and 2 such a quantity of tiotropium 1 'can, and NK ₁ receptor antagonist 2 contain that each single dose 5 ug 1' and 25 ug 2, 5 ug 1 ' and 50 µg 2 , 5 µg 1' and 100 µg 2 , 5 µg 1 ' and 200 µg 2 , 5 µg 1' and 300 µg 2 , 5 µg 1 ' and 400 µg 2 , 5 µg 1' and 500 µg 2 , 5 µg 1 ' and 600 µg 2 , 5 µg 1' and 700 µg 2 , 5 µg 1 ' and 800 µg 2 , 5 µg 1' and 900 µg 2 , 5 µg 1 ' and 1000 µg 2 , 10 µg 1 ' and 25 µg 2 , 10 µg 1' and 50 µg 2 , 10 µg 1 ' and 100 µg 2 , 10 µg 1' and 200 µg 2 , 10 µg 1 ' and 300 µg 2 , 10 µg 1' and 400 µg 2 , 10 µg 1 ' and 500 µg 2 , 10 µg 1' and 600 µg 2 , 10 µg 1 ' and 700 µg 2 , 10 µg 1' and 800 µg 2 , 10 µg 1 ' and 900 µg 2 , 10 µg 1' and 1000 µg 2 , 18 µg 1 ' and 25 µg 2 , 18 µg 1' and 50 µg 2 , 18 µg 1 ' and 100 µg 2 , 18 µg 1' and 200 µg 2 , 18 µg 1 ' and 300 µg 2 , 18 µg 1 ' and 400 µg 2 , 18 µg 1 ' and 500 µg 2 , 18 µg 1' and 600 µg 2 , 18 µg 1 ' and 700 µg 2 , 18 µg 1' and 800 µg 2 , 18 µg 1 ' and 900 µg 2 , 18 µg 1' and 1000 µg 2 , 20 µg 1 ' and 25 µg 2 , 20 µg 1' and 50 µg 2 , 20 µg 1 ' and 100 µg 2 , 20 µg 1' and 200 µg 2 , 20 µg 1 ' and 300 µg 2 , 20 µg 1 ' and 400 µg 2 , 20 µg 1' and 500 µg 2 ; 20 µg 1 ' and 600 µg 2 , 20 µg 1' and 700 µg 2 , 20 µg 1 ' and 800 µg 2 , 20 µg 1' and 900 µg 2 , 20 µg 1 ' and 1000 µg 2 , 36 µg 1' and 25 µg 2 , 36 µg 1 ' and 50 µg 2 , 36 µg 1' and 100 µg 2 , 36 µg 1 ' and 200 µg 2 , 36 µg 1' and 300 µg 2 , 36 µg 1 ' and 400 µg 2 , 36 µg 1 ' and 500 µg 2 , 36 µg 1' and 600 µg 2 , 36 µg 1 ' and 700 µg 2 , 36 µg 1' and 800 µg 2 , 36 µg 1 ' and 900 µg 2 , 36 µg 1' and 1000 µg 2 , 40 µg 1 ' and 25 µg 2 , 40 µg 1' and 50 µg 2 , 40 µg 1 ' and 100 µg 2 , 40 µg 9' and 200 µg 2 , 40 µg 1 ' and 300 µg 2 , 40 µg 1 ' and 400 µg 2 , 40 µg 1' and 500 µg 2 or 40 µg 1 ' and 600 µg 2 , 40 µg 1' and 700 µg 2 , 40 µg 1 ' and 800 µg 2 , 40 µg 1' and 900 µg 2 , 40 µg 1 ' and 1000 µg 2 can be applied.

If the combination of active ingredients in which 1 is tiotropium bromide is used as the combination of 1 and 2 preferred according to the invention, the active ingredient amounts of 1 ' and 2 applied per single dose correspond to the subsequent amounts of 1 and 2 applied per single dose: 6 µg 1 and 25 µg 2 , 6 µg 1 and 50 µg 2 , 6 µg 1 and 100 µg 2 , 6 µg 1 and 200 µg 2 , 6 µg 1 and 300 µg 2 , 6 µg 1 and 400 µg 2 , 6 µg 1 and 500 µg 2 , 6 µg 1 and 600 µg 2 , 6 µg 1 and 700 µg 2 , 6 µg 1 and 800 µg 2 , 6 µg 1 and 900 µg 2 , 6 µg 1 and 1000 µg 2 , 12 µg 1 and 25 µg 2 , 12 µg 1 and 50 µg 2 , 12 µg 1 and 100 µg 2 , 12 µg 1 and 200 µg 2 , 12 µg 1 and 300 µg 2 , 12 µg 1 and 400 µg 2 , 12 µg 1 and 500 µg 2 , 12 µg 1 and 600 µg 2 , 12 µg 1 and 700 µg 2 , 12 µg 1 and 800 µg 2 , 12 µg 1 and 900 µg 2 , 12 µg 1 and 1000 µg 2 , 21.7 µg 1 and 25 µg 2 , 21.7 µg 1 and 50 µg 2 , 21.7 µg 1 and 100 µg 2 , 21.7 µg 1 and 200 µg 2 , 2 1.7 µg 1 and 300 µg 2 , 21.7 µg 1 and 400 µg 2 , 21.7 µg 1 and 500 µg 2 , 21.7 µg 1 and 600 µg 2 , 21.7 µg 1 and 700 µg 2 , 21.7 µg 1 and 800 µg 2 , 21.7 µg 1 and 900 µg 2 , 21.7 µg 1 and 1000 µg 2 , 24.1 µg 1 and 25 µg 2 , 24.1 µg 1 and 50 µg 2 , 24.1 µg 1 and 100 µg 2 , 24.1 µg 1 and 200 µg 2 , 24.1 µg 1 and 300 µg 2 , 24.1 µg 1 and 400 µg 2 , 24.1 µg 1 and 500 µg 2 , 24.1 µg 1 and 600 µg 2 , 24.1 µg 1 and 700 µg 2 , 24.1 µg 1 and 800 µg 2 , 24.1 µg 1 and 900 µg 2 , 24.1 µg 1 and 1000 µg 2 , 43.3 µg 1 and 25 µg 2 , 43.3 µg 1 and 50 µg 2 , 43.3 µg 1 and 100 µg 2 , 43.3 µg 1 and 200 µg 2 , 43.3 µg 1 and 300 µg 2 , 43.3 µg 1 and 400 µg 2 , 43.3 µg 1 and 500 µg 2 , 43.3 µg 1 and 600 µg 2 , 43.3 µg 1 and 700 µg 2 , 43.3 µg 1 and 800 µg 2 , 43.3 µg 1 and 900 µg 2 , 43.3 µg 1 and 1000 µg 2 , 48.1 µg 1 and 25 µg 2 , 48.1 µg 1 and 50 µg 2 , 48.1 µg 1 and 100 µg 2 , 48.1 µg 1 and 200 µg 2 , 48.1 µg 1 and 300 µg 2 , 48.1 µg 1 and 400 µg 2 , 48.1 µg 1 and 500 µg 2 , 48.1 µg 1 and 600 µg 2 , 48.1 µg 1 and 700 µg 2 , 48.1 µg 1 and 800 µg 2 , 48.1 µg 1 and 900 µg 2 or 48.1 µg 1 and 1000 µg 2 .

If the combination of active ingredients in which 1 is tiotropium bromide monohydrate is used as the combination of 1 and 2 preferred according to the invention, the active ingredient amounts of 1 ' and 2 administered per single dose above correspond to the subsequent amounts of 1 and 2 administered per single dose: 6.2 µg 1 and 25 µg 2 , 6.2 µg 1 and 50 µg 2 , 6.2 µg 1 and 100 µg 2 , 6.2 µg 1 and 200 µg 2 , 6.2 µg 1 and 300 µg 2 , 6.2 µg 1 and 400 µg 2 , 6.2 µg 1 and 500 µg 2 , 6.2 µg 1 and 600 µg 2 , 6.2 µg 1 and 700 µg 2 , 6.2 µg 1 and 800 µg 2 , 6.2 µg 1 and 900 µg 2 , 6.2 µg 1 and 1000 µg 2 , 12.5 µg 1 and 25 µg 2 , 12.5 µg 1 and 50 µg 2 , 12.5 µg 1 and 100 µg 2 , 12.5 µg 1 and 200 µg 2 , 12.5 µg 1 and 300 µg 2 , 12.5 µg 1 and 400 µg 2 , 12.5 µg 1 and 500 µg 2 , 12.5 µg 1 and 600 µg 2 , 12.5 µg 1 and 700 µg 2 , 12.5 µg 1 and 800 µg 2 , 12.5 µg 1 and 900 µg 2 , 12.5 µg 1 and 1000 µg 2 , 22.5 µg 1 and 25 µg 2 , 22.5 µg 1 and 50 µg 2 , 22.5 µg 1 and 100 µg 2 , 22.5 µg 1 and 200 µg 2 , 22.5 µg 1 and 300 µg 2 , 22.5 µg 1 and 400 µg 2 , 22.5 µg 1 and 500 µg 2 , 22.5 µg 1 and 600 µg 2 , 22.5 µg 1 and 700 µg 2 , 22.5 µg 1 and 800 µg 2 , 22.5 µg 1 and 900 µg 2 , 22.5 µg 1 and 1000 µg 2 , 25 µg 1 and 25 µg 2 , 25 µg 1 and 50 µg 2 , 25 µg 1 and 100 µg 2 , 25 µg 1 and 200 µg 2 , 25 µg 1 and 300 µg 2 , 25 µg 1 and 400 µg 2 , 25 µg 1 and 500 µg 2 , 25 µg 1 and 600 µg 2 , 25 µg 1 and 700 µg 2 , 25 µg 1 and 800 µg 2 , 25 µg 1 and 900 µg 2 , 25 µg 1 and 1000 µg 2 , 45 µg 1 and 25 ug 2 , 45 ug 1 and 50 ug 2 , 45 ug 1 and 100 ug 2 , 45 ug 1 and 200 ug 2 , 45 ug 1 and 300 ug 2 , 45 ug 1 and 400 ug 2 , 45 ug 1 and 500 µg 2 , 45 µg 1 and 600 µg 2 , 45 µg 1 and 700 µg 2 , 45 µg 1 and 800 µg 2 , 45 µg 1 and 900 µg 2 , 45 µg 1 and 1000 µg 2 , 50 µg 1 and 25 µg 2 , 50 µg 1 and 50 µg 2 , 50 µg 1 and 100 µg 2 , 50 µg 1 and 200 µg 2 , 50 µg 1 and 300 µg 2 , 50 µ g 1 and 400 µg 2 , 50 µg 1 and 500 µg 2 , 50 µg 1 and 600 µg 2 , 50 µg 1 and 700 µg 2 , 50 µg 1 and 800 µg 2 , 50 µg 1 and 900 µg 2 or 50 µg 1 and 1000 µg 2 .

The active compound combinations according to the invention from 1 and 2 are preferably administered by inhalation. For this purpose, components 1 and 2 must be provided in inhalable dosage forms. Inhalable dosage forms include inhalable powders, metered-dose aerosols containing propellants or propellant-free inhalation solutions.

Inhalable powders according to the invention containing the combination of active substances 1 and 2 can consist solely of the active substances mentioned or of a mixture of the active substances mentioned with physiologically tolerable auxiliaries. In the context of the present invention, the term propellant-free inhalation solutions also includes concentrates or sterile, ready-to-use inhalation solutions. The dosage forms according to the invention can contain the active ingredient combination from 1 and 2 either together in one or in two separate dosage forms. These dosage forms which can be used in the context of the present invention are described in detail in the following part of the description.

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

The inhalable powders according to the invention can contain 1 and 2 either alone or as a mixture with suitable physiologically acceptable auxiliaries.

If the active ingredients 1 and 2 are contained in a mixture with physiologically acceptable excipients, the following physiologically acceptable excipients can be used to prepare these inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, Maltose), oligosaccharides and polysaccharides (e.g. dextrans), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these additives. Mono- or disaccharides are preferably used, the use of lactose or glucose being preferred, particularly but not exclusively in the form of their hydrates. Lactose, most preferably lactose monohydrate, is used as an auxiliary as particularly preferred in the sense of the invention.

In the context of the inhalable powders according to the invention, the auxiliaries have a maximum average particle size of up to 250 μm, preferably between 10 and 150 μm, particularly preferably between 15 and 80 μm. If appropriate, it may appear sensible to add finer excipient fractions with an average particle size of 1 to 9 μm to the excipients mentioned above. The latter finer excipients are also selected from the group of excipients that can be used. Finally, to produce the inhalable powders according to the invention, micronized active ingredient 1 and 2 , preferably with an average particle size of 0.5 to 10 μm, particularly preferably 1 to 6 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 be provided and applied either in the form of a single powder mixture which contains both 1 and 2 or in the form of separate inhalable powders which contain only 1 and 2 .

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

An inhaler which is particularly preferred for use of the pharmaceutical combination according to the invention in inhalettes can be seen in FIG. 1. This inhaler (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 which is provided with a sieve 5 fastened via a sieve housing 4 , one with a deck 3 connected inhalation chamber 6 , on which a pusher 8 provided with two ground needles 7 and movable against a spring 8 is provided, as well as a mouthpiece 12 which is hinged to the housing 1 , the deck 3 and a cap 11 via an axis 10 .

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

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

Inhalation aerosols containing propellant gas according to the invention can contain 1 and 2 dissolved in the propellant gas or in dispersed form. Here, 1 and 2 can be contained in separate dosage forms or in a common dosage form, where 1 and 2 can either be both dissolved, both dispersed or in each case only one component dissolved and the other dispersed. The propellant gases which can be used to produce the inhalation aerosols according to the invention are known from the prior art. Suitable propellants are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halogenated hydrocarbons such as chlorinated and / or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The above-mentioned propellant gases can be used alone or in mixtures thereof. Particularly preferred propellant gases are halogenated alkane derivatives selected from the group consisting of TG11, TG12, TG134a and TG227. Of the above-mentioned halogenated hydrocarbons, TG134a (1,1,1,2-tetrafluoroethane) and TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof are preferred according to the invention.

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

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

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

The above-mentioned inhalation aerosols containing propellant gas according to the invention can by means of inhalers known in the prior art (MDIs = metered dose inhalers) can be applied. Accordingly, another aspect relates to the present invention, pharmaceuticals in the form of as described above propellant-containing aerosols in connection with one or more  Administration of these aerosols suitable inhalers. Furthermore, the present invention inhalers, characterized in that they protrude contain described propellant-containing aerosols according to the invention. The present invention further relates to cartridges equipped with a suitable valve can be used in a suitable inhaler and the one of the above-mentioned propellant gas-containing Inhalation aerosols included. Suitable cartridges and filling processes this cartridge with the propellant-containing inhalation aerosols according to the invention are known from the prior art.

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

The active compound combination according to the invention is particularly preferably applied in the form of propellant-free inhalation solutions and inhalation suspensions. Suitable solvents for this purpose are aqueous or alcoholic, preferably ethanolic, solutions. The solvent can only be water or it is a mixture of water and ethanol. The relative proportion of ethanol to water is not limited, but the maximum limit is preferably up to 70 volume percent, in particular up to 60 volume percent and particularly preferably up to 30 volume percent. The remaining volume percentages are filled up with water. The solutions and suspensions containing 1 and 2 , separately or together, are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. Acids selected from inorganic or organic acids can be used to adjust this pH. Examples of particularly suitable inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid. Examples of particularly suitable organic acids are: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid and others. Preferred inorganic acids are hydrochloric acid, sulfuric acid. It is also possible to use the acids which already form an acid addition salt with one of the active ingredients. Ascorbic acid, fumaric acid and citric acid are preferred among the organic acids. If appropriate, mixtures of the acids mentioned can also be used, in particular in cases of acids which, in addition to their acidifying properties, also have other properties, for. B. as flavors, antioxidants or complexing agents, such as citric acid or ascorbic acid. According to the invention, hydrochloric acid is particularly preferably used to adjust the pH.

According to the invention, the addition of Editic acid (EDTA) or one of the known salts thereof, sodium edetate, as Stabilizer or complexing agent can be dispensed with. Other embodiments include this connection (s). In such a preferred embodiment, the content is based on Sodium edetate below 100 mg / 100 ml, preferably below 50 mg / ml, particularly preferably below 20 mg / ml.

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

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

Preferred co-solvents are those that contain hydroxyl groups or other polar ones Contain groups, for example alcohols - especially isopropyl alcohol, glycols - in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, Glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. In this context, everyone under auxiliary and additives understood pharmacologically acceptable substance that is not an active ingredient, however together with the active ingredient (s) in the pharmacologically suitable Solvent can be formulated to match the qualitative properties of the Improve drug formulation. These substances preferably develop none or in the Context with the desired therapy no significant or at least none undesirable pharmacological effects. Auxiliaries and additives include z. B. surfactants such. B. soy lecithin, oleic acid, sorbitan esters, such as Polysorbates, polyvinylpyrrolidone other stabilizers, complexing agents, Antioxidants and / or preservatives that affect the life of the ensure or extend finished pharmaceutical formulation, flavorings, Vitamins and / or other additives known in the art. To The additives also include pharmacologically acceptable salts such as for example sodium chloride as isotonants.

The preferred auxiliaries include antioxidants, for example Ascorbic acid, if not already used to adjust the pH, Vitamin A, Vitamin E, tocopherols and the like in the human organism occurring vitamins or provitamins.

Preservatives can be used to pre-formulate Protect contamination with germs. The are suitable as preservatives known in the art, especially cetylpyridinium chloride, Benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the  concentration known from the prior art. The above Preservatives are preferably in concentrations of up to 50 mg / 100 ml, particularly preferably between 5 and 20 mg / 100 ml.

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

For the application of the propellant-free inhalation solutions according to the invention especially those inhalers that contain a small amount of a liquid formulation of the therapeutically necessary dosage within a few seconds can nebulize aerosol that is therapeutically suitable for inhalation. As part of the In the present invention, those nebulisers are preferred in which one Amount less than 100 µL, preferably less than 50 µL, particularly preferred between 20 and 30 µL of active ingredient solution, preferably with a stroke to an aerosol with an average particle size of less than 20 microns, preferred less than 10 microns, can be atomized so that the inhalable portion of the Aerosols already correspond to the therapeutically effective amount.

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

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

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 fixed in the housing upper part, and the at one end a nozzle body with the nozzle or nozzle arrangement wearing,  
• A hollow piston with valve body,
• - An output flange in which the hollow piston is attached, and which is in Housing upper part is located,
• - a locking mechanism, which is located in the upper part of the housing,
• - A spring housing with the spring inside, on the upper part of the housing is rotatably supported by means of a pivot bearing,
• - A lower housing part, which is on the spring housing in the axial direction is attached.

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

The valve body is preferably attached to the end of the hollow piston that the Nozzle body is facing.

The nozzle in the nozzle body is preferably microstructured, that is to say manufactured by micro technology. Microstructured nozzle bodies are disclosed, for example, in WO-94/07607; reference is hereby made to this document, in particular to FIG. 1 and its description disclosed therein. The nozzle body consists, for. B. from two firmly connected plates made of glass and / or silicon, of which at least one plate has one or more microstructured channels that connect the nozzle inlet side with the nozzle outlet side. On the nozzle outlet side there is at least one round or non-round opening 2 to 10 micrometers deep and 5 to 15 micrometers wide, the depth preferably being 4.5 to 6.5 micrometers and the length being 7 to 9 micrometers.

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

Accordingly, the beam directions meet 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 over the Atomized nozzle openings in an inhalable aerosol. The preferred particle or droplet sizes of the aerosol are up to 20 micrometers, preferably 3 up to 10 micrometers.

The locking mechanism contains a spring, preferably a cylindrical one helical compression spring, as storage for the mechanical energy. The feather acts on the output flange as a jump piece, its movement through the position a locking member is determined. The path of the output flange is indicated by a upper and a lower stop precisely limited. The spring is preferred over a power transmission gear, e.g. B. a screw-type gearbox, by an external Torque excited when turning the upper housing part against the Spring housing is generated in the lower part of the housing. In this case, include that Upper part of the housing and the output flange of a single or multi-speed wedge gear.

The locking member with engaging locking surfaces is ring-shaped around the output flange arranged. There is e.g. B. from a radially elastically deformable ring made of plastic or metal. The ring is perpendicular to the plane Atomizer axis arranged. After tensioning the spring, they slide Locking surfaces of the locking member in the way of the output flange and prevent relaxing the spring. The locking element is triggered by a button. The Trigger button is connected or coupled to the locking member. To trigger the Locking mechanism, the release button parallel to the ring plane is preferred into the atomizer, shifted; the deformable ring in the Ring plane deformed. Design details of the locking mechanism are in the WO 97/20590.  

The lower part of the housing is pushed over the spring housing in the axial direction and covers the storage, the drive of the spindle and the storage container for the Fluid.

When the atomizer is actuated, the upper housing part is against the Lower housing part rotated, the lower housing part taking the spring housing with it. The spring is compressed via the screw-type thrust gear excited, and the barrier engages automatically. The angle of rotation is preferably a integer fraction of 360 degrees, e.g. B. 180 degrees. Simultaneously with tensioning the spring becomes the driven part in the upper part of the housing by a predetermined path moved, the hollow piston is inside the cylinder in the pump housing withdrawn, causing a subset of the fluid from the reservoir into the High pressure space is sucked in before the nozzle.

If necessary, several can be added to the atomizer one after the other interchangeable reservoir containing atomizing fluid inserted and to be used. The storage container contains the aqueous one according to the invention Aerosol formulation.

The atomization process is done by gently pressing the trigger 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 exits the atomizer nozzle in atomized form.

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

The components of the atomizer (nebulizer) are of one function according to suitable material. The housing of the atomizer and - as far as it is the function allows - other parts are preferably made of plastic, e.g. B. in Injection molding process. For medical purposes, be physiological harmless materials used.

In this patent application accompanying Fig. 2a / b, are the same as the Fig. 6a / b of WO 97/12687, show the nebuliser (Respimat®) is described with which the aqueous aerosol preparations according to the invention can advantageously be inhaled.

Fig. 2a shows a longitudinal section through the atomiser with the spring biased while FIG. 2b shows a longitudinal section through the atomiser with the spring relaxed.

The upper housing part ( 51 ) contains the pump housing ( 52 ), at the end of which the holder ( 53 ) for the atomizing nozzle is attached. The nozzle body ( 54 ) and a filter ( 55 ) are located in the holder. The hollow piston ( 57 ) fastened in the output flange ( 56 ) of the locking tensioning mechanism partially protrudes into the cylinder of the pump housing. The hollow piston carries the valve body ( 58 ) at its end. The hollow piston is sealed by means of the seal ( 59 ). Inside the upper part of the housing is the stop ( 60 ), against which the output flange rests when the spring is relaxed. The stop ( 61 ) is located on the output flange, against which the output flange rests when the spring is tensioned. After tensioning the spring, the locking member ( 62 ) slides between the stop ( 61 ) and a support ( 63 ) in the upper part of the housing. The release button ( 64 ) is connected to the locking member. The upper part of the housing ends in the mouthpiece ( 65 ) and is closed with the clip-on protective cap ( 66 ).

The spring housing ( 67 ) with compression spring ( 68 ) is rotatably mounted on the upper part of the housing by means of the snap lugs ( 69 ) and rotary bearings. The lower housing part ( 70 ) is pushed over the spring housing. The replaceable reservoir ( 71 ) for the fluid ( 72 ) to be atomized is located within the spring housing. The storage container is closed with the stopper ( 73 ) through which the hollow piston protrudes into the storage container and with its end is immersed in the fluid (supply of active substance solution).

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

The nebulizer described above is suitable, the invention Nebulize aerosol preparations into an aerosol suitable for inhalation.

If the formulation according to the invention by means of the above Technology (Respimat®), the applied mass should be at least 97%, preferably at least 98% of all actuations of the inhaler (hub) of a defined one Quantity with a tolerance range of at most 25%, preferably 20% of this quantity correspond. Between 5 and 30 mg of formulation as are preferred per stroke Defined mass applied, particularly preferably between 5 and 20 mg.  

However, the formulation according to the invention can also be used by means other than that Inhalers described above, for example jet stream inhalers, be nebulized.

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

The propellant-free inhalation solutions or suspensions according to the invention can be used in addition to the above, intended for application in the Respimat Solutions and suspensions also as concentrates or sterile ready-to-use Inhalation solutions or suspensions are available. Let out of the concentrates for example by adding isotonic saline solutions Generate ready-to-use formulations. Sterile ready to use Formulations can be made using energy-powered stand or portable Nebulizers that inhale aerosols using ultrasound or compressed air after the Generate the Venturi principle or other principles.

Accordingly, another aspect of the present invention relates Medicines in the form of propellant-free as described above Inhalable solutions or suspensions, as concentrates or sterile ready-to-use formulations are available in conjunction with a Administration of these solutions suitable device, characterized in that this device is an energy-operated stand or portable nebulizer, the inhalable aerosols using ultrasound or Compressed air generated according to the Venturi principle or other principles.

The following examples serve to further explain the present Invention, but without the scope of the invention to the following to limit exemplary embodiments.  

raw materials tiotropium

The tiotropium bromide used in the formulation examples below can be as described in European patent application EP 418 716 A1, be preserved.

Crystalline can also be used to produce the inhalable powders according to the invention Tiotropium bromide monohydrate can be used. This crystalline Tiotropium bromide monohydrate is as described below Procedure available.

In a suitable reaction vessel, 15.0 kg of tiotropium bromide are introduced into 25.7 kg of water. The mixture is heated to 80-90 ° C and stirred at a constant temperature until a clear solution is formed. Activated carbon (0.8 kg), moist with water, is slurried in 4.4 kg of water, this mixture is added to the solution containing tiotropium bromide and rinsed with 4.3 kg of water. The mixture thus obtained is stirred at 80-90 ° C. for at least 15 minutes and then filtered through a heated filter into an apparatus preheated to a jacket temperature of 70 ° C. The filter is rinsed with 8.6 kg of water. The contents of the apparatus are cooled to 3-5 ° C per 20 minutes to a temperature of 20-25 ° C. With cold water cooling, the apparatus is cooled further to 10-15 ° C and the crystallization is completed by stirring for at least one hour. The crystals are isolated using a suction filter, the isolated crystal slurry is washed with 9 L of cold water (10-15 ° C) and cold acetone (10-15 ° C). The crystals obtained are dried at 25 ° C. for 2 hours in a stream of nitrogen.
Yield: 13.4 kg of tiotropium bromide monohydrate (86% of theory).

The crystalline tiotropium bromide monohydrate obtained in this way is known Process micronized to the active ingredient in the form of the average particle size to provide, which corresponds to the specifications of the invention.  

formulation Examples

A) Inhalation powder

Inhalation aerosols containing propellant gas

1) Suspension aerosol

2) Suspension aerosol

3) Suspension aerosol

4) Suspension aerosol

Claims (36)

1. Medicament characterized by a content of one or more anticholinergics ( 1 ) in combination with one or more NK ₁ receptor antagonists ( 2 ), optionally in the form of their enantiomers, mixtures of the enantiomers or in the form of the racemates, optionally in the form of Solvates or hydrates and optionally together with a pharmaceutically acceptable auxiliary. 2. Medicament according to claim 1, characterized in that the active ingredients 1 and 2 are either contained together in a single dosage form or in two separate dosage forms. 3. Medicament according to one of claims 1 or 2, characterized in that 1 is selected from the group consisting of tiotopium salts, oxitropium salts or ipratropium salts, preferably tiotropium salts. 4. Medicament according to one of claims 1 to 3, characterized in that 1 is contained in the form of the chloride, bromide, iodide, methanesulfonate, para-toluenesulfonate or methyl sulfate, preferably in the form of the bromide. 5. Medicament according to one of claims 1 to 4, characterized in that 2 is selected from the group consisting of BIIF 1149, FK-888, NKP 608C, NKP 608A, CGP 60829, SR 48968 (Saredutant), SR 140333 (Nolpitantium besilate / chloride), LY 303870 (Lanepitant), MEN-11420 (Nepadutant), SB 223412, MDL-105172A, MDL-103896, MEN-11149, MEN- 11467, DNK 333A, SR-144190, YM-49244, YM-44778 , ZM-274773, MEN-10930, S-19752, Neuronorm, YM-35375, DA-5018, MK-869, L-754030, CJ-11974, L-758298, DNK-33A, 6b-I, CJ-11974 , TAK-637, GR 205171 and the arylglycinamide derivatives of the general formula 3
wherein
R ¹ and R ² together with the N to which they are attached form a ring of the formula
form where r and s are 2 or 3;
R ⁶ H, -C ₁ -C ₅ alkyl, C ₃ -C ₅ alkenyl, propynyl, hydroxy (C ₂ -C ₄ ) alkyl, methoxy (C ₂ -C ₄ ) alkyl, di (C ₁ -C ₃ ) alkylamino (C ₂ -C ₄ ) alkyl, amino (C ₂ -C ₄ ) alkyl, amino, di (C ₁ -C ₃ ) alkylamino, monofluoro to perfluoro (C ₁ -C ₂ ) alkyl, N-methylpiperidinyl Represents pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl,
R ^{7 has} one of the meanings (a) to (d),

• a) Hydroxy
• b) 4-piperidinopiperidyl,
  wherein R ¹⁶ and R ¹⁷ independently of one another are H, (C ₁ -C ₄ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, hydroxy (C ₂ -C ₄ ) alkyl, dihydroxy (C ₂ -C ₄ ) alkyl, (C ₁ -C ₃ ) alkoxy (C ₂ -C ₄ ) alkyl, phenyl (C ₁ -C ₄ ) alkyl or di (C ₁ -C ₃ ) alkylamino (C ₂ - C ₄ ) alkyl,

R ⁸ H means
optionally in the form of their enantiomers and mixtures of the enantiomers, optionally in the form of their racemates. 6. Medicament according to one of claims 1 to 5, characterized in that 2 is selected from the group consisting of BIIF 1149, CGP 60829, MK-869, CJ-11974, GR 205171 and the arylglycinamide derivatives of the general formula 3 , wherein
R ¹ and R ² together with the N to which they are attached form a ring of the formula
form where s is 2 or 3;
R ⁷ for a group
wherein R ¹⁶ and R ¹⁷ independently of one another are H, (C ₁ -C ₄ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, hydroxy (C ₂ -C ₄ ) alkyl, dihydroxy (C ₂ -C ₄ ) alkyl, (C ₁ -C3) alkoxy (C ₂ -C ₄ ) alkyl, phenyl (C ₁ -C ₄ ) alkyl or di (C ₁ -C ₃ ) alkylamino (C ₂ - C ₄ ) alkyl,
R ⁸ H means
optionally in the form of their enantiomers and mixtures of the enantiomers, and optionally in the form of their racemates. 7. Medicament according to one of claims 1 to 6, characterized in that the weight ratios of 1 to 2 are in a range from 1: 300 to 50: 1, preferably from 1: 250 to 40: 1. 8. Medicament according to one of claims 1 to 7, characterized in that a single application corresponds to a dosage of the active ingredient combination 1 and 2 from 0.01 to 10000 µg, preferably from 0.1 to 2000 µg. 9. Medicament according to one of claims 1 to 8, characterized in that that it is in the form of a dosage form suitable for inhalation. 10. Medicament according to claim 9, characterized in that it is a Dosage form selected from the group inhalation powder, metered aerosols containing propellant gas and inhalation solutions free of propellant gas or -suspensions. 11. Medicament according to claim 10, characterized in that it is an inhalation powder which 1 and 2 in admixture with suitable physiologically acceptable auxiliaries selected from the group consisting of monosaccharides, disaccharides, oligo- and polysaccharides, polyalcohols, salts, or mixtures of these auxiliaries contains with each other. 12. inhalation powder according to claim 11, characterized in that the Excipient a maximum average particle size of up to 250 microns, preferably has between 10 and 150 microns. 13. Capsules characterized by a content of inhalation powder after Claim 11 or 12. 14. Medicament according to claim 10, characterized in that it is an inhalation powder which contains only active ingredients 1 and 2 as components. 15. Medicament according to claim 10, characterized in that it is a propellant-containing inhalation aerosol which contains 1 and 2 in dissolved or dispersed form. 16. propellant inhalation aerosol according to claim 15, characterized characterized in that it contains hydrocarbons such as n-propane, n- Butane or isobutane or halogenated hydrocarbons such as chlorinated and / or fluorinated derivatives of methane, ethane, propane, butane, Contains cyclopropane or cyclobutane. 17. propellant gas inhalation aerosol according to claim 16, characterized characterized in that the propellant gas TG11, TG12, TG134a, TG227 or Mixtures thereof, preferably TG134a, TG227 or a mixture thereof represents.   18. propellant gas inhalation aerosol according to claim 15, 16 or 17, characterized characterized in that there may be one or more others Components selected from the group consisting of cosolvents, Stabilizers, surfactants, antioxidants, Contains lubricants and means for adjusting the pH. 19. propellant gas inhalation aerosol according to one of claims 15 to 18, characterized in that it can contain up to 5% by weight of active ingredient 1 and / or 2 . 20. Medicament according to claim 10, characterized in that it is a propellant-free inhalation solution or suspension that acts as Solvent water, ethanol or a mixture of water and ethanol contains. 21. inhalation solution or suspension according to claim 20, characterized characterized in that the pH is 2-7, preferably 2-5. 22. inhalation solution or suspension according to claim 21, characterized characterized in that the pH is selected from the group by means of an acid consisting of hydrochloric acid, hydrobromic acid, nitric acid, Sulfuric acid, ascorbic acid, citric acid, malic acid, tartaric acid, Maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and Propionic acid or mixtures thereof. 23. inhalation solution or suspension according to one of claims 20 to 22, characterized in that they optionally further co-solvents and / or contains auxiliaries. 24. inhalation solution or suspension according to claim 23, characterized characterized in that it contains components as co-solvents 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.   25. inhalation solution or suspension according to one of claims 23 or 24, characterized in that they are surface-active substances as auxiliaries Stabilizers, complexing agents, antioxidants and / or Preservatives, flavors, pharmacologically harmless Contains salts and / or vitamins. 26. inhalation solution or suspension according to claim 25, characterized characterized in that they actedic acid as a complexing agent or a salt of Editic acid, preferably sodium edetate, contains. 27. inhalation solution or suspension according to claim 25 or 26, characterized marked that they are selected as antioxidants, compounds the group consisting of ascorbic acid, vitamin A, vitamin E and Contains tocopherols. 28. inhalation solution or suspension according to claim 25, 26 or 27, characterized characterized in that they selected compounds as preservatives from cetylpyridinium chloride, benzalkonium chloride, benzoic acid and Contains benzoates. 29. inhalation solution or suspension according to any one of claims 23 to 28, characterized in that it contains besides the active ingredients 1 and 2 and the solvent only bezalkonium chloride and sodium edetate. 30. inhalation solution or suspension according to any one of claims 23 to 28, characterized in that it contains only benzalkonium chloride in addition to the active ingredients 1 and 2 and the solvent. 31. inhalation solution or suspension according to any one of claims 20 to 30, characterized in that it is a concentrate or a sterile ready-to-use inhalation solution or suspension. 32. Use of a capsule according to claim 13 in an inhaler, preferred in the handihaler. 33. Use of an inhalation solution according to one of claims 20 to 30 for nebulization in an inhaler according to WO 91/14468 or an inhaler as described in FIGS . 6a and 6b of WO 97/12687. 34. Use of an inhalation solution according to claim 31 for nebulization in an energy-operated standing or portable nebulizer that inhalable aerosols using ultrasound or compressed air after Venturi principle or other principles generated. 35. Use of a composition according to any one of claims 1 to 31 for the manufacture of a medicament for the treatment of inflammatory or obstructive respiratory diseases respiratory diseases.