JP2007500149A - Drug comprising PDEIV inhibitor and anticholinergic agent for treating respiratory diseases - Google Patents

Abstract

  The present invention relates to a novel pharmaceutical composition based on a salt of a PDE IV inhibitor and an anticholinergic agent, its preparation and use for the treatment of respiratory diseases.

Description

Detailed Description of the Invention

The present invention relates to a novel pharmaceutical composition based on a salt of a PDE IV inhibitor and an anticholinergic agent, its preparation and use for treating respiratory diseases.
DESCRIPTION OF THE INVENTION The present invention relates to a novel pharmaceutical composition based on a PDE IV inhibitor and an anticholinergic salt of formula 1 , its preparation and use for treating respiratory diseases.
The anticholinergic agent used within the scope of the present invention is represented by the following formula 1

(Wherein, X ^- anion with a single negative charge, preferably fluorine anion, chlorine anion, bromine anion, iodine anion, sulfate anion, phosphate anion, methanesulfonic acid, nitrate, maleate anions, acetate Anion selected from the group consisting of an anion, a citrate anion, a fumarate anion, a tartrate anion, an oxalate anion, a succinate anion, a benzoate anion and a p-toluenesulfonate anion.)
Optionally racemates, enantiomers, salts in the form of their hydrates.
Preferably, the salt of formula 1 wherein X ⁻ is a fluorine anion, a chlorine anion, a bromine anion, a 4-toluenesulfonate anion and a methanesulfonate anion, preferably an anion having one negative charge selected from a bromine anion. Optionally used in the form of racemates, enantiomers, hydrates thereof.
Most preferably, the salt of formula 1 wherein X ^- is a negative anion selected from the chlorine anion, bromine anion and methanesulfonate anion, preferably a bromine anion, optionally a racemate, enantiomer, Used in the form of hydrates.
Particularly preferred according to the invention are salts of the formula 1 in which X ^- is a bromine anion.
Formula 1-en

(In the formula, X ⁻ has the above-mentioned meaning.)
The enantiomers having are particularly interesting according to the invention.
Surprisingly, when the anticholinergic agent of formula 1 is used with PDE IV inhibitor 2 , it may show unexpected beneficial therapeutic effects in the treatment of respiratory inflammatory and / or obstructive diseases. it can.
This effect is observed when the two active substances are administered simultaneously in a single active substance formulation or when they are administered sequentially in separate formulations. According to the present invention, it is preferred to administer the two active substance components simultaneously in a single formulation.
In the aforementioned pharmaceutical combination, the active substance may be combined in a single preparation or contained in two separate preparations. Pharmaceutical compositions containing active substances 1 and 2 in a single formulation are preferred according to the invention.
According to the present invention, preferred PDE IV inhibitor 2 in the combination of the present invention is enprofylline, theophylline, roflumilast, ariflo (silomilast), CP-325,366, BY343, D-4396 (Sch-351591), AWD-12 -281 (GW-842470), N- (3,5-dichloro-1-oxopyridin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide, NCS-613, pumafentin, (-) p- [(4aR ^* , 10bS ^* )-9-ethoxy-1,2,3,4,4a, 10b-hexahydro-8-methoxy-2methylbenzo [s] [1,6] naphthyridin-6-yl] -N, N-diisopropylbenzamide, ((R)-(+)-1- (4-bromobenzyl))-4-[(3-cyclopentyloxy) -4-methoxyphenyl] -2-pyrrolidone, 3- (cyclopentyloxy- 4-methoxyphenyl) -1- (4-N '-[N-2-cyano-S-methylisothioureido] benzyl) -2-pyrrolidone, cis [4-cyano-4- (3-cyclopentyloxy-4 -Methoxyphenyl) Rohexane-1-carboxylic acid], 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexane-1-one, cis [4-cyano-4- (3-cyclo Propylmethoxy-4-difluoromethoxyphenyl) cyclohexane-1-ol], (R)-(+)-ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidin-2-ylidene] acetate, (S) -(-)-Ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidine-2-ylidene] acetate, CDP840, Bay-198004, D-4418, PD-168787, T-440, T-2585, Allophylline, Atizolam, V-11294A, Cl-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370, 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (2 -Thienyl) -9H-pyrazolo [3,4 c] -1,2,4-triazolo [4,3-a] pyridine and 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (tert- Butyl) -9H-pyrazolo [3,4 c] -1,2,4 Selected from the group consisting of -triazolo [4,3-a] pyridine, optionally in the form of a racemate, enantiomer, diastereomer, or optionally a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof. It is.
In a preferred embodiment of the invention, PDE IV inhibitor 2 is enprofylline, roflumilast, ariflo (silomilast), AWD-12-281 (GW-842470), N- (3,5-dichloro-1-oxopyridine. -4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide, T-440, T-2585, allophylline, cis [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1 -Carboxylic acid], 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexane-1-one, cis [4-cyano-4- (3-cyclopropylmethoxy- 4-Difluoromethoxyphenyl) cyclohexane-1-ol], PD-168787, Atizolam, V-11294A, Cl-1018, CDC-801, D-22888, YM-58997, Z-15370, 9-cyclopentyl-5,6 -Dihydro-7-ethyl-3- (2-thienyl) -9H-pyrazolo [3,4 c] -1,2,4-triazolo [4,3-a] pyri And 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (tert-butyl) -9H-pyrazolo [3,4 c] -1,2,4-triazolo [4,3-a] pyridine Is optionally selected in the form of racemates, enantiomers, diastereomers or optionally pharmaceutically acceptable acid addition salts or hydrates thereof.

In another preferred embodiment of the present invention, PDE IV inhibitor 2 is roflumilast, ariflo (silomilast), AWD-12-281 (GW-842470), allophylline, Z-15370, 2-carbomethoxy-4-cyano. -4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexane-1-one, cis [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexane-1-ol], Atizolam, 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (2-thienyl) -9H-pyrazolo [3,4 c] -1,2,4-triazolo [4,3-a)] pyridine , And 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (tert-butyl) -9H-pyrazolo [3,4 c] -1,2,4-triazolo [4,3-a] pyridine As the compound 2 of the present invention, roflumilast, Z-15370, and AWD-12-281 are particularly preferable.
In yet another preferred embodiment of the invention, PDE IV inhibitor 2 is 2- (4-fluorophenoxy) -N- {4-[(6-fluoro-2-hydroxybenzoylamino) methyl] benzyl} nicotine. Amido, 2- (4-fluorophenoxy) -N- {4-[(5-fluoro-2-hydroxybenzoylamino) methyl] benzyl} nicotinamide, 2- (4-fluorophenoxy) -N- {4- [ (3-Hydroxy-4-methylbenzoylamino) methyl] benzyl} nicotinamide, 2- (4-fluorophenoxy) -N- {4-[(3hydroxybenzoylamino) methyl] benzyl} nicotinamide, 2- (4 -Fluorophenoxy) -N- {4-[(2-hydroxybenzoylamino) methyl] benzyl} nicotinamide, 2- (4-fluorophenoxy))-N- {4-[(4-hydroxybenzoylamino) methyl] Benzyl} nicotinamide, 2- (4-fluorophenoxy) -N- {4-[(2-hydroxy-4-methylbenzoyla N) methyl] benzyl} nicotinamide, 2- (4-fluorophenoxy) -N- {4-[(3-hydroxy-2-methylbenzoylamino) methyl] benzyl} nicotinamide, 2- (4-fluorophenoxy) -N- {4-[(2-hydroxy-5-methylbenzoylamino) methyl] benzyl} nicotinamide, 5-fluoro-2- (4-fluorophenoxy) -N- {4-[(2-hydroxybenzoylamino ) Methyl] benzyl} nicotinamide, 5-fluoro-2- (4-fluorophenoxy) -N- {4-[(2-hydroxyacetylamino) methyl] benzyl} nicotinamide, 5-fluoro-2- (4- Fluorophenoxy) -N- {4-[(4-hydroxybenzoylamino) methyl] benzyl} nicotinamide, 3- (3- {4-[(3-hydroxybenzoylamino) methyl] benzylcarbamoyl} pyridin-2-yloxy ) Benzoic acid ethyl ester, 3- (3- {4-[(2-hydroxyphenacetylamino) methyl] ben Rucarbamoyl} pyridin-2-yloxy) benzoic acid ethyl ester, 3- (3- {4-[(3-hydroxyphenacetylamino) methyl] benzylcarbamoyl} pyridin-2-yloxy) benzoic acid ethyl ester, 3- (3 -{4-[(4-hydroxyphenacetylamino) methyl] benzylcarbamoyl} pyridin-2-yloxy) benzoic acid ethyl ester, compound (2.a) and compound (2.b) represented by the following formulae

Are optionally selected in the form of racemates, enantiomers, diastereomers, or optionally pharmaceutically acceptable acid addition salts or hydrates thereof.
The pharmaceutically acceptable salt forms of the combinations of the compounds of the invention are in most cases prepared by conventional means. When the component compound has a carboxylic acid group, an appropriate salt can be formed by reacting the compound with an appropriate base to obtain the corresponding base addition salt. Examples of such bases include alkali metal hydroxides including potassium hydroxide, sodium hydroxide, lithium hydroxide; alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; alkali metal alkoxides such as , Potassium ethanolate, sodium propanolate; various organic bases such as piperidine, diethanolamine, N-methylglutamine. Aluminum salts of the component compounds of the present invention are also included.
In the case of certain component compounds, acid addition salts such as hydrohalides such as hydrochloride, hydrobromide, hydroiodide by treating the compound with a pharmaceutically acceptable organic or inorganic acid Other mineral acids such as sulfates, nitrates, phosphates and their corresponding salts; alkyl- and mono-arylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate; acetic acid Other organic acids such as salts, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate and their corresponding salts can be formed.
Accordingly, pharmaceutically acceptable acid addition salts of the component compounds of the present invention include acetate, adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate). ), Bisulfate, bisulfite, bromide, butyrate, camphorsulfonate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate , Dihydrogen phosphate, dinitrobenzoate, dodecyl sulfonate, ethane sulfonate, fumarate, galactarate (from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamic acid Salt, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hypurate, hydrochloride, hydrobromide, hydroiodic acid Salt, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfone Acid salt, methylbenzoate, hydrogen monophosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectate, persulfate, phenylacetate, Examples include, but are not limited to, 3-phenylpropionate, phosphate, phosphonate, and phthalate.

Particularly preferred examples of the pharmacologically acceptable acid addition salt of Compound 2 of the present invention are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid. And a pharmaceutically acceptable salt selected from salts of tartaric acid, 1-hydroxy-2-naphthalenecarboxylic acid or maleic acid. If desired, a mixture of the above acids can also be used to prepare salt 2 .
In the pharmaceutical compositions of the invention, compound 2 can exist in the form of their racemates, enantiomers or mixtures thereof. Separation of enantiomers from racemates can be performed using methods known in the art (eg, by chromatography on chiral phases, etc.).
In one aspect, the invention relates to a pharmaceutical composition as described above, which contains, in addition to a therapeutically effective amount of 1 and 2 , a pharmaceutically acceptable carrier. In another aspect, the invention relates to a pharmaceutical composition as described above, which does not contain any pharmaceutically acceptable carrier in addition to the therapeutically effective amount of 1 and 2 . The present invention also relates to the use of a therapeutically effective amount of salt 1 to prepare a pharmaceutical composition containing PDE IV inhibitor 2 for treating inflammatory or obstructive diseases of the respiratory tract. Preferably, the present invention relates to the use as described above for preparing a pharmaceutical composition for treating asthma or COPD.
Within the scope of the present invention, compounds 1 and 2 can be administered simultaneously or sequentially, and it is preferred according to the invention that compounds 1 and 2 are administered simultaneously.
The invention further relates to the use of a therapeutically effective amount of salt 1 and PDEIV inhibitor 2 to treat inflammatory or obstructive respiratory diseases, in particular asthma or COPD.
The ratio that active substances 1 and 2 can be used in the active substance combination of the present invention is variable. Active substances 1 and 2 can possibly exist in the form of their solvates or hydrates. Depending on the choice of compounds 1 and 2, the mass ratios that can be used within the scope of the invention will vary based on the different molecular weights of the various salt forms.
In general, the pharmaceutical combination according to the invention can contain compounds 1 and 2 in a mass ratio in the range of 1: 100 to 100: 1, preferably 1:80 to 80: 1. One ariflo of the most preferred compounds as component 2, roflumilast, or, in particularly preferred pharmaceutical combination containing a AWD-12-281, 1 and 2 weight ratio, 1 and 2 1: 50 to 50: 1, More preferably, it is most preferably in the range of 1:30 to 30: 1.
For example, without limiting the scope of the present invention, a preferred combination of 1 and PDE-IV inhibitor 2 (e.g., as Ariflo, Roflumilast or AWD-12-281) has the following mass ratio: 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; 21: 1; 22: 1; 23: 1; 24: 1; 25: 1; 26: 1; 27: 1; 28: 1; 29: 1; 30: 1.

1 with a pharmaceutical composition of the invention comprising a second combination agent is usually 1 and 2 single dose per 0.1～10000Myug, preferably 1～5000Myug, more preferably 10～3000Myug, even more preferably 100 to Administered to be present together at a dose of 2000 μg. For example, the combination of 1 and 2 of the present invention comprises 1 and PDE-IV inhibitor 2 (for example, as Ariflo, Roflumilast or AWD-12-281) in a single dose with a total dosage of 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 360μg, 365μg, 370μg, 375μg, 380μg, 385μg, 390μg, 395μg, 400μg, 405μg, 410μg, 415μg, 420μg, 425μg, 430μg, 435μg, 440μg, 445μg, 450μg, 455μg, 460μg, 465μg, 470μg, 475μg, 480μg 485μg, 490μg, 495μg, 500μg, 505μg, 510μg, 515μg, 520μg, 525μg, 530μg, 535μg, 540μg, 545μg, 550 g, 555μg, 560μg, 565μg, 570μg, 575μg, 580μg, 585μg, 590μg, 595μg, 600μg, 605μg, 610μg, 615μg, 620μg, 625μg, 630μg, 635μg, 640μg, 645μg, 650μg, 655μg, 660μg, 665μg, 670μg 675μg, 680μg, 685μg, 690μg, 695μg, 700μg, 705μg, 710μg, 715μg, 720μg, 725μg, 730μg, 735μg, 740μg, 745μg, 750μg, 755μg, 760μg, 765μg, 770μg, 775μg, 780μg, 795μg, 790μg 800μg, 805μg, 810μg, 815μg, 820μg, 825μg, 830μg, 835μg, 840μg, 845μg, 850μg, 855μg, 860μg, 865μg, 870μg, 875μg, 880μg, 885μg, 890μg, 895μg, 900μg, 905μg, 910μg, 915μg, 920μg, 915μg 925μg, 930μg, 935μg, 940μg, 945μg, 950μg, 955μg, 960μg, 965μg, 970μg, 975μg, 980μg, 985μg, 990μg, 995μg, 1000μg, 1005μg, 1010μg, 1015μg, 1025μg, μ25, 1030μg, 35g 1050μg, 1055μg, 1060μg, 1065μg, 1070μg, 1075μg,

1080μg, 1085μg, 1090μg, 1095μg, 1100μg, 1105μg, 1110μg, 1115μg, 1120μg, 1125μg, 1130μg, 1135μg, 1140μg, 1145μg, 1150μg, 1155μg, 1160μg, 1165μg, 1170μg, 1175μg, 1170μg, 1175μg, 1170μg, 1175μg 1205μg, 1210μg, 1215μg, 1220μg, 1225μg, 1230μg, 1235μg, 1240μg, 1245μg, 1250μg, 1255μg, 1260μg, 1265μg, 1270μg, 1275μg, 1280μg, 1285μg, 1290μg, 1395μg, 1330g, 1395μg, 1330g 1330μg, 1335μg, 1340μg, 1345μg, 1350μg, 1355μg, 1360μg, 1365μg, 1370μg, 1375μg, 1380μg, 1385μg, 1390μg, 1395μg, 1400μg, 1405μg, 1410μg, 1415μg, 1420μg, 445 1455μg, 1460μg, 1465μg, 1470μg, 1475μg, 1480μg, 1485μg, 1490μg, 1495μg, 1500μg, 1505μg, 1510μg, 1515μg, 1520μg, 1525μg, 1530μg, 1535μg, 1545μg, 1545μg, 1545μg 1580μg, 1585μg, 1590μg, 1595μg, 1600μg, 1605μg, 1610μg, 1615μg, 1620μg, 1625μg, 1630μg, 1635μg, 1640μg, 1645μg, 1650μg, 1655μg, 1660μg, 1695μg, 1670μg, 1675μg 1705μg, 1710μg, 1715μg, 1720μg, 1725μg, 1730μg, 1735μg, 1740μg, 1745μg, 1750μg, 1755μg, 1760μg, 1765μg, 1770μg, 1775μg, 1780μg, 1785μg, 1790μg, 1595μg, 1895μg, 1795μg 1830μg, 1835μg, 1840μg, 1845μg, 1850μg, 1855μg, 1860μg, 1865μg, 1870μg, 1875μg, 1880μg, 1885μg, 1890μg, 1895μg, 1900μg, 1905μg, 1910μg, 1945μg, 1920μg, 1945μg, 1945μg 1955μg, 1960μg, 1965μg, 1970μg, 1975μg, 1980μg, 1985μg, 1990μg, 1995μg, 2000μg, 2005μg, 2010μg, 2015μg, 2020μg, 2025μg, 2030μg, 2035μg, 2040μg, 2045μg, 2050μg, 2055μg, 2055μg, 2055μg, 2055μg, 2055μg, 2055μg, 2080μg, 2085μg, 2090μg, 2095μg, 2100μg, 2105μg, 2110μg, 2115μg, 2120μg, 2125μg, 2130μg, 2135μg, 2140μg, 2145μg, 2150μg, 2155μg, 2160μg, 2165μg, 2170μg, 2175μg, 2170μg, 2175μg, 2170μg, 2175μg 2205μg, 2210μg, 2215μg, 2220μg, 2225μg, 2230μg, 2235μg, 2240μg, 2245μg,

2250μg, 2255μg, 2260μg, 2265μg, 2270μg, 2275μg, 2280μg, 2285μg, 2290μg, 2295μg, 2300μg, 2305μg, 2310μg, 2315μg, 2320μg, 2325μg, 2330μg, 2335μg, 2340μg, 2345μg, 2340μg, 2345μg 2375μg, 2380μg, 2385μg, 2390μg, 2395μg, 2400μg, 2405μg, 2410μg, 2415μg, 2420μg, 2425μg, 2430μg, 2435μg, 2440μg, 2445μg, 2450μg, 2455μg, 2460μg, 2465μg, 2470μg, 2465μg, 2465μg 2500μg, 2505μg, 2510μg, 2515μg, 2520μg, 2525μg, 2530μg, 2535μg, 2540μg, 2545μg, 2550μg, 2555μg, 2560μg, 2565μg, 2570μg, 2575μg, 2580μg, 2585μg, 2590μg, 2595g, 2590μg, 2595g 2625μg, 2630μg, 2635μg, 2640μg, 2645μg, 2650μg, 2655μg, 2660μg, 2665μg, 2670μg, 2675μg, 2680μg, 2685μg, 2690μg, 2695μg, 2700μg, 2705μg, 2710μg, 2715μg, 2720μg, 2715μg 2750μg, 2755μg, 2760μg, 2765μg, 2770μg, 2775μg, 2780μg, 2785μg, 2790μg, 2795μg, 2800μg, 2805μg, 2810μg, 2815μg, 2820μg, 2825μg, 2830μg, 2835μg, 2845μg, 2845μg, 2845μg, 2845μg 2870μg, 2885μg, 2880μg, 2895μg, 2890μg, 2905μg, 2900μg, 2915μg, 2910μg, 2925μg, 2920μg, 2935μg, 2930μg, 2945μg, 2940μg, 2955μg, 2950μg, 2965μg, 2960μg, 2975μg, 2960μg, 2960μg, 2960μg It is contained so as to be 3000 μg or the like. These doses given for the single doses specified above should not be construed to be limited to the numerical values explicitly mentioned, but are meant solely as doses disclosed as examples. It will be appreciated that doses that can vary around the above values in the range of about +/- 25 μg are also encompassed by the values given as an example. In these dose ranges, active substances 1 and 2 can be present in the mass ratios indicated above.

For example, without limiting the scope of the invention thereto, the combination of 1 and 2 of the present invention is 1 (for example when bromide is used as the preferred combination partner) and PDE-IV inhibitor 2 (for example, Aliflo, (As roflumilast or AWD-12-281) can be included in amounts such that the following amounts of active substance are administered per dose: 40 μg 1 and 25 μg 2 , 40 μg 1 and 50 μg 2, 2 1 and 100μg of 40 [mu] g, 2 1 and 200μg of 40 [mu] g, 2 1 and 300μg of 40 [mu] g, 2 1 and 400μg of 40 [mu] g, of 2,40μg 1 and 500μg of 40 [mu] g 1 and 2 of the 600 [mu] g, 40 [mu] g of 1 and 700 [mu] g, 2 1 and 800μg of 40 [mu] g, 2 1 and 900μg of 40 [mu] g, 2 1 and 1000μg of 40 [mu] g, 2 1 and 1250μg of 40 [mu] g, 2 1 and 1500μg of 40 [mu] g, 40 [mu] g 1 and the 2 1750Myug, 1 of 40μg and 2000μg of 2, 2 1 and 25μg of 60 [mu] g, 2 1 and 50μg of 60 [mu] g, 2 1 and 100μg of 60 [mu] g, 1 and 200μg of 60 [mu] g 2, of 60 [mu] g 1 and 300μg of 2, 2 1 and 400μg of the 60μg, 2 1 and 500μg of the 60μg, 60μg 2 of 1 and 600 [mu] g, 2 1 and 700μg of 60 [mu] g, 2 1 and 800μg of 60 [mu] g, 2 1 and 900μg of 60 [mu] g, 2 1 and 1000μg of 60 [mu] g, 2 1 and 1250μg of 60 [mu] g, and 1 60 [mu] g 2 of 1500 [mu] g, 2 1 and 1750μg of 60 [mu] g, 2 1 and 2000μg of 60 [mu] g, 2 1 and 5μg of 80 [mu] g, 2 1 and 50μg of 80 [mu] g, 1 and 100μg of 80 [mu] g 2, 1 and 200μg of 80 [mu] g 2, 2 1 and 300μg of 80 [mu] g, 2 1 and 400μg of 80 [mu] g, 2 1 and 500μg of 80 [mu] g, 2 1 and 600μg of 80 [mu] g, 2 1 and 700μg of 80 [mu] g, 2 1 and 800μg of 80 [mu] g, 2 of 1 and 1000μg of 2,80μg 1 and 900μg of 80 [mu] g, 2 1 and 1250μg of 80 [mu] g, 2 1 and 1500μg of 80 [mu] g, 2 1 and 1750μg of 80 [mu] g, 2 1 and 2000μg of 80 [mu] g, of 100μg 1 and 25 μg 2 , 100 μg 1 and 50 μg 2 , 100 μg 1 and 100 μg 2 , 100 μg 1 and 200 μg 2 , 100 μg 1 and 300 μg 2 , 100 μg 1 and 400 μg 2 , 100 μg 1 and 2 of 500 [mu] g, 2 1 and 600μg of 100 [mu] g, 2 1 and 700μg of 100 [mu] g, 2 1 and 800μg of 100 [mu] g, 2 1 and 900μg of 100 [mu] g, 1 and 1000μg of 100 [mu] g 2, 1 and 1250μg of 100 [mu] g 2 2 of 1 and 1500μg of 100 [mu] g, 2 1 and 1750μg of 100 [mu] g, 2 1 and 2000μg of 100 [mu] g, 2 1 and 25μg of 150 [mu] g, 2 1 and 50μg of 150 [mu] g, 1 and 2 of the 100 [mu] g of 150 [mu] g, of 150 [mu] g 1 and 200 μg 2 , 150 μg 1 and 300 μg 2 , 150 μg 1 and 400 μg 2 , 150 μg 1 and 500 μg 2 , 150 μg 1 and 600 μg 2 , 150 μg 1 and 700 μg 2 , 150 μg 1 and 2 of 800 [mu] g, 2 1 and 900μg of 150 [mu] g, 2 1 and 1000μg of 150 [mu] g, 2 1 and 1250μg of 150 [mu] g, 2 1 and 1500μg of 150 [mu] g, 1 and 1750μg of 150 [mu] g 2, 1 and 2000μg of 150 [mu] g 2 , 200μg 1 and 25μg 2 , 200μg 1 and 50μg 2 , 200μg 1 and 100μg 2 , 200μg 1 and 200μg 2 , 200μg 1 and 300μg 2 , 200μg 1 and 400μg 2 , 200 μg 1 and 500 μg 2 , 200 μg 1 and 600 μg 2 , 200 μg 1 and 700 μg 2 , 200 μg 1 and 800 μg 2 , 200 μg 1 and 900 μg 2 , 200 μg 1 and 1000 μg 2 , 200 μg 2 1 and 1250Myug, 2 1 and 1500μg of 200 [mu] g, 2 1 and 1750μg of 200 [mu] g, 2 1 and 2000μg of 200 [mu] g, 2 1 and 25μg of 250 [mu] g, 1 and 50μg of 250 [mu] g 2, 2 1 and 100μg of 250 [mu] g, 2 1 and 200μg of 250 [mu] g, 2 1 and 300μg of 250 [mu] g, 2 1 and 400μg of 250 [mu] g, 2 1 and 500μg of 250 [mu] g, 2 1 and 600μg of 250 [mu] g, 250 μg 1 and 700 μg 2 , 250 μg 1 and 800 μg 2 , 250 μg 1 and 900 μg 2 , 250 μg 1 and 1000 μg 2 , 250 μg 1 and 1250 μg 2 ,

250 μg 1 and 1500 μg 2 , 250 μg 1 and 1750 μg 2 , 250 μg 1 and 2000 μg 2 , 400 μg 1 and 25 μg 2 , 400 μg 1 and 50 μg 2 , 400 μg 1 and 100 μg 2 , 400 μg 1 and 200 μg 2 , 400 μg 1 and 300 μg 2 , 400 μg 1 and 400 μg 2 , 400 μg 1 and 500 μg 2 , 400 μg 1 and 600 μg 2 , 400 μg 1 and 700 μg 2 , 400 μg 1 and 800 μg 2 , 400 μg 1 and 900 μg 2 or 400 μg 1 and 1000 μg 2 , 400 μg 1 and 1250 μg 2 , 400 μg 1 and 1500 μg 2 , 400 μg 1 and 1750 μg 2 , 400 μg 1 and 2000 μg 2 , 500μg 1 and 25μg 2 , 500μg 1 and 50μg 2 , 500μg 1 and 100μg 2 , 500μg 1 and 200μg 2 , 500μg 1 and 300μg 2 , 500μg 1 and 400μg 2 , 500 μg 1 and 500 μg 2 , 500 μg 1 and 600 μg 2 , 500 μg 1 and 700 μg 2 , 500 μg 1 and 800 μg 2 , 500 μg 1 and 900 μg 2 or 500 μg 1 and 1000 μg 2 , 500 μg 1 and 2 of 1250Myug, 2 1 and 1500μg of 500 [mu] g, 2 1 and 1750μg of 500 [mu] g, 2 1 and 2000μg of 500 [mu] g, 2 1 and 25μg of 600 [mu] g, 1 and 50μ of 600 [mu] g 2 , 600μg 1 and 100μg 2 , 600μg 1 and 200μg 2 , 600μg 1 and 300μg 2 , 600μg 1 and 400μg 2 , 600μg 1 and 500μg 2 , 600μg 1 and 600μg 2 , 600 μg 1 and 700 μg 2 , 600 μg 1 and 800 μg 2 , 600 μg 1 and 900 μg 2 , 600 μg 1 and 1000 μg 2 , 600 μg 1 and 1250 μg 2 , 600 μg 1 and 1500 μg 2 , 2 of 1 and 1750μg of 600 [mu] g, 2 1 and 2000μg of 600 [mu] g, 2 1 and 25μg of 700 [mu] g, 2 1 and 50μg of 700 [mu] g, 2 1 and 100μg of 700 [mu] g, 2 1 and 200μg of 700 [mu] g, of 700 [mu] g 1 and 300 μg 2 , 700 μg 1 and 400 μg 2 , 700 μg 1 and 500 μg 2 , 700 μg 1 and 600 μg 2 , 700 μg 1 and 700 μg 2 , 700 μg 1 and 800 μg 2 , 700 μg 1 and 2 of 900 [mu] g, 2 1 and 1000μg of 700 [mu] g, 2 1 and 1250μg of 700 [mu] g, 2 1 and 1500μg of 700 [mu] g, 2 1 and 1750μg of 700 [mu] g, 1 and 2000μg of 700 [mu] g 2, 1 and 25μg of 800μg 2 , 800μg 1 and 50μg 2 , 800μg 1 and 100μg 2 , 800μg 1 and 200μg 2 , 800μg 1 and 300μg 2 , 800μg 1 and 400μg 2 , 800μg 1 2 of 500 [mu] g, 2 1 and 600μg of 800 [mu] g, 2 1 and 700μg of 800 [mu] g, 2 1 and 800 [mu] g of 800 [mu] g, 2 1 and 900μg of 800 [mu] g, 1 and 1000μg of 800 [mu] g 2, 1 and 1250μg of 800 [mu] g 2, 2 1 and 1500μg of 800 [mu] g, 2 1 and 1750μg of 800 [mu] g, 2 1 and 2000μg of 800 [mu] g, 2 1 and 25μg of 900 [mu] g, 2 1 and 50μg of 900 [mu] g, 2 1 and 100μg of 900 [mu] g, 900 μg 1 and 200 μg 2 , 900 μg 1 and 300 μg 2 , 900 μg 1 and 400 μg 2 , 900 μg 1 and 500 μg 2 , 900 μg 1 and 600 μg 2 , 900 μg 1 and 700 μg 2 , 900 μg 1 and 800 μg 2 , 900 μg 1 and 900 μg 2 , 900 μg 1 and 1000 μg 2 , 900 μg 1 and 1250 μg 2 , 900 μg 1 and 1500 μg 2 , 900 μg 1 and 1750 μg 2 , 900 μg 1 and 2 of 2000 [mu] g, 2 1 and 25μg of 1000 [mu] g, 2 1 and 50μg of 1000 [mu] g, 2 1 and 100μg of 1000 [mu] g, 2 1 and 200μg of 1000 [mu] g, 1 and 300μg of 1000 [mu] g 2, 1 and 400μg of 1000 [mu] g 2, 2 1 and 500μg of 1000 [mu] g, 2 1 and 600μg of 1000 [mu] g, 2 1 and 700μg of 1000 [mu] g, 2 1 and 800μg of 1000 [mu] g, 2 1 and 900μg of 1000 [mu] g 1000 μg 1 and 1000 μg 2 , 1000 μg 1 and 1250 μg 2 , 1000 μg 1 and 1500 μg 2 , 1000 μg 1 and 1750 μg 2 or 1000 μg 1 and 2000 μg 2 .

The above examples of possible doses that can be applied to the combination of the present invention should be understood as indicating doses for a single application. However, these examples are understood as not excluding the possibility of administering the combination of the present invention multiple times. Some patients in need of treatment can receive multiple inhalation applications. As an example, a patient can receive the combination of the present invention, for example, 2 or 3 times in the morning of each treatment day (eg, 2 or 3 puffs by powder inhaler, MDI, etc.). Since the above dose examples are understood only as dose examples for a single application (ie per puff), multiple applications of the combination of the present invention result in multiple administrations of the above examples. The application of the combination of the present invention may depend on, for example, the duration of action of the anticholinergic agent once a day or twice a day or once every 2 or 3 days.
It is further emphasized that the above dose examples should only be understood as examples of metered doses. In other words, the above dosage examples should be understood as effective amounts of the combination of the present invention that do not actually reach the lungs. It will be apparent to those skilled in the art that the dose delivered to the lung is often less than the metered dose of active ingredient administered.
The combination agent of the active substances 1 and 2 of the present invention is preferably administered by inhalation. For this, 1 and 2 must be useful in a form suitable for inhalation. The inhalation preparations of the present invention include inhalation powders, propellant-containing quantitative aerosols or inhalation solutions that do not contain propellants. The inhalable powders according to the invention containing a combination of active substances 1 and 2 may consist of the active substance alone or a mixture of active substance and physiologically acceptable excipients. The term carrier within the scope of the present invention may optionally be used in place of the term excipient. The term inhalation solution without propellant within the scope of the present invention includes concentrates or sterile solutions for inhalation prepared at the time of use. The formulations according to the invention may contain the combination of active substances 1 and 2 together in one formulation or in two separate formulations. These formulations that can be used within the scope of the present invention are described in further detail in the next part of the specification.

A) Powder for inhalation containing a combination of active substances 1 and 2 according to the invention:
Inhalable powders according to the invention may contain in admixture with 1 and 2 alone or an appropriate physiologically acceptable excipients.
When active substances 1 and 2 are present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients should be used to prepare the inhalable powder of the present invention Can be: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose, trehalose), oligosaccharides or polysaccharides (e.g. dextran), polyhydric alcohols (e.g. sorbitol, mannitol, xylitol) , Cyclodextrins (e.g. α-cyclodextrin, β-cyclodextrin, χ-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin), salts (e.g. sodium chloride, calcium carbonate) or these A mixture of excipients with each other. Monosaccharides or disaccharides are preferably used, and lactose, trehalose or glucose is preferably used, and in particular, in the form of hydrates, if not all.
The maximum average particle size of excipients within the inhalable powders of the invention is up to 250 μm, preferably 10 to 150 μm, most preferably 15 to 80 μm. It may often be appropriate to add a fine excipient portion with an average particle size of 1-9 μm to the excipient. These fine excipients are selected from the group of possible excipients described above. Finally, to prepare the inhalable powder of the present invention, micronized active substances 1 and 2 having an average particle size of preferably 0.5 to 10 μm, more preferably 1 to 6 μm are added to the excipient mixture. Processes for producing the inhalable powders according to the invention by grinding and micronizing and finally mixing the components together are known from the prior art. The inhalable powders according to the invention can be prepared and administered in the form of a single powder mixture containing both 1 and 2, or in the form of individual inhalable powders containing only 1 or 2 .

The inhalable powders according to the invention can be administered using inhalers known from the prior art. Inhalable powders according to the invention containing physiologically acceptable excipients in addition to 1 and 2 can be used, for example, using a metering chamber as described in US Pat. No. 4,706,630 or German patent application 36 25 It can be administered by an inhaler that delivers a single dose from the supply by other means as described in 685. Inhalable powders according to the invention containing 1 and 2 optionally together with physiologically acceptable excipients are used, for example, using an inhaler known by the name Turbuhaler® or, for example, European Patent No. It can be administered using the inhaler disclosed in 237507A. Preferably, the inhalable powder of the present invention containing physiologically acceptable excipients in addition to 1 and 2 is, for example, a capsule used in an inhaler described in International Application No. 94/28958 (so-called To produce inhalettes).
A particularly preferred inhaler for using the combination of the agents of the present invention in Inhalette is shown in FIG.
This inhaler (handy heller) for inhaling a powdered pharmaceutical composition from a capsule comprises a housing 1 having two windows 2, a deck 3 having an air inlet and a screen 5 fixed by a screen housing 4, and A suction chamber 6 connected to a deck 3 with a push button with a movable counter for two sharp pins 7 and a spring 8, and a spindle 10 that allows the housing 1 and deck 3 to be opened and closed quickly The mouthpiece 12 connected to the cover 11 and the air through hole 13 for adjusting the flow resistance are characterized.
When the inhalable powder of the present invention is filled into the above-mentioned preferred capsules (Inhalette), the amount to be filled in each capsule is 1 to 50 mg, preferably 3 to 45 mg, more preferably 5 to 40 mg per capsule. Must be an inhalable powder. According to the invention, these capsules contain 1 and 2 doses as described above for each single dose, either together or separately.

B) Propellant gas driven inhalation aerosol containing the combination of active substances 1 and 2 of the present invention:
The inhalation aerosol containing the propellant gas of the present invention can contain substances 1 and 2 in a form dissolved or dispersed in the propellant gas. 1 and 2 can be present in separate formulations or a single formulation, both 1 and 2 are dissolved or both are dispersed or only one of the components is dissolved and the other is dispersed. Propellants that can be used to prepare the inhalation aerosols of the invention are known from the prior art. Suitable propellant gases are selected from hydrocarbons such as n-propane, n-butane or isobutane or halogen hydrocarbons such as methane, ethane, propane, butane, cyclopropane or cyclobutane fluorinated derivatives. The propellant gas can be used by itself or in a mixture. Particularly preferred propellant gases are selected from TG11, TG12, TG134a (1,1,1,2-tetrafluoroethane) and TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof. The propellant gases TG134a and TG227 and mixtures thereof are preferred.
The propellant-driven inhalation aerosols of the present invention can include other components such as co-solvents, stabilizers, surfactants, antioxidants, lubricants or pH adjusters. All of these ingredients are known in the art.
Inhalation aerosols containing the propellants according to the invention can contain up to 5 wt.% Of active substances 1 and / or 2 . The aerosol of the present invention is, for example, 0.002-5 wt.%, 0.01-3 wt.%, 0.015-2 wt.%, 0.1-2 wt.%, 0.5-2 wt.%, Or 0.5-1 wt.%. Contains active substance 1 and / or 2 .
When the active substances 1 and / or 2 are present in a dispersed form, the average particle diameter of the active substance particles is preferably up to 10 μm, preferably 0.1 to 5 μm, more preferably 1 to 5 μm.
The propellant-driven inhalation aerosol of the present invention can be administered using an inhaler known in the art (MDI = metered dose inhaler).
Accordingly, in another aspect, the invention relates to a pharmaceutical composition in the form of a propellant-driven aerosol in combination with one or more inhalers suitable for administering these aerosols. Furthermore, this invention relates to the inhaler characterized by containing the said injection gas containing aerosol of this invention. The invention also relates to a cartridge comprising a suitable valve that can be used in a suitable inhaler and containing one of the propellant-containing inhalation aerosols of the invention. Suitable cartridges and methods for filling these cartridges with inhalable aerosols containing the propellant gas of the invention are known from the prior art.

C) Inhalable solution or suspension containing no propellant containing the combination of active substances 1 and 2 of the present invention:
Solutions or suspensions for inhalation that do not contain the propellant of the present invention contain, for example, an aqueous or alcohol solvent, preferably an ethanol solvent, and optionally an ethanol solvent mixed with an aqueous solvent. When a water / ethanol solvent mixture is used, the relative proportion of ethanol compared to water is not limited, with a maximum of up to 70% by volume, in particular up to 60% by volume of ethanol. The remaining capacity uses water. Solutions or suspensions containing 1 and 2 separately or together are adjusted to pH 2-7, preferably 2-5, using a suitable acid. The pH can be adjusted using an acid selected from inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid. Preferred inorganic acids are hydrochloric acid and sulfuric acid. It is also possible to use an acid that has already formed an acid addition salt with one of the active substances. Of the organic acids, ascorbic acid, fumaric acid, and citric acid are preferred. If desired, in particular in addition to the oxidizing properties, other properties such as, for example, in the case of flavourants, antioxidants or complexing agents, for example citric acid or ascorbic acid, can be used a mixture of said acids. Can be used. According to the invention, it is particularly preferred to use hydrochloric acid to adjust the pH.
According to the present invention, the addition of edetic acid (EDTA) or one of its known salts, sodium edetate, as a stabilizer or complexing agent is not necessary for the present invention. Other embodiments can contain this compound or these compounds. In a preferred embodiment, the content based on sodium edetate is less than 100 mg / 100 ml, preferably less than 50 mg / 100 ml, more preferably less than 20 mg / 100 ml. In general, inhalable solutions with a content of sodium edetate of 0-10 mg / 100 ml are preferred.
Co-solvents and / or other excipients can be added to inhalation solutions that do not contain the propellant of the present invention. Preferred co-solvents are those having a hydroxyl group or other polar group, for example alcohol-especially isopropyl alcohol, glycol-especially propylene glycol, polyethylene glycol, polypropylene glycol, glycoether, glycerol, polyoxyethylene alcohol or polyoxyethylene fatty acid Ester. The terms excipients and additives in this context are not active substances but can be combined with one or more substances in a physiologically suitable solvent to improve the qualitative properties of the active substance formulation. Indicates a pharmacologically acceptable substance. Preferably, these substances have no pharmacological action, no perceptible pharmacological action in connection with the desired treatment, and at least no undesirable pharmacological action. As excipients and additives, soy lecithin, oleic acid, sorbitan esters, eg surfactants such as polysorbate, polyvinylpyrrolidone, other stabilizers, complexing agents, guarantee or extend the life of the final pharmaceutical formulation Antioxidants and / or preservatives, flavoring agents, vitamins and / or other additives known in the art are included. Additives also include physiologically acceptable salts such as sodium chloride as isotonic agents.

Preferred excipients include, for example, antioxidants such as ascorbic acid, if not already used to adjust pH, vitamin A, vitamin E, tocophenol or similar vitamins or provitamins occurring in the human body. Agent is included.
Preservatives can be used to protect the formulation from contamination by pathogens. Suitable preservatives are those known in the art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid salts such as benzoic acid or sodium benzoate in concentrations known from the prior art. The preservative is preferably present at a concentration of up to 50 mg / 100 ml, more preferably 5-20 mg / 100 ml.
A preferred formulation contains only benzalkonium chloride and edetic acid in addition to the combination of solvent water and active substances 1 and 2 . In other preferred embodiments, no sodium edetate is present.
The propellant-free inhalation solution of the present invention is administered using an inhaler of the kind that can inject a small amount of a liquid formulation in a therapeutically required amount within seconds that produces an aerosol that is particularly suitable for therapeutic inhalation. The Preferred nebulizers within the scope of the present invention provide an amount of active substance solution of less than 100 μl, preferably less than 50 μl, more preferably 20-30 μl, such that the inhalable part of the aerosol represents a therapeutically effective amount. Preferably, the spray can be sprayed to form an aerosol having an average particle size of less than 20 μm, preferably less than 10 μm, by a single spraying action.
This type of device for delivering a metered dose of a liquid pharmaceutical composition for inhalation without propellant is described, for example, in International Application No. 91/14468 and International Application No. 97/12687 (see in particular FIGS. 6a and 6b). )It is described in. The nebulizer described therein is known under the name Respimat®.
This nebulizer (Respimat®) can be advantageously used to produce an inhalable aerosol of the present invention containing a combination of active substances 1 and 2 . The shape is cylindrical, the convenient size length is from less than 9 cm to 15 cm, and the width is 2-4 cm, so the patient can carry the device anywhere. The nebulizer sprays a certain amount of pharmaceutical formulation using high pressure through a small nozzle to produce an inhalable aerosol.

A preferred atomizer consists essentially of an upper housing portion, a pump housing, a nozzle, a locking mechanism, a spring housing, a spring, and a storage container.
A pump housing including a nozzle body fixed to the top of the housing and having the nozzle or nozzle arrangement at one end;
-Hollow plunger with valve body,
A power take-off flange to which the hollow plunger is fixed and in the upper part of the housing;
-A locking mechanism in the upper part of the housing,
A spring housing in which a spring is rotatably mounted on the top of the housing by means of a rotating bearing;
-Featuring a lower housing part attached to the spring housing in the axial direction.
A hollow plunger with a valve body corresponds to the device disclosed in WO 97/12687. It partially projects into the cylinder of the pump housing and can move axially within the cylinder. Reference is made in particular to FIGS. 1 to 4, especially FIG. 3 and the relevant parts of the description. 5-60 Mpa (about 50-600 bar), preferably 10-60 Mpa (about 100-600 bar) by the hollow plunger with the valve body when the spring is actuated is liquid, metering active substance solution at the end of high pressure Added. A volume of 10-50 μl per spray is preferred, a volume of 10-20 μl is more preferred, and a volume of 15 μl is most preferred.
The valve body is preferably attached to the end of the hollow plunger facing the nozzle body.
The nozzles in the nozzle body are preferably microstructured, i.e. manufactured by microtechnology. A microstructured valve body is disclosed, for example, in International Application No. 94/07607, and the contents of that specification, in particular FIG. 1 therein, are incorporated herein by reference.
The nozzle body is made of, for example, glass and / or silicon with two sheets secured together, at least one having one or more microstructured channels connecting the nozzle inlet end to the nozzle outlet end. At the nozzle exit end there is at least one round or non-round hole of depth 2-10μm (μ), width 5-15μm (μ), depth 4.5-6.5μm (μ), length 7-9μm (μ) Is preferred.

When there are a plurality of nozzle holes, preferably two, the spray directions of the nozzles of the nozzle body may be parallel to each other or may be inclined with respect to the direction of the nozzle holes. In a nozzle body with at least two nozzle holes at the outlet end, the spray directions may be at an angle of 20 to 160 ^o , preferably 60 to 150 ^o , most preferably 80 to 100 ^o with respect to each other. Good. The nozzle holes are preferably arranged at intervals of 10 to 200 μm (μ), more preferably at intervals of 10 to 100 μm (μ), and most preferably at 30 to 70 μm (μ). A spacing of 50 μm (μ) is most preferred. Therefore, the spray direction matches the area of the nozzle hole.
The liquid pharmaceutical preparation hits the nozzle body at an entry pressure of up to 600 bar, preferably 200 to 300 bar, and is sprayed through the nozzle hole into the inhalation aerosol. The preferred particle size or droplet of the aerosol is up to 20 μm (μ), preferably 3 to 10 μm (μ).
The locking mechanism has a spring, preferably a cylindrical compression coil spring, for storing mechanical energy. The spring acts on the power take-off flange as an actuating part with a movement determined by the position of the locking part. The movement of the power take-off flange is precisely limited by the upper and lower stops. The spring is preferably biased by an external torque generated when the upper part of the housing rotates relative to the lower spring housing via a power step-up gear, for example a helical thrust gear. In this case, the housing upper part and the power take-off flange have single or plural V-shaped gears.
The locking portion with which the locking surface is engaged is arranged in a ring around the power take-off flange. For example, it consists of a plastic or metal ring that is inherently elastically deformable in the radial direction. The rings are arranged in a plane at an angle perpendicular to the atomizer axis. After the spring is biased, the locking surface of the locking portion moves into the passage of the power take-off flange, preventing the spring from loosening. The locking part is actuated by a button. The actuating button is connected or coupled to the locking portion. To activate the locking mechanism, the actuating button is moved parallel to the annular surface, preferably into the atomizer, so that the deformable ring is deformed at the annular surface. Details of the construction of the locking mechanism are described in International Application No. 97/20590.

The lower portion of the housing is pushed axially onto the spring housing and includes a mounting portion, a spindle drive portion, and a liquid storage container.
When the atomizer is activated, the upper part of the housing rotates relative to the lower part holding the spring housing. The spring is thereby compressed and biased by the coil thrust gear, and the locking mechanism is automatically engaged. The rotation angle is preferably an integer part of 360 degrees, for example 180 degrees. As soon as the spring is biased, the power take-off at the top of the housing moves a certain distance, and the hollow plunger is pulled into the cylinder of the pump housing, resulting in a portion of the liquid from the reservoir to the high pressure chamber in front of the nozzle. Sucked.
If desired, a number of replaceable storage containers containing the liquid to be sprayed can be pushed into the atomizer one after another and subsequently used. The storage container contains the aqueous aerosol formulation of the present invention.
The spraying process begins by pressing the activation button gently. As a result, the locking mechanism opens the passage in the power take-off part. A biased spring pushes the plunger into the pump housing cylinder. Liquid exits the atomizer nozzle in the form of a spray.
Details of the configuration are disclosed in International Application Nos. 97/12683 and 97/20590, which are included herein.
Atomizer (nebulizer) parts are manufactured from materials suitable for their function. Where possible with the atomizer housing, the other parts are also preferably made from plastic, for example by injection molding. In the case of medical use, a physiologically safe material is used.

FIG. 6a / b of International Application No. 97/12687 shows a Respimat® nebulizer that can be advantageously used to inhale the aqueous aerosol formulation of the present invention. FIG. 6a of International Application No. 97/12687 is a longitudinal section in an atomizer with a spring biased, while FIG. 6b of International Application No. 97/12687 is a longitudinal section in an atomizer with a loose spring. FIG.
The housing upper part (51) has a pump housing (52), and a holder (53) for an atomizer nozzle is attached to the end of the pump housing (52). Within the holder are a nozzle body (54) and a filter (55). A hollow plunger (57) fixed to the power take-off flange (56) of the locking mechanism partially protrudes into the cylinder of the pump housing. At its end, a hollow plunger is provided with a valve body (58). The hollow plunger is sealed by a seal (59). A stop (60) on which the power take-off flange rests when the spring is loose is located inside the top of the housing. The stop (61) on which the power take-off flange rests when the spring is biased is on the power take-off flange. After the spring is biased, the locking portion (62) moves between the stop (61) and the support (63) at the top of the housing. The actuating button (64) is connected to the locking part. The upper end of the housing is a base (65), which is sealed by a protective cover (66) that can be placed thereon.
A spring housing (67) having a compression spring (68) is rotatably attached to the upper portion of the housing by a snap-in lug (69) and a rotary bearing. The lower housing part (70) is pushed onto the spring housing. There is a replaceable storage container (71) of liquid (72) to be sprayed inside the spring housing. The storage container is sealed with a stopper (73), the hollow plunger protrudes into the storage container, and its end is immersed in the liquid (supply part of the active substance solution).
The spindle (74) of the mechanical counter is attached to the outside of the spring housing. The drive pinion (75) is at the end of the spindle facing the top of the housing. There is a slider (76) on the spindle.
The nebulizer is suitable for nebulizing the aerosol formulation of the present invention resulting in an aerosol suitable for inhalation.
When the formulation of the present invention is nebulized using the above method (Respimat®), the amount expelled in at least 97%, preferably at least 98% of all inhaler movements (spraying movements) is: The constant amount allowed should correspond to 25% or less, preferably 20% of this amount. Preferably 5-30 mg, most preferably 5-20 mg of the formulation is delivered as a constant mass for each movement.

However, the formulations of the present invention can be nebulized using inhalers other than those described above, for example, jet stream inhalers or other fixed nebulizers.
Thus, in another aspect, the invention is combined with a device suitable for administering these formulations in the form of inhalable solutions or suspensions containing no propellant, preferably with Respimat®. The combined pharmaceutical preparation. Preferably, the present invention relates to a propellant-free inhalable solution or suspension characterized by a combination of active substances 1 and 2 according to the invention together with a device known under the name Respimat®. Furthermore, the present invention relates to the inhalation device, preferably Respimat (registered trademark), characterized in that it comprises a solution or suspension for inhalation which does not contain the propellant of the present invention.
According to the invention, inhalable solutions containing active substances 1 and 2 in a single formulation are preferred. The term “single formulation” includes, for example, a formulation containing two components 1 and 2 disclosed in International Application No. 00/23037 in a two-chamber cartridge. This reference is incorporated herein in its entirety.
Solutions or suspensions for inhalation that do not contain the propellant of the present invention include concentrates or sterile solutions or suspensions for inhalation prepared at the time of use, or the above solutions designed for use in Respimat®. Can take the form of a suspension. Preparations at the time of use can be made, for example, by adding isotonic saline from the concentrate. A ready-to-use sterile formulation can be administered using a self-supporting or portable energy-operated nebulizer that produces an inhalable aerosol by ultrasound or compressed air according to the Venturi principle or other principles.
Thus, in another aspect, the invention is suitable for administering these solutions in the form of concentrates or inhalable solutions or suspensions that do not contain the propellant in the form of a ready-to-use sterile formulation. A pharmaceutical composition in combination with a device, wherein the device is a self-supporting or portable energy-operated nebulizer that produces an aerosol for inhalation by ultrasound or compressed air according to the Venturi principle or otherwise. It relates to the pharmaceutical composition.

2)

3)

Formulation Examples The following examples of formulations that can be obtained analogously to methods known in the art are intended to illustrate the invention in more detail without limiting the invention to the contents of these examples. In the following example, the enantiomerically pure form of the preferred enantiomer of the bromide of formula 1 (i.e. formula 1-en) is used as an active ingredient.
Inhalable powder:
1)

2)

3)

5)

6)

7)

Four)

Five)

6)

7)

9)

8)

9)

8)

9)

8)

9)

11)

12)

13)

Ten)

11)

12)

13)

^* ) 2 = The following compounds:
2- (4-Fluorophenoxy) -N- {4-[(2hydroxy-3-methylbenzoylamino) methyl] benzyl} nicotinamide, 3- (3- {4-[(3-hydroxybenzoylamino) methyl] Benzylcarbamoyl} pyridin-2-yloxy) benzoic acid ethyl ester, 2- (4-fluorophenoxy) -N- {4-[(6-fluoro-2-hydroxybenzoylamino) methyl] benzyl} nicotinamide, 2- ( 4-fluorophenoxy) -N- {4-[(5-fluoro-2-hydroxybenzoylamino) methyl] benzyl} nicotinamide, 2- (4-fluorophenoxy) -N- {4-[(3-hydroxy- 4-methylbenzoylamino) methyl] benzyl} nicotinamide, 2- (4-fluorophenoxy) -N- {4-[(3hydroxybenzoylamino) methyl] benzyl} nicotinamide, 2- (4-fluorophenoxy)- N- {4-[(2-hydroxybenzoylamino) methyl] benzyl} nicotinamide, 2- (4 -Fluorophenoxy) -N- {4-[(4-hydroxybenzoylamino) methyl] benzyl} nicotinamide, 2- (4-fluorophenoxy) -N- {4-[(2-hydroxy-4-methylbenzoylamino) ) Methyl] -benzyl} nicotinamide, 2- (4-f fluorophenoxy) -N- {4-[(3-hydroxy-2-methylbenzoylamino) methyl] benzyl} nicotinamide, 2- (4-fluorophenoxy) ) -N- {4-[(2-hydroxy-5-methylbenzoylamino) methyl] benzyl} nicotinamide, 5-fluoro-2- (4-fluorophenoxy) -N- {4-[(2-hydroxybenzoyl Amino) methyl] benzyl} nicotinamide, 5-fluoro-2- (4-fluorophenoxy) -N- {4-[(2-hydroxyacetylamino) methyl] benzyl} nicotinamide, 5-fluoro-2- (4- Fluorophenoxy) -N- {4-[(4-hydroxybenzoylamino) methyl] benzyl} nicotinamide, 3- (3- {4-[(3- Droxybenzoylamino) methyl] benzylcarbamoyl} -pyridin-2-yloxy) benzoic acid ethyl ester, 3- (3- {4-[(2-hydroxyphenacetylamino) methyl] benzylcarbamoyl} pyridin-2-yloxy) Benzoic acid ethyl ester, 3- (3- {4-[(3-hydroxyphenacetylamino) methyl] benzylcarbamoyl} pyridin-2-yloxy) benzoic acid ethyl ester, 3- (3- {4-[(4- Hydroxyphenacetylamino) methyl] benzylcarbamoyl} pyridin-2-yloxy) benzoic acid ethyl ester, compound (2.a) and compound (2.b) represented by the following formulae

Optionally in the form of racemates, enantiomers, diastereomers and optionally pharmaceutically acceptable acid addition salts and hydrates thereof.

2) 懸濁液エアゾール:

3) 懸濁液エアゾール:

B) Propellant-containing inhalation aerosol:
1) Suspension aerosol:

2) Suspension aerosol:

3) Suspension aerosol:

It is a particularly preferred inhaler for using the combination of the agents of the present invention in Inhalette.

Claims (23)

Formula 1 below

(Wherein, X ^- anion with a single negative charge, preferably fluorine anion, chlorine anion, bromine anion, iodine anion, sulfate anion, phosphate anion, methanesulfonic acid, nitrate, maleate anions, acetate Anion selected from the group consisting of an anion, a citrate anion, a fumarate anion, a tartrate anion, an oxalate anion, a succinate anion, a benzoate anion and a p-toluenesulfonate anion.)
Wherein the salt of formula 1 is optionally a racemate, an enantiomer, a hydration thereof, and a pharmaceutical composition characterized in that it comprises one or more of the salts represented by formula (1) together with one or more PDE IV inhibitors (2). The PDE IV inhibitor (2) may optionally be in the form of an enantiomer, a mixture of enantiomers or a racemate thereof, and optionally in the form of a solvate or hydrate. Wherein said pharmaceutical composition may optionally be in combination with a pharmaceutically acceptable excipient. 2. A pharmaceutical composition according to claim 1, characterized in that the active substances 1 and 2 are both present in a single formulation or in two separate formulations. 3. A pharmaceutical composition according to claim 1 or 2, characterized in that the compound of formula 1 is present in the form of an enantiomer of the following formula 1-en .

PDE IV inhibitor 2 is enprofylline, theophylline, roflumilast, ariflo (siromilast), CP-325,366, BY343, D-4396 (Sch-351591), AWD-12-281 (GW-842470), N- (3, 5-dichloro-1-oxopyridin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide, NCS-613, pumafentin, (-) p-[(4aR ^* , 10bS ^* )-9-ethoxy- 1,2,3,4,4a, 10b-Hexahydro-8-methoxy-2methylbenzo [s] [1,6] naphthyridin-6-yl] -N, N-diisopropylbenzamide, ((R)-(+) -1- (4-bromobenzyl))-4-[(3-cyclopentyloxy) -4-methoxyphenyl] -2-pyrrolidone, 3- (cyclopentyloxy-4-methoxyphenyl) -1- (4-N ′ -[N-2-cyano-S-methylisothioureido] benzyl) -2-pyrrolidone, cis [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid], 2 -Carbomethoxy-4-sia No-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexane-1-one, cis [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexane-1-ol] , (R)-(+)-ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidine-2-ylidene] acetate, (S)-(-)-ethyl [4- (3-cyclopentyloxy- 4-methoxyphenyl) pyrrolidine-2-ylidene] acetate, CDP840, Bay-198004, D-4418, PD-168787, T-440, T-2585, allophylline, atizolam, V-11294A, Cl-1018, CDC-801 , CDC-3052, D-22888, YM-58997, Z-15370, 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (2-thienyl) -9H-pyrazolo [3,4 c] -1 , 2,4-triazolo [4,3-a] pyridine, and 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (tert-butyl) -9H-pyrazolo [3,4 c] -1, Optionally selected from the group consisting of 2,4-triazolo [4,3-a] pyridine Pharmaceutical according to claim 1, 2 or 3, characterized in that it is selected in the form of a semi-compound, enantiomer, diastereomer, or optionally a pharmacologically acceptable acid addition salt thereof, or a hydrate thereof. Composition. Compound 2 is enprofylline, roflumilast, ariflo (silomilast), AWD-12-281 (GW-842470), N- (3,5-dichloro-1-oxopyridin-4-yl) -4-difluoromethoxy-3 -Cyclopropylmethoxybenzamide, T-440, T-2585, allophylline, cis [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid], 2-carbomethoxy-4- Cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexane-1-one, cis [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexane-1-ol] , PD-168787, Atizolam, V-11294A, Cl-1018, CDC-801, D-22888, YM-58997, Z-15370, 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (2- Thienyl) -9H-pyrazolo [3,4 c] -1,2,4-triazolo [4,3-a] pyridine and 9-cyclopentyl-5,6-dihydro-7-ene R-3- (tert-butyl) -9H-pyrazolo [3,4 c] -1,2,4-triazolo [4,3-a] pyridine, optionally racemates, enantiomers, diastereomers 5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is selected in the form of a pharmacologically acceptable acid addition salt thereof or a hydrate thereof. Compound 2 is roflumilast, ariflo (silomilast), AWD-12-281 (GW-842470), allophylline, Z-15370, 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxy Phenyl) cyclohexane-1-one, cis [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexane-1-ol], atizolam, 9-cyclopentyl-5,6-dihydro-7- Ethyl-3- (2-thienyl) -9H-pyrazolo [3,4 c] -1,2,4-triazolo [4,3-a)] pyridine, and 9-cyclopentyl-5,6-dihydro-7- From the group consisting of ethyl-3- (tert-butyl) -9H-pyrazolo [3,4 c] -1,2,4-triazolo [4,3-a] pyridine, optionally racemates, enantiomers, diastereomers Or optionally, in the form of a pharmacologically acceptable addition salt thereof, or a hydrate thereof, The pharmaceutical according to any one of claims 1 to 5, Composition. PDE IV inhibitor 2 is 2- (4-fluorophenoxy) -N- {4-[(6-fluoro-2-hydroxybenzoylamino) methyl] benzyl} nicotinamide, 2- (4-fluorophenoxy) -N -{4-[(5-Fluoro-2-hydroxybenzoylamino) methyl] benzyl} nicotinamide, 2- (4-fluorophenoxy) -N- {4-[(3-hydroxy-4-methylbenzoylamino) methyl ] Benzyl} nicotinamide, 2- (4-fluorophenoxy) -N- {4-[(3hydroxybenzoylamino) methyl] benzyl} nicotinamide, 2- (4-fluorophenoxy) -N- {4-[( 2-hydroxybenzoylamino) methyl] benzyl} nicotinamide, 2- (4-fluorophenoxy))-N- {4-[(4-hydroxybenzoylamino) methyl] benzyl} nicotinamide, 2- (4-fluorophenoxy ) -N- {4-[(2-hydroxy-4-methylbenzoylamino) methyl] benzyl} nicotinamide, 2- (4-fluoro Lophenoxy) -N- {4-[(3-hydroxy-2-methylbenzoylamino) methyl] benzyl} nicotinamide, 2- (4-fluorophenoxy) -N- {4-[(2-hydroxy-5- Methylbenzoylamino) methyl] benzyl} nicotinamide, 5-fluoro-2- (4-fluorophenoxy) -N- {4-[(2-hydroxybenzoylamino) methyl] benzyl} nicotinamide, 5-fluoro-2- (4-Fluorophenoxy) -N- {4-[(2-hydroxyacetylamino) methyl] benzyl} nicotinamide, 5-fluoro-2- (4-fluorophenoxy) -N- {4-[(4-hydroxy Benzoylamino) methyl] benzyl} nicotinamide, 3- (3- {4-[(3-hydroxybenzoylamino) methyl] benzylcarbamoyl} pyridin-2-yloxy) benzoic acid ethyl ester, 3- (3- {4- [(2-Hydroxyphenacetylamino) methyl] benzylcarbamoyl} pyridin-2-yloxy) benzoic acid Ethyl ester, 3- (3- {4-[(3-hydroxyphenacetylamino) methyl] benzylcarbamoyl} pyridin-2-yloxy) benzoic acid ethyl ester, 3- (3- {4-[(4-hydroxyphena Cetylamino) methyl] benzylcarbamoyl} pyridin-2-yloxy) benzoic acid ethyl ester, compound (2.a) and compound (2.b) represented by the following formulae

Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof, optionally selected from the group consisting of racemic compounds, enantiomers, diastereomers, or hydrates thereof. 2. The pharmaceutical composition according to 2. A mass ratio between 1 and 2 according to any one of claims 1 to 7, characterized in that it is in the range of about 1: 100 to 100: 1, preferably 1:80 to 80: 1. Pharmaceutical composition.   9. A pharmaceutical composition according to any one of claims 1 to 8, characterized in that it is in the form of a formulation suitable for inhalation.   10. The pharmaceutical composition according to claim 9, which is a preparation selected from an inhalable powder, a propellant-containing quantitative aerosol and an inhalable solution containing no propellant. Contains 1 and 2 mixed with a suitable physiologically acceptable excipient selected from monosaccharides, disaccharides, oligosaccharides, polysaccharides, polyhydric alcohols, salts or mixtures of these excipients 11. The pharmaceutical composition according to claim 10, which is an inhalable powder.   12. Inhalable powder according to claim 11, characterized in that the maximum average particle size of the excipient is up to 250 [mu] m, preferably 10 to 150 [mu] m. 13. The pharmaceutical composition according to claim 12, which is a powder for inhalation containing only active substances 1 and 2 as ingredients. 11. The pharmaceutical composition according to claim 10, which is a propellant-containing inhalation aerosol containing 1 and 2 in a dissolved or dispersed form.   Propellant gas contains hydrocarbons such as n-propane, n-butane or isobutane or halogen hydrocarbons such as chlorinated and / or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane 15. The propellant-containing inhalable aerosol according to claim 14,   16. The propellant-containing inhalation aerosol according to claim 15, characterized in that the propellant gas is TG11, TG12, TG134a, TG227 or a mixture thereof, preferably TG134a, TG227 or a mixture thereof. 17. Propellant-containing inhalable aerosol according to any one of claims 14 to 16, characterized in that it can contain up to 5% by weight of active substance 1 and / or 2 .   11. The pharmaceutical composition according to claim 10, which is a solution for inhalation not containing a propellant containing water, ethanol or a mixture of water and ethanol as a solvent.   19. Inhalation solution according to claim 18, characterized in that it optionally contains other co-solvents and / or excipients.   As a co-solvent contains hydroxyl groups or other polar groups such as alcohols, especially isopropyl alcohol, glycols, especially propylene glycol, polyethylene glycol, polypropylene glycol, glycoethers, glycerol, polyoxyethylene alcohol and polyoxyethylene fatty acid esters 20. The solution for inhalation according to claim 19, comprising an ingredient.   It comprises surfactants, stabilizers, complexing agents, antioxidants and / or preservatives, flavoring agents, pharmacologically acceptable salts and / or vitamins as excipients. The solution for inhalation according to 19 or 20.   22. Inhalation solution according to claim 21, characterized in that it contains edetic acid or a salt of edetic acid, preferably sodium edetate, as a complexing agent.   Use of the composition according to any one of claims 1 to 22 for the preparation of a medicament for the treatment of inflammatory or obstructive respiratory diseases, in particular asthma or COPD.

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