JP2007500148A - Medicament containing PDEIV inhibitor and novel anticholinergic agent and use of the medicament for treating respiratory diseases - Google Patents

Abstract

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

Description

Detailed Description of the Invention

The present invention relates to a novel pharmaceutical composition based on a PDEIV inhibitor and a salt of a novel anticholinergic agent, a process for its production and use in the treatment of respiratory diseases.
(Description of the invention)
The present invention relates to a novel pharmaceutical composition based on a PDEIV inhibitor and a novel anticholinergic drug 1 salt, a process for its production and use in the treatment of respiratory diseases.
Within the scope of the present invention, the anticholinergic agent used is a salt represented by Formula 1.

(Wherein X ⁻ represents an anion having one negative charge, preferably fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate An anion selected from the group consisting of rate, oxalate, succinate, benzoate and p-toluenesulfonate is shown.)
The salt of formula 1 preferably represents an anion having one negative charge, wherein X ⁻ in the formula is selected from the group consisting of fluoride, chloride, bromide, 4-toluenesulfonate and methanesulfonate, preferably A salt exhibiting bromide is used.
More preferably, a salt of formula 1 is used in which X ⁻ represents one negatively charged anion selected from the group consisting of chloride, bromide and methanesulfonate, preferably bromide.
Wherein, X ^- is a salt of formula 1 showing the bromide, particularly preferred in the present invention.
Surprisingly, the use of an anticholinergic agent of formula 1 together with one or more PDEIV inhibitors 2 has unexpected and beneficial therapeutic effects in the treatment of inflammatory and / or obstructive diseases of the respiratory tract. You can see.
This effect can be seen both when the two active ingredients are administered simultaneously in a single active ingredient formulation and when they are administered sequentially in separate formulations. In the present invention, it is preferable to administer two active ingredients simultaneously in a single formulation.
In the scope of the present invention, when referring to compound 1 ′, it is intended to indicate a pharmacologically effective cation of the following formula contained in salt 1.

In the pharmaceutical combination, the active ingredients may be mixed in a single preparation or may be contained in two separate formulations.
In the present invention, a pharmaceutical composition comprising active ingredients 1 and 2 in a single preparation is preferred.
According to the present invention, preferred PDEIV inhibitors 2 in the combination of the present invention are enprofylline, theophylline, roflumilast, ariflo (siromilast), CP-325, 366, BY343, D-4396 (Sch-351591), AWD-12 281 (GW-842470), N- (3,5-dichloro-1-oxo-pyridin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide, NCS-613, pumafentine, (- ) 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-methyl-isothioureido] benzyl) -2-pyrrolidone, cis [4-cyano-4- (3-cyclopentyloxy-4) -Met Xylphenyl) 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], (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- ( t-butyl) -9H-pyrazo B [3,4-c] -1,2,4-triazolo [4,3-a] pyridine selected from the group consisting of racemates, enantiomers, diastereoisomers and pharmacologically acceptable It can be in the form of acid addition salts and hydrates.

  In a preferred embodiment of the present invention, PDEIV inhibitor 2 is enprofylline, roflumilast, ariflo (silomilast), AWD-12-281 (GW-842470), N- (3,5-dichloro-1-oxo-pyridine- 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- (t-butyl) -9H-pyrazolo [3,4-c] -1,2,4-triazolo [4,3-a] pyridine These may be in the form of racemates, enantiomers, diastereoisomers and pharmaceutically acceptable acid addition salts and hydrates.

In another preferred embodiment of the invention, the PDEIV inhibitor 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 Selected from -cyclopentyl-5,6-dihydro-7-ethyl-3- (t-butyl) -9H-pyrazolo [3,4-c] -1,2,4-triazolo [4,3-a] pyridine However, roflumilast, Z-15370 and AWD-12-281 are particularly preferred as compound 2 in the present invention.
In yet another preferred embodiment of the invention, the PDEIV inhibitor is 2- (4-fluoro-phenoxy) -N- {4-[(6-fluoro-2-hydroxy-benzoylamino) -methyl] -benzyl. } Nicotinamide, 2- (4-fluoro-phenoxy) -N- {4-[(5-fluoro-2-hydroxy-benzoylamino) -methyl] -benzyl} nicotinamide, 2- (4-fluoro-phenoxy) -N- {4-[(3-hydroxy-4-methyl-benzoylamino) methyl] benzyl} nicotinamide, 2- (4-fluoro-phenoxy) -N- {4-[(3hydroxy-benzoylamino)- Methyl] -benzyl} nicotinamide, 2- (4-fluoro-phenoxy) -N- {4-[(2-hydroxy-benzoylamino) methyl] -benzyl} nicotinamide, 2- (4-fluoro-phenoxy)- N- {4-[(4-hydroxy-benzoylamino) methyl] -benzyl} nicotinamide, 2- (4-fluoro-phenoxy) -N- {4-[(2-hydroxy-4- Til-benzoylamino) methyl] -benzyl} nicotinamide, 2- (4-fluoro-phenoxy) -N- {4-[(3-hydroxy-2-methyl-benzoylamino) methyl] -benzyl} nicotinamide, 2 -(4-Fluoro-phenoxy) -N- {4-[(2-hydroxy-5-methyl-benzoylamino) methyl] -benzyl} nicotinamide, 5-fluoro-2- (4-fluoro-phenoxy) -N -{4-[(2-hydroxy-benzoylamino) methyl] -benzyl} nicotinamide, 5-fluoro-2- (4-fluoro-phenoxy) -N- {4-[(2-hydroxy-acetylamino) methyl ] -Benzyl} nicotinamide, 5-fluoro-2- (4-fluoro-phenoxy) -N- {4-[(4-hydroxy-benzoylamino) methyl] -benzyl} nicotinamide, 3- (3- {4 -[(3-Hydroxy-benzoylamino) methyl] -benzylcarbamoyl} -pyridin-2-yloxy) benzoic acid ethyl ester, 3- (3- {4-[(2-hydroxy -Phenacetylamino) methyl] -benzylcarbamoyl} -pyridin-2-yloxy) benzoic acid ethyl ester, 3- (3- {4-[(3-hydroxy-phenacetylamino) methyl] -benzylcarbamoyl} -pyridine- 2-yloxy) benzoic acid ethyl ester, 3- (3- {4-[(4-hydroxy-phenacetylamino) methyl] -benzylcarbamoyl} -pyridin-2-yloxy) benzoic acid ethyl ester, compound (2. a) and compound (2.b):

These may be in the form of racemates, enantiomers, diastereoisomers and pharmaceutically acceptable acid addition salts and hydrates.
The pharmaceutically acceptable salt forms of the combination of compounds according to the invention are mostly prepared by conventional means. When the component compound has a carboxylic acid group, a suitable salt can be formed by reacting the compound with a suitable base to form the corresponding base addition salt. Examples of such bases include alkali metal hydroxides including potassium hydroxide, sodium hydroxide and lithium hydroxide, alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide, potassium Examples include alkali metal alkoxides such as ethanolate and sodium propanolate, and various organic bases such as piperidine, diethanolamine and N-methylglutamine. Moreover, the aluminum salt of the component compound of this invention is also mentioned.
In certain component compounds, acid addition salts such as hydrohalides such as hydrochloride, hydrobromide, hydroiodide, etc. by treating the compound with pharmaceutically acceptable organic and inorganic acids (Hydrohalides), other inorganic acids and corresponding salts such as sulfates, nitrates, phosphates, etc., alkylaryl sulfonates and monoaryl sulfonates such as ethane sulfonate, toluene sulfonate and benzene sulfonate, and other organic acids and acetates, Corresponding salts such as tartrate, maleate, succinate, citric acid, benzoate, salicylate, ascorbate and the like can be formed.
Accordingly, pharmaceutically acceptable acid addition salts of the component compounds of the present invention include acetate, adipate, alginate, alginate, aspartate, benzoate, benzenesulfonate (besylate), heavy salt. Sulfate, bisulfite, bromide, butyrate, camphorsulfonate, caprylate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, phosphorus dihydrogen Acid salt, dinitrobenzoate, dodecyl sulfate, ethane sulfonate, fumarate, galactarate (from mucoic acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, Hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy Roxyethane sulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methyl Benzoate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamonate, 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 include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, And pharmaceutically acceptable salts selected from the salts of tartaric acid, 1-hydroxy-2-naphthalenecarboxylic acid or maleic acid. If desired, salt 2 can be prepared using a mixture of the acids.
In the pharmaceutical composition of the present invention, Compound 2 may exist in the form of a racemate, an enantiomer or a mixture thereof. To separate an enantiomer from a racemate, a method known in this field (for example, chromatography in a chiral phase, etc.) may be used.
One aspect of the present invention relates to said pharmaceutical composition comprising a pharmaceutically acceptable carrier in addition to a therapeutically effective amount of 1 and 2. Another aspect of the present invention relates to the aforementioned pharmaceutical composition which does not contain a pharmaceutically acceptable carrier in addition to a therapeutically effective amount of 1 and 2.
The present invention also relates to the use of a therapeutically effective amount of salt 1 for the manufacture of a pharmaceutical composition containing a PDEIV inhibitor 2 for the treatment of inflammatory or obstructive airway diseases. Preferably, the present invention relates to said use for producing a pharmaceutical composition for the treatment of asthma or COPD.

Within the scope of the present invention, compounds 1 and 2 may be administered simultaneously or sequentially, but in the present invention, simultaneous administration of compounds 1 and 2 is preferred.
The invention also relates to the use of a therapeutically effective amount of salt 1 and PDEIV inhibitor 2 for the treatment of inflammatory or obstructive respiratory diseases, especially asthma or COPD.
The ratio of active ingredients 1 and 2 that can be used in the active ingredient combination of the present invention varies. Active ingredients 1 and 2 may be present in the form of solvates or hydrates. Depending on the choice of compounds 1 and 2, the mass ratio that can be used within the scope of the present invention will vary due to the difference in molecular weight of the various salt forms.
In general, the pharmaceutical combinations of the present invention should contain compounds 1 and 2 in a weight ratio of 1: 100 to 100: 1, preferably 1:80 to 80: 1. In particularly preferred pharmaceutical combinations comprising one of the most preferred compounds as component 2 aliflo, roflumilast or AWD-12-281, 1 ′ and 2 are about 1:50 to 50: 1, more preferably 1:20. A range present in a ratio of ˜20: 1 is most preferred as a mass ratio of 1 to 2.
Although not limiting the present invention, for example, preferred combinations of 1 ′ and PDE-IV inhibitor 2 (eg, Ariflo, Roflumilast or AWD-12-281) may be included in the following mass ratios. 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 pharmaceutical composition of the present invention comprising a combination of 1 and 2 is usually 0.01 to 10,000 μg, preferably 0.1 to 5000 μg, more preferably 1 to 3000 μg, further preferably 10 to 2000 μg, more preferably 20 to 1500 μg, Preferably, 1 and 2 are administered together in a single dose of 50 to 1200 μg. For example, the combination of 1 and 2 of the present invention includes a total dose of about 100 μg, 105 μg, 110 μg, 115 μg, 120 μg, 125 μg, 130 μg, 135 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 , 295μg, 300μg, 305μg, 310μg, 315μg, 320μg, 325μg, 330μg, 335μg, 340μg, 345μg, 350μg, 355μg, 360μg, 365μg, 370μg, 375μg, 380μg, 385μg, 390μg, 395μg, 410μg, 405μg, 410μg , 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, 540 μg, 535 μg , 545μg, 550μg, 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 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 855μg, 860μg, 865μg, 870μg, 875μg, 880μg, 885μg, 890μg, 895μg, 900μg, 905μg, 910μg, 915μg, 920μg, 925μg, 930μg, 935μg, 940μg, 945μg, 950μg, 955μg, 960μg, 965μg, 970μg 980μg, 985μg, 990μg, 995μg, 1000μg, 1005μg, 1010μg, 1015μg, 1020μg, 1025μg, 1030μg, 1035μg, 1040μg, 1045μg, 1050μg, 1055μg, 1060μg, 1065μg, 1070μg, 1075μg, 1075μg, 1075μg, 1075μg 1105μg, 1110μg, 1115μg, 1120μg, 1125μg, 1130μg, 1135μg, 1140μg 1145 μg 1150 μg 1155 μg 1125 μg 1270 μg 1275 μg , 1395μg, 1400μg, 1405μg, 1410μg, 1415μg, 1420μg, 1425μg, 1430μg, 1435μg, 1440μg, 1445μg, 1450μg, 1455μg, 1460μg, 1465μg, 1470μg, 1475μg, 1480μg, 1485μg, 1480μg, , 1520μg, 1525μg, 1530μg, 1535μg, 1540μg, 1545μg, 1550μg, 1555μg, 1560μg, 1565μg, 1570μg, 1575μg, 1580μg, 1585μg, 1590μg, 1595μg, 1600μg, 1605μg, 1610μg, 1605μg, 1610μg, 1605μg , 1645 μg, 1650 μg, 1655 μg, 1660 μg, 1665 μg, 1670 μg, 1675 μg, 1680 μg, 1685 μg, 1690 μg, 1695 μg, 1700 μg, 1705 μg, 1710 μg, 1715 μg, 1720 μg, 1730 μg, 1730 μg, 1730 μg, 1730 μg, 1730 μg , 1770μg, 1775μg, 1780μg, 1785μg, 1790μg, 1795μg, 1800μg, 1805μg, 1810μg, 1815μg, 1820μg, 1825μg, 1830μg, 1835μg, 1840μg, 1845μg, 1850μg, 1855μg, 1855μg 1895μg, 1900μg, 1905μg, 1910μg, 1915μg, 1920μg, 1925μg, 1930μg, 1935μg, 1940μg, 1945μg, 1950μg, 1955μg, 1960μg, 1965μg, 1970μg, 1975μg, 1980μg, 1985μg, 1990, 1985μg, 1990 The amount of 1 'and PDE-IV inhibitor 2 (eg, Ariflo, Roflumilast or AWD-12-281) is included. The recommended dose for a single dose as described above should not be considered limited to the values actually described, but as the dose disclosed as an example. Of course, the above-mentioned values given as examples are also included in doses that are increased or decreased within the range of about ± 2.5 μg. In such a dosage range, the active ingredients 1 'and 2 may be present in the mass ratios described above.

  Without limiting the scope of the present invention, for example, in the combination of 1 and 2 according to the present invention, 1 ′ and a PDE-IV inhibitor 2 (eg Ariflo, Roflumilast or AWD-12-281) It may be contained in the following amounts for each administration. 16.5 µg 1 'and 25 µg 2, 16.5 µg 1' and 50 µg 2, 16.5 µg 1 'and 100 µg 2, 16.5 µg 1' and 200 µg 2, 16.5 µg 1 'and 300 µg 2, 16.5 µg 1 'and 400 µg 2, 16.5 µg 1' and 500 µg 2, 16.5 µg 1 'and 600 µg 2, 16.5 µg 1' and 700 µg 2, 16.5 µg 1 'and 800 µg 2, 16.5 μg 1 ′ and 900 μg 2, 16.5 μg 1 ′ and 1000 μg 2, 16.5 μg 1 ′ and 1250 μg 2, 16.5 μg 1 ′ and 1500 μg 2, 16.5 μg 1 ′ and 1750 μg 2, 16.5 µg 1 'and 2000 µg 2, 33.0 µg 1' and 25 µg 2, 33.0 µg 1 'and 50 µg 2, 33.0 µg 1' and 100 µg 2, 33.0 µg 1 'and 200 µg 2, 33.0 μg 1 ′ and 300 μg 2, 33.0 μg 1 ′ and 400 μg 2, 33.0 μg 1 ′ and 500 μg 2, 33.0 μg 1 ′ and 600 μg 2, 33.0 μg 1 ′ and 700 μg 2, 33.0 μg 1 ′ and 800 μg 2, 33.0 μg 1 ′ and 900 μg 2, 33.0 μg 1 ′ and 1000 μg 2, 33.0 μg 1 ′ and 1250 μg 2, 33.0 μg 'And 1500 µg 2, 33.0 µg 1' and 1750 µg 2, 33.0 µg 1 'and 2000 µg 2, 49.5 µg 1' and 25 µg 2, 49.5 µg 1 'and 50 µg 2, and 49.5 µg 1 'And 100µg 2, 49.5µg 1' and 200µg 2, 49.5µg 1 'and 300µg 2, 49.5µg 1' and 400µg 2, 49.5µg 1 'and 500µg 2, 49.5µg 1 'And 600µg 2, 49.5µg 1' and 700µg 2, 49.5µg 1 'and 800µg 2, 49.5µg 1' and 900µg 2, 49.5µg 1 'and 1000µg 2, 49.5µg 1 'And 1250μg 2, 49.5μg 1' and 1500μg 2, 49.5μg 1 'and 1750μg 2, 49.5μg 1' and 2000μg 2, 82.5μg 1 'and 25μg 2, 82.5μg 1 'And 50 µg 2, 82.5 µg 1' and 100 µg 2, 82.5 µg 1 'and 200 µg 2, 82.5 µg 1' and 300 µg 2, 82.5 µg 1 'and 400 µg 2, and 82.5 µg 1 'And 500 µg 2, 82.5 µg 1' and 600 µg 2, 82.5 µg 1 'and 700 µg 2, 82.5 µg 1' and 800 µg 2, 82.5 µg 1 'and 90 0 µg 2, 82.5 µg 1 'and 1000 µg 2, 82.5 µg 1' and 1250 µg 2, 82.5 µg 1 'and 1500 µg 2, 82.5 µg 1' and 1750 µg 2, 82.5 µg 1 ' 2000 µg 2, 165.0 µg 1 'and 25 µg 2, 165.0 µg 1' and 50 µg 2, 165.0 µg 1 'and 100 µg 2, 165.0 µg 1' and 200 µg 2, 165.0 µg 1 ' 300 µg 2, 165.0 µg 1 'and 400 µg 2, 165.0 µg 1' and 500 µg 2, 165.0 µg 1 'and 600 µg 2, 165.0 µg 1' and 700 µg 2, 165.0 µg 1 ' 800 μg 2, 165.0 μg 1 ′ and 900 μg 2, 165.0 μg 1 ′ and 1000 μg 2, 165.0 μg 1 ′ and 1250 μg 2, 165.0 μg 1 ′ and 1500 μg 2, 165.0 μg 1 ′ 1750 μg 2, 165.0 μg 1 ′ and 2000 μg 2, 206.2 μg 1 ′ and 25 μg 2, 206.2 μg 1 ′ and 50 μg 2, 206.2 μg 1 ′ and 100 μg 2, 206.2 μg 1 ′ 200 µg 2, 206.2 µg 1 'and 300 µg 2, 206.2 µg 1' and 400 µg 2, 206.2 µg 1 'and 500 µg 2, 206.2 1 'and 600 µg 2, 206.2 µg 1' and 700 µg 2, 206.2 µg 1 'and 800 µg 2, 206.2 µg 1' and 900 µg 2, 206.2 µg 1 'and 1000 µg 2, 206.2 µg μg 1 ′ and 1250 μg 2, 206.2 μg 1 ′ and 1500 μg 2, 206.2 μg 1 ′ and 1750 μg 2, 206.2 μg 1 ′ and 2000 μg 2, 412.5 μg 1 ′ and 25 μg 2, 412.5 μg 1 ′ and 50 μg 2, 412.5 μg 1 ′ and 100 μg 2, 412.5 μg 1 ′ and 200 μg 2, 412.5 μg 1 ′ and 300 μg 2, 412.5 μg 1 ′ and 400 μg 2, 412.5 μg 1 ′ and 500 μg 2, 412.5 μg 1 ′ and 600 μg 2, 412.5 μg 1 ′ and 700 μg 2, 412.5 μg 1 ′ and 800 μg 2, 412.5 μg 1 ′ and 900 μg 2, 412.5 μg 1 ′ and 1000 μg 2, 412.5 μg 1 ′ and 1250 μg 2, 412.5 μg 1 ′ and 1500 μg 2, 412.5 μg 1 ′ and 1750 μg 2, 412.5 μg 1 ′ and 2000 μg 2.

  When an active ingredient combination in which 1 represents bromide is used as a preferred combination of 1 and 2 according to the present invention, the dosages of active ingredients 1 ′ and 2 given as one example given in one administration are Corresponds to a single dose of 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, and 20 μg 1 1250μg 2, 20μg 1 and 1500μg 2, 20μg 1 and 1750μg 2, 20μg 1 and 2000μg 2, 40μg 1 and 25μg 2, 40μg 1 and 50μg 2, 40μg 1 and 100μg 2, 40 μg 1 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, 40 μg 1 and 600 μg 2, 40 μg 1 and 700 μg 2, 40μg 1 and 800μg 2, 40μg 1 and 900μg 2, 40μg 1 and 1000μg 2, 40μg 1 and 1250μg 2, 40μg 1 and 1500μg 2, 40μg 1 and 1750μg 2, 40μg 1 and 2000μg 2, 60μg 1 and 25μg 2, 60μg 1 and 50μg 2, 60μg And 100 μg 2, 60 μg 1 and 200 μg 2, 60 μg 1 and 300 μg 2, 60 μg 1 and 400 μg 2, 60 μg 1 and 500 μg 2, 60 μg 1 and 600 μg 2, 60 μg 1 and 700 μg 2, 60μg 1 and 800μg 2, 60μg 1 and 900μg 2, 60μg 1 and 1000μg 2, 60μg 1 and 1250μg 2, 60μg 1 and 1500μg 2, 60μg 1 and 1750μg 2 60 μg 1 and 2000 μg 2, 100 μg 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 400μg 2, 100μg 1 and 500μg 2, 100μg 1 and 600μg 2, 100μg 1 and 700μg 2, 100μg 1 and 800μg 2, 100μg 1 and 900μg 2, 100μg 1 100μg 1 and 1250μg 2, 100μg 1 and 1500μg 2, 100μg 1 and 1750μg 2, 100μg 1 and 2000μg 2, 200μg 1 and 25μg 2, 200μg 1 and 50μg 2, 200μg 1 and 100μg 2, 200μg 1 and 200μg 2 200 μg 1 and 300 μg 2, 200 μg 1 and 400 μg 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 1 and 1250 μg 2, 200 μg 1 and 1500 μg 2, 200 μg 1 and 1750 μg 2, 200 μg 1 and 2000 μg 2, and 250 μg 1 25 μg 2, 250 μg 1 and 50 μg 2, 250 μg 1 and 100 μg 2, 250 μg 1 and 200 μg 2, 250 μg 1 and 300 μg 2, 250 μg 1 and 400 μg 2, 250 μg 1 and 500 μg 2, 250 μg 1 and 600 μg 2, 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, 500 μg 1 and 25 μg 2, 500 μg 1 and 50 μg 2, 500 μg 1 and 100 μg 2, 500 μg 1 and 200μg 2, 500μg 1 and 300μg 2, 50 0 μg 1 and 400 μg 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, 500 μg 1 and 1000 μg 2, 500 μg 1 and 1250 μg 2, 500 μg 1 and 1500 μg 2, 500 μg 1 and 1750 μg 2, 500 μg 1 and 2000 μg 2.

Although examples of possible dosages suitable for the combinations of the present invention have been described, it should be understood that these refer to dosages in a single administration. However, these examples should not be understood as excluding the possibility of administering the combination of the present invention multiple times. Patients can also receive multiple inhalation doses depending on medical needs. In one example, a patient can receive the combination of the present invention 2-3 times in the morning, eg, every treatment day (eg, 2-3 inhalations using a powder inhaler, MDI, etc.). The above-described dosage examples are to be understood merely as examples of dosages per single administration (ie, single inhalation), and multiples of the above examples if the combination of the present invention is administered multiple times. Of dose. For example, the combination of the present invention can be administered once a day, or twice a day or once every two or three days depending on the effective time of the anticholinergic drug.
It is further emphasized that the above dosage examples should only be understood as quantified dosage examples. In other words, the above dosage examples should not be understood as the effective dosage at which the combination of the present invention actually reaches the lungs. It will be apparent to those skilled in the art that the amount delivered to the lung is usually less than the dose of active ingredient administered in a quantified manner.

  The combination of active ingredients 1 and 2 according to the invention is preferably administered by inhalation. To that end, ingredients 1 and 2 must be available in a form suitable for inhalation. According to the present invention, inhalable formulations include inhalable powders, quantified aerosols containing propellants, and inhalable solutions containing no propellants. An inhalable powder according to the present invention containing a combination of active ingredients 1 and 2 may consist of only the active ingredient or a mixture of the active ingredient and a pharmaceutically acceptable excipient. Within the scope of the present invention, the term carrier may be used in place of the term excipient. The term propellant-free inhalable solution within the scope of the present invention also includes concentrates or ready-to-use sterile inhalation solutions. The preparations of the present invention may be a combination of active ingredients 1 and 2 combined into one formulation or may be included as two separate formulations. Formulations that can be used within the scope of the present invention are described in more detail in the next part of the specification.

A) Inhalable powder comprising a combination of active ingredients 1 and 2 according to the invention:
Inhalable powders according to the present invention may contain only 1 and 2, or 1 and 2 in admixture with suitable pharmaceutically acceptable excipients.
When active ingredients 1 and 2 are present as a mixture with pharmaceutically acceptable excipients, the inhalable powders of the present invention can be prepared using the following pharmaceutically acceptable excipients. Monosaccharides (eg glucose or arabinose), disaccharides (eg lactose, saccharose, maltose, trehalose), oligosaccharides and polysaccharides (eg dextran), polyhydric alcohols (eg sorbitol, mannitol, xylitol), cyclo Dextrins (for example, α-cyclodextrin, β-cyclodextrin, χ-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin), salts (for example, sodium chloride, calcium carbonate), or these additives A mixture of forms. Preferably, monosaccharides or disaccharides are used, with the use of lactose, trehalose or glucose being preferred, and without limitation, the hydrate form is particularly preferred.
In the range of inhalable powders according to the invention, the maximum average particle size of the excipient is up to 250 μm, preferably 10-150 μm, most preferably 15-80 μm. It may be considered appropriate to add a finer excipient fraction with an average particle size of 1-9 μm to the excipient. Finer excipients are also selected from the group of usable excipients listed herein above. Finally, to prepare the inhalable powder of the present invention, finely divided active ingredients 1 and 2, preferably having an average particle size of 0.5 to 10 μm, more preferably 1 to 6 μm, are added to the excipient mixture. The method for producing the inhalable powder of the present invention by pulverizing, pulverizing and finally mixing the respective components is known from the prior art. The inhalation powders of the present invention can be prepared and administered either in a single powder mixture containing both 1 and 2, or in the form of separate inhalation powders containing only 1 or 2 each. .

The inhalable powders according to the invention can be administered using inhalers known from the prior art. Inhalable powders according to the invention comprising one or more pharmaceutically acceptable excipients in addition to 1 and 2 can be administered in a single dose from a source using a metering chamber as described, for example, in US4570630A It can be administered by an inhaler that releases the quantity or by other means as described in DE 3625685A. Inhalable powders according to the invention, which may contain 1 and 2 and also pharmaceutically acceptable excipients, are for example inhalers known under the name “Turbuhaler®”. Or can be administered using an inhaler such as that disclosed, for example, in EP237507A. Preferably, the inhalable powder of the present invention containing pharmaceutically acceptable excipients in addition to 1 and 2 is filled into capsules used in inhalers as described in WO94 / 28958 (so-called inhalettes). Form.
FIG. 1 shows a particularly preferred inhaler for using the pharmaceutical combination of the invention in inhalette state.
This inhaler (“Handy Heller”) for inhaling a powdered pharmaceutical composition from a capsule has a housing 1 comprising two windows 2 and an air inlet and is fixed via a screen housing 4. A deck 3 provided with a screen 5, a suction chamber 6 connected to the deck 3 and having a push button 9 provided with two pointed pins 7 and movable with respect to a spring 8, and a housing 1 via a spindle 10. It is characterized by a mouthpiece 12 that is connected to the deck 3 and the cover 11 and can be opened and closed in a flip-up manner, and an air hole 13 for adjusting the flow resistance.
When the inhalable powder of the present invention is filled into capsules (inhalers) for the above preferred use, the amount to be filled in each capsule is preferably 1 to 30 mg per capsule. In the present invention, these capsules contain 1 or 1 'and 2 doses for each administration described above together or separately.

B) Propellant gas driven inhalation aerosol comprising a combination of active ingredients 1 and 2:
In the propellant gas-containing inhalation aerosol according to the present invention, the active ingredients 1 and 2 are dissolved in the propellant gas or contained in a dispersed state. 1 and 2 can be present in separate formulations or single preparations, in which 1 and 2 are both dissolved or dispersed, or one component is dissolved and the other is dispersed Either. Propellant gases that can be used for the preparation of the inhaled aerosols according to the invention are known from the prior art. A suitable propellant gas is selected from hydrocarbon compounds such as n-propane, n-butane or isobutane and halohydrocarbon compounds such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. . The propellant gas can be used alone or as a mixture thereof. Particularly preferred propellant gases are TG11, TG12, TG134a (1,1,1,2-tetrafluoroethane) and TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof. Among them, a propellant gas of TG134a, TG227, and a mixture thereof is preferable.
The propellant-driven inhalation aerosol of the present invention can also contain other components such as cosolvents, stabilizers, surfactants, antioxidants, lubricants and pH adjusters. All of these components are known in the art.
The propellant gas-containing inhalation aerosol according to the present invention may contain up to 5% by mass of active ingredient 1 and / or 2. For example, the aerosol of the present invention contains 0.002 to 5% by mass, 0.01 to 3% by mass, 0.012 to 2% by mass, 0.1 to 2% by mass, 0.5 to 2% by mass, or 0.5 to 1% by mass of the active ingredient 1 and / or 2. % Is included.
When the active ingredients 1 and / or 2 are present in a dispersed state, the average particle diameter of the active ingredient particles is preferably up to 10 μm, more preferably 0.1 to 6 μm, more preferably 1 to 5 μm.
The propellant-driven inhalation aerosol according to the present invention described above can be administered using an inhaler known in the art (metered dose inhaler (MDI)).
Accordingly, another aspect of the present invention relates to a propellant-driven aerosol state pharmaceutical composition in combination with one or more inhalers suitable for administering a propellant-driven aerosol. Furthermore, the present invention relates to an inhaler characterized in that it contains the propellant gas-containing aerosol according to the present invention. The invention also relates to a cartridge provided with a suitable valve, which can be used in a suitable inhaler and which contains one of the propellant gas-containing inhalation aerosols according to the invention. Suitable cartridges, as well as methods for filling the cartridges with the propellant gas-containing inhalation aerosol according to the invention are known from the prior art.

C) A propellant-free inhalable solution or suspension comprising a combination of active ingredients 1 and 2 according to the invention:
Inhalable solutions and suspensions containing no propellant according to the invention contain, for example, an aqueous or alcoholic solvent, preferably an ethanolic solvent, but ethanolic solvents and aqueous solvents may be mixed. When using a mixture of an aqueous solvent and an ethanolic solvent, the relative ratio of ethanol to water is not limited, but up to 70% by volume of ethanol, more preferably up to 60% by volume. The remaining volume is made up of water. Solutions or suspensions containing 1 and 2 separately or together are adjusted to a pH value of 2-7, preferably 2-5, using a suitable acid. The pH value may be adjusted using an acid selected from inorganic acids 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. Recommended inorganic acids are hydrochloric acid and sulfuric acid. It is also possible to use an acid that forms an acid addition salt with one of the active ingredients. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the above acids can also be used, in particular in addition to the acidifying properties, for example acids having properties as perfumes, antioxidants or complexing agents, such as citric acid or ascorbic acid. In such a case, it is better to use a mixture. According to the invention, it is particularly preferred to adjust the pH value with hydrochloric acid.

In the present invention, it is not necessary in the formulation of the present invention to add edetic acid (EDTA) or one of its known salts, sodium edetate, as a stabilizer or complexing agent. Depending on the embodiment, one or more compounds may be included. 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, an inhalation solution with a sodium edetate content in the range of 0-10 mg / 100 ml is preferred.
Co-solvents and / or other excipients can be added to the inhalation solution containing no propellant according to the invention. Preferred cosolvents are those containing hydroxyl groups or other polar groups such as alcohols, especially isopropyl alcohol, glycols, especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and poly Oxyethylene fatty acid esters. The terms excipients and additives herein are not active substances per se, but can be formulated with one or more active substances in a pharmacologically suitable solvent. Means any pharmacologically acceptable substance capable of improving the qualitative properties of a formulation comprising These substances preferably have no pharmacological action. Alternatively, it is preferable that there is no pharmacological action that can be easily recognized in the context of the desired therapy, or at least no undesirable pharmacological action. Examples of excipients and additives include soy lecithin, oleic acid, sorbitan esters such as polysorbate, surfactants such as polyvinylpyrrolidone, other stabilizers, complexing agents, and maintenance of the quality of the final pharmaceutical formulation. Antioxidants and / or preservatives, flavoring agents, vitamins and / or other additives known in the art that guarantee or extend the duration may be mentioned. Examples of the isotonic agent include pharmacologically acceptable salts such as sodium chloride.
Preferred excipients include, for example, antioxidants such as ascorbic acid when not used for pH adjustment, as well as vitamin A, vitamin E, tocopherols and similar vitamins and provitamins produced in the human body. Can be mentioned.

Preservatives can be used to protect the formulation from contamination with pathogens. Suitable preservatives are those known in the art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoates such as benzoic acid or sodium benzoate known in the art. The preservative is preferably present at a concentration in the range of up to 50 mg / 100 ml, more preferably 5-20 mg / 100 ml.
Preferred formulations contain only benzalkonium chloride and sodium edetate, in addition to water as solvent and the combination of active ingredients 1 and 2. There are also recommended embodiments that do not contain sodium edetate.
The propellant-free inhalation solution of the present invention is an inhaler of the type that is capable of producing a suitable aerosol for therapeutic inhalation, particularly by atomizing a small dose of a liquid dosage formulation within a few seconds. Is administered. Within the scope of the present invention, an active ingredient solution in an amount of less than 100 μL, preferably less than 50 μL, more preferably 20-30 μL can be atomized, preferably in a single spray operation, resulting in an average particle size A preferred inhaler is an inhaler capable of producing an aerosol having a diameter of less than 20 μm, preferably less than 10 μm, such that an inhalable amount of aerosol corresponds to a therapeutically effective amount.
Inhalation devices of the type that release a metered amount of a liquid pharmaceutical composition without a propellant are described, for example, in international patent applications WO 91/14468 and WO 97/12687 (see in particular FIGS. 6a and 6b). The nebulizers (devices) described therein are known under the name “Respimat®”.

This nebulizer (“Respimat®”) can be effectively utilized to produce an inhalation aerosol of the present invention that includes a combination of active ingredients 1 and 2.
Because the device is cylindrical and easy to handle with a length of 9-15 cm and a width of less than 2-4 cm, the patient can always carry it. This nebulizer sprays a predetermined amount of a pharmaceutical formulation from a small nozzle using high pressure to generate an inhalation aerosol.
A preferred atomizer consists essentially of an upper housing part, a pump housing, a nozzle, a locking mechanism, a spring housing, a spring, and a storage container,
A pump housing fixed to the upper housing part and including a nozzle body with a nozzle or nozzle device at one end thereof,
-A hollow plunger with a valve body,
A power take-off flange with a hollow plunger fixed therein and arranged in the upper housing part;
-A locking mechanism located in the upper housing part,
-A spring housing which houses a spring inside and is pivotally attached to the upper housing part by means of a rotary bearing;
-Characterized by a lower housing part mounted axially on the spring housing.
A hollow plunger with a valve body corresponds to the device disclosed in WO 97/12687. The hollow plunger partially protrudes into the cylinder of the pump housing, and can move in the cylinder in the axial direction. It is described in particular in FIGS. 1 to 4, in particular in FIG. 3 and the associated description. The hollow plunger with valve body is 5-60 Mpa (about 50-600 bar), preferably 10-60 Mpa (about 50-60 bar) at the high pressure end for the fluid, i.e. the metered active ingredient solution, at the moment when the spring is actuated. Exert a pressure of 100-600 bar). The amount by one spray is preferably 10 to 50 μL, particularly preferably 10 to 20 μL, and most preferably 15 μL.

The valve body is preferably attached to the end of the hollow plunger facing the valve body.
The nozzles in the nozzle body preferably have a fine structure, i.e. are produced by microtechnology. A nozzle body having a fine structure is disclosed in, for example, WO 94/07607, and the contents of the present specification, particularly FIG. 1 and the related description are referred to.
The nozzle body is composed of, for example, two strongly bonded glass and / or silicon sheets, and at least one of the two sheets has a groove made of one or more fine structures. The nozzle inlet end is connected to the nozzle outlet end. The nozzle exit end has at least one circular or non-circular opening having a depth of 2 to 10 μm and a width of 5 to 15 μm, preferably a depth of 4.5 to 6.5 μm and a length of 7 to 9 μm.
When there are a plurality of nozzle openings, preferably two, the spray directions of the nozzles in the nozzle body may extend parallel to each other, or may be inclined with respect to each other in the nozzle opening direction. In a nozzle body having at least two nozzle openings at the outlet end, the direction of spraying should be at an angle of 20-160 °, preferably 60-150 °, most preferably 80-100 ° relative to each other. The nozzle openings are preferably arranged at an interval of 10 to 200 μm, more preferably 10 to 100 μm, and most preferably 30 to 70 μm. A spacing of 50 μm is most preferred. Therefore, the spray direction is matched in the vicinity of the nozzle opening.

The liquid pharmaceutical preparation hits the nozzle body at an inlet pressure of up to 600 bar, preferably 200-300 bar, and is atomized through the nozzle opening into an inhaled aerosol state. The preferred particle size of the aerosol or droplet size is up to 20 μm, preferably 3 to 10 μm.
The locking mechanism has a spring, preferably a cylindrical compression coil spring, for storing mechanical energy. This spring acts on the power take-out flange as the operating member, and the movement of the flange is determined by the position of the lock member. This movement of the power take-off flange is precisely defined by upper and lower stops. Due to the external torque generated when the upper housing part rotates counter to the spring housing in the lower housing part, the spring is preferably deflected via a power booster, for example a helical thrust gear. In this case, the upper housing part and the power take-off flange have a single or multiple V-shaped gears.
A locking member having a meshing locking surface is arranged in a ring around the power take-off flange. The locking member is made of, for example, a plastic or metal ring that can be elastically deformed in the radial direction. This ring is arranged in a plane perpendicular to the atomizer axis. After deflecting the spring, the locking surface of the locking member moves into the passage of the power take-off flange to prevent the spring from loosening. The locking member is actuated by a button. This actuating button is connected or coupled to the locking member. In order to activate the locking mechanism, the actuating button is moved parallel to the ring plane, preferably into the atomizer, whereby the deformable ring is deformed in the ring plane. Details regarding the configuration of the locking mechanism are described in WO 97/20590.

A lower housing portion is fitted axially from the top of the spring housing to accommodate the mounting, spindle drive and fluid reservoir.
When the nebulizer is activated, the upper housing part rotates relative to the lower housing part, and the lower housing part rotates the spring housing together. As a result, the spring is compressed and deflected by the helical thrust gear and the locking mechanism is automatically fitted. The rotation angle is preferably an integer degree of 360 degrees, for example, 180 degrees. At the same time as the spring is deflected, the power take-off in the upper housing part moves a predetermined distance and the hollow plunger is pulled back into the cylinder in the pump housing, so that part of the fluid is sucked from the storage container. And delivered to the high pressure chamber in front of the nozzle.
If desired, a number of replaceable storage containers containing the fluid to be sprayed can be pushed sequentially into the sprayer and used continuously. The storage container contains the aqueous aerosol preparation according to the invention.
The spraying process is started by lightly pressing the activation button. As a result, the lock mechanism opens the passage for the power take-out member. The deflected spring pushes the plunger into the cylinder of the pump housing. The fluid becomes mist and is discharged from the nozzle of the sprayer.
Further details on the structure are disclosed in PCT applications WO 97/12683 and WO 97/20590, which are hereby incorporated by reference.

The nebulizer components are made of materials suitable for that purpose. The nebulizer housing, as well as other parts, if permitted for operation, are likewise made, preferably of plastic, for example by injection moulding. Physiologically safe materials are used for medicinal purposes.
Fig. 6a / b of WO 97/12687 shows a nebulizer ("Respimat®") that can be used advantageously for inhalation of an aqueous aerosol formulation according to the invention.
FIG. 6a of WO 97/12687 is a longitudinal section of the sprayer with the spring deflected, while FIG. 6b of WO 97/12687 is a longitudinal section of the sprayer with the spring relaxed.
The upper housing part (51) accommodates the pump housing (52), at the end of which is attached a holder (53) for the sprayer nozzle. The holder has a nozzle body (54) and a filter (55). A hollow plunger (57) fixed in the power take-out flange (56) of the locking mechanism partially protrudes into the cylinder of the pump housing. The hollow plunger carries a valve body (58) at its end. The hollow plunger is sealed by sealing means (59). There is a stop (60) inside the upper housing part, and when the spring is loose, the power take-off flange abuts the stop. There is a stop (61) on the power take-off flange, and when the spring is deflected, the power take-off flange abuts against this stop. After deflection of the spring, the locking member (62) moves between the stop (61) in the upper housing part and the support (63). An activation button (64) is connected to the locking member. The upper housing part terminates with a mouthpiece (65) and 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 housing portion by a click (69) that snaps into place and a rotary bearing. The lower housing part (70) is placed over the spring housing. Inside the spring housing is a replaceable storage container (71) for the fluid (72) to be sprayed. The storage container is sealed with a stopper (73), the hollow plunger protrudes into the storage container through the stopper, and the end thereof is immersed in the fluid (supply of the active ingredient solution).
A mechanical counter spindle (74) is mounted in the cover of the spring housing. At the end of the spindle facing the upper housing part is a drive pinion (75). A slider (76) is disposed on the spindle.
The nebulizer is suitable for spraying the aerosol formulation of the present invention and produces an aerosol suitable for inhalation.
When the formulation of the present invention is nebulized using the method described above (“Respimat®”), it is released with an achievement of at least 97%, preferably at least 98% of the total operation (spray activation) of the inhaler. The amount may be an amount corresponding to a tolerance of 25% or less, preferably 20% or less with respect to the specified amount. Preferably, 5-30 mg, most preferably 5-20 mg of the formulation is released as a defined amount in a single spray action.

However, the formulations of the present invention can also be nebulized by inhalers other than those described above, for example, jet stream inhalers or other stationary atomizers.
Accordingly, a further aspect of the present invention is a pharmaceutical formulation in the form of an inhalable solution or suspension that does not contain a propellant as described above, and is suitable for administration of this formulation, preferably “Respimat”. And a pharmaceutical formulation in the form of an inhalation solution or suspension containing no propellant, in combination with (registered trademark) ”. Preferably, a propellant-free inhalation solution or suspension characterized by the combination of active ingredients 1 and 2 according to the invention, combined with a device known under the name “Respimat®” It relates to the inhalation solution or suspension. Furthermore, the present invention comprises an inhalation device, preferably “Respimat” (registered), characterized in that it contains an inhalation solution or suspension that does not contain the propellant of the present invention as described hereinbefore. Trademark) ”.
According to the invention, inhalable solutions containing active ingredients 1 and 2 in a single preparation are preferred. The term “single preparation” is intended to include preparations in which two components 1 and 2 are contained in a cartridge having two chambers as disclosed, for example, in WO 00/23037. The entire publication is cited herein.

Propellant-free inhalable solutions or suspensions according to the invention include concentrates or ready-to-use sterile inhalable solutions or suspensions, as well as the above solutions and suspensions designed for “Respimat®” It can be in a liquid state. In the case of a concentrate, a ready-to-use formulation can be made, for example, by adding isotonic saline. Ready-to-use sterile formulations can be administered using an energy-driven self-supporting or portable nebulizer that uses ultrasonic or compressed air to generate an inhalable aerosol according to Venturi's principle or other principles it can.
Accordingly, another aspect of the present invention relates to a pharmaceutical composition in the form of a concentrate or a ready-to-use aseptic formulation which does not contain a propellant as described above and which is in the form of an inhalation solution or suspension. A device suitable for administering a solution, i.e., an energy-driven self-supporting or portable nebulizer that uses ultrasonic or compressed air to generate inhalable aerosols according to the Venturi principle or other methods To a pharmaceutical composition in combination with a device characterized by
The following examples are intended to explain the present invention in more detail, and the scope of the present invention is not limited to the following embodiments by way of example. First, the preparation of Compound 1 that is not known in the art will be described.

1) Preparation of compound of formula 1 (bromide salt state)
1.1: 9-methyl-fluorene-9-carboxylic acid a) methyl 9-methyl-fluorene-9-carboxylate:
A sodium ethoxide solution is prepared from 7.6 g (0.33 mol) of sodium and 300 ml of ethanol, and 69.6 g (0.33 mol) of 9-fluorenecarboxylic acid is added in small portions. After the addition is complete, the mixture is stirred at ambient temperature for 2.5 hours. Thereafter, it is evaporated to dryness, the residue is suspended in 600 ml of dimethylformamide and 93.96 g (0.662 mol) of methyl iodide are added dropwise. The mixture is stirred at constant temperature for 3 hours. The resulting turbid solution is poured into 500 ml of water and 300 ml of diethyl ether with cooling to perform extraction. The organic phase is washed with water and 10% sodium carbonate solution, dried and evaporated to dryness. The residue is purified by column chromatography. Eluent: cyclohexane / ethyl acetate = 96: 4
Yield: 12.61 g of white crystals (= 16% of theory), melting point: 108-109 ° C.
b) 9-methyl-fluorene-9-carboxylic acid
12.6 g (0.053 mol) of methyl 9-methyl-fluorene-9-carboxylate and 53 ml of 2 molar aqueous sodium hydroxide solution are stirred in 120 ml of 1,4-dioxane for 24 hours at ambient temperature. Dioxane is distilled off, water is added to bring the total volume to 300 ml and extracted with diethyl ether. The aqueous phase is acidified with 3 molar aqueous hydrogen chloride solution, crystallized and filtered.
Yield: 11.25 g of white crystals (= 95% of theory), melting point: 168-169 ° C.

1.2: Tropenol 9-methyl-fluorene-9-carboxylate
6.73 g (0.03 mol) 9-methyl-fluorene-9-carboxylic acid was suspended in 60 ml dichloromethane, mixed with 5.0 g oxalyl chloride and 1 drop dimethylformamide, then stirred at ambient temperature for 1 hour. Finally, the solvent is distilled off. The remaining acidic chloride is used in the next step without further purification. 4.18 g (0.03 mol) tropenol and 4.27 g (0.033 mol) diisopropylethylamine are suspended in 100 ml dichloroethane and the acid chloride is added dropwise to 30 ml dichloroethane at 35-40 ° C. Thereafter, the mixture is stirred at 40 ° C. for 24 hours. The suspension is diluted with dichloromethane and extracted with dilute hydrochloric acid. The organic phase is washed with water and then dried over MgSO ₄ , and the product is converted to the hydrochloride salt using aqueous hydrogen chloride in diethyl ether. Remove solvent. For purification, the precipitated hydrochloride is dissolved in water and extracted with diethyl ether. The aqueous phase is basified with 10% aqueous sodium carbonate solution and extracted with dichloromethane. The organic phase is dried over MgSO ₄ and the solvent is distilled off.
Yield: 4.40 g of yellow oil (= 42% of theory)
1.3: Scopine 9-methyl-fluorene-9-carboxylate
2.5 g (0.007 mol) of tropenol 9-methyl-fluorene-9-carboxylate is suspended in about 25 ml of dimethylformamide and mixed with 0.13 g (0.001 mol) of vanadium pentoxide. A solution prepared by dissolving 1.43 g (0.015 mol) of H ₂ O ₂ -urea in about 5.5 ml of water is dropped at 60 ° C. and stirred at 60 ° C. for 6 hours. After cooling to 20 ° C., the precipitate formed is filtered off with suction, the filtrate is adjusted to pH 2 with 4N hydrochloric acid and mixed with Na ₂ S ₂ O ₅ dissolved in water. The resulting solution is evaporated to dryness and the residue is extracted with dichloromethane / water. The acidic aqueous phase is basified with Na ₂ CO ₃ and then extracted with dichloromethane, and the organic phase is dried and concentrated with Na ₂ SO ₄ . In addition, about 0.4 ml of acetyl chloride is added at ambient temperature and the mixture is stirred for 1 hour. After extraction with 1N hydrochloric acid, the aqueous phase is made basic and extracted with dichloromethane. The organic phase is washed with water and dried over Na ₂ SO ₄ . Thereafter, the solvent is distilled off. The crude product is purified by recrystallization from diethyl ether.
Yield: 1.8 g of white crystals (= 71% of theory)

1.4: scopin 9-methyl-fluorene-0-carboxylate methobromide
1.8 g (0.005 mol) of scopine 9-methyl-fluorene-9-carboxylate is dissolved in 30 ml of acetonitrile and reacted with 2.848 g (0.015 mol) of 50% methyl bromide solution in acetonitrile. The reaction mixture is left at ambient temperature for 3 days, during which time the product crystallizes. The precipitated crystals are collected and purified by recrystallization from diethyl ether.
Yield: 1.6 g of white crystals (= 70% of theory), melting point: 214 ° C.
Calculated elemental analysis C (62.13) H (5.93) N (4.26)
Found C (62.23) H (6.05) N (4.32).

2) Formulation Examples The following formulation examples can be obtained in the same manner as known in the art, but these are for explaining the present invention in more detail. Is not limited.
Inhalable powder:
1)

2)

3)

4)

5)

6)

7)

8)

9)

10)

11)

12)

13)

^*) 2 = represents the following compounds, respectively.
2- (4-Fluoro-phenoxy) -N- {4-[(2hydroxy-3-methyl-benzoylamino) -methyl] -benzyl} -nicotinamide, 3- (3- {4-[(3-hydroxy -Benzoylamino) -methyl] -benzylcarbamoyl} -pyridin-2-yloxy) -benzoic acid ethyl ester, 2- (4-fluoro-phenoxy) -N- {4-[(6-fluoro-2-hydroxy-benzoyl) Amino) -methyl] -benzyl} nicotinamide, 2- (4-fluoro-phenoxy) -N- {4-[(5-fluoro-2-hydroxy-benzoylamino) -methyl] -benzyl} nicotinamide, 2- (4-Fluoro-phenoxy) -N- {4-[(3-hydroxy-4-methyl-benzoylamino) methyl] benzyl} nicotinamide, 2- (4-fluoro-phenoxy) -N- {4-[( 3hydroxy-benzoylamino) -methyl] -benzyl} nicotinamide, 2- (4-fluoro-phenoxy) -N- {4-[(2-hydroxy-benzoylamino) methyl] -benzyl} ni Tinamide, 2- (4-fluoro-phenoxy) -N- {4-[(4-hydroxy-benzoylamino) methyl] -benzyl} nicotinamide, 2- (4-fluoro-phenoxy) -N- {4- [ (2-hydroxy-4-methyl-benzoylamino) methyl] -benzyl} nicotinamide, 2- (4-fluoro-phenoxy) -N- {4-[(3-hydroxy-2-methyl-benzoylamino) methyl] -Benzyl} nicotinamide, 2- (4-fluoro-phenoxy) -N- {4-[(2-hydroxy-5-methyl-benzoylamino) methyl] -benzyl} nicotinamide, 5-fluoro-2- (4 -Fluoro-phenoxy) -N- {4-[(2-hydroxy-benzoylamino) methyl] -benzyl} nicotinamide, 5-fluoro-2- (4-fluoro-phenoxy) -N- {4-[(2 -Hydroxy-acetylamino) methyl] -benzyl} nicotinamide, 5-fluoro-2- (4-fluoro-phenoxy) -N- {4-[(4-hydroxy-benzoylamino) methyl] -benzi L} nicotinamide, 3- (3- {4-[(3-hydroxy-benzoylamino) methyl] -benzylcarbamoyl} -pyridin-2-yloxy) benzoic acid ethyl ester, 3- (3- {4-[( 2-Hydroxy-phenacetylamino) methyl] -benzylcarbamoyl} -pyridin-2-yloxy) benzoic acid ethyl ester, 3- (3- {4-[(3-hydroxy-phenacetylamino) methyl] -benzylcarbamoyl} -Pyridin-2-yloxy) benzoic acid ethyl ester, 3- (3- {4-[(4-hydroxy-phenacetylamino) methyl] -benzylcarbamoyl} -pyridin-2-yloxy) benzoic acid ethyl ester, compound 2 . a and compound 2. b:

These may be in the form of racemates, enantiomers, diastereoisomers and pharmaceutically acceptable acid addition salts and hydrates.
B) Inhalable aerosol containing propellant

1) Suspension aerosol

2) Suspension aerosol

3) Suspension aerosol

Figure 2 shows a particularly preferred inhaler for administering a pharmaceutical combination of the invention filled in inhalettes.

Claims (24)

One or more salts of the formula 1 and

(Wherein X ⁻ represents an anion having one negative charge, preferably fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate An anion selected from the group consisting of rate, oxalate, succinate, benzoate and p-toluenesulfonate is shown.)
A pharmaceutical composition comprising one or more PDEIV inhibitors (2),
A pharmaceutical composition, which may be in the form of an enantiomer, a mixture of enantiomers, a racemate, a solvate or a hydrate, together with a pharmaceutically acceptable excipient.   The pharmaceutical composition according to claim 1, wherein the active ingredients 1 and 2 are present in a single formulation or are contained in two separate formulations.   The PDEIV inhibitor 2 is enprofylline, theophylline, roflumilast, ariflo (silomilast), CP-325, 366, BY343, D-4396 (Sch-351591), AWD-12-281 (GW-842470), N- ( 3,5-dichloro-1-oxo-pyridin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide, NCS-613, pumafentine, (-) 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-methyl-isothioureido] benzyl) -2-pyrrolidone, 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], (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- (t-butyl) -9H-pyrazolo [3, Composed of 4-c] -1,2,4-triazolo [4,3-a] pyridine 3. A pharmaceutical composition according to claim 1 or 2 selected from the group and may be in the form of racemates, enantiomers, diastereoisomers and pharmacologically acceptable acid addition salts and hydrates.   Compound 2 is enprofylline, roflumilast, ariflo (silomilast), AWD-12-281 (GW-842470), N- (3,5-dichloro-1-oxo-pyridin-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- All], 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-ethyl-3- (t-butyl) -9H-pyrazolo [3,4-c] -1,2,4-triazolo [4,3-a] pyridine selected from the group consisting of racemates, mirror images 4. The pharmaceutical composition according to any one of claims 1 to 3, which may be in the form of isomers, diastereoisomers and pharmacologically acceptable acid addition salts and hydrates.   The compound 2 is roflumilast, ariflo (silomilast), AWD-12-281 (GW-842470), allophylline, Z-15370, 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoro Methoxyphenyl) 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- (t-butyl) -9H-pyrazolo [3,4-c] -1,2,4-triazolo [4,3-a] pyridine selected from the group consisting of racemates, enantiomers, The pharmaceutical composition according to any one of claims 1 to 4, which may be in the form of diastereoisomers and pharmacologically acceptable acid addition salts and hydrates.   Compound 2 is selected from the group consisting of roflumilast, Z-15370 and AWD-12-281 and is in the form of racemates, enantiomers, diastereoisomers and pharmaceutically acceptable acid addition salts and hydrates The pharmaceutical composition according to any one of claims 1 to 5, which may be The PDEIV inhibitor is 2- (4-fluoro-phenoxy) -N- {4-[(6-fluoro-2-hydroxy-benzoylamino) -methyl] -benzyl} nicotinamide, 2- (4-fluoro- Phenoxy) -N- {4-[(5-fluoro-2-hydroxy-benzoylamino) -methyl] -benzyl} nicotinamide, 2- (4-fluoro-phenoxy) -N- {4-[(3-hydroxy -4-methyl-benzoylamino) methyl] benzyl} nicotinamide, 2- (4-fluoro-phenoxy) -N- {4-[(3hydroxy-benzoylamino) -methyl] -benzyl} nicotinamide, 2- ( 4-Fluoro-phenoxy) -N- {4-[(2-hydroxy-benzoylamino) methyl] -benzyl} nicotinamide, 2- (4-fluoro-phenoxy) -N- {4-[(4-hydroxy- Benzoylamino) methyl] -benzyl} nicotinamide, 2- (4-fluoro-phenoxy) -N- {4-[(2-hydroxy-4-methyl-benzoylamino) methyl] -benzyl} nico Tinamide, 2- (4-fluoro-phenoxy) -N- {4-[(3-hydroxy-2-methyl-benzoylamino) methyl] -benzyl} nicotinamide, 2- (4-fluoro-phenoxy) -N- {4-[(2-hydroxy-5-methyl-benzoylamino) methyl] -benzyl} nicotinamide, 5-fluoro-2- (4-fluoro-phenoxy) -N- {4-[(2-hydroxy-benzoyl Amino) methyl] -benzyl} nicotinamide, 5-fluoro-2- (4-fluoro-phenoxy) -N- {4-[(2-hydroxy-acetylamino) methyl] -benzyl} nicotinamide, 5-fluoro- 2- (4-Fluoro-phenoxy) -N- {4-[(4-hydroxy-benzoylamino) methyl] -benzyl} nicotinamide, 3- (3- {4-[(3-hydroxy-benzoylamino) methyl ] -Benzylcarbamoyl} -pyridin-2-yloxy) benzoic acid ethyl ester, 3- (3- {4-[(2-hydroxy-phenacetylamino) methyl] -benzylcarba Moyl} -pyridin-2-yloxy) benzoic acid ethyl ester, 3- (3- {4-[(3-hydroxy-phenacetylamino) methyl] -benzylcarbamoyl} -pyridin-2-yloxy) benzoic acid ethyl ester, 3- (3- {4-[(4-hydroxy-phenacetylamino) methyl] -benzylcarbamoyl} -pyridin-2-yloxy) benzoic acid ethyl ester, compound (2. a) and compound (2.b):

The pharmaceutical composition according to claim 1 or 2, which is selected from the group consisting of racemic compounds, enantiomers, diastereoisomers and pharmaceutically acceptable acid addition salts and hydrates. .   8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the mass ratio of 1 to 2 is in the range of about 1: 100 to 100: 1, preferably 1:80 to 80: 1. . 9. A mass ratio of 1 ′ to 2 represented by the following formula is in the range of about 1:50 to 50: 1, preferably 1:20 to 20: 1. The pharmaceutical composition according to 1.

  The pharmaceutical composition according to any one of claims 1 to 9, wherein the pharmaceutical composition is in a dosage form suitable for inhalation.   11. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is a preparation selected from inhalable powders, propellant-containing quantitative aerosols and inhalable solutions not containing propellants.   Said pharmaceutical composition together with a suitable pharmaceutically acceptable excipient selected from monosaccharides, disaccharides, oligosaccharides and polysaccharides, polyhydric alcohols, salts or mixtures of these excipients with one another 12. The pharmaceutical composition according to claim 11, which is an inhalable powder containing 1 and 2.   13. Inhalable powder according to claim 12, characterized in that the maximum average particle size of the excipient is up to 250 [mu] m, preferably in the range of 10 to 150 [mu] m.   The pharmaceutical composition according to claim 13, wherein the pharmaceutical composition is an inhalable powder containing the active ingredients 1 and 2 as sole ingredients.   The pharmaceutical composition according to claim 11, wherein the pharmaceutical composition is a propellant-containing inhalation aerosol containing the substances 1 and 2 in a dissolved or dispersed state.   The propellant gas includes hydrocarbon compounds such as n-propane, n-butane or isobutane or halohydrocarbon compounds such as chlorinated derivatives and / or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. A propellant-containing inhalation aerosol according to claim 15.   The propellant-containing inhalation aerosol according to claim 16, wherein the propellant gas is TG11, TG12, TG134a, TG227, or a mixture thereof, preferably TG134a, TG227, or a mixture thereof.   The propellant-containing inhalation aerosol according to any one of claims 15 to 17, wherein the propellant-containing inhalation aerosol may contain up to 5% by mass of the active ingredient 1 'and / or 2.   The pharmaceutical composition according to claim 11, wherein the pharmaceutical composition is an inhalable solution containing no propellant containing water, ethanol or a mixture of water and ethanol as a solvent.   20. The inhalation solution according to claim 19, wherein the inhalable solution may contain other co-solvents and / or excipients.   The inhalable solution may contain, for example, alcohols, especially isopropyl alcohol, glycols, especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene as cosolvent components containing hydroxyl groups or other polar groups 21. The inhalation solution according to claim 20, comprising alcohols and polyoxyethylene fatty acid esters.   The inhalable solution contains surfactants, stabilizers, complexing agents, antioxidants and / or preservatives, flavoring agents, pharmacologically acceptable salts and / or vitamins as excipients. The inhalation liquid according to claim 20 or 21, wherein   23. Inhalation solution according to claim 22, characterized in that the inhalable solution contains edetic acid or edetate as a complexing agent, preferably sodium edetate.   24. Use of a composition according to any one of claims 1 to 23 for the manufacture of a medicament for the treatment of inflammatory or obstructive respiratory diseases, especially asthma or COPD.

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