JP2007500150A - Combinations of anticholinergics and steroids and their use to treat respiratory disorders by inhalation - Google Patents

Abstract

  The present invention relates to novel pharmaceutical compositions based on steroids and salts of anticholinergics, processes for their preparation and their use in the treatment of respiratory diseases.

Description

Detailed Description of the Invention

The present invention relates to novel pharmaceutical compositions based on steroids and salts of anticholinergic agents, processes for their preparation and their use in the treatment of respiratory complaints.
DESCRIPTION OF THE INVENTION The present invention relates to novel pharmaceutical compositions based on steroids and salts of formula 1 anticholinergics, processes for their preparation and their use in the treatment of respiratory diseases.
Within the present invention, the anticholinergic agent used is a salt of formula 1 :

(Wherein X ⁻ represents an anion having one negative charge, preferably fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, Selected from the group consisting of tartrate, oxalate, succinate, benzoate and para-toluenesulfonate, optionally showing anion in the form of racemates, enantiomers and their hydrates)

Preferably, a salt of formula 1 is used, where
X ⁻ represents one negatively charged anion and is selected from fluoride, chloride, bromide, 4-toluenesulfonate and methanesulfonate, preferably bromide, optionally racemates, enantiomers and their An anion in the form of a hydrate.
Most preferably, a salt of formula 1 is used, where
X ⁻ represents one negatively charged anion, selected from chloride, bromide and methanesulfonate, preferably bromide, optionally in the form of racemates, enantiomers and their hydrates Indicates.
According to the invention, salts of the formula 1 in which X ⁻ represents bromine are particularly preferred.
Of particular interest according to the invention are the enantiomers of the formula 1-en :

(Wherein X ⁻ may have the above meaning).
Surprisingly, an unexpected beneficial therapeutic effect is seen in the treatment of inflammatory and / or obstructive diseases of the airways when the anticholinergics of formula 1 are used with one or more steroids 2. obtain.
The beneficial therapeutic effects can be seen both when the two active agents are administered simultaneously in a single active agent formulation and when they are administered sequentially in separate formulations. According to the invention, it is preferred to administer the two active substances simultaneously in a single formulation.
In the above pharmaceutical combinations, the active substances can be combined in a single formulation or included in two separate formulations. According to the invention, pharmaceutical compositions comprising active substances 1 and 2 in a single formulation are preferred.
According to the present invention, the preferred steroids 2 also referred to as corticosteroids are methylprednisolone, prednisone, butixocort propionate, RPR-106541, flunisolide, beclomethasone, triamcinolone, budesonide, Fluticasone, mometasone, ciclesonide, rofleponide, ST-126, dexamethasone, 6α, 9α-difluoro-17α-[(2-furanylcarbonyl) oxy] -11β-hydroxy-16α-methyl-3-oxo-androsta 1,4-diene-17β-carbothioic acid (S) -fluoromethyl ester, and 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4- 1 shows a compound selected from diene-17β-carbothioic acid (S)-(2-oxo-tetrahydro-furan-3S-yl) ester.

Preferably, compound 2 is flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, ST-126, dexamethasone, 6α, 9α-difluoro-17α-[(2-furanylcarbonyl) oxy] -11β- Hydroxy-16α-methyl-3-oxo-androst-1,4-diene-17β-carbothioic acid (S) -fluoromethyl ester, and 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo- 17α-propionyloxy-androst-1,4-diene-17β-carbothioic acid (S)-(2-oxo-tetrahydro-furan-3S-yl) ester. More preferably, compound 2 comprises budesonide, fluticasone, mometasone, ciclesonide, and 6α, 9α-difluoro-17α-[(2-furanylcarbonyl) oxy] -11β-hydroxy-16α-methyl-3-oxo-androst Selected from 1,4-diene-17β-carbothioic acid (S) -fluoromethyl ester, more preferably, compound 2 is selected from butesonide, fluticasone, mometasone, ciclesonide.
Within the scope of the present invention, reference to steroid 2 includes reference to salts of derivatives that can be formed from steroids. Examples of possible salts or derivatives include sodium salt, sulfobenzoate, phosphate, isonicotinate, acetate, propionate, dihydrogen phosphate, palmitate, pivalate or furoate. In some cases, the compounds of formula 2 may also occur in their hydrate form. Reference to steroid 2 within the scope of the present invention includes reference to compound 2 in the form of their diastereomers, mixtures of diastereomers or in the form of racemates.

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 that does not contain a pharmaceutically acceptable carrier in addition to a therapeutically effective amount of 1 and 2 .
Furthermore, the invention relates to the use of a therapeutically effective amount of salt 1 for the manufacture of a pharmaceutical composition also containing steroid 2 for the treatment of inflammatory or obstructive diseases of the respiratory tract. Preferably, the 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 compounds 1 and 2 are preferably administered simultaneously.
The invention further relates to the use of a therapeutically effective amount of salt 1 and steroid 2 for the treatment of inflammatory or obstructive respiratory diseases, especially asthma or COPD.
The ratio of active substances 1 and 2 that can be used in the active substance combinations according to the invention varies. Active substances 1 and 2 may be present 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 present invention will vary based on the molecular weight differences of the various compounds and their different efficacy. In general, the pharmaceutical combination of the present invention may comprise cation 1 and steroid 2 in a mass ratio ranging from 1: 250 to 250: 1, preferably from 1: 150 to 150: 1. In a particularly preferred pharmaceutical combination comprising in addition to 1 for example a compound selected from the group consisting of budesonide, fluticasone, mometasone and ciclesonide, the mass ratio of 1 to 2 is most preferably about 1:40 to 40: 1. More preferably, it is in the range of 1:30 to 30: 1.

For example, without limiting the scope of the invention, a preferred combination of 1 and 2 according to the invention may comprise 1 and the preferred steroid 2 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, 21: 1, 22: 1, 23: 1, 24: 1, 25: 1, 26: 1, 27: 1, 28: 1, 29: 1, 30: 1.
The pharmaceutical composition of the present invention containing a combination of 1 and 2 is usually 0.1 to 10,000 μg, preferably 1 to 5000 μg, more preferably 10 to 3000 μg, and still more preferably 100 to 2000 μg per administration. It is administered as it exists together. For example, a combination of 1 and 2 of the present invention comprises 1 and steroid 2 (eg budesonide, fluticasone, mometasone, ciclesonide) such that the total dose in a single dose is: about 100 μg 105μg, 110μg, 115μg, 120μg, 125μg, 130μg, 135μg, 140μg, 145μg, 150μg, 155μg, 160μg, 165μg, 170μg, 175μg, 180μg, 185μg, 190μg, 195μg, 200μg, 205μg, 210μg, 215μg, 220μg , 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 , 355μg, 360μg, 365μg, 370μg, 375μg, 380μg, 385μg, 390μg, 395μg, 400μg, 405μg, 410μg, 415μg, 420μg, 425μg, 430μg, 435μg, 440μg, 445μg, 450μg, 455μg, 460μg, 465μg, 470μg , 480μg, 485μg, 490μg, 495μg, 500μg, 505 μg, 510 μg, 515 μg, 520 μg, 525 μg, 530 μg, 535 μg, 540 μg, 545 μg, 550 μg, 555 μg, 560 μg, 565 μg, 570 μg, 575 μg, 580 μg, 585 μg, 590 μg, 595 μg, 600 μg, 605 μg, 610 μg, 615 μg, 620 μg 630μg, 635μg, 640μg, 645μg, 650μg, 655μg, 660μg, 665μg, 670μg, 675μg, 680μg, 685μg, 690μg, 695μg, 700μg, 705μg, 710μg, 715μg, 720μg, 725μg, 730μg, 735μg, 740μg, 745μg 755 μg, 760 μg, 765 μg, 770 μg, 775 μg, 780 μg, 785 μg, 790 μg, 795 μg, 800 μg, 805 μg, 810 μg, 815 μg, 820 μg, 825 μg, 830 μg, 835 μg, 840 μg, 845 μg, 850 μg, 855 μg, 860 μg, 865 μg, 870 μg 880μg, 885μg, 890μg, 895μg, 900μg, 905μg, 910μg, 915μg, 920μg, 925μg, 930μg, 935μg, 940μg, 945μg, 950μg, 955μg, 960μg, 965μg, 970μg, 975μg, 980μg, 985μg, 990μg, 995g 1005μg, 1010μg, 1015μg, 1020μg, 1025μg, 1030μg, 1035μg, 1040μg, 1045μg, 1050μg 1055μg, 1060μg, 1065μg, 1070μg, 1075μg, 1080μg, 1085μg, 1090μg, 1095μg, 1100μg, 1105μg, 1110μg, 1115μg, 1120μg, 1125μg, 1130μg, 1135μg, 1145μg, 1150μg, 1145μg, 1150μg, 1145μg, 1150μg 1180μg, 1185μg, 1190μg, 1195μg, 1200μg, 1200μg, 1210μg, 1215μg, 1220μg, 1225μg, 1230μg, 1235μg, 1240μg, 1245μg, 1250μg, 1255μg, 1260μg, 1265μg, 1270μg, 1275μg, 1270μg, 1275μg, 1270μg, 1275μg 1305μg, 1310μg, 1315μg, 1320μg, 1325μg, 1330μg, 1335μg, 1340μg, 1345μg, 1350μg, 1355μg, 1360μg, 1365μg, 1370μg, 1375μg, 1380μg, 1385μg, 1390μg, 1595μg, 1415μg 1430μg, 1435μg, 1440μg, 1445μg, 1450μg, 1455μg, 1460μg, 1465μg, 1470μg, 1475μg, 1480μg, 1485μg, 1490μg, 1495μg, 1500μg, 1505μg, 1510μg, 1515μg, 1520μg, 1515g, 1520μg, 1520g 1555μg, 1560μg, 1565μg, 1570μg, 1575μg, 1580μg, 1585μg, 1590μg, 1595μg, 1600μg, 1605μg, 1610μg, 1615μg, 1620μg, 1625μg, 1630μg, 1635μg, 1665μg, 1645μg, 665μg 1680μg, 1685μg, 1690μg, 1695μg, 1700μg, 1705μg, 1710μg, 1715μg, 1720μg, 1725μg, 1730μg, 1735μg, 1740μg, 1745μg, 1750μg, 1755μg, 1760μg, 1770μg, 1770μg, 1770μg, 1770μg, 1770μg 1805μg, 1810μg, 1815μg, 1820μg, 1825μg, 1830μg, 1835μg, 1840μg, 1845μg, 1850μg, 1855μg, 1860μg, 1865μg, 1870μg, 1875μg, 1880μg, 1885μg, 1890μg, 1895μg, 1895μg, 1895μg, 1895μg 1930 μg, 1935 μg, 1940 μg, 1945 μg, 1950 μg, 1955 μg, 1960 μg, 1965 μg, 1970 μg, 1975 μg, 1980 μg, 1985 μg, 1990 μg, 1995 μg, 2000 μg, etc.

It will be apparent to those skilled in the art that the doses shown per single dose specified above should not be recognized as being limited to the numerical values actually set forth. Variations of about ± 2.5 μg, particularly in the minority range, are also included as will be apparent to those skilled in the art. In these dosage ranges, active substances 1 and 2 may be present in the above mass ratio.
For example, without limiting the scope of the present invention, the combinations of 1 and 2 of the present invention are as follows for each single dose:
40 μg 1 and 25 μg 2 , 40 μg 1 and 50 μg 2 , 40 μg 1 and 100 μg 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 2 of the 500 [mu] g, 1 and 600μg of 2 40 [mu] g, 2 1 and 700μg of 40 [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, 1 to 60μg and 25 μg 2 , 60 μg 1 and 50 μg 2 , 60 μg 1 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 , 60 μg 1 and 800 μg 2 , 60 μg 1 and 900 μg 2 , 60 μg 1 and 1000 μg 2 , 80 μg 1 and 25 μg 2 , 80 μg 1 and 50 μg 2 , 80 μg 1 and 100 μg 2 , 80 μg 1 and 200 μg 2 , 80 μg 1 and 300 μg 2 , 80 μg 1 and 400 μg 2 , 80 μg 1 and 500 μg 2 , 80 μg 1 and 600 μg 2 , 80 μg 1 and 700 μg 2 , 80 μg 1 and 800 μg 2 , 80 μg 1 and 900 μg 2 , 80 μg 1 and 1000 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 400 μg 2 , 100 μg 1 and 500 μg 2 , 100 μg 1 and 600 μg 2 , 100 μg 1 and 700 μg 2 , 100 μg 1 and 800 μg 2 , 100 μg 1 and 900 μg 2 , 100 μg 1 and 1000 μg 2 , 150 μg 1 and 25 μg 2 , 150 μg 1 and 50 μg 2 , 150 μg 1 and 100 μg 2 , 150 μg 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 800 μg 2 , 150 μg 1 and 900 μg 2 , 150 μg 1 and 1000 μg 2 , 200 μg 1 and 25 μg 2 , 200 μg 1 and 50 μg 2 , 200 μg 1 and 100 μg 2 , 200 μg 1 and 200 μg 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 , 250 μg 1 and 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 , 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 , 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 2 of the 200 [mu] g, 1 and 300μg of 2 500 [mu] g, 1及of 500 [mu] g 2 of 400 [mu] g, 2 1 and 500 [mu] g of 500 [mu] g, 2 1 and 600μg of 500 [mu] g, 2 1 and 700μg of 500 [mu] g, 1 and 800μg of 500 [mu] g 2, 1 and 1000μg of 2 or 500 [mu] g of 1 and 900μg of 500 [mu] g 2 , 600 μg 1 and 25 μg 2 , 600 μg 1 and 50 μg 2 , 600 μg 1 and 100 μg 2 , 600 μg 1 and 200 μg 2 , 600 μg 1 and 300 μg 2 , 600 μg 1 and 400 μg 2 , 600 μg 1 and 500 μg 2 , 600 μg 1 and 600 μg 2 , 600 μg 1 and 700 μg 2 , 600 μg 1 and 800 μg 2 , 600 μg 1 and 900 μg 2 or 600 μg 1 and 1000 μg 2 , 700 μg 1 and 25 μg 2 , 700 μg 1 and 50 μg 2 , 700 μg 1 and 100 μg 2 , 70 μg 1 and 200 μg 2 , 700 μg 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 900 μg 2 , 700 μg 1 and 1000 μg 2 , 800 μg 1 and 25 μg 2, 2 1 and 50μg of 800 [mu] g, 1 and 100μg of 800 [mu] g 2, 2 1 and 200μg of 800 [mu] g, 2 1 and 300μg of 800 [mu] g, 2 1 and 400μg of 800 [mu] g, 2 1 and 500μg of 800 [mu] g, 2 1 and 600μg of 800 [mu] g, 2 1 and 700μg of 800 [mu] g, 2 of 1 and 800 [mu] g of 800 [mu] g, 2 1 and 900 [mu] g of 800 [mu] g, 2 1 and 1000μg 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, of 900 [mu] g 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 900 μg 1 800 μg 2 , 900 μg 1 and 900 μg 2 , 900 μg 1 and 1000 μg 2 , 1000 μg 1 and 25 μg 2 , 1000 μg 1 and 50 μg 2 , 1000 μg 1 and 100 μg 2 , 1000 μg 1 and 200 μg 2 , 1000 μg 1 and 300 μg 2 , 1000 μg 1 and 400 μg 2 , 1000 μg 1 and 500 μg 2 , 1000 μg 1 and 600 μg 2 , 1000 μg 1 and 700 μg 2 , 1000 μg 1 and 800 μg 2 , 1000μg 1 and 900μg 2 or 1000μg 1 and 1000μ g 2
Cation 1 (eg when bromide is used as a preferred combination partner) and steroid 2 (eg budesonide, fluticasone, mometasone, ciclesonide).

The above examples of doses that may be applicable to the combinations of the present invention should be understood as referring to doses per single application. However, these examples should not be understood as excluding the possibility of administering the combination of the present invention multiple times. Depending on the need for the drug, the patient can also receive multiple inhalation applications. By way of example, a patient may receive a combination of the invention, eg, 2 or 3 times each morning on each treatment day (eg, 2 or 3 puffs with a powder inhaler, MDI, etc.). As the above dosage, the examples should be understood as merely dosage examples per single application (ie per puff), and multiple applications of the combination of the present invention will result in multiple dosages of the above examples. Lead. The application of the combination of the invention can be, for example, once a day or twice a day or once every 2 or 3 days depending on the duration of action of the anticholinergic agent.
It is further emphasized that the above dosage examples are to be understood as examples of quantification only. In other words, the above dosage examples are not to be understood as effective dosages of the combination of the present invention that actually reach the lungs. It will be apparent to those skilled in the art that the dose delivered to the lung is generally lower than the amount of active ingredient administered.

The active ingredient combinations 1 and 2 according to the invention are preferably administered by inhalation. To that end, ingredients 1 and 2 must be available in a form suitable for inhalation. Inhalation preparations according to the invention include inhalable powders, propellant-containing quantitative aerosols or inhalable solutions that do not contain propellants. The inhalable powder of the present invention containing a combination of active ingredients 1 and 2 may consist of only the active ingredient, or may consist of a mixture of the active ingredient and physiologically acceptable excipients. May be. Within the scope of the present invention, the term carrier can optionally be used in place of the term excipient. Also within the scope of the present invention, the term inhalable solution containing no propellant includes concentrates or ready-to-use sterile inhalation solutions. This formulation according to the invention may contain the combination of active ingredients 1 and 2 either together in one formulation or in two separate formulations. Such 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 invention may contain only 1 and 2 , or 1 and 2 mixed with suitable physiologically acceptable excipients. When active ingredients 1 and 2 are present as a mixture with physiologically acceptable excipients, the following physiologically acceptable excipients can be used to prepare inhalable powders according to the present invention. Monosaccharides (eg glucose or arabinose), disaccharides (eg lactose, saccharose, maltose, trehalose), oligosaccharides and polysaccharides (eg dextran), polyhydric alcohols (eg sorbitol, mannitol, xylitol), cyclo Dextrin (eg, α-cyclodextrin, β-cyclodextrin, x-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin), salts (eg, sodium chloride, calcium carbonate), or these excipients Mixture of each other. 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. Inhalation powders according to the invention comprising 1 or 2 and one or more physiologically acceptable excipients in addition to 1 and 2 , for example, from a source using a metering chamber as described in US Pat. It can be administered by an inhaler that releases a dose or by other means as described in DE 3625685A. 1 and 2 , and inhalable powders according to the invention which may also contain physiologically acceptable excipients, for example, include 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 physiologically acceptable excipients in addition to 1 and 2 is filled into capsules for use in inhalers as described, for example, in WO 94/28958 (so-called inhalettes) Formation).
FIG. 1 shows a particularly preferred inhaler for using the pharmaceutical combination of the present invention in an inhalette. 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 powders of the present invention are packed into capsules (inhalers) for the above preferred use, the amount packed in each capsule should be 1-30 mg per capsule. These capsules contain, according to the present invention, the above 1 or 2 doses for each single dose, either 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 methane, ethane, propane, butane, cyclopropane or cyclobutane, preferably fluorinated derivatives. Is done. 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), TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof. Preferred are propellant gases of TG134a, TG227 and mixtures thereof.
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) Propellant-free inhalation solution or suspension comprising a combination of active ingredients 1 and 2 according to the invention:
The inhalation solution without the propellant according to the invention contains, for example, an aqueous or alcoholic solvent, preferably an ethanolic solvent, and may optionally contain an ethanolic solvent mixed with the aqueous solvent. When a mixture of aqueous and ethanolic solvents is used, the relative ratio of ethanol to water is not limited, but preferably the maximum value of ethanol is up to 70% by volume, 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 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 without the 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 inhalation solution that does not use the propellant of the present invention is a special type of inhalation that can atomize a small therapeutic dosage liquid formulation within a few seconds to produce an aerosol suitable for therapeutic inhalation. It is administered using a container. 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 inhalable aerosol of the present invention comprising a combination of active ingredients 1 and 2 . Due to its cylindrical and affordable size of 9-15 cm length and 2-4 cm width, this device can be used by the patient at any time. Nebulizers spray a certain amount of pharmaceutical formulation through a small nozzle using high pressure to produce an inhalable aerosol.
A preferred sprayer consists essentially of an upper housing part, a pump housing, a nozzle, a locking device, a spring housing, a spring and a storage container, characterized by:
A pump housing fixed to the upper housing part and comprising at one end a nozzle body having a nozzle or nozzle arrangement;
A hollow plunger having a valve body,
A power take-off flange in which a hollow plunger is fixed and located in the upper housing part;
A locking device located in the upper housing part,
A spring housing having a spring contained therein and rotatably mounted on the upper housing part by a rotary bearing;
A lower housing part fixed axially on the spring housing.

A hollow plunger having a valve body corresponds to the device disclosed in WO 97/12687. It projects partly into the cylinder part of the pump housing and is axially movable within the cylinder. In particular, please refer to FIGS. 1-4, in particular FIG. 3 and the relevant parts of the description. The hollow plunger with valve body is high pressure when the spring is actuated, in fluid, metered active substance solution, 5-60 Mpa (about 50-600 bar), preferably 10-60 MPa (about 100-600 bar) )give. An amount of 10-50 microliters is preferred, an amount of 10-20 microliters is particularly preferred, and an amount of 15 microliters per spray is most preferred.
The valve body is preferably attached to the end of the hollow plunger facing the valve body.
The nozzles in the nozzle body are preferably manufactured by microstructure, ie microtechnology. Microstructure nozzle bodies are disclosed, for example, in WO 94/07607; references, in particular FIG. 1 therein and related descriptions, are the subject of the present invention. The nozzle body consists of, for example, two sheets of glass and / or silicon tightly bonded together, at least one of which has one or more microstructured channels connecting the nozzle inlet end to the nozzle outlet end. The nozzle exit end has at least one round or non-round opening with a depth of 2 to 10 microns and a width of 5 to 15 microns, and the depth is preferably between 4.5 and Although 6.5 microns, the length is preferably 7-9 microns. In the case of a plurality, preferably two nozzle openings, the direction of spray of the nozzle in the nozzle body may extend parallel to the other, or is related to the other in the direction of the nozzle opening. Or incline. In a nozzle body with at least two nozzle openings at the outlet end, the direction of spraying is at an angle of 20-160 °, preferably 60-150 °, most preferably 80-100 ° relative to the other. Also good. The nozzle openings are preferably arranged with a spacing of 10 to 200 microns, more preferably 10 to 100 microns, and most preferably 30 to 70 microns. A space of 50 microns is most preferred. The direction of spray will therefore be met around the nozzle opening. The liquid pharmaceutical formulation strikes a nozzle body with an inlet pressure of up to 600 bar, preferably 200-300 bar and is sprayed into an inhalable aerosol through the nozzle opening. The preferred particle or droplet size of the aerosol is up to 20 microns, preferably 3-10 microns.

The locking device includes a spring, preferably a cylindrical compression coil spring, as a store for mechanical energy. The spring acts as an actuating member on the power take-off flange and its movement is measured by the position of the locking member. The travel 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 housing part rotates against the spring housing in the lower housing part via a power step-up gear, for example a helical thrust gear. In this case, the upper housing portion and the power take-off flange have single or multiple V-shaped gears.
A locking member having an engaging locking surface is disposed in a ring around the power take-off flange. It consists, for example, of a plastic or metal ring that is essentially elastically deformable in the radial direction. The ring is placed in a plane at the correct angle with respect to the atomizer axis. After spring biasing, the locking surface of the locking member moves into the passage of the power take-off flange and prevents the spring from relaxing. The locking member is actuated by a button. The actuation button is connected or coupled to the locking member. In order to actuate the locking device, the actuating button moves parallel to the annular plane, preferably into the sprayer; this causes the deformable ring to deform in the annular plane. Details of the structure of the locking device are described in WO 97/20590.

The lower housing part is pushed axially beyond the spring housing and covers the mounting, spindle drive and fluid reservoir. When the nebulizer is activated, the upper housing part is rotated relative to the lower housing part, which takes it with the spring housing. The spring is thereby compressed and biased by the helical thrust gear and the locking device automatically engages. The angle of rotation is preferably an integer-number fraction of 360 degrees, for example 180 degrees. As soon as the spring is biased, the power take-off part in the upper housing part moves along a predetermined distance and the hollow plunger is withdrawn into the cylinder in the pump housing, so that some fluid is It is sucked out of the storage container and transferred into a high pressure chamber in the center of the nozzle.
If desired, many of the replaceable storage containers containing the fluid to be sprayed can be pushed to the sprayer one after another and used continuously. The storage container contains the aqueous aerosol formulation of the present invention. The spraying process is started by gently pressing the activation button. As a result, the locking device opens up the passage for the power take-off member. The biased spring pushes the plunger into the cylinder of the pump housing. The fluid leaves the sprayer nozzle in spray form.

Further details of the construction are disclosed in PCT applications WO 97/12683 and WO 97/20590, which are referred to herein. The components of the nebulizer are made of materials that are suitable for that purpose. The atomizer housing, and other parts as well, if its work is allowed, are preferably made of plastic, for example by injection molding. For pharmaceutical purposes, physiologically safe materials are used.
FIG. 6a / b of WO 97/12687 shows a nebulizer (Respimat®) that can be advantageously used to inhale the aqueous aerosol formulation of the present invention. FIG. 6a of WO 97/12687 shows a cross-sectional view of a sprayer with a biased spring, while FIG. 6b of WO 97/12687 shows a cross-sectional view of a sprayer with a relaxed spring. The upper housing part (51) includes a pump housing (52) at the end of which is attached a holder (53) for the sprayer nozzle. Within the holder is a nozzle body (54) and a filter (55). A hollow plunger (57) secured to the power take-off flange (56) of the locking device partially protrudes into the cylinder of the pump housing. At its end, the hollow plunger carries the valve body (58). The hollow plunger is sealed off by a seal (59). Inside the upper housing part is a stop (60) on which the power take-off flange contacts when the spring is relaxed. Above the power take-off flange is a stop (61) on which the power take-off flange contacts when the spring is biased. After the spring bias, the locking member (62) moves between the support (63) and the stop (61) in the upper housing part. The actuating button (64) is connected to the locking member. The upper housing part ends in the mouthpiece (65) and is sealed off by a protective cover (66) that can be placed thereon. A spring housing (67) with a compression spring (68) is rotatably mounted on the upper housing part by means of a snap-in lug (69) and a rotary bearing. The lower housing part (70) pushes 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 off by a stopper (73) through which the hollow plunger protrudes into the storage container and is immersed in the fluid at its end (feeding of the active substance solution). A mechanical counter spindle (74) is mounted in the cover of the spring housing. At the end of the spindle face, the upper housing part is a drive pinion (75). The slider (76) is a member of the spindle.

The nebulizer is suitable for nebulizing the aerosol formulation of the present invention to produce an aerosol suitable for inhalation. When the formulation of the present invention is atomized using the above method (Respimat®), the amount delivered is at least 97%, preferably at least 98% of all inhaler operations (spray actuation). % Should correspond to the specified amount with a tolerance of 25% or less, preferably 20% of this amount. Preferably 5-30 mg of the formulation, most preferably 5-20 mg of the formulation is delivered as a defined amount in each actuation.
However, the formulations of the present invention can also be atomized by other inhalers, such as jet stream inhalers or other fixed nebulizers.
Accordingly, a further aspect of the present invention is combined with a device suitable for administration of a pharmaceutical formulation in the form of an inhalation solution or suspension without the use of a propellant as described above, preferably “Respimat®”. The present invention relates to a pharmaceutical formulation in the form of an inhalation solution or suspension without using a propellant. 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 is characterized in that it contains a propellant-free inhalation solution or suspension according to the present invention as previously described herein, preferably said “Respimat®”. It is about.

According to the invention, an inhalation solution containing active ingredients 1 and 2 in a single formulation is preferred. The term “single formulation” also includes formulations containing two components 1 and 2 in a two-chamber cartridge, as disclosed for example in WO 00/23037. This publication is incorporated herein by reference in its entirety.
Propellant-free inhalation solutions or suspensions according to the invention are concentrates or ready-to-use sterile inhalation solutions or suspensions, as well as the above solutions and suspensions designed for “Respimat®”. 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 produces inhalable aerosols using ultrasound or compressed air according to the Venturi principle or other principles .
Accordingly, another aspect of the present invention relates to a pharmaceutical composition in the form of an inhalation solution or suspension that does not use a propellant as described above in the form of a concentrate or ready-to-use sterile formulation. A device suitable for administering fluids, i.e., an energy-driven, self-supporting or portable nebulizer that generates inhalable aerosols using ultrasound or compressed air 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.
The following formulation examples that can be obtained in a manner similar to methods known in the art are intended to further illustrate the present invention and are not intended to limit the scope of the invention.

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Formulation Examples The following examples of formulations that can be obtained in a manner similar to methods known in the art are provided to better illustrate the present invention without limiting the invention to the content of these examples. belongs to. In the examples below, the enantiomerically pure form of the preferred enantiomer of the bromide of formula 1 (ie formula 1-en ) is used as the active ingredient.
Inhalable powder :
1)

2)

3)

4)

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5)

6)

7)

8)

２）サスペンションエアロゾル

３）サスペンションエアロゾル

４）サスペンションエアロゾル

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

2) Suspension aerosol

3) Suspension aerosol

4) Suspension aerosol

Figure 2 shows a particularly preferred inhaler for using the pharmaceutical combination of the present invention in an inhalette.

Claims (23)

Formula 1 salt:

(Wherein X ⁻ represents an anion having one negative charge, preferably fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, Selected from the group consisting of tartrate, oxalate, succinate, benzoate and para-toluenesulfonate, the salt of formula 1 may be in the form of racemates, enantiomers and hydrates thereof)
1 or 2 and 1 or 2 or more steroids ( 2 ), which may be in the form of an enantiomer, a mixture of enantiomers or a racemic compound thereof. Said pharmaceutical composition, which may be in the form of a solvate or hydrate and may contain pharmaceutically acceptable excipients. The pharmaceutical composition according to claim 1, wherein the active substances 1 and 2 are present together in a single formulation or in separate formulations. The compound of Formula 1 is represented by the formula 1-en:

A pharmaceutical composition according to claim 1 or 2 which is present in the form of an enantiomer of Steroid 2 is methylprednisolone, prednisone, butyxocoat propionate, RPR-106541, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, ST-126, dexamethasone, 6α, 9α-difluoro-17α- [(2-Furanylcarbonyl) oxy] -11β-hydroxy-16α-methyl-3-oxo-androst-1,4-diene-17β-carbothioic acid (S) -fluoromethyl ester, and 6α, 9α-difluoro -11β-Hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioic acid (S)-(2-oxo-tetrahydro-furan-3S-yl) ester The pharmaceutical composition according to any one of claims 1 to 3, which is selected from the group consisting of: Compound 2 is sodium salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, to any one of claims 1 to 4 in the form of salts or derivatives including pivalate or furoate The pharmaceutical composition as described. Steroid 2 is flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, ST-126, dexamethasone, 6α, 9α-difluoro-17α-[(2-furanylcarbonyl) oxy] -11β-hydroxy-16α -Methyl-3-oxo-androst-1,4-diene-17β-carbothioic acid (S) -fluoromethyl ester, and 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyl The oxy-androst-1,4-diene-17β-carbothioic acid (S)-(2-oxo-tetrahydro-furan-3S-yl) ester is selected from the group consisting of: The pharmaceutical composition as described. Steroid 2 is budesonide, fluticasone, mometasone, ciclesonide, and 6α, 9α-difluoro-17α-[(2-furanylcarbonyl) oxy] -11β-hydroxy-16α-methyl-3-oxo-androsta-1,4 The pharmaceutical composition according to any one of claims 1 to 6, which is selected from the group consisting of -diene-17β-carbothioic acid (S) -fluoromethyl ester. 8. A pharmaceutical composition according to any one of claims 1 to 7, wherein the mass ratio of 1 and 2 is in the range of about 1: 250 to 250: 1, preferably 1: 150 to 150: 1.   9. A pharmaceutical composition according to any one of claims 1 to 8 in the form of a formulation suitable for inhalation.   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. Inhalable powder comprising 1 and 2 together with a suitable physiologically acceptable excipient selected from monosaccharides, disaccharides, oligosaccharides, polysaccharides, polyhydric alcohols, salts or mixtures of these excipients The pharmaceutical composition according to claim 10.   12. Inhalable powder according to claim 11, wherein the excipient has a maximum average particle size of up to 250 [mu] m, preferably from 10 to 150 [mu] m. The pharmaceutical composition according to claim 10, which is an inhalable powder containing only active substances 1 and 2 as ingredients. 11. A pharmaceutical composition according to claim 10 which is an inhalable aerosol containing a propellant comprising 1 and 2 in dissolved or dispersed form.   A propellant comprising a hydrocarbon such as n-propane, n-butane or isobutane, or a halohydrocarbon such as chlorinated and / or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. Item 15. An inhalable aerosol containing the propellant according to item 14.   16. An inhalable aerosol containing a propellant according to claim 15, wherein the propellant is TG11, TG12, TG134a, TG227 or a mixture thereof, preferably TG134a, TG227 or a mixture thereof. Inhalable aerosol containing a propellant according to any one of claims 14 to 16, which may contain up to 5% by weight of active substance 1 and / or 2 .   The pharmaceutical composition according to claim 10, which is an inhalable solution containing no propellant and containing water, ethanol or a mixture of water and ethanol as a solvent.   19. An inhalable solution according to claim 18, which may contain other co-solvents and / or excipients.   As cosolvents, components containing hydroxyl groups or other polar groups, such as alcohols, in particular isopropyl alcohol, glycols, in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycoethers, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters 20. An inhalable solution according to claim 19 comprising:   21. The excipient according to claim 19 or 20, comprising a surfactant, stabilizer, complexing agent, antioxidant and / or preservative, flavoring agent, pharmacologically acceptable salt and / or vitamin as an excipient. Inhalable solution.   The inhalable solution according to claim 21, comprising as a complexing agent edetic acid or a salt of edetic acid, preferably sodium edetate.   23. Use of a composition according to any one of claims 1 to 22 for the manufacture of a medicament for the treatment of inflammatory or obstructive respiratory diseases, in particular asthma or COPD.

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