COMBINATION OF AN ANTICOLINERGIC AND A STEROID AND ITS
USE TO TREAT RESPIRATORY DISORDERS BY INHALATION
FIELD OF THE INVENTION The present invention relates to new pharmaceutical compositions based on steroids and salts of an anticholinergic, to processes for preparing them and to their use in the treatment of respiratory diseases. Description of the invention The present invention relates to new pharmaceutical compositions based on steroids and salts of an anticholinergic of formula 1, to processes for preparing them and to their use in the treatment of respiratory diseases. In the scope of the present invention the anticholinergic agents used are the salts of formula 1
wherein X - indicates an anion with a single negative charge, preferably an anion selected from the group that REF. : 169309 consists of fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate, optionally in the form of racemates, enantiomers, and hydrates of these. Preferably, the salts of formula 1 are used in which X - denotes an anion with a single negative charge selected from fluoride, chloride, bromide, 4-toluenesulfonate and methanesulfonate, preferably bromide, optionally in the form of the racemates, enantiomers , and hydrates of these. Most preferably, the salts of formula 1 are used in which X - denotes an anion with a single negative charge selected from the chloride, bromide and methanesulfonate, preferably bromide ", optionally in the form of the racemates, enantiomers, and hydrates According to the invention, the salt of formula 1 in which X-indicates bromide is especially preferred, and according to the invention, the enantiomers of formula 1 are of particular interest.
wherein X - may have the meanings that have been mentioned hereinabove. Surprisingly, an unexpected beneficial therapeutic effect can be observed in the treatment of inflammatory and / or obstructive diseases of the respiratory tract if the anticholinergic of formula 1 is used with one or more steroids 2. The beneficial therapeutic effect mentioned above can be observed both when the two active substances are administered simultaneously in a single formulation of the active substance and when they are administered successively in different formulations. According to the invention, it is preferable to administer the ingredients of the two active substances simultaneously in a single formulation. In the pharmaceutical combinations mentioned above, the active substances can be combined in a single preparation or be contained in two different formulations. According to the invention, pharmaceutical compositions containing the active substances 1 and 2 in a single preparation are preferred. According to the present invention, preferred steroids 2 which are also optionally referred to as corticosteroids, indicate compounds selected from methyl prednisolone, prednisone, butyclocort ponate, PR-106541, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, ST-126, dexamethasone, 6a, 9a-difluoro-17a- [(2-furanylcarbonyl) oxy] -β-β-hydroxy-16a-methyl-3-oxo-androsta-1-4-fluoroethyl ester -diene-17P-carbothioic, and ester (S) - (2-oxo-tetrahydro-furan-3S-yl) of 6a, 9a-difluoro-lip-hydroxy-lSa-methyl-3-oxo-17a-ponyloxy- androsta-1, 4 -diene-17β-carbothioic. Preferably, compound 2 is selected from flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, ST-126, dexamethasone, ester (S) -fluoromethyl acid 6a, 9a-difluoro-17a- [(2 -furanylcarbonyl) oxy] -lip-hydroxy-16a-methyl-3-oxo-androsta-1,4-diene-17p-carbothioic ester and (S) - (2-oxo-tetrahydro-furan-3S-yl) ester of 6a acid, 9a-difluoro-β-β-hydroxy-16a-methyl-3-oxo-17a-propionyloxy-androsta-1,4-diene-17P-carbothioic acid. More preferably, compound 2 is selected from budesonide, fluticasone, mometasone, ciclesonide, and (S) -6-, 9a-difluoro-17 - [(2-furanylcarbonyl) oxy] -lip-hydroxy-16a- (6) -sulfuric acid ester methyl-3-oxo-androsta-1, -diene-17p-carbothioic, more preferably compound 2 is selected from budesonide, fluticasone, mometasone, ciclesonide. Any reference to the spheroids 2_ within the scope of the present invention includes a reference to the salts or derivatives that can be formed from the spheroids. Examples of possible salts or derivatives include: sodium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates. In some cases the compounds of formula 2 may also be in the form of their hydrates. Any reference to steroids 2 within the scope of the present invention also includes a reference to the compounds 2_ in the form of their diastereomers, mixtures of distereomers or in the form of the racemates. In one aspect, the present invention relates to the pharmaceutical compositions mentioned above which contain, in addition to the therapeutic effective amounts of 1 and 2, a pharmaceutically acceptable carrier. In another aspect, the present invention relates to the pharmaceutical compositions mentioned above that do not contain any pharmaceutically acceptable carriers in addition to the therapeutic effective amounts of 1 and 2. The present invention also relates to to the use of therapeutically effective amounts of the salts 1 to prepare a pharmaceutical composition that also contains the steroids 2_ to treat inflammatory or obstructive diseases of the respiratory tract. Preferably, the present invention relates to the use mentioned above for preparing a pharmaceutical composition for treating asthma or COPD. In the scope of the present invention, compounds 1 and 2 can be administered simultaneously or in succession, although according to the invention it is preferable to administer compounds 1 and 2 simultaneously. The present invention further relates to the use of therapeutically effective amounts of salts 1 and steroids 2 to treat inflammatory or obstructive respiratory diseases, especially asthma or COPD. The proportions in which the active substances 1 and 2_ can be used in the combinations of the active substance according to the invention are variable. The active substances 1 and _ may be present in the form of their solvates or hydrates. Depending on the choice of compounds 1 and 2_, the proportions by weight that can be used within the scope of the present invention vary based on the different molecular weights of the different compounds and their different potencies. As a rule, the pharmaceutical combinations according to the invention may contain cation 1 and a steroid 2 in proportions by weight in the range of 1: 250 to 250: 1, preferably 1: 150 to 150: 1. In especially preferred pharmaceutical combinations containing in addition to 1 a compound selected for example from the group consisting of budesonide, fluticasone, mometasone, and ciclesonide such as steroid 2, the weight proportions of 1 to 2 are most preferably the range from about 1:40 to 40: 1, more preferably from 1:30 to 30: 1. For example, without thereby restricting the scope of the invention, the preferred combinations of 1 and 2 according to the invention may contain 1 and one of the preferred steroids mentioned above in the proportions by weight as follows: 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 compositions according to the invention containing the combinations of 1 and 2 are normally administered such that 1 and 2 are both present in doses of 0.1 to 10,000μ, preferably 1 to 5,000μ9, more preferably 10 to 3,000. μ, even better from 100 to 2,000μ per single dose. For example, combinations of 1 and 2 according to the invention contain an amount of 1 and of steroid 2 (such as, for example, budesonide, fluticasone, mometasone, ciclesonide) such that the total dosage per single dose is approximately 100μ9, 105μ , ??? μ ^, 115μ,
120μg / 130μ, 135μ, ± 0μ < 3, 1 5 g, 150μ9, 155 g,
160μ9, ± 65μ < 3, 170 / xg, 175 g, 180 9, 185μ9, 190μ9, 195μ9,
200 g; 205μ < 3, 210 g, 215 / -g, 220μ, 225μ9, 230μ9, 235 g,
240 / g, 2 5μ < 3, 250 9, 255 9, 260 g, 265μ, 270μ9, 275μg,
280μg; 2? 5μ < 3, 290μ < 3, 295 g, 300 g, 305 g, 310 μ 9, 315 g,
320 g / 325 9, 320μ, 335 9, 340 g / 345 g / 350 g, 55 g,
360 9, 365μ9, 3? 0μ < 3, 375 g, 380, 385 g, 390 g, 395 g, 00 g, 410μ, 15 g, 420 g, 25μg, 430μ9, 435μg, ^ g, 445μ < 3, 450μg, 455g, 460g, 465g, 470μg, 475 9,
480 9, 4 &5μ < 3, 490μ < 3, 95 9, 500 9, 505 9, 510μ9, 515μ9,
520, 525 g, 530μ, 535μ9, 540μ9, 545, 555μg,
560μ, 565μ9, 570μ9, 575μg, 580μg, 585μ9, 590μ, 595μg
600μg, 605μ9, ß! 0 < 3, 615μg, d20μg, 625 < 3, 630μ < 3, 635μgí
64? ?, 645μ9, 650μg, 655μg, 660, 665μg, 670μ < 3, 675μgí 680μ9, 685μ9, 690μ9, 695μ9, 700μ9, 705μ9, 710μ9, 715μ9,
720 ^,. 725μg, 730μ9, 7 5μ9, 7 0 9, 45μ9, 750μ9, 755μ9,
76C ^ g, 765μg, 77C ^ g, 775 9, 780μ9, 785μ9, 90μ9, 95μ9,
B00 \ ig, 805μ9, 810μ £, 815μ9, 820 9, 825μ9, 83C ^ g, 835μ9,
840μg / 845μg; 850μ9, 855μ9, 860μ9, 865μ9, 870μ9, 875μ9,
880μg, 885μ9, 890μ9, 8 5μ9, 900μ9, 905μ9, 910μ9, 915μ9,
920μg / 925μg, 930μ9, 935μ9, 940μ3, 945μ9, 950μ9, 955μ9,
960ig, 65μ9, 970μ9, 975μ9, 80μ9, 985μ9, 990μ9, 995μ9,
1. 000μ9, l.OC ^ g, 1. 010μ9, 1.015μ9, 1.020μ9, 1 .025 9,
1. 030μ ?, 1,035 ^ g, 1. 0 0μ9, 1.?45μ9, 1.050μ9, 1 .055μ9,
1. 060μ < 3, 1.065μ, 1. 070μ9, 1.075pg, 1.080μ9, 1 .085μ9,
1. 090μ9, 1.095μg / 1. 100μ9, 1.105μ9, 1110μ9, 1 • 115 g,
1. 12 (^ g, 1.125μ9, 1. 130μ3, 1.135μ9, 1140μ9, 1 .145 g,
1. 150 / xg, 1.155μ9, 1. 160 ^ g, 1.165 9, 1.1? 0μ, 1 |175μ9,
1. 180 / ig, 1,185 9, 1. 190μ9, 1195 / ig, 1,200 9, 1,205 9,
1. 210 ig, 1.215μ9, 1. 220μ9, 1,225μg, 1,230 9, 1 .235μ3
1. 240 ^ g, 1.245μ9, 1. 250 9, 1.255 g, 1.260 9, 1.265 9,
1. 270 / ig, 1275 9, 1. 280 9, 1285 ^ g, 1290 9, 1, 295 9,
1. 300 / xg, 1305 9, 1. 310 9, 1.315 / ig, 1.320 9, 1 .325 9,
1. 330 ^ g, 1.335 9, 1. 340 9, 1.345μ9, 1.350 9, 1.355μ9,
1. 360 / g, 1.365μ9 / 1 · 370 9, 1.375μg, 1.380 9, 1 .385μ9,
1. 390 ig, 1.395μ9 # 1 · 400 9, 1.405 ^ g-, 1.410μ9, 1 · 15 9,
1 - . 1 -420 / g, 1425 9, 1. 430 g, 1.435 / ig, 1.44C ^ g, 1.445 9 /
1. 450 xg, 1,455 9, 1. 60 9, 1,465 / ig, 1,470 9, 1 - 75 9,
1. 480 ig, 1,485 9, 1. 490 g, 1,495 ig, 1,500 9, 1,505 9, 1,510 / ig, 1,515 / g, 1,520ig, 1,525 / ug, 1,530 / g, 1,535,
1. #
For example, without thereby restricting the scope of the invention, the combinations of 1 ^ and 2_ according to the invention may contain an amount of cation 1 (if, for example, bromide is used as the preferred partner in the combination) and steroid 2 (such as, for example, budesonide, fluticasone, mometasone, ciclesonide) such that, for each single dose, 40 / jg of 1 and 25 / xg of 2_, 40 g of 1 and 5 (^ g of .2, 40 xg of 1 and lOO / xg of 2, 40 / g of 1 and 200 g of 2, 4 (^ g of 1 and 300 ^ g of 2, (^ g of 1 and 400 ^ g of 2, 0 ^ g of 1 and 500 9 of 2, 40 9 of 1 and 600 / g of 2, 40 ^ g of 1 and ^ 00 g of 2, 40μ of 1 and 800μ9 of 2, 40μ9 of 1 and 900 of 2, 40μg of 1 and l.OC ^ g of 2, 60μg of 1 and 25g of 2, 60μg of 1 and 50g of 2, 60μg of 1 and 100g of 2, 60g of 1 and 200μg of 2, 60g of 1 and 300 9 of 2, 60 g of 1 and 00 μg of 2, 60 g of 1 and 500 g of 2, 60 μg of 1 and 600 g of 2, 60 g of 1 and 700 μg of 2, 60 g of 1 and 800 g of 2, 60μg of 1 and 900 9 of 2, 60g of 1 and 1,000μ9 of 2, 80 of 1 and 25μg of 2, 80 g of 1 and 50 g of 2, 80 g of 1 and 100 g of 2, 80 g of 1 and 200 g of 2, 80 g of 1 and 300 g of 2, 80 μg of 1 and 400 g of 2, 80 μg 1 and 500 μg of 2, 80 g of 1 and 600 g of 2, 80 g of 1 and 700 g of 2, 80 g of 1 and 800 g of 2, 80 μg of 1 and 900 9 of 2, 80 μg of 1 and 1,000 9 of 2, 100 9 of 1 and 25 g of 2, 100 g of 1 and 50μg of 2, 100μg of 1 and 100μ9 of 2, 100μg of 1 and 200g of 2, 100g of 1 and 300g of 2 , 100μg of 1 and 00 g of 2, 100 g of 1 and 500 g of 2, 100 g of 1 and 600 g of 2, 100 g of 1 and 700 g of 2, 100 g of 1 and 800 g of 2, 100 / xg of 1 and 900 / g of 2, lOC ^ g of 1 and l.OOO ^ g of 2, 150 ^ g of 1 and 25 ^ g of 2, 15C ^ g of 1 and 50 g of 2, 150 g of 1 and 100 g of 2, 150 g of 1 and 200 g of 2, 150 g of 1 and 300 μg of 2, 150 g of 1 and 00 μg of 2, 150 μg of 1 and 500 g of 2, 150 μg of 1 and 60C ^ g of 2, 150μg of 1 and 70 (^ g of 2, 150 g of 1 and 80 (_ ^ g of 2, 150μg of 1 and 90C ^ g of 2, 150μg of 1 and l.OOC ^ g of 2, 200 g of 1 and 25 g of 2, 20C ^ g of 1 and 50μg of 2, 20C ^ g of 1 and 100 g of 2, 20C ^ g of 1 and 200μg of 2, 20 (^ g of 1 and 300 g of 2, 20C ^ g of 1 and 400μg of 2, 200g of 1 and 500μg of 2, 200μg of 1 and 600μg of 2, 200g of 1 and? 00μ < 3 of 2, 200 g of 1 and 80C ^ g of 2, 200μg of 1 and 90C ^ g of 2, 200μg of 1 and l.OOC ^ g of 2, 25C ^ g of 1 and 25 g of 2, 250μg of 1 and 50μ of 2, 250g of 1 Y 100μg of 2, 25C ^ g of 1 and 200μg of 2, 25C ^ g of 1 and 300 g of 2, 250μ of 1 and 400μg of 2, 250μg of 1 and 500 g of 2, 250 g of 1 and 600 g of 2, 250 μg of 1 and 2 μ ^ of 2, 250 μg of 1 and 80 C ^ g of 2, 250 9 of 1 and 900 μg of 2.25 C ^ g of 1 and 1,000 g of 2, 0C ^ g of 1 and 25 g of 2, 400μg of 1 and 50μg of 2, 40C ^ g of 1 and 100 g of 2, 40 (^ g of 1 and 200μg of 2, 0C ^ g of 1 and 300 g of 2, 0 (^ g of 1 and 400 g of 2, 40C ^ g of 1 and 500 g of 2, 40C ^ g of 1 and 600μg of 2, 40C ^ g of 1 and 700μg of 2, 400μg of 1 and 800g of 2, 400μg of 1 and 90C ^ g of 2 or 400μg of 1 and 1,000 g of 2, 50μμ of 1 and 25μ of 2, 500g of 1 and 50μg of 2, 500μg of 1 and 100 g of 2, 500 μg of 1 and 200 μg of 2, 500 μg of 1 and 300 μg of 2, 500 μg of 1 and 400 μg of 2, 500 g of 1 and 500 g of 2, 500 g of 1 and 600 μg of 2, 500 μg of 1 and 70 C ^ g of 2, 500 g of 1 and 80 (^ g of 2, 500 g of 1 and 900 / g of 2 or 500 ^ g of 1 and 1,000 / zg of 2, 600 / zg of 1 and 25μg of 2, 600 ^ g of 1 and 5C ^ g of 2, 600 ^ g of 1 and lOO g of 2, SOOjug of 1 and 200 9 of 2, 600 ^ g of 1 and 300 g of 2, 600 ^ g of 1 and 400 xg of 2, 600 ^ g of 1 and 500 / xg of 2, 600 g of 1 and 600 / g of 2, 600 ig of 1 and 700 / zg of 2, 600 ^ g of 1 and 80C ^ g of 2, 600 g of 1 and 900 g of 2 or 600μg of 1 and l.OOC ^ g of 2, 700 ^ g of 1 and 25μ9 of 2, 700μg of -1 and 50 g of 2, 700 μg of 1 and 100 9 of 2, 700 ^ g of 1 and 200 μg of 2, 700 g of 1 and 300 g of 2, 700 g of 1 and 0 C ^ g of 2, 700 g of 1 and 50C ^ g of 2, 700 g of 1 and 60C ^ g of 2, 700 g of 1 and 70C ^ g of 2, 700μg of 1 and 80C ^ g of 2, 700 g of 1 and 900 g of 2 , 700μg of 1 and 1,000μg of 2, 800g of 1 and 25g of 2, 800μg of 1 and 50g of 2, 800μg of 1 and 100μg of 2, 800g of 1 and 20C ^ g of 2, 800 / xg of 1 and 30C ^ g of 2, 800μg of 1 and 0 (^ g of 2, 800μg of 1 and 50C ^ g of 2, 800 g of 1 and 60C ^ g of 2, 8C ^ g of 1 and 70C ^ g of 2, 800 g of 1 and 80C ^ g of 2, 800 g of 1 and 90C ^ g of 2, 800μg of 1 and l.OOC ^ g of 2, 900μg of 1 and 25 g of 2, 900 9 of 1 and 50 9 of 2, 900 9 of 1 and 100 9 out of 2, 900 g of 1 and 200 μg of 2, 900 g of 1 and 300 9 of 2, 900 g of 1 and 400 g of 2, 900 μg of 1 and 500 g of 2, 900 g of 1 and 600 μg of 2, 900 g of 1 and ^ 00μg of 2, 900g of 1 and 800μ9 of 2_, 900μg of 1 and 900g of 2, 900g of 1 and 1,000 of 2, 1,000μ9 of 1 and 25μ9 of 2, 1,000 of 1 and 50 9 of 2, 1,000μ9 of 1 and 100 of 2, 1,000ig of 1 and 200 of 2, 1,000μg of 1 and 300μ9 of 2, l.OOC ^ g of 1 and 400 g of 2, lOOO ^ g of 1 and 500 g of 2,?. ??? μ ^ of 1 and 600 5 of 2, 1,000μ of 1 and 700 g of 2, 1,000 9 of 1 and 800μ9 of 2, l.OOO/jg of 1 and 900μ of 2 or 1.OOC ^ g of 1 and l.OOO ^ g of 2. The aforementioned examples of possible doses applicable for the combinations according to the invention should be understood as referring to doses per single application. However, it should not be understood that these examples exclude the possibility of administering the combinations according to the invention multiple times. Depending on the medical needs, patients can also receive multiple inhalative applications. As an example, patients can receive combinations according to the invention, for example, two or three times (for example two or three puffs with a powder inhaler, an MDI etc) on the morning of each day of treatment. As the examples of doses mentioned above are only to be understood as examples of single application doses (ie by puff) the multiple application of the combinations according to the invention results in multiple doses of the examples mentioned above. The application of the compositions according to the invention can be, for example, once a day or, depending on the duration of action of the anticholinergic agent, twice a day, or once every 2 or 3 days. Furthermore, it is emphasized that the examples of doses mentioned above should be understood only as examples of doses, measured. In other words, the dose examples mentioned above should not be understood as the effective doses of the combinations according to the invention which in fact reach the lung. It is obvious to the person skilled in the art that the dose reaching the lung is generally less than the measured dose of the active ingredients administered. The combinations of active substances 1 and 2 according to the invention are preferably administered by inhalation. For this purpose, ingredients 1 and 2 have to be available in suitable forms for inhalation. Inhalable preparations according to the invention include inhalable powders, aerosols with metered doses containing propellants or inhalable solutions without propellants. The inhalable powders according to the invention containing the combination of the active substances 1 and 2 can consist only of the active substances or a mixture of the active substances with excipients that are acceptable from a physiological point of view. In the scope of the present invention, the term "vehicle" may be optionally used in place of the term "excipient". Within the scope of the present invention, the term "inhalable solutions without propellant" also includes ready-to-use sterile inhalable concentrates or solutions. The preparations according to the invention can contain the combination of active substances 1 and 2 either in a formulation or in two different formulations. These formulations that can be used within the scope of the present invention are described in more detail in the following part of the specification. A) Inhalable powder containing the combinations of active substances 1 and 2 according to the invention: The inhalable powders according to the invention can contain 1 and 2 either alone or in a mixture with physiologically acceptable excipients. If active substances 1 and 2 are present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients can be used to prepare these inhalable powders according to the invention: monosaccharides (for example, glucose or arabinosa), disaccharides (e.g., lactose, sucrose, maltose, trehalose), oligo and polysaccharides (e.g., dextran), polyalcohols (e.g., sorbitol, mannitol, xylitol), cyclodextrins (e.g., α-cyclodextrin, β-cyclodextrin, ? -cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl-p-cyclodextrin), salts (eg, sodium chloride, calcium carbonate) or mixtures of these excipients with each other. Preferably, "mono or disaccharides are used, with the use of lactose, trehalose or glucose being preferred, especially, but not exclusively, in the form of their hydrates.
In the scope of the inhalable powders according to the invention, the excipients have a maximum average particle size of up to 250μt ?, preferably between 10 and ???, most preferably between 15 and d? Μp ?. Sometimes it may be appropriate to add to the "excipient mentioned above finer fractions of excipient with an average particle size of 1 to 9μ?" These finer excipients are also selected from the group of possible excipients listed hereinabove. Finally, in order to prepare the inhalable powders according to the invention, the micronized active substance 1 and 2 is added to the excipient mixture, preferably with an average particle size of 0.5 to 10 μa, more preferably 1. at 6μt? The processes for producing the inhalable powders according to the invention by grinding and micronising and finally mixing the ingredients together are known from prior arts.The inhalable powders according to the invention can be prepared and administered well in the form of a mixture of single powder containing 1 and 2 or in the form of different inhalable powders containing only 1 or 2. Inhalable powders according to the invention can be administered using known inhalers from previous techniques. Inhalable powders according to the invention containing one or more physiologically acceptable excipients in addition to 1 and 2 can be administered, for example, by inhalers that deliver a single dose from a reservoir using a metering chamber as described in the US. 457063 OA, or by other means as described in DE 36 25 685 A. Inhalable powders according to the invention containing 1 and 2 optionally together with a physiologically acceptable excipient can be administered, for example, using the known inhaler with the name of Turbuhaler® or using inhalers as described, for example, in EP 237507 A. Preferably, the inhalable powders according to the invention containing physiologically acceptable excipient in addition to 1 and 2_ are packaged in capsules (for produce the so-called inhalants) that are used in inhalers as described, for example, in WO 94 / 28958. An especially preferred inhaler for using the pharmaceutical combination according to the invention in inhalants is shown in Figure 1. This inhaler (Handyhaler) for inhaling powdered pharmaceutical compositions from capsules is characterized by a housing 1 containing two windows 2, a platform 3 in that there are air inlet holes and that is provided with a filter 5 fixed by a filter housing 4, an inhalation chamber 6 connected to the platform 3 in which there is a push button 9 provided with two sharp pins 7 and movable in opposite direction to a spring 8, and a nozzle 12 that is connected to the housing 1, the. platform 3 and to a cover 11 by a rod 10 to allow it to open
0 shock closure, as well as air intakes 13 to adjust the flow resistance. If the inhalable powders according to the invention are packaged in capsules (inhalers) for the preferred use described above, the amounts packaged in each capsule should be 1 to 30 mg per capsule. These capsules contain, according to the invention, either together or separately, the doses of 1 or 2 mentioned above in the present specification for each single dose. B) Propellant gas-powered inhalation aerosols containing the combinations of active substances 1 and 2: The aerosols for inhalation containing propellant gas according to the invention may contain the substances
1 and 2_ dissolved in the propellant gas or in dispersed form. 1 and
2 may be present in different formulations or in a single preparation, in which 1 and 2 are both dissolved, the two dispersed or only one component is dissolved and the other is dispersed. The propellant gases which can be used to prepare the aerosols for inhalation according to the invention are known from previous techniques. Suitable propellant gases are selected from hydrocarbons, such as n-propane, n-butane or isobutane and halohydrocarbons such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The propellant gases mentioned above can be used alone or as mixtures with each other. Especially preferred propellant gases are halogenated derivatives of alkanes selected from TG11, TG12, TG134a (1, 1, 1, 2 -tetrafluoroethane) and TG227 (1, 1, 2, 3, 3, 3-heptafluoropropane) and mixtures thereof. these, of which the propellant gases TG134a, TG227 and mixtures of these are preferred. The aerosols for inhalation driven by propellants according to the invention may also contain other ingredients such as co-solvents, stabilizers, surfactants, antioxidants, lubricants and pH adjusters. All these ingredients are known in the art. The aerosols for inhalation containing propellant gas according to the invention can contain up to 5% by weight of the active substance 1 and / or 2. The aerosols according to the invention contain, for example, 0.002 to 5% by weight, 0.01 to 3% by weight, 0.015 to 2% by weight, 0.1 to 2% by weight, 0.5 to 2% by weight or 0.5 to 1% by weight of active substance 1 and / or 2. If the active substances 1 and / or 2 are present in dispersed form, the particles of the active substance preferably have a mean particle size of up to? μp ?, preferably from 0.1 to 6μp ?, more preferably from 1 to 5μta . The aerosols for inhalation driven by propellants according to the invention mentioned above can be administered using inhalers known in the art (MDI = metered dose inhalers). Accordingly, in another aspect, the present invention relates to pharmaceutical compositions in the form of propellant-driven aerosols as described hereinabove combined with one or more inhalers suitable for administering these aerosols. Furthermore, the present invention relates to inhalers which are characterized in that they contain the aerosols containing the propellant gas described above according to the invention. The present invention also relates to cartridges equipped with a suitable valve which can be used in a suitable inhaler and which contain one of the aerosols for inhalation containing propellant gas mentioned above according to the invention. The cartridges and methods suitable for filling said cartridges with the inhalable aerosols containing propellant gas according to the invention are known from prior art. C) Inhalable solutions or suspensions without propellant containing the combinations of active substances 1 and 2 according to the invention: The inhalable solutions and suspensions without propellant according to the invention contain, for example, aqueous or alcoholic solvents, preferably ethanolic, optionally ethanolic solvents mixed with aqueous solvents. If mixtures of aqueous / ethanolic solvents are used the relative proportion of ethanol compared with water is not limited but preferably the maximum is up to 70 volume percent, more especially up to 60 volume percent ethanol. The rest of the volume is water. The solutions or suspensions containing 1 and 2, independently or in combination, are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. The pH can be adjusted using acids selected from inorganic or organic acids. Examples of especially suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid. Examples of especially 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 etc. The preferred inorganic acids are hydrochloric and sulfuric acids. It is also possible to use acids that have already formed an acid addition salt with one of the active substances. Of organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the above acids can be used, especially in the case of acids having other properties in addition to their acidifying qualities, for example, as flavorants, antioxidants or complete agents, such as, for example, citric acid or Ascorbic acid According to the invention, the use of hydrochloric acid to adjust the pH is especially preferred. According to the invention, the addition of editic acid (EDTA) or of one of the known salts thereof, sodium editate, as a stabilizer or complexing agent is not necessary in the present formulation. Other embodiments may contain this compound or these compounds. In a preferred embodiment the content based on sodium editate is less than 100 mg / 100 ml, preferably less than 50 mg / 100 ml, more preferably less than 20 mg / 100 ml. Generally, inhalable solutions in which the sodium editate content is from 0 to 10 mg / 100 ml are preferred. Co-solvents and / or other excipients may be added to the inhalable solutions without propellant according to the invention. Preferred co-solvents are those containing hydroxyl groups or other polar groups, for example, alcohols - especially isopropyl alcohol, glycols - especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. In this context the terms excipients and additives indicate any pharmaceutically acceptable substance which is not an active substance but which can be formulated with the active substance or substances in the suitable solvent from a pharmacological point of view in order to improve the qualitative properties of the formulation of the active substance. Preferably, these substances do not have a pharmacological effect or, with respect to the desired therapy, do not have an appreciable or at least undesirable pharmacological effect. The excipients and additives include, for example, surfactants such as soybean lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and / or preservatives which ensure or prolong the life at room temperature. the final pharmaceutical formulation, flavors, vitamins and / or other additives known in the art. The additives also include pharmaceutically acceptable salts such as sodium chloride as isotonic agents. Preferred excipients include antioxidants such as, for example, ascorbic acid provided it has not previously been used to adjust the pH, vitamin A, vitamin E, tocopherols and similar vitamins and provitamins found in the human body. Preservatives may be used to protect the formulation against pathogen contamination. Suitable preservatives are those which are known in the art, especially cetyl pyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from prior art. The preservatives mentioned above are preferably present in concentrations of up to 50mg / 100ml, more preferably between 5 and 20mg / l00ml. Preferred formulations contain, in addition to water as solvent and the combination of active substances 1 and 2, only benzalkonium chloride and sodium editate. In another preferred embodiment, the sodium editate is not present. The inhalable non-propellant solutions according to the invention are administered in particular using inhalers of the type which is capable of nebulizing a small amount of a liquid formulation at the therapeutic dose in a few seconds to produce an aerosol suitable for therapeutic inhalation. Within the scope of the present invention, preferred inhalers are those in which an amount of less than 100%, preferably less than 5C ^ L, more preferably between 20 and 3C ^ L of the solution of the active substance can be nebulized preferably in a spray to form an aerosol with an average particle size of less than 20μp, preferably less than? ? μt ?, so that the inhalable part of the aerosol corresponds to the effective amount from a therapeutic point of view. Such an apparatus for the propellant-free administration of a measured amount of a liquid pharmaceutical composition for inhalation is described, for example, in International Patent Application WO 91/14468 and also in WO 97/12687 (compare, in particular , Figures 6a and 6b). The nebulizers (devices) described in these references are known as Respimat®. This nebulizer (Respimat®) can be used advantageously to produce the inhalable aerosols according to the invention containing the combination of active substances 1 and 2. Due to its cylindrical shape and manageable size of less than 9 to 15 cm in length and 2 to 4 cm wide, the patient can wear this device all the time. The nebulizer sprays a defined volume of the pharmaceutical formulation using high pressures through small nozzles to produce inhalable aerosols. The preferred atomizer consists essentially of a housing upper part, a pump housing, a nozzle, a locking mechanism, a spring housing, a spring and a storage container, characterized by a pump housing which is fixed to the upper part of the housing and comprising at one end a nozzle body with the nozzle or nozzle adapter, - a hollow plunger with valve body, a power take-off flange on which the hollow plunger is fixed and which is located on the upper part of the housing, a locking mechanism located on the upper part of the housing, a spring housing containing inside the spring, which is rotatably mounted on the upper part of the housing by means of a rotating bearing, - a lower part of the housing that is fitted in the spring housing in the axial direction. The hollow plunger with the valve body corresponds to a device described in WO 97/12687. It projects partially into the cylinder of the pump casing and can be moved axially inside the cylinder. Reference is made especially to Figures 1 to 4, especially to Figure 3, and to the relevant parts of the description. The hollow plunger with the valve body exerts a pressure of 5 to 60 MPa (approximately 50 to 600 bars), preferably 10 to 60 MPa (approximately 100 to 600 bars) in the liquid, the measured amount of the active substance solution , at its high pressure end at the moment when the spring is actuated. Volumes of 10 to 50 microliters are preferred, although volumes of 10 to 20 microliters are especially preferred and the most especially preferred is a volume of 15 microliters per spray.
The valve body is preferably installed at the end of the hollow piston opposite the valve body. The nozzle in the body of the nozzle is preferably microstructured, that is, produced by microtechnology. The microstructured nozzle bodies are described, for example, in WO 94/07607; in the present specification reference is made to the contents of this specification, especially to Figure 1 of this reference and the associated description. The nozzle body consists, for example, of two sheets of glass and / or silicone firmly connected to each other, at least one of which has one or more microstructured channels connecting the inlet end of the nozzle to the outlet end of the nozzle. the nozzle. At the exit end of the nozzle there is at least one round or non-round opening of 2 to 10 micrometers in depth and 5 to 15 micrometers in width, preferably being 4.5 to 6.5 micrometers in depth while the length is preferably 7 to 9 micrometers. In the case of multiple nozzle openings, preferably two, the spray directions of the nozzles in the nozzle body may extend parallel to each other or they may be inclined relative to each other in the direction of opening of the nozzle. In a nozzle body with at least two nozzle openings at the outlet end the spray directions can have an angle of 20 to 150 ° to each other, preferably 60 to 150 °, most preferably 80 to 100 °. The nozzle apertures are preferably arranged at a spacing of 10 to 200 micrometers, more preferably 10 to 100 micrometers, most preferably 30 to 70 micrometers. 50 micrometer spacings are most preferred. Therefore, the spray directions will converge in the vicinity of the nozzle openings. The liquid pharmaceutical preparation collides with the body of the nozzle with an inlet pressure of up to 600 bar, preferably 200 to 300 bar, and is atomized in an inhalable aerosol through the nozzle openings. Preferred sizes of aerosol particles or droplets are up to 20 microns, preferably 3 to 10 microns. The locking mechanism contains a spring, preferably a helical compression spring with a cylindrical section, which acts as a storage for the mechanical energy. The spring acts on the PTO flange as a transmitting member whose movement is determined by the position of a blocking member. The movement of the PTO flange is precisely limited by an upper and lower stop. The spring is preferably inclined, by means of a power multiplier gear, for example a helical traction gear, by a torque which occurs when the upper part of the housing is rotated in the opposite direction to the spring housing in the lower part of the housing. In this case, the upper part of the housing and the PTO flange have a single or multiple V-gear. The locking member with engaged locking surfaces is arranged in a ring around the PTO flange. It consists, for example, of a plastic or metal ring that is inherently radially deformable elastically. The ring is arranged in a plane with right angles to the axis of the atomizer. After the inclination of the spring, the blocking surfaces of the locking member move in the path of the PTO flange and prevent the spring from relaxing. The blocking member is operated by a push button. The push button is connected or coupled to the blocking member. In order to operate the locking mechanism, the push button moves parallel to the annular plane, preferably in the atomizer; this produces the deformation of the deformable ring in the annular plane. The details of the construction of the locking mechanism are indicated in WO 97/20590. The lower part of the housing is pushed axially on the spring housing and covers the support, the spring device and the liquid storage container. When the atomizer is activated the upper part of the carcass rotates with respect to the lower part of the housing, dragging the lower part of the housing to the spring housing. In this way, the spring is compressed and tilted by the helical traction gear and the locking mechanism engages automatically. The angle of rotation is preferably a whole numerical fraction of 360 degrees, for example 180 degrees. At the same time that the spring is tilted, the PTO part in the upper part of the housing moves along a certain distance, the hollow piston is removed inside the cylinder in the pump casing, and as a result part of the liquid is sucked from the storage container into the high pressure chamber in front of the nozzle. If desired, several interchangeable storage containers containing the liquid to be atomized one after the other and used successively can be introduced into the atomizer. The storage container contains the liquid aerosol preparation according to the invention. The atomization process is initiated by gently pressing the button. As a result, the locking mechanism opens the path of the PTO member. The inclined spring introduces the plunger into the cylinder of the pump casing. The liquid leaves the nozzle of the atomizer in atomized form. In PCT Applications WO 97/12683 and WO 97/20590, which are referenced herein, additional details of the construction are described. The components of the atomizer (nebulizer) are made of a material that is suitable for its purpose. The atomizer housing and, if the operation permits, also other parts, are preferably made of plastics, for example by injection molding. For medical purposes, safe materials are used from a physiological point of view. Figures 6a / b of WO 97/12687, show the nebulizer (Respimat®) which can be advantageously used to inhale the aqueous aerosol preparations according to the invention. Figure 6a of WO 97/12687 shows a longitudinal section of the atomizer with the spring biased while Figure 6b of WO 97/12687 shows a longitudinal section of the atomizer with the spring relaxed. The upper part of the casing (51) contains the pump casing (52) at the end of which the support (53) of the atomizer nozzle is installed. In the support is the body of the nozzle (54) and a filter (55). The hollow piston (57) fixed on the power take-off flange (56) of the locking mechanism projects partially into the cylinder of the pump casing. At its end, the hollow piston carries the valve body (58). The hollow plunger is sealed by the closure (59). Inside the upper part of the housing is the stop (60) with which the PTO flange comes into contact when the spring is relaxed. On the PTO flange is the stop (61) with which the PTO flange comes into contact when the spring is tilted. After the inclination of the spring the locking member (62) moves between the stop (61) and a support (63) on the upper part of the housing. The button (64) is connected to the blocking member. The upper part of the housing ends in the nozzle (65) and is sealed by the protective cover (66) that can be placed in it. The spring housing (67) with the compression spring (68) is rotatably mounted on the upper part of the housing by the snap-fit tabs (69) and the rotary bearing. The lower part of the casing (70) is pushed on the spring housing. The interchangeable storage container (71) of the liquid is inside the spring housing. (72) that is going to be atomized. The storage container is sealed by a plug (73) through which the hollow plunger projects into the interior of the storage container and is immersed at its end in the liquid (source of the active substance solution).
The rod (74) for the mechanical counter is mounted on the cover of the spring housing. At the end of the spring in front of the upper part of the housing is the drive pinion (75). The sliding guide (76) is located on the rod. The nebulizer described above is suitable for nebulizing the aerosol preparations according to the invention to produce an aerosol suitable for inhalation. If the formulation according to the invention is nebulized using the method described above (Respimat®) the amount administered should correspond to a defined amount with a tolerance of not more than 25%, preferably 20% of this amount in at least 97%, preferably at least 98% of all operations of the inhaler (spray actions). Preferably, between 5 and 30 mg of formulation, most preferably between 5 and 20 mg of formulation are administered as a defined mass in each action. However, the formulation according to the invention can also be hebulised by inhalers other than those described above, for example, air-jet inhalers or other stationary nebulxers. Accordingly, in a further aspect, the invention relates to pharmaceutical formulations in the form of inhalable solutions or suspensions without propellant, as described above, combined with a suitable device for administering these formulations, preferably together with Respimat® . Preferably, the invention relates to inhalable solutions or suspensions without propellant characterized by the combination of the active substances 1 and 2 according to the invention together with the device known as Respimat®. In addition, the present invention relates to the inhalation devices mentioned above, preferably. Respimat®, characterized in that they contain the inhalable solutions or suspensions without propellant according to the invention as described hereinabove. According to the invention, inhalable solutions containing active substances 1 and 2 in a single preparation are preferred. The term "single preparation" also includes preparations containing the two ingredients 1 and 2_ in two-chamber cartridges, as described, for example, in 00/23037. In the present specification reference is made to this publication in its entirety. The inhalable non-propellant solutions or suspensions according to the invention may take the form of ready-to-use sterile inhalable concentrates or solutions or suspensions, as well as solutions and suspensions mentioned above designed for use in a Respimat®. Ready-to-use formulations can be produced from concentrates, for example, by the addition of isotonic saline solutions. Ready-to-use sterile formulations can be administered using independent or portable power-driven nebulizers that produce inhalable aerosols by ultrasound or compressed air by the Venturi principle or other principles. Accordingly, in another aspect, the present invention relates to pharmaceutical compositions in the form of inhalable solutions or suspensions without propellant as described hereinabove in the form of ready-to-use sterile concentrates or formulations, combined with a suitable device for administering these solutions, characterized in that the device is an independent or portable nebulizer powered by energy that produces inhalable aerosols by ultrasound or compressed air by the Venturi principle or other methods. The following Examples serve to illustrate the present invention in more detail without restricting the scope of the invention to the following exemplary embodiments. Examples of Formulations The following examples of formulations, which can be obtained analogously with methods known in the art, serve to illustrate the present invention further without restricting it to the contents of these examples. In the following examples 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 powders: 1) Ingredients μg per capsule 1-en (bromide) 250 budesonide 200 lactose 12,050 Total 12,500
- 2) Ingredients ^ g per capsule 1-en (bromide) 200 Propionate 125 fluticasone lactose 4.675 Total 5,000)
)
Ingredients μg per capsule
1-en (bromide) 100 budesonide 125 lactose 4,775 Total 5,000)
)
)
Sprays for inhalation containing propellant
Aerosol suspension Ingredients% by weight
1-in (bromide) 0.1 budesonide 0.4 soy lecithin 0.2
TG 134a: TG227 = 2: 3 to 100
Aerosol suspension
Aerosol suspension:
Ingredients% by weight
1-in (bromide) - 0.1
Mometasone Puroate X 0.6. ¾0 Isopropyl myristate 0.1 TG 227 to 100 4) Aerosol suspension:
It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers