RU2361586C2 - Combination from anticholinergic and steroid and its application for treatment of diseases of respiratory tracts by inhalation - Google Patents

Abstract

FIELD: medicine. ^ SUBSTANCE: invention relates pharmaceutics and medicine area and concerns pharmaceutical combinations for treatment of diseases of the respiratory tracts including a chemical combination of the formula (1) and one or several steroids. ^ EFFECT: increase of efficiency of a composition. ^ 22 cl, 1 ex

Description

The present invention relates to new pharmaceutical (medicinal) compositions based on steroids and salts of an anticholinergic agent, to a method for their preparation, and also to their use in the treatment of respiratory diseases.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides new pharmaceutical (medicinal) compositions based on steroids and salts of an anticholinergic agent of formula 1 , a method for their preparation, as well as their use in the treatment of respiratory diseases.

As anticholinergics according to the present invention, salts of the formula 1 are used .

in which X ^- is a singly charged anion, preferably an anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and n -toluenesulfonate, optionally in the form of their racemates, enantiomers and hydrates.

Preferably, salts of formula 1 are used in which X ^- is a singly charged anion selected from the group consisting of fluoride, chloride, bromide, 4-toluenesulfonate and methanesulfonate, preferably bromide, optionally in the form of their racemates, enantiomers and hydrates.

It is more preferable to use salts of formula 1 in which X ^- is a singly charged anion selected from the group consisting of chloride, bromide and methanesulfonate, preferably bromide, optionally in the form of their racemates, enantiomers and hydrates.

Most preferred according to the invention is a salt of formula 1 in which X ^- is bromide.

Of particular interest according to the present invention are the enantiomers of the formula 1-en

in which X ^- may have the above meanings.

When creating the invention, it was found that when using an anticholinergic agent of the formula 1 in combination with one or more steroids 2 , the positive therapeutic effect unexpectedly manifests itself in the treatment of inflammatory and / or obstructive respiratory diseases.

The above positive therapeutic effect can occur with the simultaneous introduction into the body of both active substances as part of one drug, and with their sequential introduction into the body as part of separate drugs. According to the invention, it is preferable to simultaneously administer both active substances into the body as part of one preparation, the components of which they are.

In the above pharmaceutical combinations of medicinal substances, the active substances can either be part of the same single dosage form, or they can be separately included in two separate dosage forms. Pharmaceutical compositions in which the active substances 1 and 2 are present in a single dosage form are preferred according to the invention.

Preferred steroids 2 , which are sometimes referred to as “corticosteroids” in the following description, according to the present invention include compounds selected from the group consisting of methylprednisolone, prednisone, butyxocort propionate, RPR-106541, flunisolid, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, cyclesonide, rofleponid, ST-126, dexamethasone, (S) -fluoromethyl ether 6α, 9α-difluoro-17α - [(2-furanylcarbonyl) oxy] -11β-hydroxy-16α-methyl-3-oxoandrosta -1,4-diene-17β-carbothioacids and (S) - (2-oxo-tetrahydrofu en-3S-yl) ester of 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propioniloksiandrosta-1,4-diene-17β-carbothioic acid.

Compound 2 is preferably selected from the group consisting of flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, cyclesonide, rofleponide, ST-126, dexamethasone, (S) -fluoromethyl ether 6α, 9α-difluoro-17α - [(2-furanylbonone hydroxy] -11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbio acids and (S) - (2-oxo-tetrahydrofuran-35-yl) ether 6α, 9α-difluoro-11β-hydroxy-16α -methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioacids. More preferably, compound 2 is selected from the group consisting of budesonide, fluticasone, mometasone, cyclesonide and (S) fluoromethyl ether 6α, 9α-difluoro-17α - [(2-furanylcarbonyl) oxy] -11β-hydroxy-16α-methyl-3- oxoandrosta-1,4-diene-17β-carbothioacids, and it is most preferable to choose compound 2 from the group comprising budesonide, fluticasone, mometasone and cyclesonide.

By steroids 2 referred to in the description of the present invention are also meant salts or derivatives that can be formed by steroids. Examples of such possible salts or derivatives include sodium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates. Under certain conditions, compounds of formula 1 may also be present as their hydrates. In addition, when referring to the description of the present invention, steroids 2 are also meant compounds 2 in the form of their diastereomers, mixtures of diastereomers or in the form of racemates.

Another object of the present invention are the above pharmaceutical compositions, which along with the active substances 1 and 2 , taken in therapeutically effective amounts, also includes a pharmaceutically acceptable carrier. The next object of the present invention are the above pharmaceutical compositions, which in addition to the active substances 1 and 2 , taken in therapeutically effective amounts, do not contain any pharmaceutically acceptable carrier.

The present invention further relates to the use of salts 1 , taken in a therapeutically effective amount, for the preparation of a steroid-containing pharmaceutical composition 2 also intended for the treatment of inflammatory or obstructive respiratory diseases. In a preferred embodiment, the present invention relates to the above use of both active ingredients for the manufacture of a pharmaceutical composition for the treatment of asthma or chronic obstructive pulmonary disease (COPD).

According to the present invention, compounds 1 and 2 can be introduced into the body simultaneously or sequentially, while in accordance with the invention, it is preferable to simultaneously administer compounds 1 and 2 to the body.

The present invention further relates to the use of salts 1 and steroids 2 , taken in therapeutically effective amounts, for the treatment of inflammatory or obstructive diseases of the respiratory tract, especially asthma or COPD.

The ratio in which both active substances 1 and 2 can be used in their combination according to the invention is a variable. The active substances 1 and 2 under certain conditions can be presented in the form of their solvates or hydrates. Depending on the selected compounds 1 and 2 , the weight ratio between the two components used according to the present invention varies due to differences in molecular weights of the various compounds, as well as due to differences in the strength of their action. The mass ratio between cation 1 and steroid 2 in the pharmaceutical drug combinations of the invention, as a rule, can be from 1: 250 to 250: 1, preferably from 1: 150 to 150: 1. In the most preferred pharmaceutical combinations, which, along with the active substance 1, contain as steroid 2 a compound selected, for example, from the group consisting of budesonide, fluticasone, mometasone and cyclesonide, the mass ratio between the active substances 1 and 2 is most preferably from about 1: 40 to 40: 1, particularly preferably 1:30 to 30: 1.

Preferred combinations of active ingredients 1 and 2 according to the invention may contain salt 1 and one of the aforementioned preferably used steroids 2 , for example, in the following weight ratios between them (but not limited to them): 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.

Typically, when using the pharmaceutical compositions of the invention containing combinations of active ingredients 1 and 2 , components 1 and 2 are co-administered into the body at a dosage of 0.1 to 10,000 μg, preferably 1 to 5,000 μg, more preferably from 10 to 3000 μg, preferably from 100 to 2000 μg. The combinations of active ingredients 1 and 2 according to the invention contain component 1 and steroid 2 (such as budesonide, fluticasone, mometasone, cyclesonide), for example, in amounts that correspond to a total dosage equal to about 100 micrograms per dose, 105 micrograms , 110 mcg, 115 mcg, 120 mcg, 125 mcg, 130 mcg, 135 mcg, 140 mcg, 145 mcg, 150 mcg, 155 mcg, 160 mcg, 165 mcg, 170 mcg, 175 mcg, 180 mcg, 185 mcg, 190 mcg, 195 mcg, 200 mcg, 205 mcg, 210 mcg, 215 mcg, 220 mcg, 225 mcg, 230 mcg, 235 mcg, 240 mcg, 245 mcg, 250 mcg, 255 mcg, 260 mcg, 265 mcg, 270 mcg, 275 mcg, 280 mcg, 285 mcg, 290 mcg, 295 mcg, 300 mcg, 305 mcg, 310 mcg, 3 15 mcg, 320 mcg, 325 mcg, 330 mcg, 335 mcg, 340 mcg, 345 mcg, 350 mcg, 355 mcg, 360 mcg, 365 mcg, 370 mcg, 375 mcg, 380 mcg, 385 mcg, 390 mcg, 395 mcg , 400 mcg, 405 mcg, 410 mcg, 415 mcg, 420 mcg, 425 mcg, 430 mcg, 435 mcg, 440 mcg, 445 mcg, 450 mcg, 455 mcg, 460 mcg, 465 mcg, 470 mcg, 475 mcg, 480 mcg, 485 mcg, 490 mcg, 495 mcg, 500 mcg, 505 mcg, 510 mcg, 515 mcg, 520 mcg, 525 mcg, 530 mcg, 535 mcg, 540 mcg, 545 mcg, 550 mcg, 555 mcg, 560 mcg, 565 mcg, 570 mcg, 575 mcg, 580 mcg, 585 mcg, 590 mcg, 595 mcg, 600 mcg, 605 mcg, 610 mcg, 615 mcg, 620 mcg, 625 mcg, 630 mcg, 635 mcg, 640 mcg, 645 mcg , 650 mcg, 655 mcg, 660 mcg, 665 mcg, 670 mcg, 675 mcg, 680 mcg, 685 mcg, 690 mcg, 695 mcg, 700 mcg, 705 mcg, 710 mcg, 715 mcg, 720 mcg, 725 mcg, 730 kg, 735 mcg, 740 mcg, 745 mcg, 750 mcg, 755 mcg, 760 mcg, 765 mcg, 770 mcg, 775 mcg, 780 mcg, 785 mcg, 790 mcg, 795 mcg, 800 mcg, 805 mcg, 810 mcg, 815 mcg, 820 mcg, 825 mcg, 830 mcg, 835 mcg, 840 mcg, 845 mcg, 850 mcg, 855 mcg, 860 mcg, 865 mcg, 870 mcg, 875 mcg, 880 mcg, 885 mcg, 890 mcg, 895 mcg , 900 mcg, 905 mcg, 910 mcg, 915 mcg, 920 mcg, 925 mcg, 930 mcg, 935 mcg, 940 mcg, 945 mcg, 950 mcg, 955 mcg, 960 mcg, 965 mcg, 970 mcg, 975 mcg, 980 mcg, 985 mcg, 990 mcg, 995 mcg, 1000 mcg, 1005 mcg, 1010 mcg, 1015 mcg, 1020 mcg, 1025 mcg, 1030 mcg, 1035 mcg, 1040 mcg, 1045 mcg, 1050 mcg, 1055 mcg, 1060 mcg, 1065 mcg, 1070 mcg, 1075 mcg, 1080 mcg, 1085 mcg, 1090 mcg, 1095 mcg, 1100 mcg, 1105 mcg, 1110 mcg, 1115 mcg, 1120 mcg, 1125 mcg, 1130 mcg, 1135 kg, 1140 mcg, 1145 mcg, 1150 mcg, 1155 mcg, 1170 mcg, 1175 mcg, 1180 mcg, 1185 mcg, 1190 mcg, 1195 mcg, 1200 mcg, 1205 mcg, 1210 mcg, 1215 mcg, 1220 mcg, 1225 mcg, 1230 mcg, 1235 mcg, 1240 mcg, 1245 mcg, 1250 mcg, 1255 mcg, 1260 mcg, 1265 mcg, 1270 mcg, 1275 mcg, 1280 mcg, 1285 mcg, 1290 mcg, 1295 mcg, 1300 mcg , 1305 mcg, 1310 mcg, 1315 mcg, 1320 mcg, 1325 mcg, 1330 mcg, 1335 mcg, 1340 mcg, 1345 mcg, 1350 mcg, 1355 mcg, 1360 mcg, 1365 mcg, 1370 mcg, 1375 mcg, 1380 mcg, 1385 mcg, 1390 mcg, 1395 mcg, 1400 mcg, 1405 mcg, 1410 mcg, 1415 mcg, 1420 mcg, 1425 mcg, 1430 mcg, 1435 mcg, 1440 mcg, 1445 mcg, 1450 mcg, 1455 mcg, 1460 mcg, 1465 mcg, 1470 mcg, 1475 mcg, 1480 mcg, 1485 mcg, 1490 mcg, 1495 mcg, 1500 mcg, 1505 mcg, 1510 mcg, 1515 mcg, 1520 mcg, 1525 mcg, 1530 mcg, 1535 mcg, 1540 mcg, 1545 mcg, 1550 mcg, 1555 mcg, 1560 mcg, 1565 mcg, 1570 mcg, 1575 mcg, 1580 mcg, 1585 mcg, 1590 mcg, 1595 mcg, 1600 mcg, 1605 μg, 1610 μg, 1615 μg, 1620 μg, 1625 μg, 1630 μg, 1635 μg, 1640 μg, 1645 μg, 1650 μg, 1655 μg, 1660 μg, 1665 μg, 1670 μg, 1675 μg, 1680 μg, 1685 μg , 1690 mcg, 1695 mcg, 1700 mcg, 1705 mcg, 1710 mcg, 1715 mcg, 1720 mcg, 1725 mcg, 1730 mcg, 1735 mcg, 1740 mcg, 1745 mcg, 1750 mcg, 1755 mcg, 1760 mcg, 1765 mcg, 1770 μg, 1775 μg, 1780 μg, 1785 μg, 1790 μg, 1795 μg, 1800 μg, 1805 μg, 1810 μg, 1815 μg, 1820 μg, 1825 μg, 1830 μg, 1835 μg, 1840 μg, 1845 μg, 1850 μg, 1855 mcg, 1860 mcg, 1865 mcg, 1870 mcg, 1875 mcg, 1880 mcg, 1885 mcg, 1890 mcg, 1895 mcg, 1900 mcg, 1905 mcg, 1910 mcg, 1915 mcg, 1920 mcg, 1925 mcg, 1930 mcg, 1935 mcg, 1940 mcg, 1945 mcg, 1950 mcg, 1955 mcg, 1960 mcg, 1965 mcg, 1970 mcg, 1975 mcg, 1980 mcg, 1985 mcg, 1990 mcg, 1995 mcg, 2000 mcg or a similar amount. Doses in which, based on a single dose, the combination of active substances proposed in the invention can be introduced into the body is not limited to the specific numerical values indicated above, which, by way of example only, reflect possible amounts. It is obvious that the combination of active substances proposed in the invention can be introduced into the body in other doses that differ from the above numerical values in one direction or another by a value in the range of approximately ± 2.5 μg, primarily in the range of tenths. In such dosage ranges, the mass ratio between the active substances 1 and 2 may correspond to the above values.

The combinations of active ingredients 1 and 2 according to the invention may contain cation 1 (if, for example, bromide is used as a preferred component of the combination according to the invention) and steroid 2 (such as budesonide, fluticasone, mometasone, cyclesonide), for example, in such quantities (but not limited to them), to provide at one time the introduction of 40 μg of the component into the body] 1 and 25 μg of component 1 , 40 μg of component 1 and 50 μg of component 1 , 40 μg of component 1 and 100 μg of component 2 , 40 μg of component 1 and 200 μg of component 2 , 40 μg component 1 and 300 μg component 2 , 40 μg component 1 and 400 μg component 2 , 40 μg component 1 and 500 μg component 2 , 40 μg component 1 and 600 μg component 2 , 40 μg component 1 and 700 μg component 2 40 μg component 1 and 800 μg component 2 , 40 μg component 1 and 900 μg component 2 , 40 μg component 1 and 1000 μg component 2 , 60 μg component 1 and 25 μg component 2 , 60 μg component 1 and 50 μg component 2 60 μg component 1 and 100 μg component 2 , 60 μg component 1 , and 200 μg component 2 , 60 μg component 1 and 300 μg component 2 , 60 μg component 1 and 400 μg component that 2 , 60 μg component 1 and 500 μg component 2 , 60 μg component 1 and 600 μg component 2 , 60 μg component 1 and 700 μg component 2 , 60 μg component 1 and 800 μg component 2 , 60 μg component 1 and 900 μg component 2 , 60 μg component 1 and 1000 μg component 2 , 80 μg component 1 and 25 μg component 2 , 80 μg component 1 and 50 μg component 2 , 80 μg component 1 and 100 μg component 2 , 80 μg component 1 and 200 μg component 2, 80 g of component 1 and component 2 300 .mu.g, 80 .mu.g of component 1 and component 2 400 .mu.g, 80 .mu.g of component 1 and component 2 500 .mu.g, 80 .mu.g of component 1 and 600 mg comp ponent 2, 80 g of component 1 and 700 g component 2, 80 g of component 1 and 800 g component 2, 80 g of component 1 and 900 g component 2, 80 g of component 1 and 1,000 g component 2, 100 g of component 1 and 25 mcg component 2 , 100 μg component 1 and 50 μg component 2 , 100 μg component 1 and 100 μg component 2 , 100 μg component 1 and 200 μg component 2 , 100 μg component 1 , and 300 μg component 2 , 100 μg component 1 and 400 μg component 2 , 100 μg component 1 and 500 μg component 2 , 100 μg component 1 and 600 μg component 2 , 100 μg component 1 and 700 μg component 2 , 100 μg component 1 and 8 00 μg component 2 , 100 μg component 1 and 900 μg component 2 , 100 μg component 1 , and 1000 μg component 2 , 150 μg component 1 and 25 μg component 2 , 150 μg component 1 and 50 μg component 2 , 150 μg component 1 and 100 μg component 2 , 150 μg component 1 and 200 μg component 2 , 150 μg component 1 and 300 μg component 2 , 150 μg component 1 and 400 μg component 2 , 150 μg component 1 and 500 μg component 2 , 150 μg component 1 and 600 g component 2, component 1 150 g and 700 g component 2, component 1 150 g and 800 g component 2, component 1 150 g and 900 g component 2, to 150 ug Ponent 1 and 1000 mcg component 2, 200 g of component 1 and 25 g of component 2, 200 g of component 1 and 50 g of component 2, 200 g of component 1 and 100 g component 2, 200 g of component 1 and 200 g component 2, 200 μg component 1 and 300 μg component 2 , 200 μg component 1 and 400 μg component 2 , 200 μg component 1 and 500 μg component 2 , 200 μg component 1 and 600 μg component 2 , 200 μg component 1 and 700 μg component 2 , 200 μg component 1 and 800 μg component 2 , 200 μg component 1 and 900 μg component 2 , 200 μg component 1 and 1000 μg component 2 , 250 μg component 1 and 25 μg component and 2 , 250 μg of component 1 and 50 μg of component 2 , 250 μg of component 1 and 100 μg of component 2 , 250 μg of component 2 , and 200 μg of component 2 , 250 μg of component 1 and 300 μg of component 2 , 250 μg of component 1 and 400 μg component 2 , 250 μg component 1 and 500 μg component 2 , 250 μg component 1 and 600 μg component 2 , 250 μg component 1 and 700 μg component 2 , 250 μg component 1 and 800 μg component 2 , 250 μg component 2 μg component 2 , 250 μg component 1 and 1000 μg component 2, 400 μg component 1 and 25 μg component 2 , 400 μg component 1 and 50 μg component 2 , 400 μg component 1 and 100 μ g component 2 , 400 μg component 1 and 200 μg component 2 , 400 μg component 1 and 300 μg component 2 , 400 μg component 1 and 400 μg component 2 , 400 μg component 1 and 500 μg component 2 , 400 μg component 1 and 600 μg component 2 , 400 μg component 1 and 700 μg component 2 , 400 μg component 1 and 800 μg component 2 , 400 μg component 1 and 900 μg component 2 or 400 μg component 1 and 1000 μg component 2 , 500 μg component 2 μg component 2 , 500 μg component 1 and 50 μg component 2 , 500 μg component 1 and 100 μg component 2 , 500 μg component 1 and 200 μg component 2 , 500 μg component enta 1 and 300 μg component 2 , 500 μg component 1 and 400 μg component 2 , 500 μg component 1 and 500 μg component 2 , 500 μg component 1 and 600 μg component 2 , 500 μg component 1 and 700 μg component 2 , 500 μg component 1 and 800 μg component 2 , 500 μg component 1 and 900 μg component 2 500 μg component 1 and 1000 μg component 2 , 600 μg component 1 and 25 μg component 2 , 600 μg component 1 and 50 μg component 2 , 600 μg component 1 , and 100 μg component 2 , 600 μg component 1 and 200 μg component 2 , 600 μg component 1 and 300 μg component 2 , 600 μg component 1 and 400 μg component 2 , 60 0 μg component 1 and 500 μg component 2 , 600 μg component 1 and 600 μg component 2 , 600 μg component 1 and 700 μg component 2 , 600 μg component 1 and 800 μg component 2 , 600 μg component 1 and 900 μg component 2 or 600 μg component 1 and 1000 μg component 2 , 700 μg component 1 and 25 μg component 2 , 700 μg component 1 and 50 μg component 2 , 700 μg component 1 and 100 μg component 2 , 700 μg component 1 and 200 μg component 2 700 g of component 1 and component 2 to 300 mcg, 700 mcg of component 1 and component 2 to 400 mcg, 700 mcg of component 1 and component 2 to 500 mcg, 700 mcg of component 1 and 600 micrograms to Ponent 2, 700 g of component 1 and 700 g component 2, 700 g of component 1 and 800 g component 2, 700 g of component 1 and 900 g component 2, 700 g of component 1 and 1,000 g component 2, 800 g of component 1 and 25 mcg component 2 , 800 μg component 1 and 50 μg component 2 , 800 μg component 1 and 100 μg component 2 , 800 μg component 1 and 200 μg component 2 , 800 μg component 1 and 300 μg component 2 , 800 μg component 1 and 400 μg component 2 , 800 μg component 1 and 500 μg component 2 , 800 μg component 1 and 600 μg component 2 , 800 μg component 1 and 700 μg component 2 , 800 μg component 1 and 800 μg component 2 , 800 μg component 1 and 900 μg component 2 , 800 μg component 1 and 1000 μg component 2 , 900 μg component 1 and 25 μg component 2 , 900 μg component 1 and 50 μg component 2 , 900 μg component 1 and 100 μg component 2 , 900 μg component 1 and 200 μg component 2 , 900 μg component 1 and 300 μg component 2 , 900 μg component 1 and 400 μg component 2 , 900 μg component 1 and 500 μg component 2 , 900 μg component 1 and 600 g component 2, component 1 900 g and 700 g component 2, component 1 900 g and 800 g component 2, component 1 900 g and 900 g component 2, 900 ug Components 1 and 1000 mcg component 2 1000 g of component 1 and 25 g of Component 2 1000 g of component 1 and 50 g of Component 2 1000 g of component 1 and 100 g component 2, 1000 g of component 1 and 200 g component 2, 1000 mcg component 1 and 300 μg component 2 , 1000 μg component 1 and 400 μg component 2 , 1000 μg component 1 and 500 μg component 2 , 1000 μg component 1 , and 600 μg component 2 , 1000 μg component 1 and 700 μg component 2 , 1000 μg component 1 and 800 μg component 2 , 1000 μg component 1 and 900 μg component 2 or 1000 μg component 1 and 1000 μg component 2.

The above examples of doses in which the active substances can be used in their combinations according to the invention are single doses, i.e. doses prescribed at one time. However, these examples should not be construed as excluding the possibility of repeated administration into the body of the combinations of active substances according to the invention. Patients, depending on the form of the disease that they suffer from, and accordingly, depending on the need for taking medications, can also repeat inhalations many times. So, for example, patients can do two or three inhalations of the combinations of active ingredients proposed in the invention every day every day of the course of treatment (for example, use a powder inhaler, a metered dose inhaler or another inhaler, for example, two or three times in one treatment session type). Since the above examples of doses are examples of only single doses (i.e., doses at which the active substances are dispensed from the inhaler when it is used once), when repeating the inhalation of the combinations of active substances according to the invention, several times in one treatment session indicated in the above In the examples, the numerical values increase by the corresponding number of times. The combinations of active substances according to the invention can be introduced into the body, for example, once a day or depending on the duration of action of a particular anticholinergic agent twice a day or once every 2 or 3 days.

In addition, it should be noted that the above dose examples are examples of only measured doses. In other words, the above examples of doses should not be construed as effective doses of the combinations of active substances according to the invention in which they actually reach the lungs. For specialists in this field, it seems obvious that the actually falling dose to the lungs is usually lower than the measured dose of the active substances leaving the inhaler.

The combinations of active substances 1 and 2 according to the invention are preferably administered by inhalation. To this end, components 1 and 2 should be presented in inhalable dosage forms. Such inhaled dosage forms according to the invention include inhaled powders, metered-dose aerosols with a propellant or inhaled solutions without a propellant. According to the invention, inhalation powders containing a combination of active substances 1 and 2 may consist only of these active substances or of a mixture thereof with physiologically compatible excipients. In some cases, the term "carrier" is also used in the description of the present invention instead of the term "excipient". In accordance with the present invention, the term “propellant-free inhalation solutions” also refers to concentrates or sterile, ready-to-use inhalation solutions. According to the invention, both active substances 1 and 2 used in combination with each other can be contained either together in one dosage form or separately in two separate dosage forms. Such dosage forms used according to the present invention are described in more detail in the subsequent part of the description.

A) Inhalation powders containing the combinations of active substances 1 and 2 according to the invention

In the inhalation powders according to the invention, the active substances 1 and 2 can be contained either individually or in admixture with acceptable physiologically harmless excipients.

If the active substances 1 and 2 are contained in the inhalation powders of the invention mixed with physiologically harmless excipients, the following physiologically harmless (compatible) excipients may be used to obtain such inhalation powders: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. , lactose, sucrose, maltose, trehalose), oligo- and polysaccharides (e.g. dextrans), polyalcohols (e.g. sorbitol, mannitol, xylitol), cyclodextrins (e.g. α-cyclodex trin, β-cyclodextrin, β-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin), salts (for example, sodium chloride, calcium carbonate) or mixtures of these auxiliary substances with each other. It is preferable to use mono- or disaccharides, while the use of lactose, trehalose or glucose is especially preferred, especially, but not exclusively, in the form of their hydrates.

The maximum average particle size of the auxiliary substances used in the inventive inhalation powders can reach 250 μm, and preferably should be from 10 to 150 μm, most preferably from 15 to 80 μm. Under certain conditions, it may be appropriate to mix their own fractions with a smaller average particle size of 1 to 9 microns to the above excipients. Similar excipients, presented in the form of particles of a smaller size, are also selected from the above-described group of excipients used in inhalation powders. In addition, upon receipt of the inventive inhalation powders, it is proposed to mix micronized active substances 1 and 2 , with an average particle size of preferably from 0.5 to 10 μm, most preferably from 1 to 6 μm, into the mixture of excipients. Methods for preparing the inhalation powders according to the invention by grinding and micronizing the components and then mixing them are known in the art. Proposed in the invention inhalation powders can be obtained and used either as a single powder mixture simultaneously containing the active substances 1 and 2 , or as separate inhalation powders, each of which contains, respectively, only one of the active substances 1 or 2 .

For administration into the body of the inhalation powders of the invention, inhalers known in the art can be used. For the introduction into the body of the inventive inhalation powders, which along with the active substances 1 and 2 also contain one or more physiologically harmless (compatible) excipients, you can use, for example, inhalers in which a single dose is dispensed from the supply container using a metering chamber described, in particular, in US Pat. No. 4,570,630, or using other devices described, in particular, in DE 3625685 A. For administration to the body of the inventive inhalation powders which contain d ystvuyuschie substances 1 and 2, optionally in combination with a physiologically acceptable (compatible) excipient can be used, for example, known Turbohaler® inhaler, respectively inhalers, as described for example in EP 237507 A. However, the invention inhalable powders which along with the active substances 1 and 2 contain physiologically acceptable (compatible) auxiliary agent, preferably packed into capsules (to produce so-called inhalettes) which are used in ngalyatorah described, e.g., in WO 94/28958.

For the administration of the pharmaceutical composition of the invention according to the invention in inhalers, it is most preferable to use the inhaler shown in the drawing attached to the description. The inhaler (pocket inhaler) shown in this drawing, intended for inhalation of powder pharmaceutical compositions from capsules containing them, is characterized by the presence of a housing 1 with two windows 2, a plate partition 3, in which air inlets are provided and which is equipped with a mesh 5 held in the assembled condition with the corresponding fastener 4 connected to the plate partition 3 of the chamber 6, into which the capsule with inhalation powder is placed and on the side of which a push button is provided 9, equipped with two polished needles 7 and made movable against the force of the spring 8, the mouthpiece 12, which is hinged with the possibility of rotation around the axis 10 connecting it to the housing 1, the plate partition 3 and the cap 11, and through holes 13 for the passage of air serving for regulating aerohydrodynamic drag.

If the inventive inhalation powders, taking into account the above preferred method of their application, are supposed to be packaged in capsules (to obtain inhalers), then it is advisable to fill each capsule with inhalation powder in an amount of 1 to 30 mg. The content in the indicated amounts of active substances used together or separately, according to the invention, corresponds to the dosages already indicated above for components 1 and 2 per one dose.

B) Compositions for aerosol inhalation containing a propellant and the combination of active ingredients 1 and 2 according to the invention

In the compositions of the invention containing propellant (dosage forms) for aerosol inhalation, active ingredients 1 and 2 may be present in dissolved or dispersed form in the propellant. In this case, the active substances 1 and 2 may be contained in separate dosage forms or in one single dosage form, moreover, these components 1 and 2 may either be present in dissolved form, or both may be present in dispersed form, or only one of them may be present in dissolved, and the other in dispersed form.

Propellants used to prepare the compositions of the invention for aerosol inhalation are known in the art. Suitable propellants for this purpose are selected from the group consisting of hydrocarbons, such as n-propane, n-butane or isobutane, and halogenated hydrocarbons, such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The above propellants can be used individually or in the form of mixtures thereof. The most preferred propellants are halogenated alkane derivatives selected from the group consisting of TG11, TG12, TG134a (1,1,1,2-tetrafluoroethane) and TG227 (1,1,1,2,3,3,3-heptafluoropropane), and also mixtures thereof, among which TG134a, TG227 propellants and mixtures thereof are preferred.

Other propellant-containing aerosol inhalation compositions according to the invention may also include other components, such as cosolvents, stabilizers, surfactants, antioxidants, lubricants, and pH adjusting agents. All such components are known in the art.

Proposed in the invention containing propellant compositions for aerosol inhalation may contain up to 5 wt.% The active substance 1 and / or 2 . So, for example, the compositions for aerosol inhalation according to the invention may contain the active substance 1 and / or 2 in an amount of from 0.002 to 5 wt.%, From 0.01 to 3 wt.%, From 0.015 to 2 wt.%, From 0 , 1 to 2 wt.%, From 0.5 to 2 wt.% Or from 0.5 to 1 wt.%.

If the active substances 1 and / or 2 are present in dispersed form, then the average particle size thereof should preferably be up to 10 μm, more preferably from 0.1 to 6 μm, most preferably from 1 to 5 μm.

To obtain aerosols from the propellant-containing compositions described above in the invention for aerosol inhalation and the introduction of such aerosols into the body, inhalers (metered-dose inhalers) known in the art can be used. In accordance with this, another object of the present invention are pharmaceutical compositions in the form of propellant-containing aerosol inhalation compositions described above in combination with one or more inhalers suitable for the preparation of such aerosols and their administration. Another object of the present invention are inhalers, characterized in that they contain the above described proposed in the invention containing propellant compositions for aerosol inhalation. The present invention also relates to interchangeable cartridges which, when equipped with an appropriate valve, can be used in a suitable inhaler and which contain one of the propellant aerosol inhalation compositions described in the invention described above. Such replaceable cans and methods for filling them with the inventive aerosol inhalation compositions containing propellant are known in the art.

C) Inhalation solutions or suspensions without propellant containing the combinations of active substances 1 and 2 according to the invention

The propellant-free inhalation solutions and suspensions of the invention contain, for example, water or alcohols, preferably ethanol, which in some cases can be used in a mixture with water. When mixtures of water with ethanol are used as solvents, the relative ethanol content in terms of the amount of water is not limited to any specific limits, however, it is preferable that the maximum ethanol content be up to 70 vol.%, Especially up to 60 vol.%. The remaining amount, missing up to 100 vol.%, Falls on water. The pH of solutions or suspensions containing components 1 and 2 individually or together, is set using suitable acids for this purpose at 2-7, preferably 2-5. Inorganic or organic acids can be used to adjust the pH to set it to the above values. Hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid can be mentioned as examples of preferred inorganic acids in this regard. As an example of the most suitable organic acids for use for these purposes, mention may be made of ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid, as well as other acids . Preferred inorganic acids are hydrochloric acid and sulfuric acid. It is also possible to use acids which, with one of the active substances, already form an acid addition salt. Among the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. Under certain conditions it is permissible to use mixtures of these acids, especially in the case of those acids that, along with their acidity-enhancing properties, have other properties, for example, as flavorings, antioxidants or complexing agents, such as citric acid or ascorbic acid. To adjust the pH, it is most preferred according to the invention to use hydrochloric acid.

According to the invention, it is possible to refuse to add to the proposed dosage form edithic acid (EDTA) or one of its known salts, in particular sodium edetate, as a stabilizer or complexing agent. However, in other embodiments, the use of this (s) compound (s) is contemplated. In one such preferred embodiment in which sodium edetate is provided, its concentration in the solution is less than 100 mg per 100 ml, preferably less than 50 mg per 100 ml, most preferably less than 20 mg per 100 ml. In principle, such inhalation solutions are preferred in which the sodium edetate content is from 0 to 10 mg per 100 ml.

Co-solvents and / or other excipients can be added to the inventive inhaled solutions without propellant. As such cosolvents, it is preferable to use those which contain hydroxyl groups or other polar groups, for example, alcohols, especially isopropyl alcohol, glycols, especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, glycerin, polyoxyethylene alcohols and polyoxyethylene fatty acid esters . Auxiliary substances and additives in this context means any pharmacologically acceptable substance that is not an active substance, but which, in order to improve the qualitative characteristics of the preparation, can be included in its composition together with the active substance (s) in a pharmacologically acceptable solvent. These substances preferably should not show any or, in view of the targeted therapeutic effect, should not show any significant or at least no undesirable pharmacological effects. Such auxiliary substances and additives include, for example, surfactants such as soya lecithin, oleic acid, sorbitan esters, in particular polysorbates, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and / or preservatives that preserve the finished pharmaceutical preparation or allow extend its shelf life, flavorings, vitamins and / or other additives known from the prior art. Such additives also include pharmacologically acceptable salts as isotonicity agents, such as, for example, sodium chloride.

Preferred excipients include antioxidants, such as, for example, ascorbic acid, unless it is already used to regulate pH, vitamin A, vitamin E, tocopherols and similar vitamins and provitamins found in the human body.

Preservatives can be used to protect the pharmaceutical product from infection by pathogenic microorganisms. As such preservatives, substances known from the prior art can be used, in particular cetyl pyridinium chloride, benzalkonium chloride or benzoic acid, respectively benzoates, such as sodium benzoate, in concentrations known from the prior art. The concentration of the above preservatives should preferably be up to 50 mg per 100 ml of solution, most preferably from 5 to 20 mg per 100 ml of solution.

Preferred pharmaceutical preparations in addition to the solvent, which is water, and combinations of active substances 1 and 2 also contain only benzalkonium chloride and sodium edetate. In another preferred embodiment, it is proposed to completely abandon the use of sodium edetate.

For inhalation of the inventive inhaled solutions without a propellant, inhalers that are most suitable for spraying a small amount of a liquid preparation in the therapeutically necessary dosage in the form of an aerosol for therapeutic use are inhaled within a few seconds. According to the present invention, inhalers are preferred which, in the best case, when they are already actuated once (in one stroke of the piston), allow to dispense a solution of the active substance or active substances in batches sprayed in the form of an aerosol with an average droplet size of less than 20 microns, preferably less than 10 microns less than 100 μl, preferably less than 50 μl, most preferably 20 to 30 μl, so that inhaled, i.e. directly entering the respiratory tract, the proportion of aerosol already corresponded to the therapeutically effective amount of the active substance or active substances.

A similar device intended for inhalation administration of a liquid pharmaceutical composition sprayed in metered amounts in the form of an aerosol without the aid of a propellant is described in detail, for example, in WO 91/14468, as well as in WO 97/12687 (in particular, FIG. 6a and 6b of this application). The nebulizers or inhalers (devices) described in these applications are also known as Respimat®.

It is such an inhaler (Respimat®) that is most appropriate to use for generating the inhalable aerosols of the invention containing a combination of active ingredients 1 and 2 . The patient can always carry a similar device with him, which, thanks to its close to cylindrical shape and hand-picked dimensions of from less than 9 to 15 cm in length and from 2 to 4 cm in width, is convenient to hold in your hand and which does not take up much space . Such an inhaler allows, due to the creation of high pressure, to spray a strictly defined volume of the drug through small nozzles with the formation of inhaled aerosols.

In a preferred embodiment, such an aerosol inhaler consists mainly of an upper casing part, a pump casing, a spray head with a nozzle or nozzle system, a locking and clamping mechanism, a casing part for accommodating a spring, a spring and a supply container, and is characterized by the presence

- a pump casing, which (casing) is fixed in the upper casing part and at one end of which there is a spray head with a nozzle, respectively a nozzle system,

- a hollow piston with a valve element,

- a driven flange in which the hollow piston is fixed and which is located in the upper body part,

- locking-clamping mechanism located in the upper body part,

- a casing part with a spring located therein, which (casing part) is mounted on the upper casing part in a rotary support with the possibility of rotation relative to this upper casing part, and

- the lower body part, axially mounted on the body part to accommodate the spring.

The above hollow piston with valve element corresponds to the device described in WO 97/12687. This hollow piston partially protrudes into the cylinder of the pump housing and can move axially in this cylinder. In this regard, it should first refer to figure 1-4 of the specified application, in particular figure 3, and the relevant sections of the description of this application. At the moment of release or descent of the spring, the hollow piston with the valve element creates on the side of its high pressure applied to the liquid, i.e. to a dosed solution of the active substance, a pressure of from 5 to 60 MPa (from about 50 to 600 bar), preferably from 10 to 60 MPa (from about 100 to 600 bar). Moreover, the volume of one portion of a medicinal product dispensed in one stroke of the piston is preferably from 10 to 50 μl, more preferably from 10 to 20 μl, most preferably 15 μl.

The valve element is preferably located at the end of the hollow piston that faces the spray head.

The nozzle in the spray head is preferably microstructured, i.e. manufactured by microtechnology methods. Microstructured spray heads are described, for example, in WO 99/16530, which is hereby incorporated by reference in its entirety, which relates in particular to FIG. 1 of the drawings attached to this application and to the description of this FIG. 1. The spray head consists, for example, of two plates of glass and / or silicon, firmly connected to each other, at least one of which has one or more microstructured channels connecting the inlet side of the nozzle with its outlet side. At least one round or non-circular hole with a depth of 2 to 10 μm and a width of 5 to 15 μm is located on the exit side of the nozzle, while preferred depths of such a hole are from 4.5 to 6.5 μm, and lengths are from 7 up to 9 microns. When using several, preferably two, spray holes, they can extend parallel to each other in the spray head and thereby form jets parallel to each other, or they can tilt toward each other in the direction of the nozzle exit side. For a spray head with at least two spray holes on the outlet side, the angle formed between the jets formed by them and the jets inclined to each other can be from 20 to 160 °, preferably from 60 to 150 °, especially from 80 to 100 °. The spray holes are preferably spaced from 10 to 200 microns, more preferably from 10 to 100 microns, more preferably from 30 to 70 microns. The most preferred distance between the spray holes is 50 μm. Accordingly, the jets formed by such spray holes intersect directly in the vicinity of them.

As mentioned above, the liquid pharmaceutical preparation is pumped to the spray head under pressure, reaching 600 bar at the inlet, preferably from 200 to 300 bar, and then sprayed through the spray holes in the form of an inhaled aerosol. The droplet size of such an aerosol is preferably up to 20 microns, more preferably from 3 to 10 microns.

The locking and clamping mechanism comprises a spring, preferably a compression coil spring, as a mechanical energy accumulator. A similar spring acts on the driven flange, which is an abruptly ejected element, the movement of which is determined by the position of the stopper. The travel of the driven flange is precisely limited by the upper and lower stops. Compression (cocking) of the spring is preferably provided by a transmission mechanism in the form of a force transducer, for example, a thrust-screw mechanism, which provides translational movement of the links under the action of external torque created when the upper housing part rotates relative to the housing part located in the lower housing part to accommodate the spring. In this case, the upper body part and the driven flange comprise a single or multiple wedge mechanism.

The stopper, together with its locking surfaces, surrounds the driven flange with a ring. Such a stopper is, for example, an elastically radially deformable ring of plastic or metal. This ring is located in a plane perpendicular to the longitudinal axis of the aerosol inhaler. After compression or cocking of the spring, the locking surfaces of the stopper are shifted to the side and are on the path of movement of the driven flange, thereby preventing the spring from being unclenched. The stop is switched off using the shutter button. Such a release button is connected or connected to the stopper. To release the locking-clamping mechanism, it is necessary to press the release button, shifting it parallel to the plane of location of the above ring and, in particular, preferably moving it inside the aerosol inhaler, which is accompanied by deformation of such a deformable ring in the plane of its location. The design features of such a locking-clamping mechanism are described in more detail in the application WO 97/20590.

The lower casing part is axially mounted on the casing part to accommodate the spring and closes the fastening elements, respectively, the supporting elements, the spindle drive and the supply container with liquid.

When the aerosol inhaler is actuated, the upper body part is rotated relative to the lower body part, with which the body part also rotates to accommodate the spring. In this case, the spring is compressed and cocked by a thrust-screw mechanism, and the locking mechanism is automatically locked in the locked position. Preferably, the angle of rotation of the upper housing part relative to the lower housing part is an integer number of times less than 360 °, for example, equal to 180 °. Simultaneously with the compression of the spring, the driven part (driven flange) moves in the upper housing part by a predetermined distance, and the hollow piston is retracted back inside the cylinder in the pump housing, as a result of which a certain portion of liquid is sucked into the high-pressure cavity located in front of the spray head .

If necessary, several replaceable consumable containers (replaceable cartridges) containing liquid sprayed in the form of an aerosol can be inserted and used into the aerosol inhaler if necessary. The expendable capacity is filled with the preparation for aerosol inhalation according to the invention.

To spray a pharmaceutical, lightly press the shutter release button. In this case, the locking mechanism unlocks the driven part (driven flange), freeing the way for it. At the same time, the compressed spring, unclenching, moves the piston into the cylinder of the pump housing. As a result, the liquid leaves the spray head of the aerosol inhaler in a finely atomized form.

Other design features of such a device are described in more detail in WO 97/12683 and WO 97/20590, which are hereby incorporated by reference in their entirety.

Parts and elements of an aerosol inhaler (atomizer) are made taking into account their functional purpose from the corresponding material. So, in particular, the body of the aerosol inhaler, as well as its other parts, if this is permissible from the point of view of their function, it is preferable to perform from plastic, for example, injection molding. In general, for the manufacture of devices intended for medical use, physiologically harmless materials are used.

For aerosol inhalation of the water-based pharmaceutical preparations of the invention, it is preferable to use an aerosol inhaler (Respimat®), which is shown in FIGS. 6a and 6b of the drawings appended to WO 97/12687. On figa of the drawings attached to the application WO 97/12687 such an aerosol inhaler is shown in longitudinal section with a compressed (cocked) spring, and on fig.6b of the drawings attached to the application WO 97/12687 this aerosol inhaler is shown in longitudinal section with a spring unclenched.

In the upper casing part (51) there is a pump casing (52), at the end of which (the casing) there is a holder (53) for the spray head. In the holder is the spray head (54) and filter (55). The hollow piston (57) fixed in the driven flange (56) of the locking-clamping mechanism partially protrudes into the cylinder of the pump housing. A valve element (58) is located at one end of this hollow piston. The hollow piston is sealed with a seal (59). The driven flange has an emphasis (60), which limits the stroke of this driven flange inside the upper body part when the spring is open. The driven flange also has a stop (61) that limits the travel of this driven flange when the spring is compressed. After the spring is compressed, the stopper (62) is displaced between the stop (61) and the support (63) in the upper housing part. A release button (64) is connected to the stop. The upper case part ends with a mouthpiece (65) and is closed by a removable protective cap put on it (66).

The housing part (67), together with the compression spring (68) located in it, is mounted on the upper housing part using latches-latches (69) and mounted in a rotary support with the possibility of rotation relative to this upper housing part. A lower housing part (70) is mounted on the housing part for accommodating the spring. Inside the housing part to accommodate the spring, there is a replaceable consumable container (71) (replaceable spray can) filled with spray liquid (72). The supply container is closed by a plug (73), through which passes a hollow piston protruding into the supply container, immersed at one of its ends in a liquid (in a solution of the active substance or active substances).

A spindle (74) for the mechanical counter is integrated in the lateral outer wall of the body part to accommodate the spring. A drive gear (75) is located at that end of this lead screw that faces the upper body part. A slider (76) is mounted on the lead screw.

The inhaler described above can be used to spray the liquid formulations of the invention in the form of an aerosol suitable for inhalation.

When using the composition of the device described above (Respimat®) for spraying the composition of the invention, a portion of the composition dispensed at at least 97%, preferably at least 98%, of all inhaler activation cycles (piston strokes) must correspond to a certain predetermined amount medicinal product with a tolerance of this amount equal to a maximum of 25%, preferably 20%. Moreover, such a predetermined portion of the composition, issued in one stroke of the piston, is preferably from 5 to 30 mg, most preferably from 5 to 20 mg.

However, for aerosol spraying of the composition of the invention, it is possible to use not only the inhaler described above, but also other types of inhalers, for example, jet inhalers or other stationary inhalers.

Accordingly, another object of the present invention is pharmaceutical preparations or compositions in the form of the above-described inhaled solutions or suspensions without a propellant in combination with a device suitable for their administration into the body, preferably in combination with a Respimat® inhaler. In this regard, in a preferred embodiment, the present invention provides inhaled solutions or suspensions without a propellant, characterized in that they comprise the combination of active ingredients 1 and 2 according to the invention and that such solutions are intended to be sprayed using a device known as Respimat® . The present invention further relates to the inhalation devices described above, preferably to a Respimat® device, which are characterized in that they contain the inhalation solutions or suspensions described above without the propellant described above.

Inhalation solutions containing the active ingredients 1 and 2 in a single dosage form are preferred according to the invention. However, the term "dosage form" also includes dosage forms in which two solutions, each of which contains respectively only one of components 1 and 2 , are separately in a two-chamber interchangeable spray can described, for example, in the application WO 00/23037. In accordance with this, the specified application is fully incorporated into the present description by reference.

The inventive inhalation solutions or suspensions without a propellant, in addition to those discussed above, which are intended for use in combination with a Respimat® device, solutions or suspensions may also be presented in the form of concentrates or sterile, ready-to-use inhalation solutions or suspensions. Ready-to-use preparations can be prepared from such concentrates by adding, for example, solutions that add isotonicity to sodium chloride solutions. For the introduction into the body of such sterile, ready-to-use preparations, stationary or portable aerosol dispensers that are powered by an energy source can be used to create inhaled aerosols using ultrasound or compressed air based on the Venturi principle or another principle.

In accordance with this, another object of the present invention are pharmaceutical compositions in the form of the above inhaled solutions or suspensions without a propellant, which are presented in the form of concentrates or sterile, ready-to-use preparations, in combination with a device suitable for administration to such solutions or suspensions, characterized in that such a device is a stationary or portable nebulizer that is powered by an energy source and creates inhaled aerosols using ultrasound Single or compressed air by the Venturi principle or other principles.

The following examples, which are purely illustrative, serve to provide a more detailed explanation of the principles underlying the present invention and do not limit its scope to the specific embodiments described below.

Examples of compositions or dosage forms

The following examples of compositions or dosage forms that can be prepared analogously to methods known from the prior art serve for a more detailed explanation of the present invention, the scope of which, however, is not limited specifically to the data given in these examples. In the examples below, the enantiomerically pure form of the preferred enantiomer of bromide of formula 1 (i.e., formula 1-en ) is used as the active ingredient.

A) Inhalation powders

one)

Components Amount in mcg per capsule 1-en (bromide) 250 budesonide 200 lactose 12050 Total 12500

2)

Components Amount in mcg per capsule 1-en (bromide) 200 fluticasone propionate 125 lactose 4675 Total 5000

3)

Components Amount in mcg per capsule 1-en (bromide) 250 mometasone furoate • Н ₂ О 250 lactose 12000 Total 12500

four)

Components Amount in mcg per capsule 1-en (bromide) 200 cyclesonide 250 lactose 12050 Total 12500

5)

Components Amount in mcg per capsule 1-en (bromide) one hundred budesonide 125 lactose 4775 Total 5000

6)

Components Amount in mcg per capsule 1-en (bromide) 150 fluticasone propionate 200 lactose 4650 Total 5000

7)

Components Amount in mcg per capsule 1-en (bromide) 150 mometasone furoate • Н ₂ О 250 lactose 4600 Total 5000

8)

Components Amount in mcg per capsule 1-en (bromide) one hundred cyclesonide 250 lactose 4650 Total 5000

B) containing propellant compositions for aerosol inhalation

1) Suspension for aerosol spraying:

Components Amount in wt.% 1-en (bromide) 0.1 budesonide 0.4 soya lecithin 0.2 TG 134a: TG227 in the ratio. 2: 3 up to 100

2) Suspension for aerosol spraying:

Components Amount in wt.% 1-en (bromide) 0.2 fluticasone propionate 0.3 isopropyl myristate 0.1 TG227 up to 100

3) Suspension for aerosol spraying:

Components Amount in wt.% 1-en (bromide) 0.1 mometasone furoate • Н ₂ О 0.6 isopropyl myristate 0.1 TG227 up to 100

4) Suspension for aerosol spraying:

Components Amount in wt.% 1-en (bromide) 0.1 cyclesonide 0.4 isopropyl myristate 0.1 TG 134a: TG227 in the ratio. 2: 3 up to 100

Claims (22)

1. Pharmaceutical combinations intended for the treatment of inflammatory or obstructive respiratory diseases, characterized in that they contain one or more salts of the formula 1

in which X ^- is a singly charged anion, preferably an anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and n -toluenesulfonate, optionally in the form of its (their) racemates, enantiomers and hydrates, in combination with one or more steroids ( 2 ), optionally in the form of its (their) enantiomers, mixtures of enantiomers or in the form of its (their) racemates, optionally in the form solvates or hydrates, and optionally compatible spot with a pharmaceutically acceptable excipient wherein steroid (2) is selected from the group consisting of methylprednisolone, prednisone, butiksokort propionate, RPR-106541, flunisolid, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, ST-126, dexamethasone, (S) -fluoromethyl ether 6α, 9α-difluoro-17α - [(2-furanylcarbonyl) oxy] -11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioacids and (S) - ( 2-oxo-tetrahydrofuran-3S-yl) ether 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene
17β-carbothioacids. 2. The pharmaceutical combination according to claim 1, characterized in that the active substances 1 and 2 are present either together in one single dosage form, or in two separate dosage forms. 3. The pharmaceutical combination according to claim 1, characterized in that the compounds of formula 1 are presented in the form of enantiomers of the formula 1-en

4. Pharmaceutical combinations according to one of claims 1 to 3, characterized in that compounds 2 are presented in the form of salts or derivatives, including sodium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates. 5. Pharmaceutical combinations according to one of claims 1 to 3, characterized in that compounds 2 are selected from the group consisting of flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, cyclesonide, rofleponide, ST-126, dexamethasone, (S) - fluoromethyl ether 6α, 9α-difluoro-17α - [(2-furanylcarbonyl) oxy] -11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioacids and (S) - (2-oxotetrahydrofuran- 3S-yl) ether 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene
17β-carbothioacids. 6. Pharmaceutical combinations according to one of claims 1 to 3, characterized in that compounds 2 are selected from the group consisting of budesonide, fluticasone, mometasone, cyclesonide and (S) -fluoromethyl ether 6α, 9α-difluoro-17α - [(2- furanylcarbonyl) oxy] -11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylic acid. 7. Pharmaceutical combinations according to one of claims 1 to 3, characterized in that the mass ratio between the active substance 1 and the active substance 2 is from 1: 250 to 250: 1, preferably from 1: 150 to 150: 1. 8. The pharmaceutical combination according to one of claims 1 to 3, characterized in that it is presented in the form of a dosage form suitable for inhalation. 9. The pharmaceutical combination according to claim 8, characterized in that the dosage form is selected from the group comprising inhalation powders containing propellant inhalation aerosols and inhalation solutions free of propellant. 10. The pharmaceutical combination according to claim 9, characterized in that it is an inhalation powder containing the active substances 1 and 2 in a mixture with acceptable physiologically harmless excipients selected from the group consisting of monosaccharides, disaccharides, oligo- and polysaccharides, polyhydric alcohols , salts and mixtures of such auxiliary substances with each other. 11. The pharmaceutical combination of claim 10, characterized in that the maximum average particle size of the auxiliary substance in the inhalation powder reaches 250 microns, preferably from 10 to 150 microns. 12. The pharmaceutical combination according to claim 9, characterized in that it is an inhalation powder that contains only its active ingredients 1 and 2 as its components. 13. The pharmaceutical combination according to claim 9, characterized in that it is a propellant-containing dosage form for aerosol inhalation containing the active substances 1 and 2 in dissolved or dispersed form. 14. The pharmaceutical combination according to item 13, wherein the aerosol inhalation dosage form contains hydrocarbons, such as n-propane, n-butane or isobutane, or halogenated hydrocarbons, such as chlorinated and / or fluorinated methane derivatives, as a propellant, ethane, propane, butane, cyclopropane or cyclobutane. 15. The pharmaceutical combination according to 14, characterized in that the propellant is TG11, TG12, TG134a, TG227 or a mixture thereof, preferably TG134a, TG227 or a mixture thereof. 16. The pharmaceutical combination according to one of paragraphs.13-15, characterized in that the content of the active substance 1 and / or 2 in the dosage form for aerosol inhalation can be up to 5 wt.%. 17. The pharmaceutical combination according to claim 9, characterized in that it is a propellant-free inhalation solution containing water, ethanol or a mixture of water with ethanol as a solvent. 18. The pharmaceutical combination according to 17, characterized in that the inhalation solution optionally contains other cosolvents and / or excipients. 19. The pharmaceutical combination according to claim 18, characterized in that the inhalation solution contains, as cosolvents, components containing hydroxyl groups or other polar groups, for example alcohols, especially isopropyl alcohol, glycols, especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers , glycerin, polyoxyethylene alcohols and esters of polyoxyethylene and fatty acids. 20. The pharmaceutical combination according to claim 18 or 19, characterized in that the inhalation solution contains surfactants, stabilizers, complexing agents, antioxidants and / or preservatives, flavoring agents, pharmacologically acceptable salts and / or vitamins as auxiliary substances. 21. The pharmaceutical combination according to claim 20, characterized in that the inhalation solution contains, as complexing agents, edinic acid or its salt, preferably sodium edetate. 22. The use of a pharmaceutical combination according to one of claims 1 to 21 for the manufacture of a medicament for the treatment of inflammatory or obstructive respiratory diseases, especially asthma or chronic obstructive pulmonary disease.