Patent EA-005111-B1 (EA)
Title: Compositions of n-(methylethylaminocarbonyl)-4-(3-methylphenylamino)-3-pyridyl-sulfonamide and cyclic oligosaccharides
Inventor: DUMIC MILJENKO
IPC: A61K31/715
Filed: 2001-01-31
Abstract: 1. Physical mixtures, characterized in that they comprise torasemide and cyclodextrins or cyclodextrin derivatives. 2. Physical mixtures according to claim 1, characterized in that torasemide is selected from a group consisting of modifications I, II, III, IV and V or any mixture thereof. 3. Physical mixtures according to claim 1, characterized in that cyclodextrin is selected from a group consisting of alpha-, beta-and nu-cyclodextrin. 4. Physical mixtures according to claim 1, characterized in that cyclodextrin derivatives are selected from the group of ethers or mixed ethers of alpha-, beta-and nu-cyclodextrins having one or more groups of anhydroglucose parts of cyclodextrin substituted with C1-6alkyl, preferably methyl, ethyl or isopropyl; hydroxyC1-6alkyl, preferably hydroxyethyl or hydroxypropyl or hydroxybutyl; carboxyC1-6alkyl, preferably carboxymethyl or carboxyethyl; C1-6alkylcarbonyl, preferably acetyl, C1-6akoxycarbonylC1-6alkyl or carboxy-C1-6alkoxy-C1-6alkyl, preferably carboxymethoxypropyl or carboxyethoxypropyl;C1-6alkoxy- carbonyloxyC1-6alkyl, preferably, 2-acetyloxypropyl. 5. Physical mixtures according to claim 1, characterized in that cyclodextrin derivatives are selected from the group of 2-hydroxypropyl-alpha-cyclodextrin, 2 hydroxypropyl-beta-cyclodextrin, 2-hydroxypropyl-nu-cyclodextrin, 2-hydroxyethyl beta-cyclodextrin, 2-hydroxyethyl-nu-cyclodextrin, 2,6-dimethyl-beta-cyclodextrin and (2-carboxymethoxy)-propyl-beta-cyclodextrin. 6. Physical mixtures according to claim 1, characterized in that torasemide and cyclodextrins or cyclodextrin derivatives are in a molar ratio from 1: 0.1 to 1: 5. 7. A method for the preparation of physical mixtures according to claim 1, characterized in that torasemide and cyclodextrins or cyclodextrin derivatives are homogenized. 8. A method for the preparation of physical mixtures according to claim 7, characterized in that the said homogenization is carried out in a mortar or in mixers. 9. A method for the preparation of physical mixtures according to claim 7, characterized in that the said mixing is carried out at temperatures from 10 degree C to 100 degree C. 10. A method for the preparation of physical mixtures according to claim 7, characterized in that the said mixing is carried out from 0.1 hour to 24 hours. 11. Physical mixtures according to claim 1, characterized in that they are used as a diuretic and as an agent for preventing heart damages or heart tissue damages caused by metabolic or ionic abnormalities associated with ischemia, in the treatment of thrombosis, angina pectoris, asthma, hypertension, nephroedema, pulmonary edema, primary and secondary aldosteronism, Batter's syndrome, tumours, glaucoma, decrease of intraocular pressure, acute or chronic bronchitis, in the treatment of cerebral edema caused by trauma, ischemia, concussion of the brain, metastases or epileptic attacks and in the treatment of nasal infections caused by allergens. 12. A pharmaceutical form, characterized in that it comprises physical mixtures according to claim 1 as the active substance in combination with one or more pharmaceutically acceptable additives such as sugar, starch, starch derivatives, cellulose, cellulose derivatives, mould release agents and antiadhesive agents and optionally agents for flowability regulation. 13. A pharmaceutical form according to claim 12, characterized in that it is a tablet, a capsule, an injection or a spray. 14. Inclusion complexes characterized in that they comprise torasemide and cyclodextrins or cyclodextrin derivatives. 15. Inclusion complexes according to claim 14, characterized in that cyclodextrin is selected from a group consisting of alpha-, beta-and nu-cyclodextrin. 16. Inclusion complexes according to claim 14, characterized in that the cyclodextrin derivatives are selected from a group of ethers or mixed ethers of alpha-, beta- and nu-cyclodextrins having one or more groups of anhydroglucose parts of cyclodextrin substituted with C1-6alkyl, preferably methyl, ethyl or isopropyl; hydroxyC1-6alkyl, preferably hydroxyethyl or hydroxypropyl or hydroxybutyl; carboxyC1-6alkyl, preferably carboxymethyl or carboxyethyl; C1-6alkylcarbonyl, preferably acetyl, C1-6alkoxycarbonylC1-6alkyl or carboxy-C1-6alkoxy-C1-6alkyl, preferably carboxymethoxypropyl or carboxyethoxypropyl; C1-6alkoxycarbonyloxy-C1-66alkyl, preferably, 2-acetyloxypropyl. 17. Inclusion complexes according to claim 14, characterized in that cyclodextrin derivatives are selected from the group of 2-hydroxypropyl-alpha-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin, 2-hydroxypropyl-nu-cyclodextrin, 2-hydroxyethyl-beta-cyclodextrin, 2-hydroxyethyl-gamma-cyclodextrin, 2,6-dimethyl-beta cyclodextrin and (2-carboxymethoxy)-propyl-beta-cyclodextrin. 18. Inclusion complexes according to claim 14, characterized in that torasemide and cyclodextrins or cyclodextrin derivatives are in a molar ratio from 1: 0.1 to 1: 5. 19. A method for the preparation of inclusion complexes according to claim 14, characterized in that torasemide and cyclodextrins or cyclodextrin derivatives are reacted in water with or without an aqueous solution of a base. 20. A method for the preparation of inclusion complexes according to claim 19, characterized in that as the aqueous solution of a base an aqueous ammonia solution is used. 21. A method for the preparation of inclusion complexes according to claim 19, characterized in that it is carried out at temperatures from 10 degree C to 100 degree C. 22. A method for the preparation of inclusion complexes according to claim 19, characterized in that it is carried out for from 0.1 hours to 7 days. 23. A method for the preparation of inclusion complexes according to claim 19, characterized in that after formation of the said inclusion complex, the water and the base are removed by drying. 24. A method for the preparation of inclusion complexes according to claim 23, characterized in that the said drying is carried out by lyophilization, spray-drying, vacuum evaporation or vacuum drying. 25. Inclusion complexes according to claim 14, characterized in that they are used as a diuretic and as an agent for preventing heart damages or heart tissue damages caused by metabolic or ionic abnormalities associated with ischemia, in the treatment of thrombosis, angina pectoris, asthma, hypertension, nephroedema, pulmonary edema, primary and secondary aldosteronism, Batter's syndrome, tumours, glaucoma, decrease of intraocular pressure, acute or chronic bronchitis, in the treatment of cerebral edema caused by trauma, ischemia, concussion of the brain, metastases or epileptic attacks and in the treatment of nasal infections caused by allergens. 26. A pharmaceutical form, characterized in that it comprises inclusion complexes according to claim 14 as the active ingredient in combination with one or more pharmaceutically acceptable additives such as sugar, starch, starch derivatives, cellulose, cellulose derivatives, mould release agents and antiadhesive agents and optionally agents for flowability regulation. 27. A pharmaceutical form according to claim 26, characterized in that it is a tablet, a capsule, an injection or a spray.