Method, compositions and kits for increasing the oral bioavailability of pharmaceutical agents

 

A method of increasing the bioavailability texana when administered orally in conjunction with cyclosporine, a method of treatment of a disease susceptible to taxane, and, accordingly, the oral pharmaceutical dosage form. The invention allows to increase the area under the pharmacokinetic curve of docetaxel with 8% after self-administration per os to 90% after the introduction of cyclosporine And due to the influence of cytochrome P-450 (isoform 3A4), but inhibition of glycoprotein-P in the mucosa of the gastrointestinal tract, which can dramatically increase the efficiency taxane in the proposed combined with cyclosporine dosage form, and the effectiveness of treatment of a disease susceptible to taxane. 3 C. and 50 C. p. F.-ly, 42 ill. 15 table.

Description text in facsimile form (see graphic part)

Claims

1. The method of increasing the bioavailability upon oral administration to a mammal taxane, including oral co-administration to the patient taxane and agent enhancing oral bioavailability, including cyclosporine.

2. The method according to p. 1, characterized in that taxon selected from a group is acceptable salts.

3. The method according to p. 1, characterized in that the reinforcing agent is administered either (a) about 0.5-24 h before, (b) less than 0.5 h before, at the same time or less than 0.5 h after, or c) about 0.5-24 h before and again less than 0.5 h before, at the same time or less than 0.5 h after injection taxane.

4. The method according to p. 1, characterized in that taxon and reinforcing agent, each entered as separate dosage forms.

5. The method according to p. 1, characterized in that taxon and reinforcing agent are introduced together in the form of combined oral dosage forms.

6. The method according to p. 1, characterized in that taxon includes paclitaxel.

7. The method according to p. 1, characterized in that taxon includes docetaxel.

8. The method according to p. 1, wherein the patient is administered about 20-1000 mg/m2target taxane in the calculation of the surface area of the patient's body.

9. The method according to p. 1, wherein the patient is administered about 2-30 mg/kg of paclitaxel per body weight of the patient.

10. The method according to p. 1, characterized in that includes cyclosporine cyclosporine D.

11. The method according to p. 1, wherein the patient is administered about 0.1-15 mg/kg reinforcing agent based on the weight of the patient's body.

12. The method according to p. 1, characterized in that the reinforcing agent includes cyclospora>4. The method according to p. 1, wherein the cyclosporin is selected from the group consisting of cyclosporin A-Z, (Me-lle-4) cyclosporine, dihydrocyclopenta And dihydrocyclopenta With, acetylcysteine and related oligopeptides produced originally Tolypocladium.

15. The method according to p. 1, wherein the reinforcing agent comprises cyclosporine G.

16. The method according to p. 1, characterized in that the reinforcing agent includes neimanmarcus cyclosporine.

17. The method according to p. 1, wherein the reinforcing agent comprises cyclosporine F.

18. A method of treating a mammal suffering from a disease susceptible to taxane, including oral co-administration to the patient taxane and agent enhancing oral bioavailability, including cyclosporine.

19. The method according to p. 18, where the disease is cancer, tumor, neoplastic growth or uncontrolled proliferation of tissue or cells, secondary to tissue damage.

20. The method according to p. 18, where the disease is selected from the group consisting of ovarian cancer, breast cancer, lung cancer, carcinoma of the head and neck, hepatocellular carcinoma, liver metastases, cancer of the urinary tract and gastrointestinal tract, Kaposi's sarcoma, policisto, b) less than 0.5 h before, at the same time or less than 0.5 h after or c) about 0.5-24 h before and again less than 0.5 h before, at the same time or less than 0.5 hours after administration taxane.

22. The method according to p. 18, characterized in that taxon and reinforcing agent are administered together in a separate oral dosage forms.

23. The method according to p. 18, characterized in that taxon and reinforcing agent are administered together in the form of combined oral dosage forms.

24. The method according to p. 18, characterized in that taxon selected from the group consisting of paclitaxel, metabolites of paclitaxel, docetaxel, prodrugs and their pharmaceutically acceptable salts.

25. The method according to p. 18, characterized in that taxon includes paclitaxel.

26. The method according to p. 18, characterized in that taxon includes docetaxel.

27. The method according to p. 18, wherein the cyclosporin is cyclosporin D.

28. The method according to p. 18, wherein the patient is administered about 20-1000 mg/m2taxane in the calculation of the surface area of the patient's body.

29. The method according to p. 18, wherein the patient is administered about 2-30 mg/kg of paclitaxel per body weight of the patient.

30. The method according to p. 18, wherein the patient is administered about 0.1-15 mg/kg reinforcing agent in A. pH

32. The method according to p. 18, wherein the reinforcing agent comprises about 5 mg/kg cyclosporine A.

33. The method according to p. 18, wherein the cyclosporin is selected from the group consisting of cyclosporin A-Z, (Me-11e-4) cyclosporine, dihydrocyclopenta And dihydrocyclopenta With, acetylcysteine and related oligopeptides produced originally Tolypocladium.

34. The method according to p. 18, wherein the reinforcing agent comprises cyclosporine G.

35. The method according to p. 18, characterized in that the reinforcing agent includes neimanmarcus cyclosporine.

36. The method according to p. 18, wherein the reinforcing agent comprises cyclosporine F.

37. Oral pharmaceutical dosage form comprising Texan and the agent that increase oral availability, including cyclosporine.

38. Dosage form under item 37, wherein taxon selected from the group consisting of paclitaxel, metabolites of paclitaxel, docetaxel, prodrugs and their pharmaceutically acceptable salts.

39. Dosage form under item 37, wherein taxon includes docetaxel.

40. Dosage form under item 37, wherein taxon includes paclitaxel.

41. Dosage form under item 37, wherein savanna form on p. 37, characterized in that taxon includes about 2-30 mg/kg of paclitaxel per body weight of the patient.

43. Dosage form on p. 37, characterized in that includes cyclosporine cyclosporine D.

44. Dosage form under item 37, wherein the cyclosporine includes (Me-11e-4) ciclosporin or cyclosporine A.

45. Dosage form on p. 37, characterized in that it includes about 0.1-15 mg/kg reinforcing agent based on the weight of the patient's body.

46. Dosage form under item 37, wherein the reinforcing agent comprises about 5 mg/kg cyclosporine A.

47. Dosage form under item 37, which is presented in the form selected from the group consisting of tablets, capsules, dripping, pills, pellets and liquid solutions, suspensions or elixirs.

48. Dosage form on p. 37, characterized in that it further includes pharmaceutically inert excipient, carrier, filler, binder, disintegrity agent, solvent, solubilizers agent, sweetener or dye.

49. Dosage form on p. 37, further comprising polyethoxysiloxane castor oil, alcohol or polyoxyethylene servicemanual.

50. Dosage form under item 37, wherein cyclosp sporine With, acetylcysteine and related oligopeptides produced originally Tolypocladium.

51. Dosage form under item 37, wherein the reinforcing agent comprises cyclosporine G.

52. Dosage form under item 37, wherein the reinforcing agent comprises neimanmarcus cyclosporine.

53. Dosage form under item 37, wherein the reinforcing agent comprises cyclosporine F.

Priorities on items and attributes:

29.02.1996 on the grounds PP.2, 24, 38 "docetaxel", "metabolites of paclitaxel", the signs of PCP.14, 33, 44, 50, "cyclosporine A-Z", "related oligopeptides produced originally Tolypocladium, signs p. 19 "cancer, tumor, neoplastic growth, p. 20 "ovarian cancer, breast cancer, lung cancer, carcinoma of the head and neck, hepatocellular carcinoma, liver metastases, cancer of the urinary organs", "polycystic kidney disease and malaria", the sign of p. 47 "dripping, pills, pellets and liquid solutions, suspensions or elixirs", the sign of p. 49 "polyethoxysiloxane castor oil" and PP.7, 10, 12, 15, 17, 26-27, 31, 34, 36, 43, 51, 53;

16.10.1996 on the grounds PP.14, 33, 44, 50 "(IU-11th-4)cyclosporine, dihydrocyclopenta And, dihydrocyclopenta, acetylserotonin And" signs p. 19 "uncontrolled proliferation of tissue or cells", p. 20, "cancer, Zheludok is 32, 41-42, 45-46;

26.10.1995 on the remaining points and characteristics of the above-mentioned items.

 

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