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Claims for Patent: 6,743,441

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Claims for Patent: 6,743,441

Title: Compositions and methods for minimizing adverse drug experiences associated with oxybutynin therapy
Abstract:The present invention provides compositions and methods for administering oxybutynin while minimizing the incidence and or severity of adverse drug experiences associated with oxybutynin therapy. In one aspect, these compositions and methods provide a lower plasma concentration of oxybutynin metabolites, such as N-desethyloxybutynin, which is presumed to be contributing at least in part to some of the adverse drug experiences, while maintaining sufficient oxybutynin plasma concentration to benefit a subject with oxybutynin therapy. The invention also provides isomers of oxybutynin and its metabolites that meet these characteristics of minimized incidence and/or severity of adverse drug experiences, and maintenance of beneficial and effective therapy for overactive bladder.
Inventor(s): Sanders; Steven W. (Salt Lake City, UT), Ebert; Charles D. (Salt Lake City, UT)
Assignee: Watson Pharmaceuticals, Inc. (Corona, CA)
Application Number:10/098,752
Patent Claims: 1. A method of treating with oxybutynin a subject having overactive bladder, while minimizing an anticholinergic or antimuscarinic adverse drug experience associated with said oxybutynin treatment therapy comprising the step of: administering as a transdermal patch, a composition comprising oxybutynin to a subject to provide a plasma area under the curve (AUC) ratio of oxybutynin to an oxybutynin metabolite of from about 0.5:1 to about 5:1, wherein the transdermal patch optionally includes a permeation enhancer.

2. The method of claim 1, wherein the AUC ratio of oxybutynin to an oxybutynin metabolite is from about 1:1 to about 5:1.

3. The method of claim 1, wherein the AUC ratio of oxybutynin to an oxybutynin metabolite is from about 0.8:1 to about 1.5:1.

4. The method of claim 1, wherein the oxybutynin in the plasma is (R)-oxybutynin, (S)-oxybutynin, or a combination thereof.

5. The method of claim 1, wherein the metabolite of oxybutynin is N-desethyloxybutynin.

6. The method of claim 5, wherein the N-desethyloxybutynin is (R)-N-desethyloxybutynin, (S)-N-desethyloxybutynin or a combination thereof.

7. The method of claim 4, wherein the AUC ratio of (R)-oxybutynin to (S)-oxybutynin is about 0.7:1.

8. The method of claim 6, wherein the AUC ratio of(R)-N-desethyloxybutynin to (R)-oxybutynin is from about 0.4:1 to about 1.6:1.

9. The method of claim 8, wherein the AUC ratio of (R)-N-desethyloxybutynin (R)-oxybutynin is about 1:1.

10. The method of claim 6, wherein the AUC ratio of (R)-N-desethyloxybutynin to (S)-N-desethyloxybutynin is from about 0.5:1 to about 1.3:1.

11. The method of claim 10, wherein the AUC ratio of (R)-N-desethyloxybutynin to (S)-N-desethyloxybutynin is about 0.9:1.

12. The method of claim 1, wherein the metabolite plasma concentration reaches a peak plasma value of less than about 8 ng/ml.

13. The method of claim 1, wherein the metabolite plasma concentration reaches a peak value of less than about 5 ng/ml.

14. The method of claim 1, wherein the adverse drug experience is an experience selected from the group consisting of: gastrointestinal/genitourinary, nervous system, cardiovascular, dermatological, and opthalmic experiences, or a combination thereof.

15. An article of manufacture for transdermal application comprising: a transdermal patch including a composition of oxybutynin and optionally including a permeation enhancer, wherein the composition provides, upon administration to a subject, a plasma AUC ratio of oxybutynin to an oxybutynin metabolite from about 0.5:1 to about 5:1, and wherein said patch minimizes an anticholinergic or antimuscarinic adverse drug experience associated with the administration of oxybutynin.

16. The article of manufacture of claim 15, wherein the AUC ratio of oxybutynin to an oxybutynin metabolite is from about 1:1 to about 5:1.

17. The article of manufacture of claim 15, wherein the AUC ratio of oxybutynin to an oxybutynin metabolite is from about 0.8:1 to about 1.5:1.

18. The article of manufacture of claim 15, wherein the oxybutynin in the plasma is (R)-oxybutynin, (S)-oxybutynin, or a combination thereof.

19. The article of manufacture of claim 15, wherein the metabolite of oxybutynin is N-desethyloxybutynin.

20. The article of manufacture of claim 19, wherein the N-desethyloxybutynin is (R)-N-desethyloxybutynin, (S)-N-desethyloxybutynin or a combination thereof.

21. The article of manufacture of claim 18, wherein the AUC ratio of (R)-oxybutynin to (S)-oxybutynin is about 0.7:1.

22. The article of manufacture of claim 20, wherein the AUC ratio of (R)-N-desethyloxybutynin to (R)-oxybutynin is from about 0.4:1 to about 1.6:1.

23. The article of manufacture of claim 22, wherein the AUC ratio of (R)-N-desethyloxybutynin to (R)-oxybutynin is about 1:1.

24. The article of manufacture of claim 20, wherein the AUC ratio of (R)-N-desethyloxybutynin to (S)-N-desethyloxybutynin is from about 0.5:1 to about 1.3:1.

25. The article of manufacture of claim 24, wherein the AUC ratio of (R)-N-desethyloxybutynin to (S)-N-desethyloxybutynin is about 0.9:1.

26. The article of manufacture of claim 15, wherein the metabolite plasma concentration reaches a peak plasma value of less than about 8 ng/ml.

27. The article of manufacture of claim 15, wherein the metabolite plasma concentration reaches a peak value of less than about 5 ng/ml.

28. The article of manufacture of claim 15, wherein the adverse drug experience is an experience selected from the group consisting of: gastrointestinal/genitourinary, nervous system, cardiovascular, dermatological, and opthalmic experiences, or a combination thereof.

29. The method of claim 1, where the permeation enhancer is a member selected from the group consisting essentially of: fatty acids, fatty acid esters, fatty alcohols, fatty acid esters of lactic acid or glycolic acid, glycerol triesters, glycerol diesters, glycerol monoesters, triacetin, short chain alcohols, and mixtures thereof.

30. The method of claim 29, wherein the permeation enhancer is triacetin.

31. The method of claim 1, wherein the oxybutynin is a mixture of R-oxybutynin and S-oxybutynin.

32. The method of claim 1, wherein the oxybutynin is R-oxybutynin.

33. The method of claim 1, wherein the oxybutynin is S-oxybutynin.

34. The article of manufacture of claim 15, where the permeation enhancer is a member selected from the group consisting essentially of: fatty acids, fatty acid esters, fatty alcohols, fatty acid esters of lactic acid or glycolic acid, glycerol triesters, glycerol diesters, glycerol monoesters, triacetin, short chain alcohols, and mixtures thereof.

35. The article of manufacture of claim 34, wherein the permeation enhancer is triacetin.

36. The article of manufacture of claim 15, wherein the oxybutynin is a mixture of R-oxybutynin and S-oxybutynin.

37. The article of manufacture of claim 15, wherein the oxybutynin is R-oxybutynin.

38. The article of manufacture of claim 15, wherein the oxybutynin is S-oxybutynin.

39. The method of claim 1, wherein the metabolite is N-desethyloxybutynin and the peak plasma concentration of N-desethyloxybutynin is from about 0.5 ng/ml to about 8 ng/ml.

40. The method of claim 1, wherein the metabolite is N-desethyloxybutynin and the peak plasma concentration of N-desethyloxybutynin is less than about 5 ng/ml.

41. The method of claim 1, wherein the metabolite is N-desethyloxybutynin and the peak plasma concentration of N-desethyloxybutynin is from about 1.0 ng/ml to about 3 ng/ml.

42. The method of claim 1, wherein the metabolite is N-desethyloxybutynin and the N-desethyloxybutynin AUC does not exceed the oxybutynin AUC by more than a ratio of about 2:1.

43. The method of claim 1, wherein the metabolite is N-desethyloxybutynin and the peak plasma concentration of N-desethyloxybutynin is about 3 ng/ml.

44. The method of claim 1, wherein the metabolite is N-desethyloxybutynin and the AUC ratio of oxybutynin to N-desethyloxybutynin is from about 0.5:1 to about 4:1.

45. The method of claim 1, wherein the metabolite is N-desethyloxybutynin and the AUC ratio of oxybutynin to N-desethyloxybutynin is from about 1:1 to 5:1.

46. The method of claim 1, wherein the metabolite is N-desethyloxybutynin and the AUC ratio of oxybutynin to N-desethyloxybutynin is from about 0.8:1 to about 2.5:1.

47. The method of claim 3, wherein the metabolite is N-desethyloxybutynin.

48. The method of claim 1, wherein oxybutynin plasma concentrations are below about 2.0 ng/ml at about 6 hours after administration.

49. The method of claim 1, wherein the metabolite is N-desethyloxybutynin and the N-desethyloxybutynin plasma concentrations are below about 2.0 ng/ml at about 6 hours after administration.

50. The method of claim 1, wherein the metabolite is N-desethyloxybutynin and oxybutynin and N-desethyloxybutynin plasma concentrations are below about 8 ng/ml at about 24 hours after initial administration.

51. The method of claim 1, wherein the metabolite is N-desethyloxybutynin and at steady state, the oxybutynin and N-desethyloxybutynin plasma concentrations are below about 8 ng/ml for the duration of administration.

52. The method of claim 51, wherein the duration of administration is from about 24 to about 96 hours.

53. The method of claim 1, wherein the patch is administered for a duration of from about 24 to about 96 hours.

54. The method of claim 10, wherein peak plasma concentration and AUC for (R)-N-desethyloxybutynin are about equal to or less than the peak plasma concentration and AUC for (S)-N-desethyloxybutynin.

55. The method of claim 8, wherein peak plasma concentration and AUC for (R)-oxybutynin are approximately equal to the peak plasma concentration and AUC for (R)-N-desethyloxybutynin.

56. The method of claim 6, wherein (R)-N-desethyloxybutynin has a peak plasma concentration of less than about 4 ng/mL.

57. The method of claim 6, wherein (R)-N-desethyloxybutynin has a peak plasma concentration between about 0.25 ng/ml to about 4 ng/ml.

58. The method of claim 6, wherein (R)-N-desethyloxybutynin has a peak plasma concentration of about 1.5 ng/ml.

59. The method of claim 6, wherein (R)-N-desethyloxybutynin has an AUC of about 100 ng.times.hr/ml.

60. The method of claim 6, wherein (R)-N-desethyloxybutynin has an AUC of from about 30 ng.times.hr/ml to about 170 ng.times.hr/ml.

61. The method of claim 6, wherein (R)-N-desethyloxybutynin plasma concentration is below about 1 ng/ml at about 6 hours after initiation of administration.

62. The method of claim 6, wherein (R)-N-desethyloxybutynin plasma concentration is below about 2 ng/ml at about 24 hours after initiation of administration.
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