METHOD OF TREATING ATROPHIC VAGINITIS

• US 20090092656A1
• Filed: 06/27/2008
• Published: 04/09/2009
• Est. Priority Date: 06/02/2006
• Status: Active Grant

• Current Assignee: Bernadette Klamerus, Fred Mermelstein, Janet A. Chollet
• Original Assignee: Bernadette Klamerus, Fred Mermelstein, Janet A. Chollet
• Inventors: Mermelstein, Fred, KLAMERUS, Bernadette, Chollet, Janet A.
• Granted Patent: US 9,675,546 B2
• Time in Patent Office: Days
• US Class Current: 424/433
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/215 of carboxylic acids
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 9/0034 Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
• CPC Class Codes: A61K 9/02 Suppositories; Bougies; Bases therefor; Ovulesapparatus for making A61J3/08; devices for introducing into the body A61M31/00
• CPC Class Codes: A61P 15/02 for disorders of the vagina
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/24 of the sex hormones

Abstract

The present invention provides novel pharmaceutical compositions containing triphenylethylene derivative compounds, and methods of using the composition for treatment of symptoms associated with atrophic vaginitis. The pharmaceutical compositions are prepared for the vaginal administration of triphenylethylene derivative compounds in single or combination therapies. Preferably, the triphenylethylene derivative is tamoxifen.

Claims

1. A pharmaceutical composition for the treatment of symptoms associated with atrophic vaginitis comprising:

a therapeutically effective amount of a triphenylethylene derivative compound, wherein the triphenylethylene derivative acts as a selective estrogen receptor modulator, and a therapeutically effective amount of a suitable carrier for vaginal administration.

2. The pharmaceutical composition of claim 1, further comprising a therapeutically effective amount of progesterone.

3. The pharmaceutical composition according to claim 1, wherein the composition is prepared as a vaginal suppository.

4. The pharmaceutical composition according to claim 1, wherein the composition is prepared as a vaginal cream.

5. The pharmaceutical composition according to claim 1, wherein the triphenylethylene derivative compound is selected from the group consisting of 2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine 2-hydroxy-1,2,3-propanetricarboxylate, a steroisomer thereof, a non-toxic pharmaceutical acceptable salt, and an ester thereof.

6. The pharmaceutical composition according to claim 1, wherein the triphenylethylene derivative compound is present in an amount of from about 0.2 mg to about 200 mg per dose.

7. The pharmaceutical composition according to claim 6, wherein the triphenylethylene derivative compound is present in an amount of from about 2 mg to about 20 mg per dose.

8. The pharmaceutical composition according to claim 2, wherein the progesterone is micronized progesterone.

9. The pharmaceutical composition according to claim 2, wherein the progesterone compound is present in an amount of from about 5.0 mg to about 500 mg per dose.

10. The pharmaceutical composition according to claim 1, further comprising at least one constituent selected from the group consisting of additives, pharmaceutically acceptable carriers, fatty acid base, a preservative, a dye, a binder, a suspending agent, a dispersing agent, a colorant, a disintegrant, a diluent, a lubricant, a plasticizer, oils, and mixtures thereof

11. The pharmaceutical composition of claim 1, wherein the triphenylethylene derivative compound is present in an amount effective to produce a tissue specific estrogenic effect.

12. The pharmaceutical composition according to claim 1, wherein the triphenylethylene derivative compound is present in an amount effective to reduce the incidence of thrombogenic events associated with a therapeutic oral dose.

13. The pharmaceutical composition according to claim 1, wherein the triphenylethylene derivative compound is present in an amount effective to reduce the incidence of a worsening of climacteric symptom associated with a therapeutic oral dose.

14. The pharmaceutical composition of claim 2, wherein the progesterone compound is present in an amount effective to produce an anti-proliferative effect on the endometrium.

15. The pharmaceutical composition according to claim 10, wherein the composition further comprises a suspending agent.

16. The pharmaceutical composition according to claim 15, wherein the suspending agent is micronized silica gel.

17. The pharmaceutical composition according to claim 16, wherein the amount of micronized silica gel is about 0.01 gm to about 0.1 gm per unit dose.

18. The pharmaceutical composition of claim 10, wherein the composition further comprises a fatty acid base.

19. The pharmaceutical composition of claim 18, wherein the fatty acid base comprises JAB base.

20. A method of treating symptoms of atrophic vaginitis in a patient in need thereof, which comprises vaginally administering an effective amount of a triphenylethylene derivative compound, and wherein the patient is a hysterectomized patient.

22. The method of claim 20, wherein the triphenylethylene compound is 2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine 2-hydroxy-1,2,3-propanetricarboxlate.

26. The method of claim 20, wherein the therapeutically effective amount of the triphenylethylene derivative compound is effective to reduce the incidence of thrombogenic events associated with oral therapy.

27. The method of claim 20, wherein the therapeutically effective amount of the triphenylethylene derivative compound is effective to reduce the incidence of a worsening of climacteric symptom associated with a oral therapy.

32. The method of claim 20, wherein the composition is administered for at least 3 months.

33. The method of claim 20, wherein the composition is administered for at least 12 months.

34. The method of claim 20, wherein the composition is administered vaginally at least one time per week.

35. The method of claim 20, wherein the composition is administered vaginally at least two times per week.

36. The method of claim 20, wherein the composition is administered vaginally at least three times per week.

37. The method according to claim 20, wherein the triphenylethylene derivative compound is administered as a vaginal suppository.

38. The method of claim 20, wherein the triphenylethylene derivative compound is administered as a vaginal cream.

21. A method of treating symptoms of atrophic vaginitis in a patient in need thereof, wherein the method comprises vaginally administering a therapeutically effective amount of a triphenylethylene derivative compound and a progesterone compound, wherein the patient is a non-hysterectomized patient.

23. The method of claim 21, wherein the triphenylethylene compound is 2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine 2-hydroxy-1,2,3-propanetricarboxlate.

24. The method of claim 21, wherein the progesterone is micronized progesterone.

25. The method of claim 21, wherein the triphenylethylene compound is tamoxifen citrate and the progesterone is micronized progesterone.

28. The method according to claim 21, wherein the therapeutically effective amount of the progesterone is effective to produce an anti-proliferative effect on the endometrium.

29. The method of claim 25, wherein the tamoxifen citrate is in an amount of about 20 mg, and the micronized progesterone is in an amount of about 15 mg, and wherein the composition has an antiproliferative effect on an endometrium.

30. The method of claim 25, wherein the tamoxifen citrate is in an amount of about 10 mg, and the micronized progesterone is in an amount of about 7.5 mg, and wherein the composition has an antiproliferative effect on an endometrium.

31. The method of claim 25, wherein the tamoxifen citrate is in an amount of about 30 mg, and the micronized progesterone is in an amount of about 30 mg, and wherein the composition has an antiproliferative effect on an endometrium.

39. The method of claim 21, wherein the composition is administered for at least 3 months.

40. The method of claim 21, wherein the composition is administered for at least 12 months.

41. The method of claim 21, wherein the composition is administered vaginally at least one time per week.

42. The method of claim 21, wherein the composition is administered vaginally at least two times per week.

43. The method of claim 21, wherein the composition is administered vaginally at least three times per week.

44. The method according to claim 21, wherein the triphenylethylene derivative compound is administered as a vaginal suppository.

45. The method of claim 21, wherein the triphenylethylene derivative compound is administered as a vaginal cream.

46. A suppository for vaginal administration, the suppository comprising:

a) about 0.2 mg to about 200 mg of a triphenylethylene compound;

b) about 1.0 g to about 2.0 g of a fatty acid base; and

c) about 0.01 g to about 0.02 g silica gel.

47. The suppository of claim 46, further comprising about 5 mg to about 500 mg progesterone.

48. The suppository of claim 46, wherein the fatty acid base comprises about 0.5 g to about 1.0 g PEG-8 distearate and about 0.5 g to about 1.0 g hydrogenated vegetable oil.

49. The suppository of claim 46 further comprising at least one of a preservative, a dye, a binder, a dispersing agent, a colorant, a disintegrant, an excipient, a diluent, a lubricant, a plasticizer, or an oil.

50. The suppository of claim 46, wherein the triphenylethylene compound is at least one of 2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine 2-hydroxy-1,2,3-propanetricarboxylate, a steroisomer thereof, a non-toxic pharmaceutical acceptable salt, or an ester thereof.

51. The suppository of claim 50, wherein the suppository contains about 10 mg to about 20 mg of at least one of 2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine 2-hydroxy-1,2,3-propanetricarboxylate, a steroisomer thereof, a non-toxic pharmaceutical acceptable salt, or an ester thereof.

57. A method of treating menopause symptoms, the method comprising vaginally administering the suppository of claim 46.

52. A cream for vaginal administration, the cream comprising:

a) about 0.2 mg to about 200 mg of a triphenylethylene compound;

b) about 0.5 g to about 2.0 g emollient cream;

c) about 0.025 mL to about 0.05 mL propylene glycol; and

d) about 0.01 g to about 0.02 g silica gel.

53. The cream of claim 52 further comprising at least one of a preservative, a dye, a binder, a dispersing agent, a colorant, a disintegrant, an excipient, a diluent, a lubricant, a plasticizer, or an oil.

54. The cream of claim 52, wherein the triphenylethylene compound is at least one of 2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine 2-hydroxy-1,2,3-propanetricarboxylate, a steroisomer thereof, a non-toxic pharmaceutical acceptable salt, or an ester thereof.

55. The cream of claim 53, wherein the suppository contains about 10 mg to about 20 mg of at least one of 2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine 2-hydroxy-1,2,3-propanetricarboxylate, a steroisomer thereof, a non-toxic pharmaceutical acceptable salt, or an ester thereof.

56. The cream of any one of claims 52-55 further comprising about 5 mg to about 500 mg progesterone.

58. A method of treating menopause symptoms, the method comprising vaginally administering an effective amount of the cream of claim 52.