Co-administration of a prostaglandin and an androgenic agent in the treatment of female sexual dysfunction

• US 20010051656A1
• Filed: 07/13/2001
• Published: 12/13/2001
• Est. Priority Date: 10/28/1997
• Status: Active Grant

• Current Assignee: Alfred P. Spivack, Leland F. Wilson, Mark S. Hanamoto, Neil Gesundheit, Paul C. Doherty Jr, Sean R. Bennett, Virgil A. Place
• Original Assignee: Alfred P. Spivack, Leland F. Wilson, Mark S. Hanamoto, Neil Gesundheit, Paul C. Doherty Jr, Sean R. Bennett, Virgil A. Place
• Inventors: Wilson, Leland F., Place, Virgil A., Gesundheit, Neil, Doherty, Paul C. Jr., Spivack, Alfred P., Bennett, Sean R., Hanamoto, Mark S.
• Granted Patent: US 6,593,313 B2
• Time in Patent Office: Days
• US Class Current: 514/530
• 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 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/15 Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
• CPC Class Codes: A61K 31/21 Esters, e.g. nitroglycerine, selenocyanates
• CPC Class Codes: A61K 31/295 Iron group metal compounds
• CPC Class Codes: A61K 31/48 Ergoline derivatives, e.g. lysergic acid, ergotamine
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/557 Eicosanoids, e.g. leukotrienes or prostaglandins
• CPC Class Codes: A61K 31/5575 having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
• CPC Class Codes: A61K 31/5585 having five-membered rings containing oxygen as the only ring hetero atom, e.g. prostacyclin
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/02 for disorders of the vagina
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: B82Y 5/00 : Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

Methods and formulations for treating female sexual dysfunction are provided. A pharmaceutical composition formulated so as to contain a selected vasoactive agent is administered to the vagina, vulvar area or urethra of the individual undergoing treatment. Suitable vasoactive agents are vasodilators, including naturally occurring prostaglandins, synthetic prostaglandin derivatives, endothelial-derived relaxation factors, vasoactive intestinal polypeptide agonists smooth muscle relaxants leukotriene inhibitors, and other. The formulations are also useful for preventing the occurrence of yeast infections, improving vaginal muscle tone and tissue health, enhancing vaginal lubrication, and minimizing excess collagen deposition. A clitoral drug delivery device is also provided.

Claims

1. A method for treating sexual dysfunction in a female individual, comprising administering to the vagina, vulvar area or urethra of the individual a pharmaceutical formulation that comprises an effective amount of a vasoactive agent selected from the group consisting of naturally occurring prostaglandins, synthetic prostaglandin derivatives, endothelial-derived relaxation factors, vasoactive intestinal polypeptide agonists, smooth muscle relaxants, leukotriene inhibitors, calcium channel blockers, phosphodiesterase inhibitors, nitrates, α

-receptor blocking agents, ergotamine drugs, antihypertensive agents, pharmacologically acceptable salts, esters, analogs, derivatives, prodrugs and inclusion complexes of any of the foregoing, and combinations thereof.

2. The method of

claim 1

, wherein the pharmaceutical formulation further includes a pharmaceutically acceptable carrier suited to vaginal, vulvar or transurethral drug administration.

3. The method of

claim 1

, wherein the vasoactive agent is a naturally occurring prostaglandin or a hydrolyzable lower alkyl ester thereof.

4. The method of

claim 3

, wherein the naturally occurring prostaglandin is selected from the group consisting of PGE₀, PGE₁, PGA₁, PGB₁, PGF_1α

, 19-hydroxy-PGA₁, 19-hydroxy-PGB₁, PGE₂, PGA₂, PGB₂, 19-hydroxy-PGA₂, 19-hydroxy-PGB₂, PGE₃, PGF_3α

, PGI₂, and combinations thereof.

5. The method of

claim 4

, wherein the naturally occurring prostaglandin is PGE₀.

6. The method of

claim 4

, wherein the naturally occurring prostaglandin is PGE₁.

7. The method of

claim 4

, wherein the naturally occurring prostaglandin is PGE₂.

8. The method of

claim 1

, wherein the vasoactive agent is a synthetic prostaglandin derivative or a hydrolyzable lower alkyl ester thereof.

9. The method of

claim 8

, wherein the synthetic prostaglandin derivative is selected from the group consisting of carboprost tromethamine, dinoprost tromethamine, gemeprost, metenoprost, sulprostone and tiaprost.

10. The method of

claim 1

, wherein the vasoactive agent is an endothelial-derived relaxation factor.

11. The method of

claim 10

, wherein the endothelial-derived relaxation factor is a nitric oxide releasing agent.

12. The method of

claim 11

, wherein the nitric oxide releasing agent is selected from the group consisting of nitroglycerin, sodium nitroprusside, NONOates, molsidomine, linsidomine (SIN-1) and S-nitrosothiols.

13. The method of

claim 1

, wherein the vasodilating agent is a vasoactive intestinal polypeptide agonist.

14. The method of

claim 1

, wherein the vasoactive agent is a smooth muscle relaxant.

15. The method of

claim 1

, wherein the vasoactive agent is a leukotriene inhibitor.

16. The method of

claim 1

, wherein the vasoactive agent is a calcium channel blocker.

17. The method of

claim 1

, wherein the vasoactive agent is a phosphodiesterase inhibitor.

18. The method of

claim 17

, wherein the phosphodiesterase inhibitor is selected from the group consisting of Type III phosphodiesterase inhibitors, Type IV phosphodiesterase inhibitors and Type V phosphodiesterase inhibitors.

19. The method of

claim 18

, wherein the phosphodiesterase inhibitor is a Type V phosphodiesterase inhibitor.

20. The method of

claim 1

, wherein the vasoactive agent is a nitrate.

21. The method of

claim 20

, wherein the vasoactive agent is selected from the group consisting of nitroglycerin, isosorbide dinitrate and erythrityl tetranitrate.

22. The method of

claim 1

, wherein the vasoactive agent is an α

-receptor blocking agent.

23. The method of

claim 22

, wherein the vasoactive agent is selected from the group consisting of prazosin, doxazosin, terazosin, tolazoline, phentolamine, phenoxyberzamine, alfuzosin, tamsulosin, indornmin, trimazosin, dibenamine and combinations thereof.

24. The method of

claim 1

, wherein the pharmaceutical formulation further includes a steroid.

25. The method of

claim 24

, wherein the steroid is selected from the group consisting of progestins, estrogens and mixtures thereof.

26. The method of

claim 1

, wherein the pharmaceutical formulation further includes a compound selected from the group consisting of steroid agonists, partial agonists and antagonists.

27. The method of

claim 26

, wherein the compound is selected from the group consisting of steroid agonists and partial agonists.

28. The method of

claim 26

, wherein the compound is selected from the group consisting of tamoxifen, cenchroman, clomiphene, droloxifene, raloxifene and pharmaceutically acceptable salts thereof.

29. The method of

claim 1

, wherein the pharmaceutical formulation additionally includes a detergent in an amount effective to increase solubility of the vasoactive agent in the vehicle and bioavailability of the agent following administration.

30. The method of

claim 3

, wherein the pharmaceutical formulation further includes an effective inhibiting amount of a compound effective to inhibit prostaglandin-degrading enzymes.

31. The method of

claim 8

, wherein the pharmaceutical formulation further includes an effective inhibiting amount of a compound effective to inhibit prostaglandin-degrading enzymes.

32. The method of

claim 1

, wherein the pharmaceutical formulation is contained within a delivery system selected to provide a predetermined agent release profile.

33. The method of

claim 32

, wherein the agent release profile is pulsatile.

34. The method of

claim 32

, wherein the agent release profile is continuous.

35. The method of

claim 32

, wherein the agent release profile is cyclical.

36. The method of

claim 32

, wherein the agent release profile is diurnal.

37. The method of

claim 1

, wherein the pharmaceutical formulation is administered vaginally.

38. The method of

claim 37

, wherein the pharmaceutical formulation is in the form of an ointment, cream, gel, solid, solution, suspension, foam or liposomal composition.

39. The method of

claim 37

, wherein the pharmaceutical formulation is contained within a vaginal ring, tampon, suppository, sponge, pillow, puff, or osmotic pump system.

40. The method of

claim 1

, wherein the pharmaceutical formulation is administered to the vulvar area.

41. The method of

claim 1

, wherein the pharmaceutical formulation is administered transurethrally.

42. The method of

claim 37

, wherein the method further comprises co-administering an androgenic agent to the vulvar area of the individual in combination with vaginal administration of the vasoactive agent.

43. The method of

claim 42

, wherein the androgenic agent is testosterone or a testosterone ester.

44. A method for preventing the occurrence of a yeast infection in a female individual, comprising vaginally administering to such individual a pharmaceutical formulation that comprises a vasoactive agent selected from the group consisting of naturally occurring prostaglandins, synthetic prostaglandin derivatives, endothelial-derived relaxation factors, vasoactive intestinal polypeptide agonists, smooth muscle relaxants, leukotriene inhibitors, calcium channel blockers, phosphodiesterase inhibitors, nitrates, α

-receptor blocking agents, ergotamine drugs, antihypertensive agents, pharmaceutically acceptable salts, esters, analogs, derivatives, prodrugs and inclusion complexes of any of the foregoing, and combinations thereof, in combination with a pharmaceutically acceptable vehicle.

45. A method for improving vaginal muscle tone and tissue health in a female individual, comprising vaginally administering to such individual a pharmaceutical formulation that comprises a vasoactive agent selected from the group consisting of naturally occurring prostaglandins, synthetic prostaglandin derivatives, endothelial-derived relaxation factors, vasoactive intestinal polypeptide agonists, smooth muscle relaxants, leukotriene inhibitors, calcium channel blockers, phosphodiesterase inhibitors, nitrates, α

-receptor blocking agents, ergotamine drugs, antihypertensive agents, pharmaceutically acceptable salts, esters, analogs, derivatives, prodrugs and inclusion complexes of any of the foregoing, and combinations thereof, in combination with a pharmacologically acceptable vehicle.

46. A method for enhancing vaginal lubrication in a female individual, comprising vaginally administering to such individual a pharmaceutical formulation that comprises a vasoactive agent selected from the group consisting of naturally occurring prostaglandins, synthetic prostaglandin derivatives, endothelial-derived relaxation factors, vasoactive intestinal polypeptide agonists, smooth muscle relaxants, leukotriene inhibitors, calcium channel phosphodiesterase blockers, phosphodiesterase inhibitors, nitrates, α

-receptor blocking agents, ergotamine drugs, antihypertensive agents, pharmaceutically acceptable salts, esters, analogs, derivatives, prodrugs and inclusion complexes of any of the foregoing, and combinations thereof, in combination with a pharmacologically acceptable vehicle.

47. A method for minimizing excess collagen deposition in a female individual, comprising vaginally administering to such individual a pharmaceutical formulation that comprises a vasoactive agent selected from the group consisting of naturally occurring prostaglandins, synthetic prostaglandin derivatives, endothelial-derived relaxation factors, vasoactive intestinal polypeptide agonists, smooth muscle relaxants, leukotriene inhibitors, calcium channel blockers, phosphodiesterase inhibitors, nitrates α

-receptor blocking agents, ergotamine drugs, antihypertensive agents, pharmaceutically acceptable salts, esters, analogs, derivatives, prodrugs and inclusion complexes of any of the foregoing, and combinations thereof in combination with a pharmacologically acceptable vehicle.

48. A pharmaceutical formulation for treating sexual dysfunction in a female individual, comprising an amount of a vasoactive agent effective to treat female sexual dysfunction, wherein the vasoactive agent is selected from the group consisting of naturally occurring prostaglandins, synthetic prostaglandin derivatives, endothelial-derived relaxation factors, vasoactive intestinal polypeptide agonists, smooth muscle relaxants, leukotriene inhibitors, calcium channel blockers, phosphodiesterase inhibitors, nitrates α

-receptor blocking agents, ergotamine drugs, antihypertensive agents, pharmaceutically acceptable salts, esters, analogs, derivatives, prodrugs and inclusion complexes of any of the foregoing, and combinations thereof, in combination with a vehicle suited to vaginal, vulvar or transurethral drug administration.

49. The pharmaceutical formulation of

claim 48

, wherein the vasoactive agent is a naturally occurring prostaglandin or a hydrolyzable lower alkyl ester thereof.

50. The pharmaceutical formulation of

claim 49

, wherein the naturally occurring prostaglandin is selected from the group consisting of PGE₀, PGE₁, PGA₁, PGB₁, PGF_1α

, 19-hydroxy-PGA₁, 19-hydroxy-PGB₁, PGE₂, PGA2, PGB₂, 19-hydroxy-PGA₂, 19-hydroxy-PGB₂, PGE₃, PGF_3α

and PGI₂, and combinations thereof.

51. The pharmaceutical formulation of

claim 48

, wherein the vasoactive agent is a synthetic prostaglandin derivative or a hydrolyzable lower alkyl ester thereof.

52. The pharmaceutical formulation of

claim 51

, wherein the synthetic prostaglandin derivative is selected from the group consisting of carboprost tromethamine, dinoprost tromethamine, dinoprostone, gemeprost, metenoprost, sulprostone and tiaprost.

53. A drug delivery device for administering a pharmaceutical formulation directly to the clitoral area of a female individual comprising an elongate patch having an upper region and a lower region, wherein the upper region includes a drug reservoir and a clitoral applicator.

54. The device of

claim 53

, wherein the clitoral applicator comprises an upwardly extending protuberance disposed over the drug reservoir and adapted to fit over the clitoral area of the individual.

55. The device of

claim 54

, wherein the drug reservoir is defined by a permeable membrane encircling the base of the protuberance and is adapted to contain a pharmaceutical formulation.

56. The device of

claim 55

, wherein the pharmaceutical formulation is effective to treat sexual dysfunction in a female individual, and comprises an effective amount of a vasoactive agent.

57. The device of

claim 53

, wherein the upper and lower regions of the patch are shaped to be coextensive with the upper and lower portions of the genitalia.

58. The device of

claim 53

, wherein the protuberance is provided with a suction tip for positioning the applicator over the clitoris.

59. A method for using the device of

claim 54

, comprising the steps of:

(a) positioning the protuberance of the clitoral applicator to extend into the clitoral hood; and

(b) maintaining the device in place for sufficient time to administer a therapeutically effective amount of the pharmaceutical formulation contained in the drug reservoir to the individual.