Treatment of female sexual dysfunction

• US 6,306,841 B1
• Filed: 03/30/2000
• Issued: 10/23/2001
• Est. Priority Date: 10/28/1997
• Status: Expired due to Term

• Current Assignee: Vivus Incorporated
• Original Assignee: Asivi, LLC
• Inventors: Wilson, Leland F., Place, Virgil A., Gesundheit, Neil, Doherty, Paul C. Jr., Spivack, Alfred P., Bennett, Sean R., Hanamoto, Mark S.
• Primary Examiner(s): Criares, Theodore J.
• Application Number:
  US09/539,484
• Time in Patent Office: 572 Days
• Field of Search: 514/149, 514/150, 514/236.5, 514/236.8, 514/573
• US Class Current: 514/149
• 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 others. 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 and/or urethra of the individual a pharmaceutical formulation that comprises an effective amount of a nitrovasodilator selected from the group consisting of sodium nitroprusside, diazenium diolates, molsidomine, linsidomine chlorhydrate, S-nitrosothiols, organic nitrates, 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 nitrovasodilator is an organic nitrate.

4. The method of claim 3, wherein the organic nitrate is selected from the group consisting of isosorbide dinitrate, erythrityl tetranitrate and amyl nitrate.

5. The method of claim 1, wherein the pharmaceutical formulation further includes a steroid.

6. The method of claim 5, wherein the steroid is selected from the group consisting of progestins, estrogens and mixtures thereof.

7. 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.

8. The method of claim 7, wherein the compound is selected from the group consisting of steroid agonists and partial agonists.

9. The method of claim 7, wherein the compound is selected from the group consisting of tamoxifen, cenchroman, clomiphene, droloxifene, raloxifene and pharmaceutically acceptable salts thereof.

10. 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.

11. The method of claim 1, wherein the pharmaceutical formulation is contained within a delivery system selected to provide a predetermined agent release profile.

12. The method of claim 11, wherein the agent release profile is pulsatile.

13. The method of claim 11, wherein the agent release profile is continuous.

14. The method of claim 11, wherein the agent release profile is cyclical.

15. The method of claim 11, wherein the agent release profile is diurnal.

16. The method of claim 1, wherein the pharmaceutical formulation is administered vaginally.

17. The method of claim 16, wherein the pharmaceutical formulation is in the form of an ointment, cream, gel, solid, solution, suspension, foam or liposomal composition.

18. The method of claim 16, wherein the pharmaceutical formulation is contained within a vaginal ring, tampon, suppository, sponge, pillow, puff, or osmotic pump system.

19. The method of claim 1, wherein the pharmaceutical formulation is administered to the vulvar area.

20. The method of claim 1, wherein the pharmaceutical formulation is administered transurethrally.

21. The method of claim 16, 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.

22. The method of claim 21, wherein the androgenic agent is testosterone or a testosterone ester.

25. The method of claim 1, wherein the nitrovasodilator is sodium nitroprusside.

26. The method of claim 1, wherein the nitrovasodilator is a diazenium diolate.

27. The method of claim 26, wherein the diazenium diolate is selected from the group consisting of (Z)-1- {N-methyl-N-[6-(N-methyl-ammoniohexyl)amino]}diazen-1-ium-1,2-diolate, (Z)-1-[N-(3-ammoniopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2-diolate, (Z)-1-{N-[3-aminopropyl]-N-[4-(3-aminopropylammonio)butyl]amino}diazen-1-ium-1,2-diolate and sodium (Z)-1-(N,N-diethylamino)-diazen-1-ium-1,2-diolate.

28. The method of claim 1, wherein the nitrovasodilator is molsidomine.

29. The method of claim 1, wherein the nitrovasodilator is linsidomine chlorhydrate.

30. The method of claim 1, wherein the nitrovasodilator is an S-nitrosothiol.

31. The method of claim 30, wherein the S-nitrosothiol is selected from the group consisting of S-nitroso-N-acetyl-d,1-penicillamine and S-nitroso-N-glutathione.

23. 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 nitrovasodilator selected from the group consisting of sodium nitroprusside, diazenium diolates, molsidomine, linsidomine chlorhydrate, S-nitrosothiols, organic nitrates, 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.

24. A method for enhancing vaginal lubrication in a female individual, comprising vaginally administering to such individual a pharmaceutical formulation that comprises a nitrovasodilator selected from the group consisting of sodium nitroprusside, diazenium diolates, molsidomine, linsidomine chlorhydrate, S-nitrosothiols, organic nitrates, 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.