Methods and formulations for the treatment of female sexual dysfunction

• US 20040259817A1
• Filed: 07/23/2004
• Published: 12/23/2004
• Est. Priority Date: 12/22/2000
• Status: Abandoned Application

• Current Assignee: Barr Laboratories Incorporated (Teva Pharmaceutical Industries Limited)
• Original Assignee: Barr Laboratories Incorporated (Teva Pharmaceutical Industries Limited)
• Inventors: Leonard, Thomas W., Waldon, R. Forrest
• Application Number:
  US10/898,104
• Publication Number:
  US 20040259817A1
• Time in Patent Office: Days
• US Class Current: 514/27
• 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 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• 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 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/12 for climacteric disorders
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications

Abstract

A pharmaceutical composition for the treatment of sexual dysfunction, particularly post-menopausal females, is provided. The composition includes a therapeutically effective amount of an estrogenic compound, androgenic compound, vasodilation compound, and a pharmaceutically acceptable carrier.

Claims

1. A pharmaceutical composition for the treatment of female sexual dysfunction, said composition comprising:

a therapeutically effective amount of a mixture of estrogenic compounds, wherein said mixture comprises salts of estrone, equilin, Δ

^8,9-dehydroestrone, 17α

-estradiol, 17α

-dihydroequilin, 17β

-dihydroequilin, 17β

-estradiol, equilenin, 17α

-dihydroequilenin, and 17β

-dihydroequilenin;

a therapeutically effective amount of at least one androgenic compound;

a therapeutically effective amount of at least one vasodilation compound; and

a pharmaceutically acceptable carrier.

3. The pharmaceutical composition according to claim 1, wherein the at least one androgenic compound is selected from the group consisting of methyltestosterone, androsterone, androsterone acetate, androstenedione, androstenediol, androsterone propionate, androsterone benzoate, androsteronediol, androsteronediol-3-acetate, androsteronediol-17-acetate, androsteronediol 3,17-diacetate, androsteronediol-17-benzoate, androsteronediol-3-acetate-17-benzoate, androsteronedione, dehydroepiandrosterone, sodium dehydroepiandrosterone sulfate, dromostanolone, dromostanolone propionate, ethylestrenol, fluoxymesterone, derdicale, nandrolone phenpropionate, nandrolone decanoate, nandrolone furylpropionate, nandrolone cyclohexane-propionate, nandrolone benzoate, nandrolone cyclohexanecarboxylate, oxandrolone, oxymetholone, stanozolol, testosterone, 17α

-methyl-19-nortestosterone, testosterone decanoate, 4-dihydrotestosterone, 5α

-dihydrotestosterone, testolactone, pharmaceutically acceptable esters and salts thereof, and combinations of any of the foregoing.

4. The pharmaceutical composition according to claim 1, wherein the at least one vasodilation compound is an alpha adrenergic antagonists.

5. The pharmaceutical composition according to claim 4, wherein the alpha adrenergic antagonist is phentolamine mesylate or phentolalmine hydrochloride.

6. The pharmaceutical composition according to claim 4, wherein the vasodilation compound further comprises apomorphine.

7. The pharmaceutical composition according to claim 1, further comprising a therapeutically effective amount of a progestin compound.

8. The pharmaceutical composition according to claim 7, wherein the progestin compound is selected from the group consisting of desogestrel, dydrogesterone, ethynodiol diacetate, medroxyprogesterone, levonorgestrel, medroxyprogesterone acetate, hydroxyprogesterone caproate, norethindrone, norethindrone acetate, norethynodrel, allylestrenol, 19-nortestosterone, lynoestrenol, quingestanol acetate, medrogestone, norgestrienone, dimethisterone, ethisterone, cyproterone acetate, chlormadinone acetate, megestrol acetate, norgestimate, norgestrel, desogestrel, trimegestone, gestodene, nomegestrol acetate, nomegestrol progesterone, 5α

-pregnan-3β

, 20α

-diol sulfate, 5α

-pregnan-3β

, 20β

-diol sulfate, 5α

-pregnan-3β

-ol-20-one, 16,5α

-pregnen-3β

-ol-20-one, 4-pregnen-20β

-ol-3-one-20-sulfate, acetoxypregnenolone, anagestone acetate, cyproterone, dihydrogesterone, flurogestone acetate, gestadene, hydroxyprogesterone acetate, hydroxymethylprogesterone, hydroxymethyl progesterone acetate, 3-ketodesogestrel, megestrol, melengestrol acetate, norethisterone and mixtures thereof.

2. (Canceled).

9. A pharmaceutical composition for the treatment of female sexual dysfunction in a pre-menopausal female, said composition comprising:

a therapeutically effective amount of at least one androgenic compound;

a therapeutically effective amount of at least one vasodilation compound; and

a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 9, wherein the at least one androgenic compound is selected from the group consisting of methyltestosterone, androstenedione, androstenediol, androsterone, androsterone acetate, androsterone propionate, androsterone benzoate, androsteronediol, androsteronediol-3-acetate, androsteronediol-17-acetate, androsteronediol 3,17-diacetate, androsteronediol-17-benzoate, androsteronediol-3-acetate-17-benzoate, androsteronedione, dehydroepiandrosterone, sodium dehydroepiandrosterone sulfate, dromostanolone, dromostanolone propionate, ethylestrenol, fluoxymesterone, derdicale, nandrolone phenpropionate, nandrolone decanoate, nandrolone furylpropionate, nandrolone cyclohexane-propionate, nandrolone benzoate, nandrolone cyclohexanecarboxylate, oxandrolone, oxymetholone, stanozolol, testosterone, 17α

-methyl-19-nortestosterone, testosterone decanoate, 4-dihydrotestosterone, 5α

-dihydrotestosterone, testolactone, pharmaceutically acceptable esters and salts thereof, and combinations of any of the foregoing.

11. The pharmaceutical composition according to claim 9, wherein the at least one vasodilation compound is an alpha adrenergic antagonist.

12. The pharmaceutical composition according to claim 11, wherein the alpha adrenergic antagonist is phentolamine mesylate or phentolamine hydrochloride.

13. The pharmaceutical composition according to claim 12, wherein the at least one vasodilation compound further comprises apomorphine.

14. The pharmaceutical composition according to claim 9, further comprising a therapeutically effective amount of a progestin compound.

15. The pharmaceutical composition according to claim 14, wherein the progestin compound is selected from the group consisting of desogestrel, dydrogesterone, ethynodiol diacetate, medroxyprogesterone, levonorgestrel, medroxyprogesterone acetate, hydroxyprogesterone caproate, norethindrone, norethindrone acetate, norethynodrel, allylestrenol, 19-nortestosterone, lynoestrenol, quingestanol acetate, medrogestone, norgestrienone, dimethisterone, ethisterone, cyproterone acetate, chlormadinone acetate, megestrol acetate, norgestimate, norgestrel, desogestrel, trimegestone, gestodene, nomegestrol acetate, nomegestrol progesterone, 5α

-pregnan-3β

, 20α

-diol sulfate, 5α

-pregnan-3β

, 20β

-diol sulfate, 5α

-pregnan-3β

-ol-20-one, 16,5α

-pregnen-3β

-ol-20-one, 4-pregnen-20β

-ol-3-one-20-sulfate, acetoxypregnenolone, anagestone acetate, cyproterone, dihydrogesterone, flurogestone acetate, gestadene, hydroxyprogesterone acetate, hydroxymethylprogesterone, hydroxymethyl progesterone acetate, 3-ketodesogestrel, megestrol, melengestrol acetate, norethisterone and mixtures thereof.

16. A pharmaceutical formulation for treating female sexual dysfunction comprising:

a therapeutically effective amount of a mixture of estrogenic compounds, wherein said mixture comprises salts of estrone, equilin, Δ

^8,9-dehydroestrone, 17α

-estradiol, 17α

-dihydroequilin, 17β

-dihydroequilin, 17β

-estradiol, equilenin, 17α

-dihydroequilenin, and 17β

-dihydroequilenin;

a therapeutically effective amount of at least one androgenic compound;

a pharmaceutically acceptable carrier; and

a therapeutically effective amount of at least one vasodilation compound administered on a performance-on-demand basis.

17. A method of treating female sexual dysfunction in a female in need of such treatment, said method comprising:

administering a combination of a therapeutically effective amount of a mixture of estrogenic compounds, wherein said mixture comprises salts of estrone, equilin, Δ

^8,9-dehydroestrone, 17α

-estradiol, 17α

-dihydroequilin, 17β

-dihydroequilin, 17β

-estradiol, equilenin, 17α

-dihydroequilenin, and 17β

-dihydroequilenin and a therapeutically effective amount of at least one androgenic compound to the female; and

administering a therapeutically effective amount of a vasodilation compound to the female.

18-51. -51. (Canceled).

52. A pharmaceutical composition for the treatment of female sexual dysfunction, said composition comprising:

a therapeutically effective amount of at least two estrogenic compounds;

a therapeutically effective amount of an androgenic compound;

a therapeutically effective amount of a vasodilation compound; and

a pharmaceutically acceptable carrier, with the proviso that the pharmaceutically carrier is not a bioerodible polymeric carrier.

53. The pharmaceutical composition according to claim 52, wherein the estrogenic compound is selected from the group consisting of estrone, 17α

-estradiol, 17β

-estradiol, equilin, 17α

-dihydroequilin, 17β

-dihydroequilin, equilenin, 17α

-dihydroequilenin, 17β

-dihydroequilenin, Δ

^8,9-dehydroestrone, 17α

-Δ

^8,9-dehydroestradiol, 17β

-Δ

^8,9-dehydroestradiol, ethinyl estradiol, estradiol valerate, 6-OH equilenin, 6-OH 17α

-dihydroequilenin, 6-OH 17β

-dihydroequilenin, and mixtures, conjugates and salts thereof.

54. The pharmaceutical composition according to claim 52, wherein the androgenic compound is selected from the group consisting of methyltestosterone, androsterone, androsterone acetate, androstenedione, androstenediol, androsterone propionate, androsterone benzoate, androsteronediol, androsteronediol-3-acetate, androsteronediol-17-acetate, androsteronediol 3,17-diacetate, androsteronediol-17-benzoate, androsteronediol-3-acetate-17-benzoate, androsteronedione, dehydroepiandrosterone, sodium dehydroepiandrosterone sulfate, dromostanolone, dromostanolone propionate, ethylestrenol, fluoxymesterone, derdicale, nandrolone phenpropionate, nandrolone decanoate, nandrolone furylpropionate, nandrolone cyclohexane-propionate, nandrolone benzoate, nandrolone cyclohexanecarboxylate, oxandrolone, oxymetholone, stanozolol, testosterone, 17α

-methyl-19-nortestosterone, testosterone decanoate, 4-dihydrotestosterone, 5α

-dihydrotestosterone, testolactone, pharmaceutically acceptable esters and salts thereof, and combinations of any of the foregoing.

55. The pharmaceutical composition according to claim 52, wherein the vasodilation compound is an alpha adrenergic antagonist.

56. The pharmaceutical composition according to claim 55, wherein the alpha adrenergic antagonist is phentolamine mesylate or phentolalmine hydrochloride.

57. The pharmaceutical composition according to claim 55, wherein the vasodilation compound further comprises apomorphine.

58. The pharmaceutical composition according to claim 52, further comprising a therapeutically effective amount of a progestin compound.

59. The pharmaceutical composition according to claim 58, wherein the progestin compound is selected from the group consisting of desogestrel, dydrogesterone, ethynodiol diacetate, medroxyprogesterone, levonorgestrel, medroxyprogesterone acetate, hydroxyprogesterone caproate, norethindrone, norethindrone acetate, norethynodrel, allylestrenol, 19-nortestosterone, lynoestrenol, quingestanol acetate, medrogestone, norgestrienone, dimethisterone, ethisterone, cyproterone acetate, chlormadinone acetate, megestrol acetate, norgestimate, norgestrel, desogestrel, trimegestone, gestodene, nomegestrol acetate, nomegestrol progesterone, 5α

-pregnan-3β

, 20α

-diol sulfate, 5α

-pregnan-3β

, 20β

-diol sulfate, 5α

-pregnan-3β

-ol-20-one, 16,5α

-pregnen-3β

-ol-20-one, 4-pregnen-20β

-ol-3-one-20-sulfate, acetoxypregnenolone, anagestone acetate, cyproterone, dihydrogesterone, flurogestone acetate, gestadene, hydroxyprogesterone acetate, hydroxymethylprogesterone, hydroxymethyl progesterone acetate, 3-ketodesogestrel, megestrol, melengestrol acetate, norethisterone and mixtures thereof.

60. A pharmaceutical composition for the treatment of female sexual dysfunction, said composition comprising:

a therapeutically effective amount of at least two estrogenic compounds;

a therapeutically effective amount of at least two androgenic compounds;

a therapeutically effective amount of at least one vasodilation compound; and

a pharmaceutically acceptable carrier.

61. The pharmaceutical composition according to claim 60, wherein the at least two estrogenic compounds are selected from the group consisting of estrone, 17α

-estradiol, 17β

-estradiol, equilin, 17α

-dihydroequilin, 17β

-dihydroequilin, equilenin, 17α

-dihydroequilenin, 17β

-dihydroequilenin, Δ

^8,9-dehydroestrone, 17α

-Δ

^8,9-dehydroestradiol, 17β

-Δ

^8,9-dehydroestradiol, ethinyl estradiol, estradiol valerate, 6-OH equilenin, 6-OH 17α

-dihydroequilenin, 6-OH 17β

-dihydroequilenin, and mixtures, conjugates and salts thereof.

62. The pharmaceutical composition according to claim 60, wherein the at least one androgenic compound is selected from the group consisting of methyltestosterone, androsterone, androsterone acetate, androstenedione, androstenediol, androsterone propionate, androsterone benzoate, androsteronediol, androsteronediol-3-acetate, androsteronediol-17-acetate, androsteronediol 3,17-diacetate, androsteronediol-17-benzoate, androsteronediol-3-acetate-17-benzoate, androsteronedione, dehydroepiandrosterone, sodium dehydroepiandrosterone sulfate, dromostanolone, dromostanolone propionate, ethylestrenol, fluoxymesterone, derdicale, nandrolone phenpropionate, nandrolone decanoate, nandrolone furylpropionate, nandrolone cyclohexane-propionate, nandrolone benzoate, nandrolone cyclohexanecarboxylate, oxandrolone, oxymetholone, stanozolol, testosterone, 17α

-methyl-19-nortestosterone, testosterone decanoate, 4-dihydrotestosterone, 5α

-dihydrotestosterone, testolactone, pharmaceutically acceptable esters and salts thereof, and combinations of any of the foregoing.

63. The pharmaceutical composition according to claim 60, wherein the at least one vasodilation compound is an alpha adrenergic antagonists.

64. The pharmaceutical composition according to claim 63, wherein the alpha adrenergic antagonist is phentolamine mesylate or phentolalmine hydrochloride.

65. The pharmaceutical composition according to claim 63, wherein the at least one vasodilation compound further comprises apomorphine.

66. The pharmaceutical composition according to claim 60, further comprising a therapeutically effective amount of a progestin compound.

67. The pharmaceutical composition according to claim 66, wherein the at least one progestin compound is selected from the group consisting of desogestrel, dydrogesterone, ethynodiol diacetate, medroxyprogesterone, levonorgestrel, medroxyprogesterone acetate, hydroxyprogesterone caproate, norethindrone, norethindrone acetate, norethynodrel, allylestrenol, 19-nortestosterone, lynoestrenol, quingestanol acetate, medrogestone, norgestrienone, dimethisterone, ethisterone, cyproterone acetate, chlormadinone acetate, megestrol acetate, norgestimate, norgestrel, desogestrel, trimegestone, gestodene, nomegestrol acetate, nomegestrol progesterone, 5α

-pregnan-3β

, 20β

-diol sulfate, 5α

-pregnan-3β

, 20α

-diol sulfate, 5α

-pregnan-3β

-ol-20-one, 16,5α

-pregnen-3β

-ol-20-one, 4-pregnen-20β

-ol-3-one-20-sulfate, acetoxypregnenolone, anagestone acetate, cyproterone, dihydrogesterone, flurogestone acetate, gestadene, hydroxyprogesterone acetate, hydroxymethylprogesterone, hydroxymethyl progesterone acetate, 3-ketodesogestrel, megestrol, melengestrol acetate, norethisterone and mixtures thereof.

68. A pharmaceutical composition for the treatment of female sexual dysfunction, said composition comprising:

a therapeutically effective amount of at least two estrogenic compounds;

a therapeutically effective amount of an androgenic compound;

a therapeutically effective amount of a vasodilation compound; and

a pharmaceutically acceptable carrier, with the proviso that the pharmaceutically acceptable carrier is not a buccal dosage unit.

69. The pharmaceutical composition of claim 68, wherein the at least two estrogenic compounds are selected from the group consisting of estrone, 17α

-estradiol, 17β

-estradiol, equilin, 17α

-dihydroequilin, 17β

-dihydroequilin, equilenin, 17α

-dihydroequilenin, 17β

-dihydroequilenin, Δ

^8,9-dehydroestrone, 17α

-Δ

^8,9-dehydroestradiol, 17β

-Δ

^8,9-dehydroestradiol, ethinyl estradiol, estradiol valerate, 6-OH equilenin, 6-OH 17α

-dihydroequilenin, 6-OH 17β

-dihydroequilenin, and mixtures, conjugates and salts thereof.

70. A method of treating female sexual dysfunction in a female in need of such treatment, said method comprising:

administering a combination of a therapeutically effective amount of at least two estrogenic compounds and a therapeutically effective amount of an androgenic compound to the female; and

administering a therapeutically effective amount of a vasodilation compound to the female.

71. The method according to claim 70, wherein the at least two estrogenic compounds are selected from the group consisting of estrone, 17α

-estradiol, 17β

-estradiol, equilin, 17α

-dihydroequilin, 17β

-dihydroequilin, equilenin, 17α

-dihydroequilenin, 17β

-dihydroequilenin, Δ

^8,9-dehydroestrone, 17α

-Δ

^8,9-dehydroestradiol, 17β

-Δ

^8,9-dehydroestradiol, ethinyl estradiol, estradiol valerate, 6-OH equilenin, 6-OH 17α

-dihydroequilenin, 6-OH 17β

-dihydroequilenin, and mixtures, conjugates and salts thereof.