Therapeutic methods of using estrogen compositions

• US 20080085877A1
• Filed: 08/10/2006
• Published: 04/10/2008
• Est. Priority Date: 08/10/2006
• Status: Abandoned Application

• Current Assignee: DrugTech Corporation (PD International Holdings LLC)
• Original Assignee: DrugTech Corporation (PD International Holdings LLC)
• Inventors: Bortz, Jonathan
• Application Number:
  US11/502,066
• Publication Number:
  US 20080085877A1
• Time in Patent Office: Days
• US Class Current: 514/182
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives

Abstract

A method for preventing or treating a catamenial migrainous disorder in a female subject comprises administering to a vulvovaginal surface of the subject a pharmaceutical composition that is bioadhesive thereto and comprises at least one estrogenic compound in an amount of about 50 μg to about 1000 μg estradiol equivalent per unit dose of the composition. A related method comprises administering to a vulvovaginal surface of the subject a pharmaceutical composition comprising at least one estrogenic compound, wherein upon administration of the composition to the vulvovaginal surface, a decline in serum estradiol concentration during a luteal phase of a menstrual cycle is moderated.

Claims

1. A method for preventing or treating a catamenial migrainous disorder in a female subject, the method comprising administering to a vulvovaginal surface of the subject a pharmaceutical composition that is bioadhesive thereto and comprises at least one estrogenic compound in an amount of about 50 μ

g to about 1000 μ

g estradiol equivalent per unit dose of the composition.

2. The method of claim 1, wherein the at least one estrogenic compound is present in the composition in an amount of about 150 μ

g to about 500 μ

g per unit dose.

3. The method of claim 1, wherein the composition has at least one non-lipoidal internal phase and at least one lipoidal external phase that is bioadhesive to the vulvovaginal surface.

4. The method of claim 1, wherein the composition releases the at least one estrogenic compound according to a release profile effective to moderate a decline in serum estradiol concentration.

5. The method of claim 1, wherein the composition releases the at least one estrogenic compound according to a release profile consistent with a once daily to once weekly schedule.

6. The method of claim 1, wherein the composition releases the at least one estrogenic compound according to a release profile consistent with a once to three times per week dosing schedule.

7. The method of claim 1, wherein the composition is administered at a frequency of about 1 to about 3 times per week.

8. The method of claim 1, wherein upon application of the composition to the vulvovaginal surface the at least one estrogenic compound is released over a period of about 3 hours to about 14 days.

9. The method of claim 8, wherein a serum estradiol concentration not greater than about 70 pg/ml is maintained in the subject during the release period.

10. The method of claim 1, wherein the composition is administered not more than about 7 days prior to anticipated menses.

11. The method of claim 10, wherein at least a baseline serum estradiol concentration is maintained in the subject from the time of administration through menses.

12. The method of claim 11, wherein the baseline serum estradiol concentration is not less than about 25 pg/ml.

14. The method of claim 1, wherein the composition is administered during menses.

15. The method of claim 14, wherein the composition exhibits sufficient bioadhesion to the vulvovaginal surface to substantially resist elution by menstrual flow.

16. The method of claim 1, wherein the at least one estrogenic compound is a steroid.

17. The method of claim 1, wherein the at least one estrogenic compound is selected from the group consisting of conjugated estrogenic hormones, estradiol, ethinyl estradiol, estriol and estrone.

18. The method of claim 1, wherein the at least one estrogenic compound is estradiol or ethinyl estradiol.

19. The method of claim 1, wherein the vulvovaginal surface to which the composition is adapted for application is a vaginal mucosal surface.

20. The method of claim 19, wherein the composition is in a form of a vaginal cream.

21. The method of claim 20, wherein the vaginal cream is administered with the aid of an applicator.

22. The method of claim 21, wherein the applicator is disposable.

23. The method of claim 22, wherein the applicator is prefilled with a unit dose amount of the vaginal cream.

24. The method of claim 20, wherein the vaginal cream has at least one nonlipoidal internal phase and at least one lipoidal external phase that is bioadhesive to the vaginal mucosal surface, and wherein upon application of the composition thereto the at least one estrogenic compound is released over a period of about 3 hours to about 14 days.

25. The method of claim 1, wherein the catamenial migrainous disorder is selected from the group consisting of pure menstrual migraine, menstrually related migraine, menstrual headache and estrogen withdrawal migraine.

13. The method of 11, wherein the baseline serum estradiol concentration is not less than about 50 pg/ml.

26. A method for preventing or treating a catamenial migrainous disorder in a female subject, the method comprising administering to a vulvovaginal surface of the subject a pharmaceutical composition comprising at least one estrogenic compound, wherein upon application of the composition to the vulvovaginal surface, a decline in serum estradiol concentration during a luteal phase of a menstrual cycle is moderated.

27. The method of claim 26, wherein the decline that is moderated occurs during the second half of the luteal phase.

28. The method of claim 26, wherein the decline that is moderated occurs within about 3 days prior to, or within about 5 days after, onset of menses.

29. The method of claim 26, wherein the decline that is moderated occurs during an estrogen depleting phase of hormonal therapy or contraception.

30. The method of claim 26, wherein the amount of the at least one estrogenic compound administered and/or the release rate of the at least one estrogenic compound from the composition is modulated to compensate for differences in absorption resulting from differing thickness of vaginal epithelium.

31. The method of claim 26, wherein the pharmaceutical composition is a vaginal cream having at least one nonlipoidal internal phase and at least one lipoidal external phase that is bioadhesive to a vaginal mucosal surface, wherein the at least one estrogenic compound is present in an amount of about 50 μ

g to about 1000 μ

g estradiol equivalent per unit dose of the vaginal cream, and wherein upon application of the composition to the vaginal mucosal surface the at least one estrogenic compound is released over a period of about 3 hours to about 14 days.

32. A method for managing serum estradiol concentration during a menstrual cycle in a female subject, the method comprising administering at least one estrogenic compound according to a regimen that comprises:

(a) a first regimen component wherein at least one estrogenic compound is administered to the subject according to a first mode of administration;

said first mode of administration resulting in maintenance of a serum estradiol concentration of at least about 50 pg/ml during most or all of the menstrual cycle, except for an estrogen depleting phase of about 5 to about 10 days in duration beginning not earlier than about 7 days prior to menses; and

(b) a second regimen component wherein at least one estrogenic compound is administered to the subject according to a second mode of administration;

said second mode of administration (i) comprising administering to a vulvovaginal surface a pharmaceutical composition that is bioadhesive thereto and comprises said at least one estrogenic compound; and

(ii) resulting in moderation of a decline in serum estradiol concentration during said estrogen depleting phase.

33. The method of claim 32, wherein the first mode of administration is by one or more routes selected from the group consisting of oral, transdermal, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transmucosal, buccal, sublingual, intravaginal, inhalation, depot injection, implantation and combinations thereof.

34. The method of claim 32, wherein the first regimen component is an element of an oral contraceptive regimen.

35. The method of claim 32, wherein the decline in serum estradiol concentration in the absence of the second regimen component would be precipitous.

36. The method of claim 35, wherein the precipitous decline in serum estradiol concentration in the absence of the second regimen component would be conducive to a migrainous disorder.

37. The method of claim 32, wherein the pharmaceutical composition administered according to the second regimen component is a vaginal cream having at least one nonlipoidal internal phase and at least one lipoidal external phase that is bioadhesive to a vaginal mucosal surface, wherein the at least one estrogenic compound is present in an amount of about 50 μ

g to about 500 μ

g estradiol equivalent per unit dose of the vaginal cream, and wherein upon application of the composition to the vaginal mucosal surface the at least one estrogenic compound is released over a period of about 3 hours to about 14 days.

38. A kit for managing serum estradiol concentration during a menstrual cycle in a female subject, the kit comprising:

(a) a first regimen component wherein at least one estrogenic compound is administered to the subject according to a first mode of administration;

said first mode of administration resulting in maintenance of a serum estradiol concentration of at least about 50 pg/ml during most or all of the menstrual cycle, except for an estrogen depleting phase of about 5 to about 10 days in duration beginning not earlier than about 7 days prior to menses; and

(b) a second regimen component wherein at least one estrogenic compound is administered to the subject according to a second mode of administration;

said second mode of administration (i) comprising administering to a vulvovaginal surface a pharmaceutical composition that is bioadhesive thereto and comprises said at least one estrogenic compound; and

(ii) resulting in moderation of a decline in serum estradiol concentration during said estrogen depleting phase.

39. The kit of claim 38, wherein said regimen comprises administration of the composition(s) by one or more routes selected from the group consisting of oral, transdermal, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transmucosal, buccal, sublingual, intravaginal, inhalation, depot injection, implantation and combinations thereof.

40. The kit of claim 38, wherein said regimen is an oral contraceptive regimen.

41. The kit of claim 38, further comprising instructions for administration of the vaginal cream to prevent or treat a catamenial migrainous disorder promoted by said regimen.

42. The kit of claim 38, further comprising an ovulation indicator.

43. The kit of claim 38, wherein the pharmaceutical composition administered according to the second regimen component is a vaginal cream having at least one nonlipoidal internal phase and at least one lipoidal external phase that is bioadhesive to a vaginal mucosal surface, wherein the at least one estrogenic compound is present in an amount of about 50 μ

g to about 500 μ

g estradiol equivalent per unit dose of the vaginal cream, and wherein upon application of the composition to the vaginal mucosal surface the at least one estrogenic compound is released over a period of about 3 hours to about 14 days.