Vaginal inserted estradiol pharmaceutical compositions and methods

• US 10,668,082 B2
• Filed: 05/09/2018
• Issued: 06/02/2020
• Est. Priority Date: 10/22/2014
• Status: Active Grant

• Current Assignee: TherapeuticsMD Inc.
• Original Assignee: TherapeuticsMD Inc.
• Inventors: Mirkin, Sebastian, Amadio, Julia M., Bernick, Brian A.
• Primary Examiner(s): Parad, Dennis J
• Application Number:
  US15/975,723
• Publication Number:
  US 20180256598A1
• Time in Patent Office: 755 Days
• Field of Search: None
• 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 31/565 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 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 9/0034 Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
• CPC Class Codes: A61K 9/0036 Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
• 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: A61K 9/4825 Proteins, e.g. gelatin gelatin capsule shells with substantial amounts of other macromolecular substances A61K9/4816
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds

Abstract

Disclosed herein is, among other things, a soft gel vaginal pharmaceutical composition and dosage form containing solubilized estradiol for the treatment of vulvovaginal atrophy (VVA) and female sexual dysfunction (FSD).

Claims

1. A method of treating vulvovaginal atrophy (VVA), comprising vaginally administering to a subject in need thereof a liquid pharmaceutical composition comprising estradiol at a dosage of 4 mcg, wherein the composition has a viscosity in the range of about 50 cP to about 1000 cP at 25°

C., and increasing the dosage of estradiol if the subject does not exhibit an improvement in a clinical response for VVA.

2. The method of claim 1, wherein the composition comprising estradiol is administered once daily for two weeks, then twice weekly thereafter.

3. The method of claim 1, wherein the estradiol is solubilized.

4. The method of claim 1, wherein a dosage form comprising the composition is manually inserted about two inches into the vagina.

5. The method of claim 1, wherein the composition comprising estradiol is encapsulated in a soft gelatin capsule.

6. The method of claim 1, wherein the subject'"'"'s clinical response is measured as an improvement in one or more clinical parameters selected from the group consisting of:

an increase in the percentage of vaginal superficial cells, a decrease in the percentage of vaginal parabasal cells, a decrease in vaginal pH, a decrease in the severity of moderate to severe dyspareunia, a decrease in vaginal dryness, a decrease in vulvar or vaginal itching or irritation, an increase of vaginal mucosa, an assessment of standard pK parameters, a change in the Female Sexual Function Index (FSFI), a visual vaginal assessment, and the subject'"'"'s self-reported response.

7. The method of claim 1, wherein the subject'"'"'s clinical response is measured by a decrease in the severity of moderate to severe dyspareunia.

8. The method of claim 1, wherein the subject'"'"'s clinical response is measured by a visual vaginal assessment or by the subject'"'"'s self-reported response.

9. The method of claim 1, comprising increasing the dosage of estradiol to 10 mcg if the subject does not exhibit an improvement in the clinical response.

10. The method of claim 1, comprising increasing the dosage of estradiol to 25 mcg if the subject does not exhibit an improvement in the clinical response.

11. The method of claim 1, comprising decreasing the dosage of estradiol if an improvement in the clinical response is achieved.

12. A method of treating vulvovaginal atrophy (VVA), comprising vaginally administering to a subject in need thereof a liquid pharmaceutical composition comprising estradiol once daily for two weeks, then twice weekly thereafter, wherein the composition comprises estradiol at a dosage of 4 mcg and wherein the composition has a viscosity in the range of about 50 cP to about 1000 cP at 25°

C.

13. The method of claim 12, wherein the estradiol is solubilized.

14. The method of claim 12, wherein a dosage form comprising the composition is manually inserted about two inches into the vagina.

15. The method of claim 12, wherein the composition comprising estradiol is encapsulated in a soft gelatin capsule.

16. A method of treating moderate to severe dyspareunia, comprising vaginally administering to a subject in need thereof a liquid pharmaceutical composition comprising estradiol at a dosage of 4 mcg, wherein the composition has a viscosity in the range of about 50 cP to about 1000 cP at 25°

C., and increasing the dosage of estradiol if the subject does not exhibit an improvement in the moderate to severe dyspareunia.

17. The method of claim 16, wherein the composition comprising estradiol is administered once daily for two weeks, then twice weekly thereafter.

18. The method of claim 16, wherein the estradiol is solubilized.

19. The method of claim 16, wherein the composition comprising estradiol is encapsulated in a soft gelatin capsule.

20. The method of claim 16, comprising increasing the dosage of estradiol to 10 mcg if the subject does not exhibit an improvement in the moderate to severe dyspareunia.

21. The method of claim 16, comprising increasing the dosage of estradiol to 25 mcg if the subject does not exhibit an improvement in the moderate to severe dyspareunia.