Vaginal inserted estradiol pharmaceutical compositions and methods

• US 10,568,891 B2
• Filed: 12/07/2016
• Issued: 02/25/2020
• Est. Priority Date: 12/21/2012
• 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:
  US15/372,385
• Publication Number:
  US 20170216310A1
• Time in Patent Office: 1,175 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 for treating the symptoms of vulvo-vaginal atrophy (VVA) comprising:

administering to a human subject having VVA a vaginal suppository comprising a liquid composition containing 4 μ

g to 25 μ

g of estradiol,

wherein the viscosity of the liquid composition is from about 50 cps to about 1000 cps at 25°

C.,

wherein the administration is conducted daily for two weeks, and twice weekly thereafter, and

wherein the treatment is effective at or within two weeks after administering the first vaginal suppository.

2. The method of claim 1, wherein adverse events associated with administering the estradiol, other than headaches, do not differ significantly from adverse events associated with administering a placebo.

3. The method of claim 1, wherein the symptoms of VVA comprise one or more symptoms selected from vaginal dryness, dyspareunia, vaginal or vulvar irritation, burning, or itching, dysuria, and vaginal bleeding associated with sexual activity.

4. The method of claim 1, comprising increasing the level of vaginal secretions in a subject, as assessed by visual examination.

5. The method of claim 1, comprising increasing the number of vaginal rugae in the subject, as assessed by visual examination.

6. The method of claim 1, comprising decreasing vaginal bleeding or petechiae in the subject, as assessed by visual examination.

7. The method of claim 1, comprising changing the color of the vaginal mucosa in the subject from transparent to pink, or from pale pink to pink, as assessed by visual examination.

8. The method of claim 1, wherein the treatment decreases the severity of at least one symptom selected from the group consisting of vaginal dryness, vulvar or vaginal itching, and dyspareunia at or within two weeks after administering the first vaginal suppository.

9. The method of claim 8, wherein the severity is measured on a scale of 0 to 3, where 0 is none, 1 is mild, 2 is moderate, and 3 is severe.

10. The method of claim 1, wherein the liquid composition further includes a solubilizing agent, wherein the solubilizing agent includes at least one C6-C12 fatty acid or a glycol, monoglyceride, diglyceride, or triglyceride ester thereof.

11. The method of claim 1, wherein the liquid composition contains 4 μ

g estradiol.

12. The method of claim 1, wherein the vaginal liquid composition contains 10 μ

g estradiol.

13. The method of claim 1, wherein the vaginal liquid composition contains 25 μ

g estradiol.

14. The method of claim 1, wherein the vaginal suppository does not include a hydrophilic gel-forming bioadhesive agent in the liquid composition.

15. The method of claim 1, wherein estradiol is the only active hormone in the vaginal suppository.

16. The method of claim 1, wherein the subject remains ambulatory for a period of time beginning about 5 minutes after administering the vaginal suppository and ending about 4 hours after administering the vaginal suppository.

17. A method for treating female sexual dysfunction, the method comprising administering to a human female subject in need thereof, a vaginal suppository comprising:

(a) a liquid composition comprising;

a therapeutically effective amount of estradiol;

a caprylic/capric triglyceride;

a non-ionic surfactant comprising PEG-6 stearate and ethylene glycol palmitostearate; and

(b) a soft gelatin capsule;

wherein the liquid composition contains from about 1 microgram to about 25 micrograms of estradiol;

wherein the viscosity of the liquid composition is from about 50 cps to about 1000 cps at 25°

C.;

wherein estradiol is the only active hormone in the vaginal suppository; and

wherein the administration is conducted daily for two weeks, and twice weekly thereafter.

18. The method of claim 17, wherein the suppository includes about 4 μ

g of estradiol, about 10 μ

g of estradiol, or about 25 μ

g of estradiol.