Soluble estradiol capsule for vaginal insertion

• US 9,180,091 B2
• Filed: 12/20/2013
• Issued: 11/10/2015
• Est. Priority Date: 12/21/2012
• Status: Active Grant

• Current Assignee: TherapeuticsMD Inc.
• Original Assignee: TherapeuticsMD Inc.
• Inventors: Bernick, Brian A., Amadio, Julia M., Persicaner, Peter H. R., Cacace, Janice Louise, Thorsteinsson, Thorsteinn, Sancilio, Frederick D., Irani, Neda
• Primary Examiner(s): TRAN, MY CHAU T
• Application Number:
  US14/136,048
• Publication Number:
  US 20140213565A1
• Time in Patent Office: 690 Days
• Field of Search: 514/182
• US Class Current: 1/1
• 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 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• 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 47/44 Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14
• 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: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/48 Preparations in capsules, e.g. of gelatin, of chocolate A61K9/0004 takes precedence; bite capsules A61K9/0056
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds

Abstract

According to various embodiments of this disclosure, pharmaceutical formulations comprising solubilized estradiol are provided. In various embodiments, such formulations are encapsulated in soft capsules which may be vaginally inserted for the treatment of vulvovaginal atrophy.

Claims

1. A vaginal suppository comprising:

a) a therapeutically effective amount of estradiol; and

b) a solubilizing agent, wherein the solubilizing agent comprises at least one C6-C12 fatty acid or a glycol, monoglyceride, diglyceride, or triglyceride ester thereof;

wherein the vaginal suppository comprises from about 1 micrograms to about 25 micrograms of estradiol;

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

wherein the vaginal suppository does not include a hydrophilic gel-forming bioadhesive agent in the solubilizing agent.

2. The vaginal suppository of claim 1, wherein the estradiol is solubilized.

3. The vaginal suppository of claim 1, wherein the estradiol is micronized.

4. The vaginal suppository of claim 1, wherein the estradiol is hydrated.

5. The vaginal suppository of claim 1, wherein the suppository comprises from about 1 microgram to about 10 micrograms of estradiol.

6. The vaginal suppository of claim 1, wherein the suppository comprises about 10 micrograms of estradiol.

7. The vaginal suppository of claim 1, wherein the suppository comprises about 5 micrograms of estradiol.

8. The vaginal suppository of claim 1, wherein the suppository comprises about 2.5 micrograms of estradiol.

9. The vaginal suppository of claim 1, wherein the suppository further comprises a capsule.

10. The vaginal suppository of claim 9, wherein the capsule is a soft gelatin capsule.

11. The vaginal suppository of claim 1, wherein the solubilizing agent comprises at least one of an ester of caproic fatty acid, an ester of caprylic fatty acid, an ester of capric fatty acid, and combinations thereof.

12. The vaginal suppository of claim 1, wherein the solubilizing agent comprises a monoglyceride, diglyceride, or triglyceride ester of the at least one C6-C12 fatty acid.

13. The vaginal suppository of claim 12, wherein the solubilizing agent comprises a caprylic/capric triglyceride.

14. A vaginal suppository comprising:

(a) a pharmaceutical composition comprising;

a therapeutically effective amount of estradiol;

a caprylic/capric triglyceride;

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

(b) a soft gelatin capsule,

wherein the pharmaceutical composition comprises from about 1 microgram to about 25 micrograms of estradiol;

wherein estradiol is the only active hormone in the pharmaceutical composition; and

wherein the pharmaceutical composition does not include a hydrophilic gel-forming bioadhesive agent.

15. A method of treating an estrogen-deficient state, the method comprising administering to a female in need thereof, a vaginal suppository comprising:

a) a therapeutically effective amount of solubilized estradiol; and

b) a solubilizing agent, wherein the solubilizing agent comprises at least one C6-C12 fatty acid or a glycol, monoglyceride, diglyceride, or triglyceride ester thereof;

wherein the vaginal suppository comprises from about 1 microgram to about 25 micrograms of estradiol;

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

wherein the vaginal suppository does not include a hydrophilic gel-forming bioadhesive agent in the solubilizing agent.

16. The method of claim 15, wherein the estrogen-deficient state is vulvovaginal atrophy.

17. The method of claim 15, wherein the estrogen-deficient state is an estrogen-deficient urinary state.

18. The method of claim 15, wherein the estrogen-deficient state is selected from the group consisting of:

vulvovaginal atrophy, dysuria, dyspareunia, estrogen-deficient urinary states, and vaginal bleeding associated with sexual activity.