Natural combination hormone replacement formulations and therapies

• US 8,987,238 B2
• Filed: 12/06/2013
• Issued: 03/24/2015
• Est. Priority Date: 06/18/2012
• Status: Active Grant

• Current Assignee: TherapeuticsMD Inc.
• Original Assignee: TherapeuticsMD Inc.
• Inventors: Bernick, Brian A., Cacace, Janice Louise, Persicaner, Peter H. R., Irani, Neda, Amadio, Julia M.
• Primary Examiner(s): Parad, Dennis J
• Application Number:
  US14/099,598
• Publication Number:
  US 20140100204A1
• Time in Patent Office: 473 Days
• Field of Search: None
• US Class Current: 514/169
• 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 47/10 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
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/24 of the sex hormones

Abstract

Estrogen and progesterone replacement therapies are provided herein. Among others, the following formulations are provided herein: solubilized estradiol without progesterone; micronized progesterone without estradiol; micronized progesterone with partially solubilized progesterone; solubilized estradiol with micronized progesterone; solubilized estradiol with micronized progesterone in combination with partially solubilized progesterone; and solubilized estradiol with solubilized progesterone.

Claims

1. A method of treating menopause-related symptoms comprising administering once daily an effective amount of a pharmaceutical composition to a subject in need thereof, the pharmaceutical composition comprising:

about 50 mg progesterone;

about 0.50 mg estradiol or about 0.52 mg estradiol hemihydrate, wherein at least about 90% of the estradiol or the estradiol hemihydrate is solubilized;

about 97.98 mg of a solubilizing agent comprising monoglycerides and diglycerides of caprylic acid and capric acid (CAPMUL MCM); and

about 1.50 mg of at least one of lauroyl macrogol-32 glycerides EP, lauroyl polyoxyl-32 glycerides NF, or lauroyl polyoxylglycerides (GELUCIRE 44/14);

wherein the estradiol or the estradiol hemihydrate, and the progesterone are uniformly dispersed in the solubilizing agent.

2. The method of claim 1, wherein the pharmaceutical composition is administered as a continuous-combined therapy regimen.

3. The method of claim 1, wherein the pharmaceutical composition is administered as a sequentially-combined therapy regimen.

4. A method of treating a symptom of menopause comprising administering an effective amount of a pharmaceutical composition comprising:

0.50 mg estradiol or about 0.52 mg estradiol hemihydrate, wherein the estradiol or estradiol hemihydrate is about 90% solubilized in the solubilizing agent;

50 mg progesterone; and

a solubilizing agent;

wherein the estradiol or the estradiol hemihydrate, and the progesterone are uniformly dispersed in the solubilizing agent; and

wherein the pharmaceutical composition is administered once daily for the treatment of symptoms associated with menopause.

5. The method of claim 4, wherein the pharmaceutical composition is administered as a continuous-combined therapy regimen.

6. The method of claim 4, wherein the pharmaceutical composition is administered as a sequentially-combined therapy regimen.

7. The method of claim 4, wherein the solubilizing agent is selected from at least one of monoglycerides, diglycerides, triglycerides, and combinations thereof, wherein the monoglycerides, diglycerides, and triglycerides are predominantly of C6-C12 fatty acid chain lengths.

8. The method of claim 7, wherein the monoglycerides, diglycerides, and triglycerides are >

50% C6-C12 fatty acid chain lengths.

9. A method of treating a menopause-related symptom comprising administering once daily an effective amount of a pharmaceutical composition comprising:

a solubilizing agent;

0.50 mg estradiol or about 0.52 mg estradiol hemihydrate, wherein the estradiol or estradiol hemihydrate is at least about 90% solubilized in the solubilizing agent; and

50 mg progesterone;

wherein the solubilizing agent comprises an oil that is predominantly a C6-C12 oil; and

wherein the estradiol or the estradiol hemihydrate, and the progesterone are uniformly dispersed in the solubilizing agent.

10. The method of claim 9, wherein the C6-C12 oil comprises C6-C12 monoglycerides and diglycerides.

11. The method of claim 10, wherein the monoglycerides and diglycerides contain an ester of caprylic acid (C8) and capric acid (C10).

12. A method of treating vasomotor symptoms in a woman comprising administering once daily an effective amount of a pharmaceutical composition comprising:

a solubilizing agent;

0.50 mg estradiol or about 0.52 mg estradiol hemihydrate, wherein the estradiol or estradiol hemihydrate is at least about 90% solubilized in the solubilizing agent; and

50 mg progesterone;

wherein the solubilizing agent comprises an oil that is predominantly a saturated C6-C12 oil; and

wherein the estradiol or the estradiol hemihydrate, and the progesterone are uniformly dispersed in the solubilizing agent.

13. The method of claim 12, wherein the C6-C12 oil comprises a glyceride of at least one C6-C12 fatty acid.

14. The method of claim 12, wherein the C6-12 oil predominantly contain an ester of caprylic acid (C8) and capric acid (C10).