Natural combination hormone replacement formulations and therapies

• US 8,846,649 B2
• Filed: 12/06/2013
• Issued: 09/30/2014
• Est. Priority Date: 11/23/2011
• 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): Krass, Frederick
• Assistant Examiner(s): Parad, Dennis J
• Application Number:
  US14/099,571
• Publication Number:
  US 20140094440A1
• Time in Patent Office: 298 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 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 9/16 Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction A61K9/20 takes precedence if the final form is a tablet; microspheres with drug-free outer coating, microcapsules A61K9/50; mixture of different granules, microcapsules, (coated) microparticles A61K9/5084; nanoparticles A61K9/51
• 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 9/4825 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 9/7023 Transdermal patches and similar drug-containing composite devices, e.g. cataplasms galenical aspects of iontophoretic devices A61K9/0009; microneedle arrays A61K9/0021; buccal patches A61K9/006
• 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

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 pharmaceutical composition comprising:

solubilized estradiol;

suspended progesterone;

and a solubilizing agent;

wherein each of the estradiol and the suspended progesterone are present in the solubilizing agent and the estradiol and progesterone are uniformly dispersed;

wherein at least about 90% of the estradiol is solubilized in the solubilizing agent; and

wherein the solubilizing agent comprises an effective amount of at least one of mono-, di-, and triglycerides containing an ester of a C6-C12 fatty acid.

2. The pharmaceutical composition of claim 1, further comprising partially solubilized progesterone, wherein the partially solubilized progesterone is solubilized in the solubilizing agent.

3. The pharmaceutical composition of claim 1, wherein the formulation is formulated as a gelatin capsule.

4. The pharmaceutical composition of claim 1, wherein said estradiol has a dosage strength of at least about 0.125 mg and wherein said progesterone has a dosage strength of at least about 25 mg.

5. The pharmaceutical composition of claim 1, wherein the ratio of progesterone to estradiol is about 24:

1, about 25;

1, about 96;

1, about 100;

1, about 192;

1, or about 200;

1.

6. A pharmaceutical composition comprising:

solubilized estradiol;

suspended progesterone; and

a solubilizing agent, the solubilizing agent comprising an effective amount of mono-, di-, and triglycerides containing an ester of a C6-C12 fatty acid;

wherein the estradiol and the suspended progesterone are present in the solubilizing agent the estradiol and progesterone are uniformly dispersed, and at least about 90% of the estradiol is solubilized in the solubilizing agent; and

wherein the estradiol does not precipitate for at least 14 days.

7. The pharmaceutical composition of claim 6, further comprising partially solubilized progesterone, wherein the partially solubilized progesterone is solubilized in the solubilizing agent.

8. The pharmaceutical composition of claim 6, wherein the composition is formulated as a gelatin capsule.

9. The pharmaceutical composition of claim 6, wherein the estradiol has a dosage strength of at least about 0.125 mg and wherein the progesterone has a dosage strength of at least about 25 mg.

10. The pharmaceutical composition of claim 6, wherein the ratio of progesterone to estradiol is about 24:

1, about 25;

1, about 96;

1, about 100;

1, about 192;

1, or about 200;

1.

11. A method of treating menopause symptoms of a woman with a uterus comprising:

administering an effective amount of a pharmaceutical composition, the pharmaceutical composition comprising solubilized estradiol, suspended progesterone, and a solubilizing agent,

wherein each of the estradiol and the suspended progesterone are present in the solubilizing agent and the estradiol and the suspended progesterone are uniformly dispersed and at least about 90% of the estradiol is solubilized in the solubilizing agent; and

wherein the solubilizing agent comprises an effective amount of at least one of mono-, di-, and triglycerides containing an ester of a C6-C12 fatty acid.

12. The method of claim 11, further comprising partially solubilized progesterone, wherein the partially solubilized progesterone is solubilized in the solubilizing agent.

13. The method of claim 11, wherein the composition is formulated in a gelatin capsule.

14. The method of claim 11, wherein the estradiol has a dosage strength of at least about 0.125 mg and wherein the progesterone has a dosage strength of at least about 25 mg.

15. The method of claim 11, wherein the ratio of progesterone to estradiol is about 24:

1, about 25;

1, about 96;

1, about 100;

1, about 192;

1, or about 200;

1.