Natural combination hormone replacement formulations and therapies

• US 8,846,648 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:
  US14/099,545
• Publication Number:
  US 20140088051A1
• Time in Patent Office: 298 Days
• Field of Search: 514/169
• 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 method of treating a menopause-related symptom in a woman comprising:

administering to the woman 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;

wherein the solubilizing agent contains an effective amount of C6-C12 oil; and

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

2. The method of claim 1, further comprising partially solubilized progesterone, the partially solubilized progesterone being solubilized in the solubilizing agent.

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

4. The method of claim 1, wherein the C6-C12 oil is selected from at least one of mono-, di-, and triglycerides and combinations thereof.

5. The method of claim 1, 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.

6. The method 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.

7. The method of claim 1, wherein the composition is bioequivalent to a 200 mg progesterone soft gel capsule and to a 2 mg estradiol tablet.

8. A method of treating a menopause symptom in a woman comprising administering a pharmaceutical composition to the woman, the pharmaceutical composition comprising:

solubilized estradiol;

suspended progesterone; and

a solubilizing agent, the solubilizing agent containing an effective amount of a C6-C12 oil;

wherein the estradiol and the suspended progesterone are present in the solubilizing agent, 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 estradiol does not precipitate for at least 14 days.

9. The method of claim 8, further comprising partially solubilized progesterone, the partially solubilized progesterone being solubilized in the solubilizing agent.

10. The method of claim 8, wherein the composition is formulated as a gelatin capsule.

11. The method of claim 8, wherein the C6-C12 oil is selected from at least one of mono-, di-, and triglycerides and combinations thereof.

12. The method of claim 8, 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.

13. The method of claim 8, 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.

14. The method of claim 8, wherein the composition is bioequivalent to a 200 mg progesterone soft gel capsule and to a 2 mg estradiol tablet.

15. A method of treating a menopause symptom comprising:

administering an effective amount of a pharmaceutical composition to a woman, the pharmaceutical composition comprising solubilized estradiol, suspended progesterone, and a solubilizing agent, the estradiol being stable in the solubilizing agent for at least 14 days;

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;

wherein at least about 90% of the estradiol is solubilized in the solubilizing agnent, and wherein the solubilizing agent contains an effective amount of a C6-C12 oil.

16. The method of claim 15, further comprising partially solubilized progesterone, the partially solubilized progesterone being solubilized in the solubilizing agent.

17. The method of claim 15, wherein the composition is formulated as a gelatin capsule.

18. The method of claim 15, wherein the C6-C12 oil is selected from at least one of mono-, di-, and triglycerides and combinations thereof.

19. The method of claim 15, 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.

20. The method of claim 15, 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.