Claims for Patent: 11,103,513

Summary for Patent: 11,103,513

Title:	Natural combination hormone replacement formulations and therapies
Abstract:	Pharmaceutical compositions for co-administering estradiol and progesterone to a human subject in need thereof are provided. In some embodiments, the pharmaceutical composition comprises solubilized estradiol, suspended progesterone, and a solubilizing agent comprising a medium chain (C6-C12) oil.
Inventor(s):	Bernick; Brian A. (Boca Raton, FL), Persicaner; Peter H. R. (Boca Raton, FL), Amadio; Julia M. (Boca Raton, FL)
Assignee:	TherapeuticsMD (Boca Raton, FL)
Application Number:	16/885,088
Patent Claims:	1. A method of treating a female human patient having vasomotor symptoms associated with estrogen deficiency, the method comprising orally administering to the female human patient in need of treatment thereof with food a capsule comprising a fill material, the fill material consisting of: a. a solubilizing agent consisting of: i. about 196 mg of mono- and diglycerides of caprylic and capric acid; and ii. about 3 mg of at least one of lauroyl macrogol-32 glycerides EP, lauroyl polyoxyl-32 glycerides NF, or lauroyl polyoxylglycerides; b. about 1 mg of 17.beta.-estradiol, wherein at least about 80% of the 17.beta.-estradiol is solubilized in the solubilizing agent; and c. about 100 mg of progesterone, wherein a first portion of the progesterone is solubilized in the solubilizing agent and a second portion of the progesterone is micronized; wherein the second portion of the progesterone is uniformly dispersed in the solubilizing agent; wherein the entire amount of the 17.beta.-estradiol and the progesterone in the capsule is present in the solubilizing agent; and wherein the administration of the capsule to the patient produces one or more pharmacokinetic parameters selected from the group consisting of: i. an area under the curve (AUC)(0-t) for 17.beta.-estradiol ranging from 561.4933 pghr/ml to 877.3333 pghr/ml; ii. a Cmax for 17.beta.-estradiol ranging from 25.9161 pg/ml to 40.4939 pg/ml; iii. an AUC(0-t) for estrone ranging from 3638.4363 pghr/ml to 5685.0567 pghr/ml; iv. a Cmax for estrone ranging from 170.6197 pg/ml to 266.5933 pg/ml; v. an AUC(0-t) for progesterone ranging from 48.0348 nghr/ml to 75.0543 nghr/ml; and vi. a Cmax for progesterone ranging from 35.6889 ng/ml to 55.7639 ng/ml. 2. The method of claim 1, wherein the patient has a uterus. 3. The method of claim 1, wherein the administration of the capsule to the patient further produces a Tmax for progesterone that ranges from 2.4 hr to 3.8 hr or a Tmax for estrone ranging from 4.4 hr to 6.9 hr. 4. The method of claim 3, wherein the administration of the capsule to the patient produces three or more of the pharmacokinetic parameters. 5. The method of claim 1, wherein the administration of the capsule to the patient produces the following pharmacokinetic parameters: a. an AUC(0-t) for 17.beta.-estradiol ranging from 561.4933 pghr/ml to 877.3333 pghr/ml; b. a Cmax for 17.beta.-estradiol ranging from 25.9161 pg/ml to 40.4939 pg/ml; c. an AUC(0-t) for estrone ranging from 3638.4363 pghr/ml to 5685.0567 pghr/ml; d. a Cmax for estrone ranging from 170.6197 pg/ml to 266.5933 pg/ml; and e. an AUC(0-t) for progesterone ranging from 48.0348 nghr/ml to 75.0543 nghr/ml. 6. The method of claim 1, wherein at least about 15% by weight of the progesterone is solubilized in the solubilizing agent, and at least about 50% by weight of the progesterone is micronized. 7. The method of claim 1, wherein up to about 15% by weight of the progesterone is solubilized in the solubilizing agent. 8. The method of claim 1, wherein the micronized progesterone has an X50 particle size of below about 15 microns, an X90 particle size of below about 25 microns, or both. 9. A method of treating a female human patient having vasomotor symptoms associated with estrogen deficiency, the method comprising orally administering to the female human patient in need of treatment thereof with food a capsule comprising a fill material, the fill material comprising: a. a solubilizing agent comprising: i. about 196 mg of mono- and diglycerides of caprylic and capric acid; and ii. about 3 mg of at least one of lauryl macrogol-32 glycerides EP, lauroyl polyoxyl-32 glycerides NF or lauroyl polyoxylglycerides; b. about 1 mg of 17.beta.-estradiol, wherein at least about 80% of the 17.beta.-estradiol is solubilized in the solubilizing agent; c. about 100 mg of progesterone, wherein a first portion of the progesterone is solubilized in the solubilizing agent and a second portion of the progesterone is micronized, and wherein up to about 15% by weight of the progesterone is solubilized in the solubilizing agent; wherein the second portion of the progesterone is uniformly dispersed in the solubilizing agent; wherein the entire amount of the 17.beta.-estradiol and the progesterone in the capsule is present in the solubilizing agent; and wherein the administration of the capsule to the patient produces one or more pharmacokinetic parameters selected from the group consisting of: i. an area under the curve (AUC)(0-t) for 17.beta.-estradiol ranging from 561.4933 pghr/ml to 877.3333 pghr/ml; ii. a Cmax for 17.beta.-estradiol ranging from 25.9161 pg/ml to 40.4939 pg/ml; iii. an AUC(0-t) for estrone ranging from 3638.4363 pghr/ml to 5685.0567 pghr/ml; iv. a Cmax for estrone ranging from 170.6197 pg/ml to 266.5933 pg/ml; v. an AUC(0-t) for progesterone ranging from 48.0348 nghr/ml to 75.0543 nghr/ml; and vi. a Cmax for progesterone ranging from 35.6889 ng/ml to 55.7639 ng/ml. 10. The method of claim 9, wherein the patient has a uterus. 11. The method of claim 9, wherein the administration of the capsule to the patient further produces a Tmax for progesterone ranging from 2.4 hr to 3.8 hr or a Tmax for estrone ranging from 4.4 hr to 6.9 hr. 12. A method of treating a female human patient having vasomotor symptoms associated with estrogen deficiency, the method comprising orally administering to the patient in need of treatment thereof with food a capsule comprising a fill material, the fill material comprising: a. a solubilizing agent comprising: i. a medium chain oil, wherein at least about 80% of fatty acid chains present in the oil are C6-C12 and the medium chain oil comprises about 60% to about 85% of the weight of the fill material; and ii. a non-ionic surfactant, wherein the non-ionic surfactant comprises about 0.1% to about 10.0% of the weight of the fill material; b. about 1 mg of 17.beta.-estradiol, wherein at least about 80% of the 17.beta.-estradiol is solubilized in the solubilizing agent; c. about 100 mg of progesterone, wherein a first portion of the progesterone is solubilized in the solubilizing agent and a second portion of the progesterone is micronized; wherein the second portion of the progesterone is uniformly dispersed in the solubilizing agent; wherein the entire amount of the 17.beta.-estradiol and the progesterone in the capsule is present in the solubilizing agent; and wherein the administration of the capsule to the patient produces one or more pharmacokinetic parameters selected from the group consisting of: i. an area under the curve (AUC)(0-t) for 17.beta.-estradiol ranging from 561.4933 pghr/ml to 877.3333 pghr/ml; ii. a Cmax for 17.beta.-estradiol ranging from 25.9161 pg/ml to 40.4939 pg/ml; iii. an AUC(0-t) for estrone ranging from 3638.4363 pghr/ml to 5685.0567 pghr/ml; iv. a Cmax for estrone ranging from 170.6197 pg/ml to 266.5933 pg/ml; v. an AUC(0-t) for progesterone ranging from 48.0348 nghr/ml to 75.0543 nghr/ml; and vi. a Cmax for progesterone ranging from 35.6889 ng/ml to 55.7639 ng/ml. 13. The method of claim 12, wherein the patient has a uterus. 14. The method of claim 12, wherein the administration of the capsule to the patient further produces a Tmax for progesterone ranging from 2.4 hr to 3.8 hr or a Tmax for estrone ranging from 4.4 hr to 6.9 hr. 15. The method of claim 12, wherein the ratio of the medium chain oil to the non-ionic surfactant is between about 60:1 to about 70:1. 16. The method of claim 12, wherein up to about 15% by weight of the progesterone is solubilized in the solubilizing agent. 17. A method of treating a female human patient having vasomotor symptoms associated with estrogen deficiency, the method comprising orally administering to the patient in need of treatment thereof with food a capsule comprising a fill material, the fill material comprising: a. a solubilizing agent; b. about 1 mg of 17.beta.-estradiol, wherein at least about 80% of the 17.beta.-estradiol is solubilized in the solubilizing agent, and wherein the 17.beta.-estradiol comprises about 0.15% to about 0.4% by weight of the fill material; c. about 100 mg of progesterone, wherein a first portion of the progesterone is solubilized in the solubilizing agent and a second portion of the progesterone is micronized, wherein up to about 20% by weight of the progesterone is solubilized in the solubilizing agent, and wherein the progesterone comprises about 30% to about 35% by weight of the fill material; and wherein the second portion of the progesterone is uniformly dispersed in the solubilizing agent; wherein the entire amount of the 17.beta.-estradiol and the progesterone in the capsule is present in the solubilizing agent; and wherein the administration of the capsule to the patient produces one or more pharmacokinetic parameters selected from the group consisting of: i. an area under the curve (AUC)(0-t) for 17.beta.-estradiol ranging from 561.4933 pghr/ml to 877.3333 pghr/ml; ii. a Cmax for 17.beta.-estradiol ranging from 25.9161 pg/ml to 40.4939 pg/ml; iii. an AUC(0-t) for estrone ranging from 3638.4363 pghr/ml to 5685.0567 pghr/ml; iv. a Cmax for estrone ranging from 170.6197 pg/ml to 266.5933 pg/ml; v. an AUC(0-t) for progesterone ranging from 48.0348 nghr/ml to 75.0543 nghr/ml; and vi. a Cmax for progesterone ranging from 35.6889 ng/ml to 55.7639 ng/ml. 18. The method of claim 17, wherein the patient has a uterus. 19. The method of claim 17, wherein the fill material further comprises a surfactant, the surfactant comprising about 0.1% to about 5% by weight of the fill material. 20. The method of claim 17, wherein the surfactant is an ionic surfactant, a non-ionic surfactant, or a combination thereof. 21. The method of claim 20, wherein the non-ionic surfactant is a medium chain fatty acid ester of polyethylene glycol. 22. The method of claim 20, wherein the non-ionic surfactant is a polyethylene glycol glyceride composed of mono-, di-, and triglycerides and mono- and diesters of polyethylene glycol. 23. The method of claim 20, wherein the non-ionic surfactant is PEG-32 glyceryl laurate EP. 24. The method of claim 20, wherein the ratio of the solubilizing agent to the non-ionic surfactant is about 65:1. 25. The method of claim 17, wherein the micronized progesterone has an X50 particle size of below about 15 microns, an X90 particle size of below about 25 microns, or both. 26. The method of claim 17, wherein the solubilizing agent comprises a medium chain oil. 27. The method of claim 26, wherein the medium chain oil comprises at least about 75% by weight of medium chain fatty acids. 28. The method of claim 19, wherein the ratio of the solubilizing agent to the surfactant is about 60:1 to about 70:1. 29. The method of claim 28, wherein the ratio of the solubilizing agent to the surfactant is about 65:1. 30. The method of claim 17, wherein up to about 15% by weight of the progesterone is solubilized in the solubilizing agent.