Claims for Patent: 11,103,516

Summary for Patent: 11,103,516

Title:	Natural combination hormone replacement formulations and therapies
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.
Inventor(s):	Bernick; Brian A. (Boca Raton, FL), Cacace; Janice Louise (Miami, FL), Persicaner; Peter H. R. (Boca Raton, FL), Irani; Neda (Palm Beach Garden, FL), Amadio; Julia M. (Boca Raton, FL), Sancilio; Frederick D. (Palm Beach Gardens, FL)
Assignee:
Application Number:	16/885,094
Patent Claims:	1. A pharmaceutical composition comprising: a fill material encapsulated in a capsule, the fill material comprising: a. two active pharmaceutical ingredients, the active pharmaceutical ingredients being about 1 mg of 17.beta.-estradiol and about 100 mg of progesterone, wherein at least about 90% of the 17.beta.-estradiol is solubilized, and wherein a first portion of the progesterone is solubilized and a second portion of the progesterone is micronized; b. a solubilizing agent for the active pharmaceutical ingredients, the solubilizing agent comprising: i. a medium chain oil comprising mono- and diglycerides of capric and caprylic acid; and ii. at least one of lauroyl macrogol-32 glycerides or lauroyl polyoxyl-32 glycerides; wherein the 17.beta.-estradiol and the progesterone in the capsule are present in the solubilizing agent; wherein the second portion of the progesterone is uniformly dispersed in the solubilizing agent; and wherein the progesterone has a solubility in the solubilizing agent of at least about 73 mg/g, and the 17.beta.-estradiol has a solubility in the solubilizing agent of at least about 10 mg/g. 2. The pharmaceutical composition of claim 1, wherein the 17.beta.-estradiol has a solubility in the solubilizing agent of at least about 12 mg/g. 3. The pharmaceutical composition of claim 1, wherein at least about 14% by weight of the progesterone is solubilized in the solubilizing agent. 4. The pharmaceutical composition of claim 1, wherein the 17.beta.-estradiol is fully solubilized in the solubilizing agent. 5. The pharmaceutical composition of claim 1, wherein the micronized progesterone has an X50 particle size value below about 15 microns, an X90 particle size value below about 25 microns, or both. 6. The pharmaceutical composition of claim 1, wherein the at least one of lauroyl macrogol-32 glycerides or lauroyl polyoxyl-32 glycerides is about 1% to about 2% by weight of the fill material. 7. The pharmaceutical composition of claim 1, wherein the progesterone is about 33% by weight of the fill material. 8. The pharmaceutical composition of claim 1, wherein the mono- and diglycerides of capric and caprylic acid are about 65% by weight of the fill material. 9. The pharmaceutical composition of claim 1, wherein the 17.beta.-estradiol does not precipitate for at least about 14 days. 10. The pharmaceutical composition of claim 1, wherein the fill material has a total weight of less than about 400 mg. 11. A pharmaceutical composition comprising: a fill material encapsulated in a soft gelatin capsule, the fill material comprising: a. two active pharmaceutical ingredients, the active pharmaceutical ingredients being about 1 mg of 17.beta.-estradiol and about 100 mg of progesterone, wherein a first portion of the progesterone is solubilized, a second portion of the progesterone is micronized, and the 17.beta.-estradiol is fully solubilized; b. a solubilizing agent for the active pharmaceutical ingredients, the solubilizing agent comprising: i. a medium chain oil comprising mono- and diglycerides; and ii. at least one of lauroyl macrogol-32 glycerides or lauroyl polyoxyl-32 glycerides; wherein the 17.beta.-estradiol and the progesterone in the capsule are present in the solubilizing agent; wherein the second portion of the progesterone is uniformly dispersed in the solubilizing agent; and wherein the progesterone has a solubility in the solubilizing agent of at least about 73 mg/g and the 17.beta.-estradiol has a solubility in the solubilizing agent of at least about 10 mg/g. 12. The pharmaceutical composition of claim 11, wherein the medium chain oil comprises mono- and diglycerides of capric and caprylic acid. 13. The pharmaceutical composition of claim 11, wherein at least about 14% by weight of the progesterone is solubilized in the solubilizing agent. 14. The pharmaceutical composition of claim 11, wherein the 17.beta.-estradiol has a solubility in the solubilizing agent of at least about 12 mg/g. 15. The pharmaceutical composition of claim 11, wherein the micronized progesterone has an X50 particle size value below about 15 microns, an X90 particle size value below about 25 microns, or both. 16. The pharmaceutical composition of claim 11, wherein the at least one of lauroyl macrogol-32 glycerides or lauroyl polyoxyl-32 glycerides is about 1% to about 2% by weight of the fill material. 17. The pharmaceutical composition of claim 11, wherein the progesterone is about 33% by weight of the fill material. 18. The pharmaceutical composition of claim 11, wherein the medium chain oil is about 65% by weight of the fill material. 19. The pharmaceutical composition of claim 11, wherein the 17.beta.-estradiol does not precipitate for at least about 14 days. 20. The pharmaceutical composition of claim 11, wherein the fill material has a total weight of less than about 400 mg. 21. A pharmaceutical composition comprising: a fill material encapsulated in a capsule, the fill material comprising: a. two active pharmaceutical ingredients, the active pharmaceutical ingredients being about 1 mg of 17.beta.-estradiol and about 100 mg of progesterone, wherein a first portion of the progesterone is solubilized, a second portion of the progesterone is micronized, and the 17.beta.-estradiol is fully solubilized; b. a solubilizing agent for the active pharmaceutical ingredients, the solubilizing agent comprising: i. a medium chain oil comprising mono- and diglycerides of capric and caprylic acid that are about 65% by weight of the fill material; and ii. at least one of lauroyl macrogol-32 glycerides or lauroyl polyoxyl-32 glycerides that is about 1% to about 2% by weight of the fill material; wherein the 17.beta.-estradiol and the progesterone in the capsule are present in the solubilizing agent; wherein the second portion of the progesterone is uniformly dispersed in the solubilizing agent; wherein the progesterone has a solubility in the solubilizing agent of at least about 73 mg/g and the 17.beta.-estradiol has a solubility in the solubilizing agent of at least about 10 mg/g, wherein the 17.beta.-estradiol does not precipitate for at least about 14 days, and wherein the progesterone is about 33% by weight of the fill material. 22. The pharmaceutical composition of claim 21, wherein at least about 14% by weight of the progesterone is solubilized in the solubilizing agent. 23. The pharmaceutical composition of claim 21, wherein the 17.beta.-estradiol has a solubility in the solubilizing agent of at least about 12 mg/g. 24. The pharmaceutical composition of claim 21, wherein the micronized progesterone has an X50 particle size value below about 15 microns, an X90 particle size value below about 25 microns, or both. 25. The pharmaceutical composition of claim 21, wherein the fill material has a total weight of less than about 400 mg. 26. A pharmaceutical composition comprising: a fill material encapsulated in a capsule, the fill material comprising: a. two active pharmaceutical ingredients, the active pharmaceutical ingredients being about 1 mg of 17.beta.-estradiol and about 100 mg of progesterone, wherein at least about 90% of the 17.beta.-estradiol is solubilized, and wherein a first portion of the progesterone is solubilized and a second portion of the progesterone is micronized; b. a solubilizing agent for the active pharmaceutical ingredients; wherein the 17.beta.-estradiol and the progesterone in the capsule are present in the solubilizing agent; wherein the second portion of the progesterone is uniformly dispersed in the solubilizing agent; and wherein the progesterone has a solubility in the solubilizing agent of at least about 73 mg/g, and the 17.beta.-estradiol has a solubility in the solubilizing agent of at least about 10 mg/g. 27. The pharmaceutical composition of claim 26, wherein the solubilizing agent comprises (i) monoglycerides and diglycerides of caprylic and capric acid; and (ii) at least one of lauroyl macrogol-32 glycerides or lauroyl polyoxyl-32 glycerides; wherein the mono- and diglycerides of capric and caprylic acid are about 65% by weight of the fill material, and the at least one of lauroyl macrogol-32 glycerides or lauroyl polyoxyl-32 glycerides is about 1% by weight of the fill material. 28. The pharmaceutical composition of claim 1, wherein up to about 14% by weight of the progesterone is solubilized in the solubilizing agent. 29. The pharmaceutical composition of claim 11, wherein up to about 14% by weight of the progesterone is solubilized in the solubilizing agent. 30. The pharmaceutical composition of claim 21, wherein up to about 14% by weight of the progesterone is solubilized in the solubilizing agent.