Claims for Patent: 10,806,697

Summary for Patent: 10,806,697

Title:	Vaginal inserted estradiol pharmaceutical compositions and methods
Abstract:	According to various embodiments of this disclosure, pharmaceutical compositions comprising solubilized estradiol are provided. In various embodiments, such compositions are encapsulated in soft capsules which may be vaginally inserted for the treatment of vulvovaginal atrophy.
Inventor(s):	Bernick; Brian A. (Boca Raton, FL), Amadio; Julia M. (Boca Raton, FL), Persicaner; Peter H. R. (Boca Raton, FL)
Assignee:	TherapeuticsMD, Inc. (Boca Raton, FL)
Application Number:	14/521,002
Patent Claims:	1. An encapsulated liquid pharmaceutical formulation comprising about 25 .mu.g of 17.beta.-estradiol uniformly dispersed in a solubilizing agent comprising a medium chain oil, wherein the medium chain oil comprises at least one C6-C12 fatty acid or a glycol, monoglyceride, diglyceride, or triglyceride ester thereof, wherein the pharmaceutical formulation (i) is a liquid at room temperature and has a viscosity in the range of about 50 cP to about 1000 cP at 25.degree. C., and (ii) does not include an amount of a hydrophilic gel-forming bioadhesive agent that increases the viscosity above about 1000 cP at 25.degree. C., and wherein after a single administration of the pharmaceutical formulation into the vagina of a patient provides, in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (C.sub.max) of 17.beta.-estradiol of about 19 pg/ml to about 29 pg/ml; and 2) a corrected geometric mean area under the curve (AUC).sub.0-24 of 17.beta.-estradiol of about 75 pg*hr/ml to about 112 pg*hr/ml, wherein the pharmaceutical formulation is encapsulated in a capsule; and wherein 17.beta.-estradiol is the only active hormone in the encapsulated pharmaceutical formulation. 2. The encapsulated liquid pharmaceutical formulation of claim 1, wherein administration of the pharmaceutical formulation to a patient provides, in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (C.sub.max) of estrone of about 9 pg/ml to about 14 pg/ml; and 2) a corrected geometric mean area under the curve (AUC).sub.0-24 of estrone of about 43 pg*hr/ml to about 65 pg*hr/ml. 3. The encapsulated liquid pharmaceutical formulation of claim of claim 1, wherein administration of the pharmaceutical formulation to a patient provides, in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (C.sub.max) of estrone sulfate of about 416 pg/ml to about 613 pg/ml; and 2) a corrected geometric mean area under the curve (AUC).sub.0-24 of estrone sulfate of about 3598 pg*hr/ml to about 5291 pg*hr/ml. 4. The encapsulated liquid pharmaceutical formulation of claim 1, wherein the medium chain oil comprises at least one of an ester of caproic fatty acid, an ester of caprylic fatty acid, an ester of capric fatty acid, and combinations thereof. 5. The encapsulated liquid pharmaceutical formulation of claim 1, wherein the medium chain oil comprises a caprylic/capric triglyceride. 6. The encapsulated liquid pharmaceutical formulation of claim 1, wherein the capsule is a soft gelatin capsule. 7. The encapsulated liquid pharmaceutical formulation of claim 5 further comprising a nonionic surfactant comprising PEG-6 stearate, PEG-32 stearate, or ethylene glycol palmitostearate. 8. The encapsulated liquid pharmaceutical formulation of claim 7, wherein (i) the caprylic/capric triglyceride and (ii) the nonionic surfactant are present in a 9:1 ratio. 9. An encapsulated liquid pharmaceutical formulation comprising about 10 .mu.g of 17.beta.-estradiol uniformly dispersed in a solubilizing agent comprising a medium chain oil, wherein the medium chain oil comprises at least one C6-C12 fatty acid or a glycol, monoglyceride, diglyceride, or triglyceride ester thereof, wherein the pharmaceutical formulation (i) is a liquid at room temperature and has a viscosity in the range of about 50 cP to about 1000 cP at 25.degree. C., and (ii) does not include an amount of a hydrophilic gel-forming bioadhesive agent that increases the viscosity above about 1000 cP at 25.degree. C., and wherein after a single administration of the pharmaceutical formulation into the vagina of a patient provides, in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (C.sub.max) of 17.beta.-estradiol of about 12 pg/ml to about 18 pg/ml; and 2) a corrected geometric mean area under the curve (AUC).sub.0-24 of 17.beta.-estradiol of about 42 pg*hr/ml to about 63 pg*hr/ml, wherein the pharmaceutical formulation is encapsulated in a capsule; and wherein 17.beta.-estradiol is the only active hormone in the pharmaceutical formulation. 10. The encapsulated liquid pharmaceutical formulation of claim 9, wherein the pharmaceutical formulation further provides a corrected geometric mean time to peak plasma concentration (T.sub.max) of 17.beta.-estradiol of about 1 hrs to about 3 hrs. 11. The encapsulated liquid pharmaceutical formulation of claim 9, wherein administration of the pharmaceutical formulation to a patient provides, in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (C.sub.max) of estrone of about 4 pg/ml to about 7 pg/ml; and 2) a corrected geometric mean area under the curve (AUC).sub.0-24 of estrone of about 20 pg*hr/ml to about 31 pg*hr/ml. 12. The encapsulated liquid pharmaceutical formulation of claim 11, wherein the pharmaceutical formulation further provides a corrected geometric mean time to peak plasma concentration (T.sub.max) of estrone of about 4 hrs to about 8 hrs. 13. The encapsulated liquid pharmaceutical formulation of claim 9, wherein administration of the pharmaceutical formulation to a patient provides, in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (C.sub.max) of estrone sulfate of about 10 pg/ml to about 16 pg/ml; and 2) a corrected geometric mean area under the curve (AUC).sub.0-24 of estrone sulfate of about 56 pg*hr/ml to about 84 pg*hr/ml. 14. The encapsulated liquid pharmaceutical formulation of claim 13, wherein the pharmaceutical formulation further provides a corrected geometric mean time to peak plasma concentration (T.sub.max) of estrone sulfate of about 4 hrs to about 7 hrs. 15. The encapsulated liquid pharmaceutical formulation of claim 9, wherein the medium chain oil comprises at least one of an ester of caproic fatty acid, an ester of caprylic fatty acid, an ester of capric fatty acid, and combinations thereof. 16. The encapsulated liquid pharmaceutical formulation of claim 9, wherein the medium chain oil comprises a caprylic/capric triglyceride. 17. The encapsulated liquid pharmaceutical formulation of claim 9, wherein the capsule is a soft gelatin capsule. 18. The encapsulated liquid pharmaceutical formulation of claim 16 further comprising a nonionic surfactant comprising PEG-6 stearate, PEG-32 stearate, or ethylene glycol palmitostearate. 19. The encapsulated liquid pharmaceutical formulation of claim 18, wherein (i) the caprylic/capric triglyceride and (ii) the nonionic surfactant are present in a 9:1 ratio. 20. An encapsulated liquid pharmaceutical formulation comprising about 4 .mu.g of 17.beta.-estradiol uniformly dispersed in a solubilizing agent comprising a medium chain oil, wherein the medium chain oil comprises at least one C6-C12 fatty acid or a glycol, monoglyceride, diglyceride, or triglyceride ester thereof, wherein the pharmaceutical formulation (i) is a liquid at room temperature and has a viscosity in the range of about 50 cP to about 1000 cP at 25.degree. C., and (ii) does not include an amount of a hydrophilic gel-forming bioadhesive agent that increases the viscosity above about 1000 cP at 25.degree. C., and wherein after a single administration of the pharmaceutical formulation into the vagina of a patient provides, in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (C.sub.max) of 17.beta.-estradiol of about 4 pg/ml to about 8 pg/ml; and 2) a corrected geometric mean area under the curve (AUC).sub.0-24 of 17.beta.-estradiol of about 16 pg*hr/ml to about 26 pg*hr/ml, wherein the pharmaceutical formulation is encapsulated in a capsule; and wherein 17.beta.-estradiol is the only active hormone in the pharmaceutical formulation. 21. The encapsulated liquid pharmaceutical formulation of claim 20, wherein the pharmaceutical formulation further provides a corrected geometric mean time to peak plasma concentration (T.sub.max) of 17.beta.-estradiol of about 0.25 hrs to about 2 hrs. 22. The encapsulated liquid pharmaceutical formulation of claim 20, wherein administration of the pharmaceutical formulation to a patient provides, in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (C.sub.max) of estrone of about 1 pg/ml to about 3 pg/ml; and 2) a corrected geometric mean area under the curve (AUC).sub.0-24 of estrone of about 8 pg*hr/ml to about 13 pg*hr/ml. 23. The encapsulated liquid pharmaceutical formulation of claim 22, wherein the pharmaceutical formulation further provides a corrected geometric mean time to peak plasma concentration (T.sub.max) of estrone of about 1 hrs to about 4 hrs. 24. The encapsulated liquid pharmaceutical formulation of claim 20, wherein administration of the pharmaceutical formulation to a patient provides, in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (C.sub.max) of estrone sulfate of about 4 pg/ml to about 7 pg/ml; and 2) a corrected geometric mean area under the curve (AUC).sub.0-24 of estrone sulfate of about 22 pg*hr/ml to about 34 pg*hr/ml. 25. The encapsulated liquid pharmaceutical formulation of claim 24, wherein the pharmaceutical formulation further provides a corrected geometric mean time to peak plasma concentration (T.sub.max) of estrone sulfate of about 1 hrs to about 3 hrs. 26. The encapsulated liquid pharmaceutical formulation of claim 20, wherein the medium chain oil comprises at least one of an ester of caproic fatty acid, an ester of caprylic fatty acid, an ester of capric fatty acid, and combinations thereof. 27. The encapsulated liquid pharmaceutical formulation of claim 20, wherein the medium chain oil comprises a caprylic/capric triglyceride. 28. The encapsulated liquid pharmaceutical formulation of claim 20, wherein the capsule is a soft gelatin capsule. 29. The encapsulated liquid pharmaceutical formulation of claim 27 further comprising a nonionic surfactant comprising PEG-6 stearate, PEG-32 stearate, or ethylene glycol palmitostearate. 30. The encapsulated liquid pharmaceutical formulation of claim 29, wherein (i) the caprylic/capric triglyceride and (ii) the nonionic surfactant are present in a 9:1 ratio.