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.

1 .- 36 . (canceled) 
     
     
         37 . A pharmaceutical composition for administering estradiol and progesterone to a human female subject having a vasomotor symptom associated with estrogen deficiency, the composition comprising:
 about 0.25 mg estradiol,   progesterone, and   a solubilizing agent, the solubilizing agent comprising a C6-C12 oil,   wherein the estradiol and the progesterone are present in the solubilizing agent, and at least 80% of the estradiol is solubilized; and   wherein administration of the composition to the subject produces, in a plasma sample from the subject, one or both parameters selected from:   (i) an area under the curve (AUC) (0-t)  for estradiol that is from 140.3733 pg·hr/ml to 219.3333 pg·hr/ml; and   (ii) a C max  for estradiol that is from 6.4790 pg/ml to 10.1235 pg/ml.   
     
     
         38 . The pharmaceutical composition of  claim 37 , wherein administration of the composition to the subject produces both an AUC (0-t)  for estradiol that is from 140.3733 pg·hr/ml to 219.3333 pg·hr/ml, and a C max  for estradiol that is from 6.4790 pg/ml to 10.1235 pg/ml. 
     
     
         39 . The pharmaceutical composition of  claim 37 , comprising about 50 mg progesterone, wherein administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from:
 (i) an AUC (0-t)  for progesterone that is from 24.0174 ng·hr/ml to 37.5272 ng·hr/ml; and   (ii) a C max  for progesterone that is from 17.8444 ng/ml to 27.8819 ng/ml.   
     
     
         40 . The pharmaceutical composition of  claim 37 , wherein
 administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from:   (i) an AUC (0-t)  for estrone that is from 909.6091 pg·hr/ml to 1421.2642 pg·hr/ml; and   (ii) a C max  for estrone that is from 42.6549 pg/ml to 66.6483 pg/ml.   
     
     
         41 . The pharmaceutical composition of  claim 37 , wherein
 administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from:   (i) an AUC (0-t)  for total estrone that is from 20.1752 ng·hr/ml to 31.5238 ng·hr/ml; and   (ii) a C max  for total estrone that is from 3.5429 ng/ml to 5.5358 ng/ml.   
     
     
         42 . A method for treating a human female subject having a vasomotor symptom associated with estrogen deficiency, the method comprising administering to the subject a pharmaceutical composition of  claim 37 , wherein the pharmaceutical composition is administered to the subject once daily for at least one month. 
     
     
         43 . A pharmaceutical composition for administering estradiol and progesterone to a human female subject having a vasomotor symptom associated with estrogen deficiency, the composition comprising:
 about 0.5 mg estradiol,   progesterone, and   a solubilizing agent, the solubilizing agent comprising a C6-C12 oil,   wherein the estradiol and the progesterone are present in the solubilizing agent, and at least 80% of the estradiol is solubilized; and   wherein administration of the composition to the subject produces, in a plasma sample from the subject, one or both parameters selected from:   (i) an area under the curve (AUC) (0-t)  for estradiol that is from 280.7467 pg·hr/ml to 438.6667 pg·hr/ml; and   (ii) a C max  for estradiol that is from 12.9580 pg/ml to 20.2469 pg/ml.   
     
     
         44 . The pharmaceutical composition of  claim 43 , wherein administration of the composition to the subject produces both an AUC (0-t)  for estradiol that is from 280.7467 pg·hr/ml to 438.6667 pg·hr/ml, and a C max  for estradiol that is from 12.9580 pg/ml to 20.2469 pg/ml. 
     
     
         45 . The pharmaceutical composition of  claim 43 , comprising about 50 mg progesterone, wherein administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from:
 (i) an AUC (0-t)  for progesterone that is from 24.0174 ng·hr/ml to 37.5272 ng·hr/ml; and   (ii) a C max  for progesterone that is from 17.8444 ng/ml to 27.8819 ng/ml.   
     
     
         46 . The pharmaceutical composition of  claim 43 , comprising about 100 mg progesterone, wherein administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from:
 (i) an AUC (0-t)  for progesterone that is from 48.0348 ng·hr/ml to 75.0543 ng·hr/ml; and   (ii) a C max  for progesterone that is from 35.6889 ng/ml to 55.7639 ng/ml.   
     
     
         47 . The pharmaceutical composition of  claim 43 , wherein administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from:
 (i) an AUC (0-t)  for estrone that is from 1819.2181 pg·hr/ml to 2842.5283 pg·hr/ml; and   (ii) a C max  for estrone that is from 85.3098 pg/ml to 133.2966 pg/ml.   
     
     
         48 . The pharmaceutical composition of  claim 43 , wherein administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from:
 (i) an AUC (0-t)  for total estrone that is from 40.3505 ng·hr/ml to 63.0476 ng·hr/ml; and   (ii) a C max  for total estrone that is from 7.0858 ng/ml to 11.0715 ng/ml.   
     
     
         49 . A method for treating a human female subject having a vasomotor symptom associated with estrogen deficiency, the method comprising administering to the subject a pharmaceutical composition of  claim 43 , wherein the pharmaceutical composition is administered to the subject once daily for at least one month. 
     
     
         50 . A pharmaceutical composition for administering estradiol and progesterone to a human female subject having a vasomotor symptom associated with estrogen deficiency comprising:
 about 1.0 mg estradiol,   progesterone, and   a solubilizing agent, the solubilizing agent comprising a C6-C12 oil,   wherein the estradiol and the progesterone are present in the solubilizing agent, and at least 80% of the estradiol is solubilized; and   wherein administration of the composition to the subject produces, in a plasma sample from the subject, one or both parameters selected from:   (i) an area under the curve (AUC) (0-t)  for estradiol that is from 561.4933 pg·hr/ml to 877.3333 pg·hr/ml; and   (ii) a C max  for estradiol that is from 25.9161 pg/ml to 40.4939 pg/ml.   
     
     
         51 . The pharmaceutical composition of  claim 50 , wherein administration of the composition to the subject produces both an AUC (0-t)  for estradiol that is from 561.4933 pg·hr/ml to 877.3333 pg·hr/ml, and a C max  for estradiol that is from 25.9161 pg/ml to 40.4939 pg/ml. 
     
     
         52 . The pharmaceutical composition of  claim 50 , further comprising 100 mg progesterone, wherein administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from:
 (i) an AUC (0-t)  for progesterone that is from 48.0348 ng·hr/ml to 75.0543 ng·hr/ml; and   (ii) and a C max  for progesterone that is from 35.6889 ng/ml to 55.7639 ng/ml.   
     
     
         53 . The pharmaceutical composition of  claim 50 , wherein administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from:
 (i) an AUC (0-t)  for estrone that is from 3638.4363 pg·hr/ml to 5685.0567 pg·hr/ml; and   (ii) a C max  for estrone that is from 170.6197 pg/ml to 266.5933 pg/ml.   
     
     
         54 . The pharmaceutical composition of  claim 50 , wherein administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from:
 (i) an AUC (0-t)  for total estrone that is from 80.7010 ng·hr/ml to 126.0953 ng·hr/ml; and   (ii) a C max  for total estrone that is from 14.1716 ng/ml to 22.1431 ng/ml.   
     
     
         55 . A method for treating a human female subject having a vasomotor symptom associated with estrogen deficiency, the method comprising administering to the subject a pharmaceutical composition of  claim 50 , wherein the pharmaceutical composition is administered to the subject once daily for at least one month