NATURAL COMBINATION HORMONE REPLACEMENT FORMULATIONS AND THERAPIES
Pharmaceutical compositions for co-administering estradiol and progesterone to a human subject having vasomotor symptoms associated with estrogen deficiency are provided. In some embodiments, the pharmaceutical composition produces certain pharmacokinetic parameters when the composition is administered to the subject.
1 . A pharmaceutical composition for co-administering estradiol and progesterone to a human subject having vasomotor symptoms associated with estrogen deficiency comprising: 1 mg of estradiol and 100 mg of progesterone;
wherein administration of the composition to the subject produces, in a serum sample from the subject, one or more pharmacokinetic parameters selected from:
(i) a steady state estradiol concentration that is from 42.29 pg/mL to 45.58 pg/mL;
(ii) a steady state estrone concentration that is from 213.79 pg/mL to 241.57 pg/mL; and
(iii) a steady state progesterone concentration that is from 386.53 pg/mL to 547.83 pg/mL.
2 . The pharmaceutical composition of claim 1 , wherein administration of the composition to the subject produces a steady state estradiol concentration that is from 42.29 pg/mL to 45.58 pg/mL.
3 . The pharmaceutical composition of claim 1 , wherein administration of the composition to the subject produces both a steady state estradiol concentration that is from 42.29 pg/mL to 45.58 pg/mL and a steady state estrone concentration that is from 213.79 pg/mL to 241.57 pg/mL.
4 . The pharmaceutical composition of claim 1 , wherein administration of the composition to the subject produces both a steady state estradiol concentration that is from 42.29 pg/mL to 45.58 pg/mL and a steady state progesterone concentration that is from 386.53 pg/mL to 547.83 pg/mL.
5 . The pharmaceutical composition of claim 1 , wherein administration of the composition to the subject produces each of: (i) a steady state estradiol concentration that is from 42.29 pg/mL to 45.58 pg/mL; (ii) a steady state estrone concentration that is from 213.79 pg/mL to 241.57 pg/mL; and (iii) a steady state progesterone concentration that is from 386.53 pg/mL to 547.83 pg/mL.
6 . A pharmaceutical composition for co-administering estradiol and progesterone to a human subject having vasomotor symptoms associated with estrogen deficiency comprising: 0.5 mg of estradiol and 100 mg of progesterone;
wherein administration of the composition to the subject produces, in a serum sample from the subject, one or more pharmacokinetic parameters selected from:
(i) a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL;
(ii) a steady state estrone concentration that is from 113.59 pg/mL to 132.08 pg/mL; and
(iii) a steady state progesterone concentration that is from 386.53 pg/mL to 547.83 pg/mL.
7 . The pharmaceutical composition of claim 6 , wherein administration of the composition to the subject produces a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL.
8 . The pharmaceutical composition of claim 6 , wherein administration of the composition to the subject produces both a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL and a steady state estrone concentration that is from 113.59 pg/mL to 132.08 pg/mL.
9 . The pharmaceutical composition of claim 6 , wherein administration of the composition to the subject produces both a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL and a steady state progesterone concentration that is from 386.53 pg/mL to 547.83 pg/mL.
10 . The pharmaceutical composition of claim 6 , wherein administration of the composition to the subject produces each of: (i) a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL; (ii) a steady state estrone concentration that is from 113.59 pg/mL to 132.08 pg/mL; and (iii) a steady state progesterone concentration that is from 386.53 pg/mL to 547.83 pg/mL.
11 . A pharmaceutical composition for co-administering estradiol and progesterone to a human subject having vasomotor symptoms associated with estrogen deficiency comprising: 0.5 mg of estradiol and 50 mg of progesterone;
wherein administration of the composition to the subject produces, in a serum sample from the subject, one or more pharmacokinetic parameters selected from:
(i) a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL;
(ii) a steady state estrone concentration that is from 113.59 pg/mL to 132.08 pg/mL; and
(iii) a steady state progesterone concentration that is from 181.41 pg/mL to 247.17 pg/mL.
12 . The pharmaceutical composition of claim 11 , wherein administration of the composition to the subject produces a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL.
13 . The pharmaceutical composition of claim 11 , wherein administration of the composition to the subject produces both a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL and a steady state estrone concentration that is from 113.59 pg/mL to 132.08 pg/mL.
14 . The pharmaceutical composition of claim 11 , wherein administration of the composition to the subject produces both a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL and a steady state progesterone concentration that is from 181.41 pg/mL to 247.17 pg/mL.
15 . The pharmaceutical composition of claim 11 , wherein administration of the composition to the subject produces each of: (i) a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL; (ii) a steady state estrone concentration that is from 113.59 pg/mL to 132.08 pg/mL; and (iii) a steady state progesterone concentration that is from 181.41 pg/mL to 247.17 pg/mL.
16 . A pharmaceutical composition for co-administering estradiol and progesterone to a human subject having vasomotor symptoms associated with estrogen deficiency comprising: 0.25 mg of estradiol and 50 mg of progesterone;
wherein administration of the composition to the subject produces, in a serum sample from the subject, one or more pharmacokinetic parameters selected from:
(i) a steady state estradiol concentration that is from 15.06 pg/mL to 18.50 pg/mL;
(ii) a steady state estrone concentration that is from 69.02 pg/mL to 73.43 pg/mL; and
(iii) a steady state progesterone concentration that is from 181.41 pg/mL to 247.17 pg/mL.
17 . The pharmaceutical composition of claim 16 , wherein administration of the composition to the subject produces a steady state estradiol concentration that is from 15.06 pg/mL to 18.50 pg/mL.
18 . The pharmaceutical composition of claim 16 , wherein administration of the composition to the subject produces both a steady state estradiol concentration that is from 15.06 pg/mL to 18.50 pg/mL and a steady state estrone concentration that is from 69.02 pg/mL to 73.43 pg/mL.
19 . The pharmaceutical composition of claim 16 , wherein administration of the composition to the subject produces both a steady state estradiol concentration that is from 15.06 pg/mL to 18.50 pg/mL and a steady state progesterone concentration that is from 181.41 pg/mL to 247.17 pg/mL.
20 . The pharmaceutical composition of claim 16 , wherein administration of the composition to the subject produces each of: (i) a steady state estradiol concentration that is from 15.06 pg/mL to 18.50 pg/mL; (ii) a steady state estrone concentration that is from 69.02 pg/mL to 73.43 pg/mL; and (iii) a steady state progesterone concentration that is from 181.41 pg/mL to 247.17 pg/mL.
21 . The pharmaceutical composition of any of claims 1 to 20 , wherein composition further comprises a solubilizing agent.
22 . The pharmaceutical composition of claim 21 , wherein the solubilizing agent comprises a medium chain (C6-C12) oil.
23 . The pharmaceutical composition of claim 22 , wherein the solubilizing agent comprises monoglycerides, diglycerides, triglycerides, or a combination thereof, wherein the monoglycerides, diglycerides, and triglycerides are predominantly of C6-C12 fatty acid chain lengths.
24 . The pharmaceutical composition of any of claims 1 to 23 , wherein the estradiol is solubilized estradiol.
25 . The pharmaceutical composition of any of claims 21 to 24 , wherein at least about 90% of the estradiol is solubilized in the solubilizing agent.
26 . The pharmaceutical composition of any of claims 1 to 25 , wherein the progesterone is suspended progesterone.
27 . The pharmaceutical composition of any of claims 21 to 26 , wherein each of the solubilized estradiol and the suspended progesterone are present in the solubilizing agent.
28 . The pharmaceutical composition of any of claims 1 - 27 , wherein the pharmacokinetic parameters are measured after at least 4 weeks of daily administration of the pharmaceutical composition to the subject.
29 . The pharmaceutical composition of any of claims 1 - 28 , wherein administration of the composition to the subject further produces in the subject a reduction in the frequency and/or severity of one or more symptoms of menopause.
30 . The pharmaceutical composition of claim 29 , wherein administration of the composition to the subject further produces in the subject a reduction in the frequency and/or severity of one or more moderate to severe vasomotor symptoms associated with menopause.
31 . The pharmaceutical composition of claim 30 , wherein the vasomotor symptoms are selected from the group consisting of hot flashes or flushes, night sweats, sweating, sleep disturbances, and combinations thereof.
32 . The pharmaceutical composition of claims 1 - 31 , wherein the pharmaceutical composition is effective at achieving a ≤1% incidence rate of endometrial hyperplasia following 12 months of therapy.
33 . A method of treating a subject having vasomotor symptoms associated with estrogen deficiency, the method comprising administering to the subject an effective amount of the pharmaceutical composition of any of claims 1 - 27 .
34 . The method of claim 33 , wherein the subject is female.
35 . The method of claim 33 or 34 , wherein the subject is a woman having a uterus.
36 . The method of any of claims 33 to 35 , wherein prior to treatment, the subject has a serum estradiol of ≤10 pg/mL.
37 . The method of any of claims 33 to 36 , wherein the method is effective at achieving a ≤1% incidence rate of endometrial hyperplasia following 12 months of therapy.