WO2018136161A1 - Natural combination hormone replacement formulations and therapies - Google Patents

Natural combination hormone replacement formulations and therapies Download PDF

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Publication number
WO2018136161A1
WO2018136161A1 PCT/US2017/064788 US2017064788W WO2018136161A1 WO 2018136161 A1 WO2018136161 A1 WO 2018136161A1 US 2017064788 W US2017064788 W US 2017064788W WO 2018136161 A1 WO2018136161 A1 WO 2018136161A1
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WIPO (PCT)
Prior art keywords
estradiol
progesterone
subject
max
auc
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PCT/US2017/064788
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English (en)
French (fr)
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WO2018136161A9 (en
Inventor
Julia M. Amadio
Brian A. Bernick
Sebastian MIRKIN
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Therapeuticsmd, Inc.
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Priority to AU2017394679A priority Critical patent/AU2017394679A1/en
Priority to RU2019115913A priority patent/RU2019115913A/ru
Priority to CN201780086119.7A priority patent/CN110290793A/zh
Priority to BR112019011655A priority patent/BR112019011655A2/pt
Priority to MX2019006513A priority patent/MX2019006513A/es
Priority to CA3045024A priority patent/CA3045024A1/en
Application filed by Therapeuticsmd, Inc. filed Critical Therapeuticsmd, Inc.
Priority to JP2019530027A priority patent/JP2020504093A/ja
Priority to KR1020197019625A priority patent/KR20200018383A/ko
Priority to EP17893482.4A priority patent/EP3548036A4/en
Publication of WO2018136161A1 publication Critical patent/WO2018136161A1/en
Priority to IL267023A priority patent/IL267023A/en
Publication of WO2018136161A9 publication Critical patent/WO2018136161A9/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • This application relates to pharmaceutical compositions and methods for hormone replacement therapy.
  • a decrease in estrogen at the time of menopause is associated with vasomotor instability (hot flushes and sweating), agitation, sleep disturbances, nervousness, mood changes, and urogenital atrophy.
  • the predominant estrogen produced by the ovaries is 17 ⁇ -estradiol, the most active of the naturally occurring human estrogens. It is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. 17 ⁇ -estradiol is used in menopausal hormone therapy.
  • estradiol may relieve or prevent many of the short-term physical and psychological consequences of estrogen deficiency. Estrogens can be considered
  • the invention provides a combination product consisting of a softgel formulation containing solubilized estradiol with micronized progesterone that can be used for the treatment of moderate to severe vasomotor symptoms associated with menopause.
  • the combination product is comprised of active ingredients that are chemically and biologically identical to endogenous estradiol and progesterone in a softgel capsule form.
  • the combination product provides a continuous combined hormone therapy regimen for menopausal women with an intact uterus who suffer from vasomotor symptoms associated with estrogen deficiency and who wish to avoid endometrial changes associated with unopposed estradiol therapy.
  • compositions for co-administering estradiol and progesterone to a subject in need of natural hormone replacement therapies are provided.
  • the pharmaceutical composition comprises: solubilized estradiol, suspended progesterone, and a solubilizing agent, wherein the solubilizing agent is a medium chain (C6- C12) oil, and wherein the pharmaceutical composition, when administered to a subject, produces in a plasma sample from the subject one or more pharmacokinetic parameters as described herein (e.g., an area under the curve (AUC) (0-t) or a C max for estradiol, progesterone, estrone, or total estrone as described herein, e.g., in Tables 18-21).
  • AUC area under the curve
  • the pharmaceutical composition comprises a solubilizing agent that comprises a glyceride of at least one C6-C12 fatty acid.
  • the glyceride ester is a mixture of mono- and diglycerides (e.g., glyceryl caprylate/caprate).
  • the fatty acid is predominantly a C8 to C10 fatty acid.
  • the pharmaceutical composition further comprises a surfactant (e.g., lauroyl polyoxyglyceride).
  • the pharmaceutical composition comprises estradiol at a dosage of about 0.05, 0.1 , 0.125, 0.15, 0.20, 0.25, 0.30, 0.35, 0.375, 0.40, 0.45, 0.50, 0.55, 0.60, 0.625, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.125, 1.25, 1.375, 1.50, 1.625, 1.75, or 2.00 mg, and comprises progesterone at a dosage of about 25, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, or 400 mg.
  • the pharmaceutical composition comprises about 0.25 mg estradiol and about 50 mg progesterone, and administration of the composition to the subject produces, in a plasma sample from the subject, one or more 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;
  • administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from: an AUC (0- t) for estrone that is from 909.6091 pg-hr/ml to 1421.2642 pg-hr/ml; and a C max for estrone that is from 42.6549 pg/ml to 66.6483 pg/ml.
  • administration of the composition to subject further produces, in a plasma sample from the subject, one or both parameters selected from: an AUC (0-t) for total estrone that is from 20.1752 ng-hr/ml to 31.5238 ng-hr/ml; and a C max for total estrone that is from 3.5429 ng/ml to 5.5358 ng/ml.
  • the pharmaceutical composition comprises about 0.25 mg estradiol and about 50 mg progesterone, and administration of the composition to a subject produces, in a plasma sample from the subject, the following parameters:
  • estrone that is from 909.6091 pg-hr/ml to 1421.2642 pg-hr/ml and (b) a C max for estrone that is from 42.6549 pg/ml to 66.6483 pg/ml; and optionally
  • a pharmaceutical composition for co-administering estradiol and progesterone to a human subject in need thereof comprises about 0.50 mg estradiol and about 50 mg progesterone, and administration of the composition to the subject produces, in a plasma sample from the subject, one or more parameters selected from: (i) an AUC (0-t) for estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml;
  • administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from: an AUC (0- t) for estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml, and a C max for estrone that is from 85.3098 pg/ml to 133.2966 pg/ml.
  • administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from: an AUC (0- t) for total estrone that is from 40.3505 ng-hr/ml to 63.0476 ng-hr/ml, and a C max for total estrone that is from 7.0858 ng/ml to 11.0715 ng/ml.
  • the pharmaceutical composition comprises about 0.50 mg estradiol and about 50 mg progesterone, and administration of the composition to a subject produces, in a plasma sample from the subject, the following parameters:
  • estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml and (b) a C max for estradiol that is from 12.9580 pg/ml to 20.2469 pg/ml;
  • a pharmaceutical composition for co-administering estradiol and progesterone to a human subject in need thereof comprises about 0.50 mg estradiol and about 100 mg progesterone, and administration of the composition to the subject produces, in a plasma sample from the subject, one or more parameters selected from:
  • administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from: an AUC (0- t) for estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml, and a C max for estrone that is from 85.3098 pg/ml to 133.2966 pg/ml.
  • administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from: an AUC (0- t) for total estrone that is from 40.3505 ng-hr/ml to 63.0476 ng-hr/ml, and a C max for total estrone that is from 7.0858 ng/ml to 11.0715 ng/ml.
  • the pharmaceutical composition comprises about 0.50 mg estradiol and about 100 mg progesterone
  • administration of the composition to a subject produces, in a plasma sample from the subject, the following parameters: (i) one or both of (a) an AUC (0-t) for estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml and (b) a C max for estradiol that is from 12.9580 pg/ml to 20.2469 pg/ml; and (ii) one or both of (a) an AUC (0-t) for progesterone that is from 48.0348 ng-hr/ml to 75.0543 ng-hr/ml and (b) a C max for progesterone that is from 35.6889 ng/ml to 55.7639 ng/ml; and optionally
  • estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml and (b) a C max for estrone that is from 85.3098 pg/ml to 133.2966 pg/ml; and optionally
  • a pharmaceutical composition for co-administering estradiol and progesterone to a human subject in need thereof comprises about 1 mg estradiol and about 100 mg progesterone, and administration of the composition to the subject produces, in a plasma sample from the subject, one or more parameters selected from:
  • administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from: an AUC (0- t) for estrone that is from 3638.4363 pg-hr/ml to 5685.0567 pg-hr/ml, and a C max for estrone that is from 170.6197 pg/ml to 266.5933 pg/ml.
  • administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from: an AUC (0- t) for total estrone that is from 80.7010 ng-hr/ml to 126.0953 ng-hr/ml, and a C max for total estrone that is from 14.1716 ng/ml to 22.1431 ng/ml.
  • the pharmaceutical composition comprises about 0.50 mg estradiol and about 100 mg progesterone, and administration of the composition to a subject produces, in a plasma sample from the subject, the following parameters:
  • the pharmaceutical composition has the blood plasma estradiol concentration profile of Figure 1. In some embodiments, the pharmaceutical composition has the blood plasma progesterone concentration profile of Figure 2. In some embodiments, the pharmaceutical composition has the blood plasma estrone concentration profile of Figure 3. In some embodiments, the pharmaceutical composition has the blood plasma total estrone concentration profile of Figure 4.
  • the one or more parameters as described herein are measured at regular intervals (e.g., about every 30 minutes, about every 60 minutes, or about every 90 minutes) or at irregular intervals over a period of time such as 24 hours or 48 hours.
  • the one or more parameters as described herein are measured at about 0.25 hr, 0.5 hr, 0.67 hr, 0.83 hr, 1 hr, 1.33 hr, 1.67 hr, 2 hr, 2.5 hr, 3 hr, 4 hr, 5 hr, 6 hr, 7 hr, 8 hr, 10 hr, 12 hr, 18 hr, 24 hr, 36 hr, or 48 hr after administering the pharmaceutical composition to the subject.
  • the one or more parameters as described herein are measured at regular or irregular intervals following the administration of a single dose or of a first dose of the pharmaceutical composition to the subject.
  • the subject has a condition that is caused at least in part by an estrogen deficiency (e.g., one or more symptoms of menopause, such as vasomotor symptoms).
  • the method comprises administering to the subject a pharmaceutical composition comprising solubilized estradiol, suspended progesterone, and a solubilizing agent that comprises a medium chain (C6-C12) oil as described herein, wherein administration of the pharmaceutical
  • the method comprises administering a pharmaceutical composition comprising estradiol at a dosage of about 0.05, 0.1 , 0.125, 0.15, 0.20, 0.25, 0.30, 0.35, 0.375, 0.40, 0.45, 0.50, 0.55, 0.60, 0.625, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.125, 1.25, 1.375, 1.50, 1.625, 1.75, or 2.00 mg, and comprising progesterone at a dosage of about 25, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, or 400 mg.
  • the method comprises administering a pharmaceutical composition comprising: estradiol at a dosage of about 0.25 mg and progesterone at a dosage of about 50 mg; estradiol at a dosage of about 0.50 mg and progesterone at a dosage of about 50 mg; estradiol at a dosage of about 0.50 mg and progesterone at a dosage of about 100 mg; estradiol at a dosage of about 1 mg and progesterone at a dosage of about 100 mg; or estradiol at a dosage of about 2 mg and progesterone at a dosage of about 200 mg.
  • the method comprises administering to the subject a
  • composition comprising about 0.25 mg estradiol and about 50 mg progesterone, wherein administration of the pharmaceutical composition produces, in a plasma sample from the subject, one or more parameters selected from:
  • administration of the pharmaceutical composition further produces, in a plasma sample from the subject, one or more parameters selected from: an AUC (0- t) for estrone that is from 909.6091 pg-hr/ml to 1421.2642 pg-hr/ml; a C max for estrone that is from 42.6549 pg/ml to 66.6483 pg/ml; an AUC (0-t) for total estrone that is from 20.1752 ng-hr/ml to 3 1 .5238 ng-hr/ml; and a C max for total estrone that is from 3.5429 ng/ml to 5.5358 ng/ml.
  • an AUC (0- t) for estrone that is from 909.6091 pg-hr/ml to 1421.2642 pg-hr/ml
  • a C max for estrone that is from 42.6549 pg/ml to 66.6483 pg/
  • the method comprises administering to the subject a
  • composition comprising about 0.25 mg estradiol and about 50 mg progesterone, wherein administration of the pharmaceutical composition produces, in a plasma sample from the subject, the following parameters:
  • estrone that is from 909.6091 pg-hr/ml to 1421 .2642 pg-hr/ml and (b) a C max for estrone that is from 42.6549 pg/ml to 66.6483 pg/ml; and optionally
  • the method comprises administering to the subject a
  • composition comprising about 0.50 mg estradiol and about 50 mg progesterone, wherein administration of the pharmaceutical composition produces, in a plasma sample from the subject, one or more parameters selected from:
  • administration of the composition to the subject further produces, in a plasma sample from the subject, one or more parameters selected from: an AUC (0- t) for estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml; a C max for estrone that is from 85.3098 pg/ml to 133.2966 pg/ml; an AUC ( o -t) for total estrone that is from 40.3505 ng-hr/ml to 63.0476 ng-hr/ml; and a C max for total estrone that is from 7.0858 ng/ml to 11.0715 ng/ml.
  • the method comprises administering to the subject a
  • composition comprising about 0.50 mg estradiol and about 50 mg progesterone, wherein administration of the pharmaceutical composition produces, in a plasma sample from the subject, the following parameters:
  • the method comprises administering to the subject a
  • composition comprising about 0.50 mg estradiol and about 100 mg progesterone, wherein administration of the pharmaceutical composition produces, in a plasma sample from the subject, one or more parameters selected from: (i) an area under the curve (AUC)(o-t) for estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml;
  • administration of the composition to the subject further produces, in a plasma sample from the subject, one or more parameters selected from: an AUC (0- t) for estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml; a C max for estrone that is from 85.3098 pg/ml to 133.2966 pg/ml; an AUC (0-t) for total estrone that is from 40.3505 ng-hr/ml to 63.0476 ng-hr/ml, and a C max for total estrone that is from 7.0858 ng/ml to 11.0715 ng/ml.
  • the method comprises administering to the subject a
  • composition comprising about 0.50 mg estradiol and about 100 mg progesterone, wherein administration of the pharmaceutical composition produces, in a plasma sample from the subject, the following parameters:
  • estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml and (b) a C max for estrone that is from 85.3098 pg/ml to 133.2966 pg/ml; and optionally
  • the method comprises administering to the subject a
  • composition comprising about 1 mg estradiol and about 100 mg progesterone, wherein administration of the pharmaceutical composition produces, in a plasma sample from the subject, one or more parameters selected from:
  • administration of the composition to the subject further produces, in a plasma sample from the subject, one or more parameters selected from: an AUC (0- t) for estrone that is from 3638.4363 pg-hr/ml to 5685.0567 pg-hr/ml; a C max for estrone that is from 170.6197 pg/ml to 266.5933 pg/ml; an AUC (0-t) for total estrone that is from 80.7010 ng-hr/ml to 126.0953 ng-hr/ml; and a C max for total estrone that is from 14.1716 ng/ml to 22.1431 ng/ml.
  • the method comprises administering to the subject a
  • composition comprising about 1 mg estradiol and about 100 mg progesterone, wherein administration of the pharmaceutical composition produces, in a plasma sample from the subject, the following parameters:
  • compositions for use in a method of treating a disease or condition that is caused at least in part by an estrogen deficiency comprise solubilized estradiol, suspended progesterone, and a solubilizing agent that comprises a medium chain (C6-C 12) oil, wherein the treatment produces, in a plasma sample from the subject, one or more pharmacokinetic parameters as described herein (e.g., an AUC (0-t) or C max for estradiol, progesterone, estrone, or total estrone as described herein, e.g., as described in any of Tables 18-21 ).
  • pharmacokinetic parameters as described herein (e.g., an AUC (0-t) or C max for estradiol, progesterone, estrone, or total estrone as described herein, e.g., as described in any of Tables 18-21 ).
  • the pharmaceutical compositions for use in a method of treating a disease or condition that is caused at least in part by an estrogen deficiency comprise estradiol at a dosage of about 0.05, 0.1 , 0.125, 0.15, 0.20, 0.25, 0.30, 0.35, 0.375, 0.40, 0.45, 0.50, 0.55, 0.60, 0.625, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1 .00, 1.125, 1 .25, 1 .375, 1.50, 1 .625, 1 .75, or 2.00 mg, and comprise progesterone at a dosage of about 25, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, or 400 mg.
  • a pharmaceutical composition for use in a method of treating a disease or condition that is caused at least in part by an estrogen deficiency comprises estradiol at a dosage of about 0.25 mg and progesterone at a dosage of about 50 mg, and produces one or more pharmacokinetic values disclosed in Table 18 following administration of a single dose of the pharmaceutical composition to a subject (e.g., about 24 hours or about 48 hours after administration).
  • a pharmaceutical composition for use in a method of treating a disease or condition that is caused at least in part by an estrogen deficiency comprises estradiol at a dosage of about 0.50 mg and progesterone at a dosage of about 50 mg, and produces one or more pharmacokinetic values disclosed in Table 19 following administration of a single dose of the pharmaceutical composition to a subject (e.g., about 24 hours or about 48 hours after administration).
  • a pharmaceutical composition for use in a method of treating a disease or condition that is caused at least in part by an estrogen deficiency comprises estradiol at a dosage of about 0.50 mg and progesterone at a dosage of about 100 mg, and produces one or more pharmacokinetic values disclosed in Table 20 following administration of a single dose of the pharmaceutical composition to a subject (e.g., about 24 hours or about 48 hours after administration).
  • a pharmaceutical composition for use in a method of treating a disease or condition that is caused at least in part by an estrogen deficiency comprises estradiol at a dosage of about 1 mg and progesterone at a dosage of about 100 mg, and produces one or more pharmacokinetic values disclosed in Table 21 following administration of a single dose of the pharmaceutical composition to a subject (e.g., about 24 hours or about 48 hours after administration).
  • FIG. 1 illustrates a semilogarithmic plot of mean plasma concentration (pg/ml) over time (hrs) for estradiol.
  • FIG. 2 illustrates a semilogarithmic plot of mean plasma concentration (ng/ml) over time (hrs) for progesterone.
  • FIG. 3 illustrates a semilogarithmic plot of mean plasma concentration (pg/ml) over time (hrs) for estrone.
  • FIG. 4 illustrates a semilogarithmic plot of mean plasma concentration (ng/ml) over time (hrs) for total estrone.
  • FIG. 5 illustrates mean change from baseline in weekly frequency of moderate to severse hot flashes for weeks 1 to 12.
  • FIG. 6 illustrates mean change from baseline in weekly severity of moderate to severse hot flashes for weeks 1 to 12.
  • FIG. 7 illustrates mean reduction in number of weekly moderate and severe VMS from week 1 through week 12 (MITT- VMS Population).
  • FIG. 8 illustrates mean reduction in severity of weekly moderate and severe VMS from week 1 through week 12 (MITT-VMS Population).
  • FIG. 9 illustrates mean reduction in number of weekly mild, moderate and severe VMS from week 1 through week 12 (MITT- VMS Population).
  • FIG. 10 illustrates mean reduction in severity of weekly mild, moderate, and severe VMS from week 1 through week 12 (MITT-VMS Population).
  • FIG. 11 illustrates percentage of subjects with ⁇ 75% decrease in the mean number of moderate and severe vasomotor symptoms (MITT- VMS Population).
  • FIG. 12 illustrates the study design.
  • FIG. 13 illustrates Mean ( ⁇ SD) Baseline- Adjusted Plasma Estradiol Concentration (pg/mL) versus Nominal Time (Linear Scale) - Sensitivity Analysis (PK Population).
  • FIG. 14 illustrates Mean Baseline- Adjusted Plasma Estradiol Concentration (pg/mL) versus Nominal Time (Semi-log Scale) - Sensitivity Analysis (PK Population).
  • FIG. 15 illustrates Mean ( ⁇ SD) Unadjusted Plasma Estradiol Concentration (pg/mL) versus Nominal Time (Linear Scale) - Sensitivity Analysis (PK Population).
  • FIG. 16 illustrates Mean Unadjusted Plasma Estradiol Concentration (pg/mL) versus Nominal Time (Semi-log Scale) - Sensitivity Analysis (PK Population).
  • FIG. 17 illustrates Mean ( ⁇ SD) Baseline-Adjusted Plasma Estrone Concentration (pg/mL) versus Nominal Time (Linear Scale) - Sensitivity Analysis (PK Population).
  • FIG. 18 illustrates Mean Baseline- Adjusted Plasma Estrone Concentration (pg/mL) versus Nominal Time (Semi-log Scale) - Sensitivity Analysis (PK Population).
  • FIG. 19 illustrates Mean ( ⁇ SD) Unadjusted Plasma Estrone Concentration (pg/mL) versus Nominal Time (Linear Scale) - Sensitivity Analysis (PK Population).
  • FIG. 20 illustrates Mean Unadjusted Plasma Estrone Concentration (pg/mL) versus Nominal Time (Semi-log Scale) - Sensitivity Analysis (PK Population).
  • FIG. 21 illustrates Mean ( ⁇ SD) Baseline- Adjusted Plasma Progesterone Concentration (ng/mL) versus Nominal Time (Linear Scale) - Sensitivity Analysis (PK Population).
  • FIG. 22 illustrates Mean Baseline- Adjusted Plasma Progesterone Concentration (ng/mL) versus Nominal Time (Semi-log Scale) - Sensitivity Analysis (PK Population).
  • FIG. 23 illustrates Mean ( ⁇ SD) Unadjusted Plasma Progesterone Concentration (ng/mL) versus Nominal Time (Linear Scale) - Sensitivity Analysis (PK Population).
  • FIG. 24 illustrates Mean Unadjusted Plasma Progesterone Concentration (ng/mL) versus Nominal Time (Semi-log Scale) - Sensitivity Analysis (PK Population).
  • AUC area under the curve
  • AUCo- ⁇ is the area under the concentration-time curve extrapolated to infinity following the administration of a dose.
  • AUCo- t is the area under the concentration-time curve from time zero to time t following the administration of a dose, wherein t is the last time point with a measurable concentration.
  • C max refers to the maximum value of blood concentration shown on the curve that represents changes in blood concentrations of an active pharmaceutical ingredient (e.g., progesterone or estradiol), or a metabolite of the active pharmaceutical ingredient, over time.
  • an active pharmaceutical ingredient e.g., progesterone or estradiol
  • t max refers to the earliest time at which the blood concentration of an active pharmaceutical ingredient (e.g., estradiol or progesterone), or a metabolite of the active pharmaceutical ingredient is at its maximum value.
  • AUC, C max , and, optionally, T max are the principal pharmacokinetic parameters that can characterize the pharmacokinetic response of a particular drug product, such as progesterone or estradiol, in an animal, especially a mammal, including human, subject.
  • bioavailability refers to the rate and extent to which an active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.
  • bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.
  • bioavailability can be measured as the amount of active ingredient in the blood (serum or plasma) as a function of time.
  • Pharmacokinetic (PK) parameters such as AUC, C max , or t max may be used to measure and assess bioavailability.
  • bioequivalent has the meaning defined in 21 C.F.R. ⁇ 320.1 (e) and refers to the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. Where there is an intentional difference in rate (e.g., in certain extended release dosage forms), certain pharmaceutical equivalents or alternatives may be considered bioequivalent if there is no significant difference in the extent to which the active ingredient or moiety from each product becomes available at the site of drug action.
  • bio-identical hormone and "body-identical” refer to an active
  • estradiol or progesterone a pharmaceutical ingredient that is structurally identical to a hormone naturally or endogenously found in the human body (e.g., estradiol or progesterone).
  • an "active pharmaceutical ingredient” means the active compound or compounds used in formulating a drug product, such as 17 ⁇ -estradiol and progesterone. APIs are generally safe for administering to animals, especially mammals, including humans, according to established governmental standards, including those
  • estradiol refers to (17 ⁇ )-estra-l ,3,5( 10)-triene-3,17-diol. Estradiol is also interchangeably called 17 ⁇ -estradiol, oestradiol, or E2, and is found endogenously in the human body. As used herein, estradiol refers to the bio-identical or body-identical form of estradiol found in the human body having the structure:
  • Estradiol is supplied in an anhydrous or hemi-hydrate form.
  • the anhydrous form or the hemihydrate form can be substituted for the other by accounting for the water or lack of water according to well-known and understood techniques.
  • the term "solubilized estradiol" means that the estradiol or a portion thereof is solubilized or dissolved in the solubilizing agent(s) or the formulations disclosed herein.
  • Solubilized estradiol may include estradiol that is about 80% solubilized, about 85% solubilized, about 90% solubilized, about 95% solubilized, about 96%> solubilized, about 97% solubilized, about 98% solubilized, about 99% solubilized or about 100% solubilized.
  • the estradiol is "fully solubilized” with all or substantially all of the estradiol being solubilized or dissolved in the solubilizing agent.
  • Fully solubilized estradiol may include estradiol that is about 97%o solubilized, about 98%> solubilized, about 99%o solubilized or about 100% solubilized.
  • Solubility can be expressed as a mass fraction (% w/w, which is also referred to as weight percent (wt %)).
  • Estrogen refers to a group of several female sex hormones produced primarily by the ovaries, including estradiol, estrone, and estriol. As used herein, unless otherwise specified, estrogen refers to estradiol.
  • progesterone refers to pregn-4-ene-3,20-dione. Progesterone is also interchangeably called P4 and is found endogenously in the human body. As used herein, progesterone refers to the bioidentical or body-identical form of progesterone found in the human body having the structure:
  • progesterone means that the progesterone or a portion thereof is solubilized or dissolved in the solubilizing agents or the formulations disclosed herein disclosed herein.
  • the progesterone is "partially solubilized” with a portion of the progesterone being solubilized or dissolved in the solubilizing agent and a portion of the progesterone being suspended in the solubilizing agent.
  • Partially solubilized progesterone may include progesterone that is about 1% solubilized, about 5% solubilized, about 10% solubilized, about 15% solubilized, about 20%> solubilized, about 30% solubilized, about 40% solubilized, about 50% solubilized, about 60% solubilized, about 70% solubilized, about 80% solubilized, about 85% solubilized, about 90% solubilized or about 95% solubilized.
  • the progesterone is "fully solubilized" with all or substantially all of the progesterone being solubilized or dissolved in the solubilizing agent.
  • Fully solubilized progesterone may include progesterone that is about 97% solubilized, about 98% solubilized, about 99% solubilized or about 100% solubilized. Solubility can be expressed as a mass fraction (% w/w, which is also referred to as wt %).
  • micronized progesterone and micronized estradiol include micronized progesterone and micronized estradiol having an X50 particle size value below about 15 microns or having an X90 particle size value below about 25 microns.
  • X50 means that one-half of the particles in a sample are smaller in diameter than a given number.
  • micronized progesterone having an X50 of 5 microns means that, for a given sample of micronized progesterone, one-half of the particles have a diameter of less than 5 microns.
  • X90 means that ninety percent (90%) of the particles in a sample are smaller in diameter than a given number.
  • solubility of a given steroid hormone can be measured using standard techniques by weighing a piece of filter paper, placing the weighed filter paper in a buchner funnel
  • glyceride refers to an ester of glycerol (1 ,2,3-propanetriol) with acyl radicals of fatty acids and is also known as an acylglycerol.
  • a "monoglyceride” or “monoacylglycerol” is produced; if two positions are esterified, a “diglyceride” or “diacylglycerol” is produced; and if all three positions of the glycerol are esterified with fatty acids, a "triglyceride” or “triacylglycerol” is produced.
  • a glyceride is “simple” if all esterified positions contain the same fatty acid; whereas a glyceride is "mixed” if the esterified positions are substituted with different fatty acids.
  • a glyceride is "complex" if it contains a combination of simple and mixed glycerides.
  • the carbons of the glycerol backbone are designated sn-1 , sn-2 and sn-3, with sn-2 being the middle carbon and sn-1 and sn-3 being the end carbons of the glycerol backbone.
  • hormone deficiency refers to a low level of one or more steroid hormones in a subject. Normal hormone levels will vary from subject to subject and can be determined via known methods. Low hormone levels may or may not be associated with symptoms including, but not limited to, fatigue, irregular bleeding, lowered libido, and depression. Conditions that can be treated with estrogen and progesterone therapy to address estrogen and progesterone deficiencies include menopause-related symptoms including vasomotor symptoms (e.g., hot flashes and night sweats).
  • hypoestrogenism related conditions and symptoms can also be treated with estrogen and progesterone therapy, including, for example and without limitation, vasomotor symptoms, sleep disturbances, mood changes, and vulvo-vaginal atrophy; and osteoporosis and other non-menopausal disease states or conditions that can be treated with supplemental estradiol and progesterone.
  • the terms "host,” “subject,” and “patient” refer to any animal, including humans, especially female animals, including female humans.
  • solubilizing agent refers to an agent or combination of agents that solubilize an active pharmaceutical ingredient (e.g., estradiol or progesterone).
  • suitable solubilizing agents include medium chain oils and other solvents and co- solvents that solubilize or dissolve an active pharmaceutical ingredient to a desirable extent.
  • Solubilizing agents suitable for use in the pharmaceutical compositions disclosed herein are pharmaceutical grade solubilizing agents (e.g. , pharmaceutical grade medium chain oils). It will be understood by those of skill in the art that other excipients or components can be added to or mixed with the solubilizing agent to enhance the properties or performance of the solubilizing agent or resulting pharmaceutical composition.
  • excipients examples include, but are not limited to, surfactants, emulsifiers, thickeners, colorants, flavoring agents, terpenes, etc.
  • the solubilizing agent is a medium chain oil and, in some other embodiments, the medium chain oil is combined with a co-solvent(s) or other excipient(s).
  • the term “medium chain” is used to describe the aliphatic chain length of fatty acid containing molecules. “Medium chain” specifically refers to fatty acids, fatty acid esters, or fatty acid derivatives that contain fatty acid aliphatic tails or carbon chains that contain, for example, 6 to 14 carbon atoms, 8 to 12 carbon atoms, or 8 to 10 carbon atoms. [0097] The terms “medium chain fatty acid” and “medium chain fatty acid derivative” are used to describe fatty acids or fatty acid derivatives with aliphatic tails (/ ' . e. , carbon chains) having 6 to 14 carbon atoms.
  • Fatty acids consist of an unbranched or branched aliphatic tail attached to a carboxylic acid functional group.
  • Fatty acid derivatives include, for example, fatty acid esters and fatty acid containing molecules, including, without limitation, mono-, di- and triglycerides that include components derived from fatty acids.
  • Fatty acid derivatives also include fatty acid esters of ethylene or propylene glycol.
  • the aliphatic tails can be saturated or unsaturated (i.e., the latter having one or more double bonds between carbon atoms). In some embodiments, the aliphatic tails are saturated (i.e. , no double bonds between carbon atoms).
  • Medium chain fatty acids or medium chain fatty acid derivatives include those with aliphatic tails having 6-14 carbons, including those that are C6-C 14, C6-C 12, C8-C 14, C8-C 12, C6-C 10, C8-C 10, or others.
  • Examples of medium chain fatty acids include, without limitation, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, and derivatives thereof.
  • the medium chain fatty acids used to prepare the various medium chain oils described herein are C8, C 10, or a combination thereof.
  • oil refers to any pharmaceutically acceptable oil, especially medium chain oils, and specifically excluding peanut oil, that can suspend or solubilize bioidentical progesterone or estradiol, including starting materials or precursors thereof, including micronized progesterone and/or micronized estradiol as described herein.
  • medium chain oil refers to an oil wherein the composition of the fatty acid fraction of the oil is substantially medium chain (i.e. , C6 to C14) fatty acids, i.e. , the composition profile of fatty acids in the oil is substantially medium chain.
  • substantially means that between 20% and 100% (inclusive of the upper and lower limits) of the fatty acid fraction of the oil is made up of medium chain fatty acids, i.e. , fatty acids with aliphatic tails (i.e., carbon chains) having 6 to 14 carbons.
  • about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 85%), about 90% or about 95% of the fatty acid fraction of the oil is made up of medium chain fatty acids.
  • alkyl content or “alkyl distribution" of an oil can be used in place of the term "fatty acid fraction" of an oil in characterizing a given oil or solubilizing agent, and these terms are used
  • medium chain oils suitable for use in the pharmaceutical compositions disclosed herein include medium chain oils wherein the fatty acid fraction of the oil is substantially medium chain fatty acids, or medium chain oils wherein the alkyl content or alkyl distribution of the oil is substantially medium chain alkyls, e.g., C6-C14 alkyls, but also including, for example, C6-C12 alkyls, C8-C12 alkyls, and C8-C10 alkyls.
  • the medium chain oils suitable for use in the pharmaceutical compositions disclosed herein are pharmaceutical grade (e.g. , pharmaceutical grade medium chain oils).
  • medium chain oils include, for example and without limitation, medium chain fatty acids, medium chain fatty acid esters of glycerol (e.g. , for example, mono-, di-, and triglycerides), medium chain fatty acid esters of propylene glycol, medium chain fatty acid derivatives of polyethylene glycol, and combinations thereof.
  • medium chain fatty acids include, for example and without limitation, medium chain fatty acids, medium chain fatty acid esters of glycerol (e.g. , for example, mono-, di-, and triglycerides), medium chain fatty acid esters of propylene glycol, medium chain fatty acid derivatives of polyethylene glycol, and combinations thereof.
  • medium chain fatty acids include, for example and without limitation, medium chain fatty acids, medium chain fatty acid esters of glycerol (e.g. , for example, mono-, di-, and triglycerides), medium chain fatty acid esters of propylene glycol, medium chain fatty acid derivatives of
  • ECN equivalent carbon number
  • ECN or "equivalent carbon number” means the sum of the number of carbon atoms in the fatty acid chains of an oil, and can be used to characterize an oil as, for example, a medium chain oil or a long-chain oil.
  • tripalmitin tripalmitic glycerol
  • Naturally occurring oils are frequently "mixed" with respect to specific fatty acids, but tend not to contain both long chain fatty acids and medium chain fatty acids in the same glycerol backbone.
  • triglycerides with ECN's of 21 -42 typically contain predominately medium chain fatty acids; while triglycerides with ECN's of greater than 43 typically contain predominantly long chain fatty acids.
  • the ECN of corn oil triglyceride in the USP would be in the range of 51-54.
  • Medium chain diglycerides with ECN's of 12-28 will often contain predominately medium chain fatty chains, while diglycerides with ECN's of 32 or greater will typically contain predominately long chain fatty acid tails.
  • Monoglycerides will have an ECN that matches the chain length of the sole fatty acid chain.
  • ECN's in the range of 6-14 contain mainly medium chain fatty acids, and monoglycerides with ECN's 16 or greater will contain mainly long chain fatty acids.
  • the average ECN of a medium chain triglyceride oil is typically 21-42.
  • medium chain triglycerides have the following composition as the exemplary oil set forth in the table below:
  • ECN of the exemplary medium chain triglycerides oil can also be expressed as a range (per the ranges set forth in the USP) of 24.9 - 27.0.
  • the ECN of the entire oil can be determined by calculating the ECN of each individual component (e.g., C8 monoglycerides, C8 diglycerides, C10 monoglycerides, and C10 diglycerides) and taking the sum of the relative percentage of the component multiplied by the ECN normalized to a monoglyceride for each component.
  • each individual component e.g., C8 monoglycerides, C8 diglycerides, C10 monoglycerides, and C10 diglycerides
  • an oil having C8 and C10 mono- and diglycerides shown in the table below has an ECN of 8.3, and is thus a medium chain oil.
  • excipients refers to non-API ingredients such as solubilizing agents, anti-oxidants, oils, lubricants, dissolution aids, terpenes, and others used in formulating pharmaceutical products.
  • treat refers to any indicia of success in the treatment or amelioration of an injury, disease, or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, disease, or condition more tolerable to the patient; slowing in the rate of degeneration or decline; or improving a patient's physical or mental well-being.
  • the treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examinations, or psychiatric evaluation.
  • the term "prevent” refers to the prophylactic treatment of a subject who is at risk of developing a condition (e.g., steroid hormone deficiency) resulting in a decrease in the probability that the subject will develop the condition.
  • a condition e.g., steroid hormone deficiency
  • terapéuticaally effective amount refers to an amount of a pharmaceutical composition or of a given steroid hormone suitable to treat a particular symptom, disorder, or disease.
  • substantially pure means that an identified component is at least about 90% pure by weight, in certain embodiments, at least about 95% pure by weight, and in still further embodiments, at least about 98% pure by weight.
  • steroid hormone refers to progesterone, 17- hydroxyprogesterone, 5 ⁇ -dihydroprogesterone, and estradiol.
  • reference product refers to PROMETRIUM for progesterone and ESTRACE tablets for estradiol, unless otherwise specified.
  • excipients refers to non-active pharmaceutical ingredients such as solubilizing agents, anti-oxidants, oils, lubricants, and others used in formulating pharmaceutical products.
  • treat refers to any indicia of success in the treatment or amelioration of an injury, disease, or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, disease, or condition more tolerable to the patient; slowing in the rate of degeneration or decline; or improving a patient's physical or mental well-being.
  • the treatment or amelioration of symptoms can be based on objective or subject parameters, including the results of a physical examination, neuropsychiatric examinations, or psychiatric evaluation.
  • this disclosure relates to pharmaceutical compositions for co- administering estradiol and progesterone to a human subject in need thereof.
  • the composition comprises estradiol, progesterone, and a solubilizing agent (e.g., a medium chain oil, e.g., a C6-C 12 oil).
  • a pharmaceutical composition comprising estradiol, progesterone, and a solubilizing agent as described herein, when
  • AUC AUC
  • C max T max parameters for estradiol, progesterone, estrone, or total estrone as described below.
  • a pharmaceutical composition for use as described herein comprises solubilized estradiol with suspended progesterone; solubilized estradiol with both partially solubilized progesterone and partially suspended progesterone; or solubilized estradiol with fully solubilized progesterone.
  • the composition comprises solubilized estradiol and suspended progesterone.
  • the underlying formulation concepts provided herein may be used with other natural or synthetic forms of estradiol and progesterone, although the natural or bio-identical forms of estradiol and progesterone are preferred.
  • the composition comprises estradiol at a dosage of about 0.05, 0.1, 0.125, 0.15, 0.20, 0.25, 0.30, 0.35, 0.375, 0.40, 0.45, 0.50, 0.55, 0.60, 0.625, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.125, 1.25, 1.375, 1.50, 1.625, 1.75, or 2.00 mg.
  • the composition comprises progesterone at a dosage of about 25, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, or 400 mg.
  • estradiol is solubilized. Solubilized estradiol may include estradiol that is approximately 80% to 100% soluble in a solubilizing agent, including
  • estradiol is micronized or partially micronized. In some embodiments, micronized estradiol has an X50 particle size value of less than about 15 microns, less than about 10 microns, less than about 5 microns or less than about 3 microns.
  • micronized estradiol has an X90 particle size value of less than about 25 microns, less than about 20 microns, or less than about 15 microns.
  • the composition comprises micronized and partially solubilized estradiol.
  • the composition comprises micronized progesterone.
  • the progesterone (or other active pharmaceutical ingredient, such as estradiol) may be micronized via any one of the multiple methods typically utilized by the ordinarily skilled artisan.
  • micronized progesterone has an X50 particle size value of less than about 15 microns, less than about 10 microns, less than about 5 microns or less than about 3 microns.
  • micronized progesterone has an X90 particle size value of less than about 25 microns, less than about 20 microns, or less than about 15 microns. Particle size may be determined in any suitable manner. For example, a Beckman Coulter LS 13 320 Laser
  • estradiol and progesterone compositions and methods of preparing such compositions are described in U.S. Patent No. 8,633,178; U.S. Publication No. 2013/0129818; U.S.
  • Estradiol and progesterone compositions of the present disclosure are prepared via blending with a solubilizing agent.
  • the solubilizing agent is a
  • the solubilizing agent is a medium chain oil comprised substantially of C6-C12 medium chains, e.g., at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the chains present in the oil are C6-C12.
  • the oil comprises at least one medium chain fatty acid such as medium chain fatty acids having at least one mono-, di-, or triglyceride, or derivatives thereof, or combinations thereof.
  • the medium chain oil comprises at least one medium chain fatty acid or propylene glycol, polyethylene glycol, or glyceride having esters of medium chain fatty acids.
  • the solubilizing agent is not peanut oil.
  • oils used to solubilize estradiol and to suspend, partially suspend and partially solubilize, or fully solubilize progesterone include medium chain fatty acid esters, (e.g., esters of glycerol, polyethylene glycol, or propylene glycol) and mixtures thereof.
  • the medium chain fatty acids are C6, C8, C10, C12, C6-C12, C8-C12, C6-C10, C8-C10, or C10-C12 fatty acids.
  • the medium chain fatty acids are saturated, or predominantly saturated, e.g., greater than about 50% saturated, greater than about 60% saturated, or greater than about 75% saturated.
  • a solubilizing agent comprises predominantly medium chain length, saturated fatty acids or derivatives thereof, specifically predominantly C8 to C12 saturated fatty acids or derivatives thereof.
  • medium chain solubilizing agents include, for example and without limitation, saturated medium chain fatty acids or derivatives of saturated medium chain fatty acids: caproic acid (C6), enanthic acid (C7), caprylic acid (C8), pelargonic acid (C9), capric acid (C10), undecylic acid (C11), lauric acid (C12), tridecylic acid (C13), or myristic acid (C14).
  • the solubilizing agent comprises oils made of these free medium chain fatty acids, oils of medium chain fatty acid esters of glycerin, propylene glycol, or ethylene glycol, or combinations thereof. These examples comprise predominantly saturated medium chain fatty acids (i. e., greater than 50% of the fatty acids are medium chain saturated fatty acids).
  • the solubilizing agent comprises predominantly C6 to C12 saturated fatty acids or derivatives of fatty acids.
  • the solubilizing agent comprises one or more mono-, di-, or triglycerides or combinations thereof.
  • exemplary glycerin based solubilizing agents include MIGLYOLs®, which are caprylic/capric triglycerides (SASOL Germany GMBH, Hamburg).
  • MIGLYOLs® includes MIGLYOL® 810 (caprylic/capric triglyceride), MIGLYOL® 812
  • caprylic/capric triglyceride MIGLYOL® 816 (caprylic/capric triglyceride), and MIGLYOL® 829 (caprylic/capric/succinic triglyceride).
  • Other caprylic/capric triglyceride solubilizing agents are likewise contemplated, including, for example: caproic/caprylic/capric/lauric triglycerides; caprylic/capric/linoleic triglycerides; or caprylic/capric/succinic triglycerides.
  • caprylic/capric mono-, di-, or triiglyceride solubilizing agents include CAPMULs® (ABITEC, Columbus, Ohio), including, but are not limited to, CAPMUL® MCM, CAPMUL® MCM C10, CAPMUL® MCM C8, CAPMUL® MCM C8 EP, and CAPMUL® 708 G .
  • CAPMULs® (ABITEC, Columbus, Ohio)
  • mono-, di-, and triglycerides of fractionated vegetable fatty acids, and combinations or derivatives thereof can be the solubilizing agent, according to embodiments.
  • the solubilizing agent can be 1 ,2,3-propanetriol (glycerol, glycerin, glycerine) esters of saturated coconut and palm kernel oil and derivatives thereof.
  • the solubilizing agent comprises one or more esters of propylene glycol, polyethylene glycol, or combinations thereof.
  • Exemplary propylene and polyethylene glycol based solubilizing agents include glyceryl mono- and di-caprylates; propylene glycol monocaprylate (e.g., CAPMUL® PG-8 or CAPMUL® PG-8 NF); propylene glycol monocaprate (e.g., CAPMUL® PG-10); propylene glycol monolaurate (e.g., CAPMUL® PG-12 EP/NF); propylene glycol mono- and dicaprylates; propylene glycol mono- and dicaprate; propylene glycol dicaprylate/dicaprate (e.g., MIGLYOL® 840); propylene glycol dilaurate (e.g., MIGLYOL® 840); propylene glycol dilaurate (e.g., MIGLYOL® 840); propylene glycol dilaurate (
  • CAPMUL® PG-2L EP/NF diethylene glycol mono ester
  • diethylene glycol mono ester e.g., TRANSCUTOL®,2-(2- Ethoxyethoxy)ethanol, GATTEFOSSE SAS, Saint-Priest, France
  • diethylene glycol monoethyl ether e.g., TRANSCUTOL®,2-(2- Ethoxyethoxy)ethanol, GATTEFOSSE SAS, Saint-Priest, France
  • commercially available fatty acid glycerol and glycol ester solubilizing agents are prepared from natural oils and therefore may comprise components in addition to the fatty acid esters that predominantly comprise and characterize the solubilizing agent.
  • Such other components may be, e.g., other fatty acid mono-, di-, and triglycerides, fatty acid mono- and diester ethylene or propylene glycols, free glycerols or glycols, or free fatty acids.
  • CAPMUL® MCM C8 describes CAPMUL® MCM C8 as being composed of mono- and diglycerides of medium chain fatty acids (mainly caprylic) and describes the alkyl content as ⁇ 1% C6, 95% ⁇ C8, ⁇ 5% C10, and ⁇ 1.5% C12 and higher.
  • MIGLYOL® 812 is generally described as a C8-C10 triglyceride because the fatty acid composition is at least about 80%> caprylic (C8) acid and capric (C10) acid.
  • transdermal pharmaceutical compositions contain from about 10% (w/w) to about 30% (w/w).
  • compositions can contain, for example, from about 14% (w/w) to about 26%> (w/w) medium-chain oil, or from about 18% (w/w) to about 22%o (w/w) medium- chain oil, or from about 10%> (w/w) to about 25% (w/w) medium-chain oil, or from about 10%> (w/w) to about 20% (w/w) medium-chain oil, or from about 10%) (w/w) to about 15% (w/w) medium-chain oil, or from about 15% (w/w) to about 20%) (w/w) medium-chain oil, or from about 20%o (w/w) to about 25% (w/w) medium-chain oil, or from about 25%o (w/w) to about 30%> (w/w) medium-chain oil.
  • compositions can contain about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29 or 30% (w/w) medium-chain oil.
  • the transdermal pharmaceutical composition includes a medium-chain oil in an amount ranging from about 10% > (w/w) to about 30%> (w/w). In some embodiments, the transdermal
  • composition includes a medium-chain oil in an amount ranging from about 15%> (w/w) to about 25% (w/w).
  • the pharmaceutical composition further comprises one or more non-ionic or ionic surfactants.
  • the non-ionic surfactant is selected from one or more of glycerol and polyethylene glycol esters of medium chain fatty acids or long chain fatty acids, for example, lauroyl macrogol-32 glycerides or lauroyl polyoxyl-32 glycerides, commercially available as GELUCIRE®, including, for example, GELUCIRE® 39/01 (glycerol esters of saturated C12-C18 fatty acids); GELUCIRE® 43/01 (hard fat NF/JPE); GELUCIRE® 44/14 (lauroyl macrogol-32 glycerides EP, lauroyl polyoxyl-32 glycerides NF, lauroyl polyoxylglycerides (USA FDA IIG)); and GELUCIRE® 50/13 (stearoyl macrogol-32 glycerides EP, stearoyl polyoxy
  • non-ionic surfactants comprise combinations of mono- and di- propylene and ethylene glycols and mono-, di-, and triglyceride combinations.
  • polyethylene glycol glyceride GELUCIRE®, GATTEFOSSE SAS, Saint- Priest, France
  • GELUCIRE® 44/14 PEG-32 glyceryl laurate EP
  • GELUCIRE® 44/14 PEG-32 glyceryl laurate EP
  • a medium chain fatty acid esters of polyethylene glycol is a polyethylene glycol glyceride composed of mono-, di- and triglycerides and mono- and diesters of
  • non-ionic surfactants include, for example and without limitation: one or more of oleic acid, linoleic acid, palmitic acid, and stearic acid.
  • non-ionic surfactants comprise polyethylene sorbitol esters, including polysorbate 80, which is commercially available under the trademark TWEEN 80® (Sigma Aldrich, St. Louis, MO).
  • Polysorbate 80 comprises approximately 60%-70% oleic acid with the remainder comprising primarily linoleic acids, palmitic acids, and stearic acids.
  • non-ionic surfactants include PEG-6 palmitostearate and ethylene glycol palmitostearate, which are available commercially as TEFOSE® 63
  • a non-ionic or ionic surfactant may be used at concentrations greater than about 0.01 %, for example at a concentration of about 0.01 %-30.0%, about 0.1 % to 10.0%, or about 1 % to 10.0%), from 10% to 30%o.
  • the pharmaceutical composition comprises about 10.0% surfactant by weight. In some embodiments, the pharmaceutical composition comprises about 15.0% surfactant by weight. In some embodiments, the pharmaceutical composition comprises about 0.1 %> to about 5.0% surfactant by weight, e.g., about 1.0 wt %>. In some embodiments, the pharmaceutical composition comprises about 5.0%> to about 15.0% surfactant by weight. In some embodiments, the pharmaceutical composition comprises about 10.0%) to about 20.0%) surfactant by weight.
  • the pharmaceutical composition comprises less than 30.0%>, less than 29.0%>, less than 28.0%, less than 27.0%, less than 26.0%, less than 25.0%, less than 24.0%, less than 23.0%, less than 22.0%, less than 21.0%, less than 20.0%, less than 19.0%, less than 18.0%, less than 17.0%, less than 16.0%, less than 15.0%), less than 14.0%, less than 1 3.0%, less than 12.0%, less than 11.0%, less than 10.0%, less than 9.0%, less than 8.0%, less than 7.0%, less than 6.0%, less than 5.0%, less than 4.0%, less than 3.0%, less than 2.0%, or less than 1.0% surfactant by weight.
  • the pharmaceutical composition further comprises one more other excipients, such as but not limited to colorants, flavoring agents, preservatives, and taste- masking agents.
  • excipients such as but not limited to colorants, flavoring agents, preservatives, and taste- masking agents.
  • colorants for example, may comprise about 0.1 % to about 2%o by weight.
  • Preservatives may comprise methyl and propyl paraben, for example, in a ratio of about 10: 1 , and at a proportion of about 0.005%) and 0.05% by weight.
  • solubilizing agents, surfactants, and other excipients used in the pharmaceutical compositions described herein are non-toxic, pharmaceutically acceptable, compatible with each other, and maintain stability of the pharmaceutical composition and the various components with respect to each other. Additionally, the combination of various components that comprise the pharmaceutical compositions will result in the desired therapeutic effect when administered to a subject.
  • solubilizing agents e.g., two or more oils
  • one or more solubilizing agents and one or more surfactants are used to form estradiol and progesterone compositions.
  • Various ratios of these solubilizing agents or solubilizing agents and surfactants can be used.
  • CAPMUL® MCM and a non- ionic surfactant can be used at ratios of about 99: 1 to about 2: 1 , including, for example and without limitation: 60:40, 65:35, 70:30, 75:25, 80: 10, 80: 15, 85:20, 90: 10, and 98: 1.
  • CAPMUL® MCM and a non- ionic surfactant can be used as rations of about 8:2 or 9: 1.
  • exemplary solubilizing agent/surfactant combinations include, without limitation: MIGLYOL®
  • the ratios of oil (e.g., medium chain fatty acid esters of monoglycerides and diglycerides) to non-ionic surfactant can be significantly higher.
  • CAPMUL® MCM and GELUCIRE® can be used in ratios of up to about 65: 1 , e.g., 8: 1 , 22: 1 , 49: 1 , 65 : 1 and 66: 1.
  • useful ratios can be 8: 1 or greater, e.g., 60 to 70: 1.
  • estradiol or progesterone is soluble in the solubilizing agent at room temperature, although it may be desirable to warm certain solubilizing agents.
  • the formulation comprises medium chain fatty acid mono- and diglycerides (e.g., CAPMUL® MCM) and polyethylene glycol glycerides (e.g., GELUCIRE®) as a surfactant
  • the oil or the surfactant can be warmed up, e.g., to about 65°C for the surfactant and less for the oil, to facilitate mixing of the oil and surfactant.
  • the estradiol can be added at this temperature, or at lower temperatures as the mixture cools, e.g., about 40°C or about 30°C, or even after the mixture has cooled to room temperature.
  • the progesterone can also be added as the mixture cools, e.g., to below about 40°C or to below about 30°C, or after the mixture has cooled to room temperature.
  • a composition of this disclosure comprises solubilized estradiol; progesterone, at least 30% (e.g., at least about 30%, about 40%, about 50%, about 60%), about 70%), about 75%), about 80%, about 85%>, or more) of the progesterone being solubilized (the balance being micronized as discussed elsewhere herein); and a solubilizing agent that is an oil, wherein the oil comprises medium chain fatty acid mono-, di-, or triglycerides, with or without a surfactant.
  • a specification for progesterone is set at >80% solubilized, ⁇ 20% micronized or >85% solubilized, ⁇ 15% micronized.
  • CAPMUL® MCM NF glycol caprylate/caprate
  • GELUCIRE® 44/14 glycol polyoxyglyceride
  • surfactant in which at least about 85% of the progesterone can be solubilized, include, e.g., the following five formulations A-E:
  • the above formulations comprise 30 to 35 wt % progesterone, 0.1 to 0.4 wt % estradiol (or estradiol hemihydrate), 55 to 75 wt % of an oil that is predominantly medium chain fatty acid mono-, di-, or triglycerides, such as CAPMUL® MCM, and 0.5 to 10 wt % of a non-ionic surfactant, such as GELUCIRE® 44/14.
  • the above formulations may be modified to comprise excipients, e.g., gelatin such as Gelatin 200 Bloom, glycerin, coloring agents such as Opatint red and white, and, optionally, MIGLYOL® 812.
  • Estradiol solubilization helps ensure high content uniformity and enhanced stability.
  • Fully solubilized progesterone formulations or partially solubilized progesterone formulations in which at least about 50% of the progesterone, e.g., at least about 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95% or more, is solubilized appear to provide improved PK-related properties.
  • compositions of this disclosure are formulated to provide desirable pharmacokinetic parameters in a subject (e.g., a female subject) to whom the composition is administered.
  • a pharmaceutical composition as described herein produces desirable pharmacokinetic parameters for progesterone in the subject.
  • a pharmaceutical composition as described herein produces desirable pharmacokinetic parameters for estradiol in the subject.
  • a pharmaceutical composition as described herein produces desirable pharmacokinetic parameters for one or more metabolites of progesterone or estradiol in the subject, for example, estrone or total estrone.
  • the concentration and metabolism of progesterone or estradiol can be measured in a sample (e.g., a blood, serum, or plasma sample) from the subject.
  • a sample e.g., a blood, serum, or plasma sample
  • Progesterone is metabolized to pregnanediols and pregnanolones, which are then conjugated to glucuronide and sulfate metabolites that are excreted or further recycled.
  • Estradiol is converted reversibly to estrone, and both estradiol and estrone can be converted to the metabolite estriol.
  • estrone In postmenopausal women, a significant proportion of circulating estrogens exist as sulfate conjugates, especially estrone sulfate. Thus, estrone can be measured with respect to “estrone” amounts (excluding conjugates such as estrone sulfate) and “total estrone” amounts (including both free, or unconjugated, estrone and conjugated estrone such as estrone sulfate).
  • compositions of this disclosure can be characterized by one or more pharmacokinetic parameters of progesterone, estradiol, or a metabolite thereof following administration of the composition to a subject or to a population of subjects.
  • AUC is a determination of the area under the curve (AUC) plotting the blood, serum, or plasma concentration of drug along the ordinate (Y-axis) against time along the abscissa (X-axis).
  • AUCs are well understood, frequently used tools in the pharmaceutical arts and have been extensively described.
  • C max is well understood in the art as an abbreviation for the maximum drug concentration in blood, serum, or plasma of a subject.
  • T max is well understood in the art as an abbreviation for the time to maximum drug concentration in blood, serum, or plasma of a subject.
  • one or more pharmacokinetic parameters e.g., AUC, C max , or T max
  • estradiol In some embodiments, one or more pharmacokinetic parameters, e.g., AUC, C max , or T max , is measured for progesterone. In some embodiments, one or more pharmacokinetic parameters, e.g., AUC, C max , or T max , is measured for estrone. In some embodiments, one or more pharmacokinetic parameters, e.g., AUC, C max , or T max , is measured for total estrone.
  • any of a variety of methods can be used for measuring the levels of progesterone, estradiol, estrone, or total estrone in a sample, including immunoassays, mass spectrometry (MS), high performance liquid chromatography (HPLC) with ultraviolet fluorescent detection, liquid chromatography in conjunction with mass spectrometry (LC-MS), tandem mass spectrometry (MS/MS), and liquid chromatography-tandem mass spectrometry (LC-MS/MS).
  • the levels of progesterone, estradiol, estrone, or total estrone are measured using a validated LC-MS/MS method. Methods of measuring hormone levels are well described in the literature.
  • the levels of progesterone, estradiol, estrone, or total estrone can be measured in any biological sample, e.g. a tissue or fluid such as blood, serum, plasma, or urine. In some embodiments, the sample is blood or plasma. In some embodiments, the levels of progesterone, estradiol, estrone, or total estrone are measured about 0.0, 0.10, 0.20, 0.05, 0.30, 0.35, 0.40, 0.45, 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, or 48 hours after dosing, or any other appropriate time period that is common or useful in determining the levels of each of the hormones.
  • the levels of progesterone, estradiol, estrone, or total estrone are measured about 18 hours, about 24 hours, about 18-36 hours, about 20-30 hours, about 22-26 hours, about 24-36 hours, about 36 hours, about 36-48 hours, about 40-48 hours, or about 48 hours after administration of a single dose or a first dose.
  • assays to determine the levels of progesterone, estradiol, estrone, or total estrone are measured one or more times every 5, 10, 15, 20, 30, 60, 120, 360, 480, 720, or 1440 minutes after administration, or combinations thereof (e.g., the first measurements are taken every 15 minutes for the first hour, followed by every 120 minutes thereafter). In embodiments, the timing of such
  • measurements are designed to accurately measure C max , T max , or AUC. Timing can be adjusted based on the given circumstances (i.e., one formulation may cause a more rapid C max , in which case the initial times would be clustered closer together, closer to time zero, or both to ensure accurate measurement of C max , T max , and AUC).
  • the C max , T max , or AUC values for progesterone, estradiol, estrone, or total estrone are measured following administration of a single dose of a pharmaceutical composition as described herein.
  • the values for C max , T max , or AUC represent a number of values taken from all the subjects in a patient population and are, therefore, mean values (e.g., arithmetic or geometric means) averaged over the entire population.
  • oral administration of a pharmaceutical composition comprising estradiol, progesterone, and a medium chain solubilizing agent as described herein to a subject, or to a population of subjects produces one or more AUC, C max , or T max parameters, or one or more mean AUC, mean C max , or mean T max parameters, respectively, for estradiol, progesterone, estrone, or total estrone as described below.
  • a pharmaceutical composition of this disclosure comprises estradiol at a dosage of about 0.25 mg and progesterone at a dosage of about 50 mg.
  • the pharmaceutical composition comprises the formulation of Formulation A in Table 1 above.
  • administration of a composition comprising about 0.25 mg estradiol and about 50 mg progesterone to a subject produces, in a plasma sample from the subject, one or both parameters selected from:
  • 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.
  • administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from:
  • compositions to the subject produce both an AUC (0-t) for progesterone that is from 24.0174 ng-hr/ml to 37.5272 ng-hr/ml, and a C max for progesterone that is from 17.8444 ng/ml to 27.8819 ng/ml.
  • administration of the composition to the subject produces, in a plasma sample from the subject,
  • administration of the composition to the subject further produces, in a plasma sample from the subject, a T max for estradiol that is from 7.2 hr to 11.3 hr. In some embodiments, administration of the composition to the subject further produces, in a plasma sample from the subject, a T max for progesterone that is from 2.4 hr to 3.8 hr.
  • administration of the pharmaceutical composition to the subject produces, in a plasma sample from the subject, one, two, three or more parameters selected from:
  • administration of the pharmaceutical composition to the subject produces both parameters (i) and (ii). In some embodiments, administration of the composition to the subject produces both parameters (i) and (iii). In some embodiments, administration of the composition to the subject produces both parameters (i) and (iv). In some embodiments, administration of the composition to the subject produces both parameters (ii) and (iii). In some embodiments, administration of the composition to the subject produces both parameters (ii) and (iv). In some embodiments, administration of the composition to the subject produces both parameters (iii) and (iv). In some embodiments, administration of the composition to the subject produces all of parameters (i), (ii), and (iii).
  • administration of the composition to the subject produces both parameters (i), (iii), and (iv). In some embodiments, administration of the composition to the subject produces both parameters (ii), (iii), and (iv). In some embodiments, administration of the composition to the subject produces all of parameters (i), (ii), (iii), and (iv).
  • administration of the pharmaceutical composition to the subject further produces, in a plasma sample from the subject, one or more parameters selected from: (i) an AUC (0-t) for estrone that is from 909.6091 pg-hr/ml to 1421.2642 pg-hr/ml;
  • administration of the pharmaceutical composition to the subject further produces, in a plasma sample from the subject, one or more parameters selected from:
  • a pharmaceutical composition comprising about 0.25 mg estradiol and about 50 mg progesterone is administered to a population of subjects in need thereof, and mean parameters are determined for samples (e.g., blood or plasma samples) from the subjects administered the composition.
  • administration of the composition to a population of subject produces, in plasma samples from the subjects, one or more of a mean AUC (0-t) for estradiol that is from 140.3733 pg-hr/ml to 219.3333 pg-hr/ml, a mean C max for estradiol that is from 6.4790 pg/ml to 10.1235 pg/ml, and a mean T max for estradiol that is from 7.2 hr to 11.3 hr.
  • administration of the composition to a population of subject produces, in plasma samples from the subjects, one or more of a mean AUC (0-t) for progesterone that is from 24.0174 ng-hr/ml to 37.5272 ng-hr/ml, a mean C max for progesterone that is from 17.8444 ng/ml to 27.8819 ng/ml, and a mean T max for progesterone that is from 2.4 hr to 3.8 hr.
  • administration of the composition to a population of subject produces, in plasma samples from the subjects, one or more of a mean AUC (0-t) for estrone that is from 909.6091 pg-hr/ml to 1421.2642 pg-hr/ml, a mean C max for estrone that is from 42.6549 pg/ml to 66.6483 pg/ml, and a mean T max for estrone that is from 4.4 hr to 6.9 hr.
  • administration of the composition to a population of subject produces, in plasma samples from the subjects, one or more of a mean AUC (0-t) for total estrone that is from 20.1752 ng-hr/ml to 31.5238 ng-hr/ml, a mean C max for total estrone that is from 3.5429 ng/ml to 5.5358 ng/ml, and a mean T max for total estrone that is from 2 hr to 3.1 hr.
  • methods of treating a subject with a pharmaceutical composition comprising estradiol and progesterone are provided.
  • the method comprises administering to the subject a pharmaceutical composition comprising about 0.25 mg estradiol and about 50 mg progesterone as described herein (e.g., a pharmaceutical composition having the formulation of Formulation A in Table 1 above), wherein administration of the pharmaceutical composition produces, in a plasma sample from the subject, one or more parameters selected from: an AUC (0-t) for estradiol that is from 140.3733 pg-hr/ml to 219.3333 pg-hr/ml; a C max for estradiol that is from 6.4790 pg/ml to 10.1235 pg/ml; a T max for estradiol that is from 7.2 hr to 11.3 hr; an AUC (0-t) for progesterone that is from 24.0174 ng-hr/ml to 37.5272 ng-hr/ml; a C max for progesterone that is from 17.8444 ng/ml to 27.8819 ng/ml
  • the method further comprises obtaining a sample from the subject (e.g., a blood or plasma sample) following administration of a single dose of the pharmaceutical composition (e.g., a pharmaceutical composition having the formulation of Formulation A in Table 1 above), and measuring one or more pharmacokinetic parameters selected from an AUC (0-t) for estradiol, a C max for estradiol, an AUC (0-t) for progesterone, a C max for progesterone, an AUC (0-t) for estrone, a C max for estrone, an AUC (0-t) for total estrone, and a C max for total estrone; wherein the presence of one or more of the following values is indicative of a therapeutically effective dose: an AUC (0-t) for estradiol that is from 140.3733 pg-hr/ml to 219.3333 pg-hr/ml; a C max for estradiol that is from 6.4790 pg/m
  • the one or more pharmacokinetic parameters are measured about 18 hours, about 24 hours, about 18-36 hours, about 20-30 hours, about 22-26 hours, about 24-36 hours, about 36 hours, about 36-48 hours, about 40-48 hours, or about 48 hours after administration of the single dose.
  • a pharmaceutical composition of this disclosure comprises estradiol at a dosage of about 0.50 mg and progesterone at a dosage of about 50 mg.
  • the pharmaceutical composition comprises the formulation of Formulation B in Table 2 above.
  • administration of a composition comprising about 0.50 mg estradiol and about 50 mg progesterone to a subject produces, in a plasma sample from the subject, one or both parameters selected from: (i) an AUC (0-t) for estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml; or
  • estradiol that is from 12.9580 pg/ml to 20.2469 pg/ml.
  • 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.
  • 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; or (ii) a C max for progesterone that is from 17.8444 ng/ml to 27.8819 ng/ml.
  • administration of the composition to the subject produces both an (AUC)(o-t) for progesterone that is from 24.0174 ng-hr/ml to 37.5272 ng-hr/ml, and a C max for progesterone that is from 17.8444 ng/ml to 27.8819 ng/ml.
  • administration of the composition to the subject produces, in a plasma sample from the subject,
  • administration of the composition to the subject further produces, in a plasma sample from the subject, a T max for estradiol that is from 7.2 hr to 11.3 hr. In some embodiments, administration of the composition to the subject further produces, in a plasma sample from the subject, a T max for progesterone that is from 2.4 hr to 3.8 hr.
  • administration of the pharmaceutical composition to the subject produces, in a plasma sample from the subject, one, two, three or more parameters selected from:
  • administration of the pharmaceutical composition to the subject produces both parameters (i) and (ii). In some embodiments, administration of the composition to the subject produces both parameters (i) and (iii). In some embodiments, administration of the composition to the subject produces both parameters (i) and (iv). In some embodiments, administration of the composition to the subject produces both parameters (ii) and (iii). In some embodiments, administration of the composition to the subject produces both parameters (ii) and (iv). In some embodiments, administration of the composition to the subject produces both parameters (iii) and (iv). In some embodiments, administration of the composition to the subject produces both parameters (iii) and (iv).
  • administration of the composition to the subject produces all of parameters (i), (ii), and (iii). In some embodiments, administration of the composition to the subject produces both parameters (i), (iii), and (iv). In some embodiments, administration of the composition to the subject produces both parameters (ii), (iii), and (iv). In some embodiments, administration of the composition to the subject produces all of parameters (i), (ii), (iii), and (iv).
  • administration of the pharmaceutical composition to the subject further produces, in a plasma sample from the subject, one or more parameters selected from:
  • estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml;
  • administration of the pharmaceutical composition to the subject further produces, in a plasma sample from the subject, one or more parameters selected from:
  • a pharmaceutical composition comprising about 0.50 mg estradiol and about 50 mg progesterone is administered to a population of subjects in need thereof, and mean parameters are determined for samples (e.g., blood or plasma samples) from the subjects administered the composition.
  • administration of the composition to a population of subject produces, in plasma samples from the subjects, one or more of a mean AUC (0-t) for estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml, a mean C max for estradiol that is from 12.9580 pg/ml to 20.2469 pg/ml, and a mean T max for estradiol that is from 7.2 hr to 11.3 hr.
  • administration of the composition to a population of subject produces, in plasma samples from the subjects, one or more of a mean AUC (0-t) for progesterone that is from 24.0174 ng-hr/ml to 37.5272 ng-hr/ml, a mean C max for progesterone that is from 17.8444 ng/ml to 27.8819 ng/ml, and a mean T max for progesterone that is from 2.4 hr to 3.8 hr.
  • administration of the composition to a population of subject produces, in plasma samples from the subjects, one or more of a mean AUC (0-t) for estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml, a mean C max for estrone that is from 85.3098 pg/ml to 133.2966 pg/ml, and a mean T max for estrone that is from 4.4 hr to 6.9 hr.
  • administration of the composition to a population of subject produces, in plasma samples from the subjects, one or more of a mean AUC (0-t) for total estrone that is from 40.3505 ng-hr/ml to 63.0476 ng-hr/ml, a mean C max for total estrone that is from 7.0858 ng/ml to 11.0715 ng/ml, and a mean T max for total estrone that is from 2 hr to 3.1 hr.
  • methods of treating a subject with a pharmaceutical composition comprising estradiol and progesterone comprise administering to the subject a pharmaceutical composition comprising about 0.50 mg estradiol and about 50 mg progesterone as described herein (e.g., a pharmaceutical composition having the formulation of Formulation B in Table 2 above), wherein administration of the pharmaceutical composition produces, in a plasma sample from the subject, one or more parameters selected from: an AUC (0-t) for estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml; a C max for estradiol that is from 12.9580 pg/ml to 20.2469 pg/ml; a T max for estradiol that is from 7.2 hr to 11.3 hr; an AUC (0-t) for progesterone that is from 24.0174 ng-hr/ml to
  • the method further comprises obtaining a sample from the subject (e.g., a blood or plasma sample) following administration of a single dose of the pharmaceutical composition (e.g., a pharmaceutical composition having the formulation of Formulation B in Table 2 above), and measuring one or more pharmacokinetic parameters selected from an AUC (0-t) for estradiol, a C max for estradiol, an AUC (0-t) for progesterone, a C max for progesterone, an AUC (0-t) for estrone, a C max for estrone, an AUC (0-t) for total estrone, and a C max for total estrone; wherein the presence of one or more of the following values is indicative of a therapeutically effective dose: an AUC (0-t) for estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml; a C max for estradiol that is from 12.9580 pg
  • the one or more pharmacokinetic parameters are measured about 18 hours, about 24 hours, about 18-36 hours, about 20-30 hours, about 22-26 hours, about 24-36 hours, about 36 hours, about 36-48 hours, about 40-48 hours, or about 48 hours after administration of the single dose.
  • a pharmaceutical composition of this disclosure comprises estradiol at a dosage of about 0.50 mg and progesterone at a dosage of about 100 mg.
  • the pharmaceutical composition comprises the formulation of Formulation C in Table 3 above.
  • administration of a composition comprising about 0.50 mg estradiol and about 100 mg progesterone to a subject produces, in a plasma sample from the subject, one or both parameters selected from:
  • estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml;
  • 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.
  • 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; or
  • administration of the composition to the subject produces both an AUC (0-t) for progesterone that is from 48.0348 ng-hr/ml to 75.0543 ng-hr/ml, and a C max for progesterone that is from 35.6889 ng/ml to 55.7639 ng/ml.
  • administration of the composition to the subject produces, in a plasma sample from the subject,
  • administration of the composition to the subject further produces, in a plasma sample from the subject, a T max for estradiol that is from 7.2 hr to 11.3 hr. In some embodiments, administration of the composition to the subject further produces, in a plasma sample from the subject, a T max for progesterone that is from 2.4 hr to 3.8 hr.
  • administration of the pharmaceutical composition to the subject produces, in a plasma sample from the subject, one or more parameters selected from:
  • administration of the pharmaceutical composition to the subject produces both parameters (i) and (ii). In some embodiments, administration of the composition to the subject produces both parameters (i) and (iii). In some embodiments, administration of the composition to the subject produces both parameters (i) and (iv). In some embodiments, administration of the composition to the subject produces both parameters (ii) and (iii). In some embodiments, administration of the composition to the subject produces both parameters (ii) and (iv). In some embodiments, administration of the composition to the subject produces both parameters (iii) and (iv). In some embodiments, administration of the composition to the subject produces all of parameters (i), (ii), and (iii).
  • administration of the composition to the subject produces both parameters (i), (iii), and (iv). In some embodiments, administration of the composition to the subject produces both parameters (ii), (iii), and (iv). In some embodiments, administration of the composition to the subject produces all of parameters (i), (ii), (iii), and (iv).
  • administration of the pharmaceutical composition to the subject further produces, in a plasma sample from the subject, one, two, three or more parameters selected from: (i) an AUC (0-t) for estrone that is from 181 9.2181 pg-hr/ml to 2842.5283 pg-hr/ml;
  • administration of the pharmaceutical composition to the subject further produces, in a plasma sample from the subject, one or more parameters selected from:
  • a pharmaceutical composition comprising about 0.50 mg estradiol and about 1 00 mg progesterone is administered to a population of subjects in need thereof, and mean parameters are determined for samples (e.g., blood and plasma samples) from the subjects administered the composition.
  • administration of the composition to a population of subject produces, in plasma samples from the subjects, one or more of a mean AUC (0-t) for estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml, a mean C max for estradiol that is from 12.9580 pg/ml to 20.2469 pg/ml, and a mean T max for estradiol that is from 7.2 hr to 11.3 hr.
  • administration of the composition to a population of subject produces, in plasma samples from the subjects, one or more of a mean AUC (0-t) for progesterone that is from 48.0348 ng-hr/ml to 75.0543 ng-hr/ml, a mean C max for progesterone that is from 35.6889 ng/ml to 55.7639 ng/ml, and a mean T max for progesterone that is from 2.4 hr to 3.8 hr.
  • administration of the composition to a population of subject produces, in plasma samples from the subjects, one or more of a mean AUC (0-t) for estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml, a mean C max for estrone that is from 85.3098 pg/ml to 133.2966 pg/ml, and a mean T max for estrone that is from 4.4 hr to 6.9 hr.
  • administration of the composition to a population of subject produces, in plasma samples from the subjects, one or more of a mean AUC (0-t) for total estrone that is from 40.3505 ng-hr/ml to 63.0476 ng-hr/ml, a mean C max for total estrone that is from 7.0858 ng/ml to 11.0715 ng/ml, and a mean T max for total estrone that is from 2 hr to 3.1 hr.
  • AUC (0-t) for total estrone that is from 40.3505 ng-hr/ml to 63.0476 ng-hr/ml
  • a mean C max for total estrone that is from 7.0858 ng/ml to 11.0715 ng/ml
  • a mean T max for total estrone that is from 2 hr to 3.1 hr.
  • the method comprises administering to the subject a pharmaceutical composition comprising about 0.50 mg estradiol and about 100 mg progesterone as described herein (e.g., a pharmaceutical composition having the formulation of Formulation C in Table 3 above), wherein administration of the pharmaceutical composition produces, in a plasma sample from the subject, one or more parameters selected from: an AUC (0-t) for estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml; a C max for estradiol that is from 12.9580 pg/ml to 20.2469 pg/ml; a T max for estradiol that is from 7.2 hr to 11.3 hr; an AUC (0-t) for progesterone that is from 48.0348 ng-hr/ml to 75.0543 ng-hr/ml; a C max for progesterone that is from 35.6889 ng/ml to 55.7639
  • the method further comprises obtaining a sample from the subject (e.g., a blood or plasma sample) following administration of a single dose of the pharmaceutical composition (e.g., a pharmaceutical composition having the formulation of Formulation C in Table 3 above), and measuring one or more pharmacokinetic parameters selected from an AUC (0-t) for estradiol, a C max for estradiol, an AUC (0-t) for progesterone, a C max for progesterone, an AUC (0-t) for estrone, a C max for estrone, an AUC (0-t) for total estrone, and a C max for total estrone; wherein the presence of one or more of the following values is indicative of a therapeutically effective dose: an AUC (0-t) for estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml; a C max for estradiol that is from 12.9580 pg
  • the one or more pharmacokinetic parameters are measured about 18 hours, about 24 hours, about 18-36 hours, about 20-30 hours, about 22-26 hours, about 24-36 hours, about 36 hours, about 36-48 hours, about 40-48 hours, or about 48 hours after administration of the single dose.
  • a pharmaceutical composition of this disclosure comprises estradiol at a dosage of about 1 mg and progesterone at a dosage of about 100 mg.
  • the pharmaceutical composition comprises the formulation of Formulation D in Table 4 above.
  • administration of a composition comprising about 1 mg estradiol and about 100 mg progesterone to a subject produces, in a plasma sample from the subject, one or both parameters selected from:
  • compositions to the subject produce 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.
  • administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from:
  • administration of the composition to the subject produces both an AUC (0-t) for progesterone that is from 48.0348 ng-hr/ml to 75.0543 ng-hr/ml, and a C max for progesterone that is from 35.6889 ng/ml to 55.7639 ng/ml.
  • administration of the composition to the subject produces, in a plasma sample from the subject, an AUC (0-t) for estradiol that is from 561.4933 pg-hr/ml to 877.3333 pg-hr/ml;
  • an AUC (0-t) for progesterone that is from 48.0348 ng-hr/ml to 75.0543 ng-hr/ml; or
  • administration of the composition to the subject further produces, in a plasma sample from the subject, a T max for estradiol that is from 7.2 hr to 11.3 hr. In some embodiments, administration of the composition to the subject further produces, in a plasma sample from the subject, a T max for progesterone that is from 2.4 hr to 3.8 hr.
  • administration of the composition to the subject produces, in a plasma sample from the subject, one, two, three or more parameters selected from:
  • estradiol (i) an AUC (0-t) for estradiol that is from 561.4933 pg-hr/ml to 877.3333 pg-hr/ml;
  • administration of the pharmaceutical composition to the subject produces both parameters (i) and (ii). In some embodiments, administration of the composition to the subject produces both parameters (i) and (iii). In some embodiments, administration of the composition to the subject produces both parameters (i) and (iv). In some embodiments, administration of the composition to the subject produces both parameters (ii) and (iii). In some embodiments, administration of the composition to the subject produces both parameters (ii) and (iv). In some embodiments, administration of the composition to the subject produces both parameters (iii) and (iv). In some embodiments, administration of the composition to the subject produces all of parameters (i), (ii), and (iii).
  • administration of the composition to the subject produces both parameters (i), (iii), and (iv). In some embodiments, administration of the composition to the subject produces both parameters (ii), (iii), and (iv). In some embodiments, administration of the composition to the subject produces all of parameters (i), (ii), (iii), and (iv).
  • administration of the pharmaceutical composition to the subject further produces, in a plasma sample from the subject, one or more parameters selected from:
  • administration of the pharmaceutical composition to the subject further produces, in a plasma sample from the subject, one or more 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;
  • a pharmaceutical composition comprising about 1 mg estradiol and about 100 mg progesterone is administered to a population of subjects in need thereof, and mean parameters are determined for samples (e.g., blood or plasma samples) from the subjects administered the composition.
  • administration of the composition to a population of subject produces, in plasma samples from the subjects, one or more of a mean AUC (0-t) for estradiol that is from 561.4933 pg-hr/ml to 877.3333 pg-hr/ml, a mean C max for estradiol that is from 25.9161 pg/ml to 40.4939 pg/ml, and a mean i max for estradiol that is from 7.2 hr to 11.3 hr.
  • administration of the composition to a population of subject produces, in plasma samples from the subjects, one or more of a mean AUC (0-t) for progesterone that is from 48.0348 ng-hr/ml to 75.0543 ng-hr/ml, a mean C max for progesterone that is from 35.6889 ng/ml to 55.7639 ng/ml, and a mean T max for progesterone that is from 2.4 hr to 3.8 hr.
  • administration of the composition to a population of subject produces, in plasma samples from the subjects, one or more of a mean AUC (0-t) for estrone that is from 3638.4363 pg-hr/ml to 5685.0567 pg-hr/ml, a mean C max for estrone that is from 170.6197 pg/ml to 266.5933 pg/ml, and a mean T max for estrone that is from 4.4 hr to 6.9 hr.
  • administration of the composition to a population of subject produces, in plasma samples from the subjects, one or more of a mean AUC (0-t) for total estrone that is from 80.7010 ng-hr/ml to 126.0953 ng-hr/ml, a mean C max for total estrone that is from 14.1716 ng/ml to 22/1431 ng/ml, and a mean 1 max for total estrone that is from 2 hr to 3.1 hr.
  • method of treating a subject with a pharmaceutical composition comprising estradiol and progesterone are provided.
  • the method comprises administering to the subject a pharmaceutical composition comprising about 1 mg estradiol and about 100 mg progesterone as described herein (e.g., a pharmaceutical composition having the formulation of Formulation D in Table 4 above), wherein administration of the pharmaceutical composition produces, in a plasma sample from the subject, one or more parameters selected from: an AUC (0-t) for estradiol that is from 561 .4933 pg-hr/ml to 877.3333 pg-hr/m; a C max for estradiol that is from 25.9161 pg/ml to 40.4939 pg/ml; a T max for estradiol that is from 7.2 hr to 11.3 hr; an AUC (0-t) for progesterone that is from 48.0348 ng-hr/ml to 75.0543 ng-hr/ml; a C max for progesterone that is from 35.6889 ng/ml to 55.7639
  • the method further comprises obtaining a sample from the subject (e.g., a blood or plasma sample) following administration of a single dose of the pharmaceutical composition (e.g., a pharmaceutical composition having the formulation of Formulation D in Table 4 above), and measuring one or more pharmacokinetic parameters selected from an AUC (0-t) for estradiol, a C max for estradiol, an AUC (0-t) for progesterone, a C max for progesterone, an AUC( 0-t) for estrone, a C max for estrone, an AUC (0-t) for total estrone, and a C max for total estrone; wherein the presence of one or more of the following values is indicative of a therapeutically effective dose: an AUC (0-t) for estradiol that is from 561.4933 pg-hr/ml to 877.3333 pg-hr/m; a C max for estradiol that is from 25.9161 pg/
  • the one or more pharmacokinetic parameters are measured about 18 hours, about 24 hours, about 18-36 hours, about 20-30 hours, about 22-26 hours, about 24-36 hours, about 36 hours, about 36-48 hours, about 40-48 hours, or about 48 hours after administration of the single dose.
  • a pharmaceutical composition of this disclosure comprises estradiol at a dosage of about 2 mg and progesterone at a dosage of about 200 mg.
  • the pharmaceutical composition comprises the formulation of Formulation E in Table 5 above.
  • administration of a pharmaceutical composition comprising about 2 mg estradiol and about 200 mg progesterone to a subject produces, in a plasma sample from the subject, one or both parameters selected from:
  • administration of the composition to the subject produces both an AUC (0-t) for estradiol that is from 1123 pg-h/ml to 1755 pg-h/ml, and a C max for estradiol that is from 52 pg/ml to 81 pg/ml.
  • administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from:
  • an AUC (0-t) for progesterone that is from 96 ng-hr/ml to 150 ng-hr/ml;
  • administration of the composition to the subject produces both an AUC (0-t) for progesterone that is from 96 ng-hr/ml to 150 ng-hr/ml, and a C max for progesterone.
  • progesterone that is from 71 ng/ml to 112 ng/ml.
  • administration of the composition to the subject produces, in a plasma sample from the subject,
  • administration of the composition to the subject further produces, in a plasma sample from the subject, a T max for estradiol that is from 7.2 hr to 11.3 hr. In some embodiments, administration of the composition to the subject further produces, in a plasma sample from the subject, a T max for progesterone that is from 2.4 hr to 3.8 hr.
  • administration of the pharmaceutical composition to the subject produces, in a plasma sample from the subject, one, two, three or more parameters selected from:
  • administration of the pharmaceutical composition to the subject produces both parameters (i) and (ii). In some embodiments, administration of the composition to the subject produces both parameters (i) and (iii). In some embodiments, administration of the composition to the subject produces both parameters (i) and (iv). In some embodiments, administration of the composition to the subject produces both parameters (ii) and (iii). In some embodiments, administration of the composition to the subject produces both parameters (ii) and (iv). In some embodiments, administration of the composition to the subject produces both parameters (iii) and (iv). In some embodiments, administration of the composition to the subject produces all of parameters (i), (ii), and (iii).
  • administration of the composition to the subject produces both parameters (i), (iii), and (iv). In some embodiments, administration of the composition to the subject produces both parameters (ii), (iii), and (iv). In some embodiments, administration of the composition to the subject produces all of parameters (i), (ii), (iii), and (iv).
  • administration of the pharmaceutical composition to the subject further produces, in a plasma sample from the subject, one or more parameters selected from:
  • administration of the pharmaceutical composition to the subject further produces, in a plasma sample from the subject, one or more parameters selected from:
  • a pharmaceutical composition comprising about 2 mg estradiol and about 200 mg progesterone is administered to a population of subjects in need thereof, and mean parameters are determined for samples (e.g., blood or plasma samples) from the subjects administered the composition.
  • administration of the composition to a population of subject produces, in plasma samples from the subjects, one or more of a mean AUC (0-t) for estradiol that is from 1123 pg-h/ml to 1755 pg-h/ml, a mean C max for estradiol that is from 52 pg/ml to 81 pg/ml, and a mean T max for estradiol that is from 7.2 hr to 11.3 hr.
  • administration of the composition to a population of subject produces, in plasma samples from the subjects, one or more of a mean AUC (0-t) for progesterone that is from 96 ng-hr/ml to 150 ng-hr/ml, a mean C max for progesterone that is from 71 ng/ml to 112 ng/ml, and a mean T max for progesterone that is from 2.4 hr to 3.8 hr.
  • administration of the composition to a population of subject produces, in plasma samples from the subjects, one or more of a mean AUC (0-t) for estrone that is from 7277 pg-hr/ml to 11370 pg-hr/ml, a mean C max for estrone that is from 341 pg/ml to 533 pg/ml, and a mean T max for estrone that is from 4.4 hr to 6.9 hr.
  • administration of the composition to a population of subject produces, in plasma samples from the subjects, one or more of a mean AUC (0-t) for total estrone that is from 161 ng-h/ml to 252 ng-h/ml, a mean C max for total estrone that is from 28 ng/ml to 44 ng/ml, and a mean T max for total estrone that is from 2 hr to 3.1 hr.
  • method of treating a subject with a pharmaceutical composition comprising estradiol and progesterone comprises administering to the subject a pharmaceutical composition comprising about 2 mg estradiol and about 200 mg progesterone as described herein (e.g., a pharmaceutical composition having the formulation of Formulation E in Table 5 above), wherein administration of the pharmaceutical composition produces, in a plasma sample from the subject, one or more parameters selected from: an AUC (0-t) for estradiol that is from 1123 pg-h/ml to 1755 pg-h/ml; a C max for estradiol that is from 52 pg/ml to 81 pg/ml; a T max for estradiol that is from 7.2 hr to 11.3 hr; an AUC (0-t) for progesterone that is from 96 ng-hr/ml to 150 ng-hr/ml; a C max for progesterone that
  • the method further comprises obtaining a sample from the subject (e.g., a blood or plasma sample) following administration of a single dose of the pharmaceutical composition (e.g., a pharmaceutical composition having the formulation of Formulation E in Table 5 above), and measuring one or more pharmacokinetic parameters selected from an AUC (0-t) for estradiol, a C max for estradiol, an AUC (0-t) for progesterone, a C max for progesterone, an AUC (0-t) for estrone, a C max for estrone, an AUC (0-t) for total estrone, and a C max for total estrone; wherein the presence of one or more of the following values is indicative of a therapeutically effective dose: an AUC (0-t) for estradiol that is from 1123 pg-h/ml to 1755 pg-h/ml; a C max for estradiol that is from 52 pg/ml to 81 pg/
  • the one or more pharmacokinetic parameters are measured about 18 hours, about 24 hours, about 18-36 hours, about 20-30 hours, about 22-26 hours, about 24-36 hours, about 36 hours, about 36- 48 hours, about 40-48 hours, or about 48 hours after administration of the single dose.
  • administration of the pharmaceutical composition as described herein results in the blood plasma estradiol concentration profile of Figure 1.
  • administration of the pharmaceutical composition results in the blood plasma progesterone concentration profile of Figure 2.
  • administration of the pharmaceutical composition results in the blood plasma estrone concentration profile of Figure 3.
  • administration of the pharmaceutical composition results in the blood plasma total estrone concentration profile of Figure 4.
  • administration of the pharmaceutical compositions as dscribed herein provide mean change from baseline in weekly frequency of moderate to severe hot flashes/flushes for weeks 1 to 12 as shown in Figure 5.
  • administration of the pharmaceutical compositions as dscribed herein provide mean change from baseline in weekly severity of moderate to severe hot flashes/flushes for weeks 1 to 12 as shown in Figure 6.
  • compositions comprising estradiol and progesterone as described herein (e.g., compositions comprising solubilized estradiol, suspended progesterone, and a medium chain solubilizing agent) can be prepared and administered in a wide variety of oral, parenteral and topical dosage forms.
  • Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient.
  • compositions can be formulated for any appropriate manner of administration, including, for example, topical, oral, nasal, intrathecal, rectal, vaginal, sublingual or parenteral administration, including subcutaneous, intravenous, intramuscular, intrasternal, intracavernous, intrameatal, or intraurethral injection or infusion.
  • administration is by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.
  • the pharmaceutically acceptable compositions can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid preparation can comprise one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington's Pharmaceutical Sciences, Mack Publishing Co, Easton PA ("Remington's").
  • a pharmaceutical composition e.g., for oral administration or delivery by injection
  • can be in the form of a liquid e.g., an elixir, syrup, solution, emulsion or suspension.
  • a pharmaceutical composition as described herein can take the form of a pill, tablet, or capsule containing the liquid oil, and thus, the composition can contain any of the following: a diluent such as lactose, sucrose, dicalcium phosphate, and the like; a disintegrant such as starch or derivatives thereof; a lubricant such as magnesium stearate and the like; and a binder such a starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose and derivatives thereof.
  • the composition can also be formulated into a suppository disposed, for example, in a polyethylene glycol (PEG) solubilizing agent.
  • PEG polyethylene glycol
  • compositions of this disclosure can be carried out via any of the accepted modes of administration.
  • administration can be, for example, intravenous, topical, subcutaneous, transcutaneous, transdermal, intramuscular, oral, intra-joint, parenteral, intra-arteriole, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intranasal, rectal, vaginal, or by inhalation.
  • a composition as described herein is administered orally.
  • a pharmaceutical composition as described herein can be administered via capsules such as soft capsules.
  • a pharmaceutical composition as described herein is administered once daily for a period of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100 days or more.
  • a pharmaceutical composition as described herein is administered daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, at least twelve months, or more.
  • a pharmaceutical composition as described herein is administered as a continuous-combined therapy regimen.
  • a 28-day or monthly regimen of daily doses is packaged in a single kit (e.g., a blister pack) having administration days identified to improve compliance and reduce associated symptoms, among others.
  • each daily dose contains both estradiol and progesterone.
  • one or more of the daily doses contains no estradiol or no progesterone.
  • Daily doses that comprise no estradiol or progesterone API may be referred to as placebos.
  • a blister pack can have a plurality of scores or perforations separating the blister pack into 28 days.
  • each day may further comprise a single blister or a plurality of blisters.
  • each unit dose may contain micronized or partially solubilized, or fully solubilized progesterone or solubilized estradiol in amounts as set forth herein, although other dose ranges may be contemplated.
  • kits having other configurations are also contemplated herein.
  • kits having such blister packs may contain any number of daily doses.
  • the pharmaceutical compositions disclosed herein are useful in treating conditions in subjects caused, at least in part, by estrogen deficiency, particularly for women with a uterus.
  • the pharmaceutical compositions disclosed herein are useful for the treatment of one or more of the following conditions: endometrial hyperplasia; secondary amenorrhea; prevention of preterm birth, when the subject has a shortened cervix; menopause-related symptoms including, for example, vasomotor symptoms; in relation to treatment of hypoestrogenism related symptoms including, for example and without limitation, hot flashes and night sweats (vasomotor symptoms), sleep disturbances, mood changes and vulvo-vaginal atrophy; and osteoporosis and other non-menopausal disease states or conditions treated with supplemental progesterone or estrogen.
  • the pharmaceutical compositions disclosed herein are useful in treating vasomotor symptoms, including but not limited to, hot flashes and night sweats.
  • the pharmaceutical compositions disclosed herein are useful for treating vasomotor symptoms, including but not limited to,
  • compositions disclosed herein are useful in treating hot flashes and night sweats.
  • the pharmaceutical compositions disclosed herein are useful in treating hot flashes.
  • this disclosure provides methods of treating such a condition by administering to the subject a composition comprising estradiol and progesterone as described herein.
  • a soft gelatin capsule contains a pharmaceutical composition comprising suspended progesterone and solubilized estradiol:
  • the encapsulated pharmaceutical composition of Table 6 may be manufactured in any suitable manner.
  • mixing may be facilitated by an impellor, agitator, or other suitable means.
  • heating or mixing may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas (N 2 ).
  • Mixing or heating for the purposes of this Example may be performed in any suitable vessel, such as a stainless steel vessel.
  • CAPMUL® MCM may be heated to between 30°C to 50°C, more preferably from 35°C to 45°C, and more preferably to 40°C ⁇ 2°C.
  • GELUCIRE® 44/14 may be added to the CAPMUL® MCM and mixed until dissolved (to increase the solubility of progesterone in the final solution, GELUCIRE® 44/14 was added at about 10% w/w). The addition may occur all at once or may occur gradually over a period of time. Heat may continue to be applied during the mixing of the GELUCIRE® 44/14 and the CAPMUL® MCM. [0227] Heat may be removed from the GELUCIRE® 44/14 and CAPMUL® MCM mixture.
  • Estradiol Hemihydrate may be added to the mixture. The addition may occur all at once or may occur gradually over a period of time. Micronized progesterone may then be added to the GELUCIRE® 44/14, CAPMUL® MCM and Estradiol Hemihydrate mixture until dissolved. The addition may occur all at once or may occur gradually over a period of time. EXAMPLE 2
  • a soft gelatin capsule contains a pharmaceutical composition having fully solubilized estradiol and partially solubilized progesterone comprising: Table 8.
  • CAPMUL® MCM is heated to 65°C.
  • GELUCIRE® 44/14 is added and mixed until dissolved. Heat is removed.
  • Estradiol is added and mixed until dissolved.
  • Micronized progesterone is then added and dispersed. The mixture is then passed through a colloid mill. The resultant fill mass can be used for encapsulation.
  • a soft gelatin capsule contains a pharmaceutical composition having fully solubilized estradiol and partially solubilized progesterone comprising: Table 9.
  • CAPMUL® MCM is heated to 65° C.
  • GELUCIRE® 44/14 is added and mixed until dissolved. Heat is removed.
  • Estradiol is added and mixed until dissolved.
  • Micronized progesterone is then added and dispersed.
  • the mixture is then passed through a colloid mill.
  • the resulting pharmaceutical composition is encapsulated in soft gelatin capsules.
  • GELUCIRE® 44/14 is heated to 65° C and CAPMUL® MCM is heated to 40° C ⁇ 5° C to achieve mixing of the oil and the surfactant before heat is removed; estradiol is added while the mixture is cooling; progesterone is added when the mixture has dropped below about 40° C; the mixture is then passed through a colloid mill one or more times, e.g., three times.
  • the objective of this study was to evaluate the pharmacokinetic and oral bioavailability of a combination capsule of 17 ⁇ -estradiol/progesterone in comparison to co-administration of the individual products ESTRACE ® and PROMETRIUM ® .
  • Key inclusion criteria for subjects included a BMI 18.50 to 29.99 kg/m 2 who were nonsmokers or ex-smokers (no smoking in the last 3 months).
  • Key exclusion criteria for subjects included consuming grapefruit juice or poppy-containing foods within 48 hours before and throughout the study, use of any hormonal agent within 14 days before the study, and use of menopausal hormone therapy within 6 months before dosing.
  • each woman After consuming a high-fat, high-calorie breakfast, each woman received a single dose of the combination (Test) capsule in 1 period of the study and single doses of the coadministered products (Reference) in each of the 2 remaining periods. Blood samples were collected within 75 minutes before dosing and post-dose at 0.25, 0.5, 0.67, 0.83, 1 , 1.33, 1.67, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36, and 48 hours after dosing to determine progesterone, free (unconjugated) estradiol, and free and total (conjugated+free, including estrone sulfates) estrone concentrations.
  • the blood samples were centrifuged at 4000 RPM for 10 minutes at 4°C to separate the plasma.
  • the plasma from samples was separated into two aliquots. 1.5 mL from the plasma sample was transferred into aliquot I, and the remaining plasma sample was transferred into aliquot II. These aliquots were stored at -30°C for interim storage, then at -70°C until completion of the analysis.
  • Progesterone, estradiol, estrone, and total estrone in human plasma was determined using the LC-MS/MS method.
  • the primary (C max , AUC 0-t , and AUCo- ⁇ ) and secondary (T max , t1 ⁇ 2, and K e ) PK parameters for each analyte were determined for each subject during each period by non-compartment analyses using baseline-adjusted concentrations.
  • Statistical analyses were conducted using the SAS® statistical software.
  • Results The mean, standard deviation (SD), geometric mean, coefficient of variation (CV %), minimum, median, and maximum were calculated for C max , AUC 0-t , AUCo- ⁇ , T max , t 1 / 2 , Kei, Keijower, K e i_upper, and AUC%Extrap_obs for progesterone, estradiol, estrone, and total estrone.
  • SD standard deviation
  • CV %Extrap_obs minimum, median, and maximum were calculated for C max , AUC 0-t , AUCo- ⁇ , T max , t 1 / 2 , Kei, Keijower, K e i_upper, and AUC%Extrap_obs for progesterone, estradiol, estrone, and total estrone.
  • Tables 10, 11, 12, and 13 For each of Tables 10-13, "Test Product (T)" refers to the progesterone + estradiol pharmaceutical composition, while
  • PROMETRIUM® progesterone
  • ESTRACE® estradiol
  • the pharmaceutical composition comprises about 0.25 mg estradiol and about 50 mg progesterone, and administration of the composition to the subject produces, in a plasma sample from the subject, one or more parameters selected from:
  • administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from: an AUC (0-t) for estrone that is from 909.6091 pg-hr/ml to 1421.2642 pg-hr/ml; and a C max for estrone that is from 42.6549 pg/ml to 66.6483 pg/ml.
  • administration of the composition to subject further produces, in a plasma sample from the subject, one or both parameters selected from: an AUC (0-t) for total estrone that is from 20.1752 ng-hr/ml to 31.5238 ng-hr/ml; and a C max for total estrone that is from 3.5429 ng/ml to 5.5358 ng/ml.
  • the pharmaceutical composition comprises about 0.25 mg estradiol and about 50 mg progesterone
  • administration of the composition to a subject produces, in a plasma sample from the subject, the following parameters: (i) one or both of (a) an AUC (0-t) for estradiol that is from 140.3733 pg-hr/ml to 219.3333 pg-hr/ml and (b) a C max for estradiol that is from 6.4790 pg/ml to 10.1235 pg/ml; and
  • a pharmaceutical composition for co-administering estradiol and progesterone to a human subject in need thereof comprises about 0.50 mg estradiol and about 50 mg progesterone, and administration of the composition to the subject produces, in a plasma sample from the subject, one or more parameters selected from: (i) an AUC (0-t) for estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml;
  • administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from: an AUC (0- t) for estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml, and a C max for estrone that is from 85.3098 pg/ml to 133.2966 pg/ml.
  • administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from: an AUC (0- t) for total estrone that is from 40.3505 ng-hr/ml to 63.0476 ng-hr/ml, and a C max for total estrone that is from 7.0858 ng/ml to 11.0715 ng/ml.
  • the pharmaceutical composition comprises about 0.50 mg estradiol and about 50 mg progesterone, and administration of the composition to a subject produces, in a plasma sample from the subject, the following parameters: (i) one or both of (a) an UQo-o for estradiol that is from 280.7467 pg-hr/ml to
  • a pharmaceutical composition for co-administering estradiol and progesterone to a human subject in need thereof comprises about 0.50 mg estradiol and about 100 mg progesterone, and administration of the composition to the subject produces, in a plasma sample from the subject, one or more parameters selected from:
  • administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from: an AUC (0-t) for estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml, and a C max for estrone that is from 85.3098 pg/ml to 133.2966 pg/ml.
  • administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from: an AUC (0-t) for total estrone that is from 40.3505 ng-hr/ml to 63.0476 ng-hr/ml, and a C max for total estrone that is from 7.0858 ng/ml to 11.0715 ng/ml.
  • the pharmaceutical composition comprises about 0.50 mg estradiol and about 100 mg progesterone
  • administration of the composition to a subject produces, in a plasma sample from the subject, the following parameters: (i) one or both of (a) an AUC (0-t) for estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml and (b) a C max for estradiol that is from 12.9580 pg/ml to 20.2469 pg/ml; and
  • a pharmaceutical composition for co-administering estradiol and progesterone to a human subject in need thereof comprises about 1 mg estradiol and about 100 mg progesterone, and administration of the composition to the subject produces, in a plasma sample from the subject, one or more parameters selected from:
  • administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from: an AUC (0- t) for estrone that is from 3638.4363 pg-hr/ml to 5685.0567 pg-hr/ml, and a C max for estrone that is from 170.6197 pg/ml to 266.5933 pg/ml.
  • administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from: an AUC (0- t) for total estrone that is from 80.7010 ng-hr/ml to 126.0953 ng-hr/ml, and a C max for total estrone that is from 14.1716 ng/ml to 22.1431 ng/ml.
  • the pharmaceutical composition comprises about 0.50 mg estradiol and about 100 mg progesterone
  • administration of the composition to a subject produces, in a plasma sample from the subject, the following parameters: (i) one or both of (a) an AUC (0-t) for estradiol that is from 561.4933 pg-hr/ml to 877.3333 pg-hr/ml and (b) a C max for estradiol that is from 25.9161 pg/ml to 40.4939 pg/ml; and (ii) one or both of (a) an AUC (0-t) for progesterone that is from 48.0348 ng-hr/ml to 75.0543 ng-hr/ml and (b) a C max for progesterone that is from 35.6889 ng/ml to 55.7639 ng/ml; and optionally
  • estrone that is from 3638.4363 pg-hr/ml to 5685.0567 pg-hr/ml and (b) a C max for estrone that is from 170.6197 pg/ml to 266.5933 pg/ml; and optionally
  • the pharmaceutical composition has the blood plasma estradiol concentration profile of Figure 1.
  • the pharmaceutical composition has the blood plasma progesterone concentration profile of Figure 2.
  • the pharmaceutical composition has the blood plasma estrone concentration profile of Figure 3.
  • the pharmaceutical composition has the blood plasma total estrone concentration profile of Figure 4.
  • the one or more parameters as described herein are measured at regular intervals (e.g., about every 30 minutes, about every 60 minutes, or about every 90 minutes) or at in-egular intervals over a period of time such as 24 hours or 48 hours.
  • the one or more parameters as described herein are measured at about 0.25 hr, 0.5 hr, 0.67 hr, 0.83 hr, 1 hr, 1.33 hr, 1.67 hr, 2 hr, 2.5 hr, 3 hr, 4 hr, 5 hr, 6 hr, 7 hr, 8 hr, 10 hr, 12 hr, 18 hr, 24 hr, 36 hr, or 48 hr after administering the pharmaceutical composition to the subject.
  • the one or more parameters as described herein are measured at regular or irregular intervals following the administration of a single dose or of a first dose of the pharmaceutical composition to the subject.
  • the subject has a condition that is caused at least in part by an estrogen deficiency (e.g., one or more symptoms of menopause, such as vasomotor symptoms).
  • the method comprises administering to the subject a pharmaceutical composition comprising solubilized estradiol, suspended progesterone, and a solubilizing agent that comprises a medium chain (C6-C 12) oil as described herein, wherein administration of the pharmaceutical
  • the method comprises administering a pharmaceutical composition comprising estradiol at a dosage of about 0.05, 0. 1 , 0. 125, 0.15, 0.20, 0.25, 0.30, 0.35, 0.375, 0.40, 0.45, 0.50, 0.55, 0.60, 0.625, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1 .00, 1 .
  • progesterone at a dosage of about 25, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, or 400 mg.
  • the method comprises administering a pharmaceutical composition comprising: estradiol at a dosage of about 0.25 mg and progesterone at a dosage of about 50 mg; estradiol at a dosage of about 0.50 mg and progesterone at a dosage of about 50 mg; estradiol at a dosage of about 0.50 mg and progesterone at a dosage of about 100 mg; estradiol at a dosage of about 1 mg and progesterone at a dosage of about 100 mg; or estradiol at a dosage of about 2 mg and progesterone at a dosage of about 200 mg.
  • the method comprises administering to the subject a
  • composition comprising about 0.25 mg estradiol and about 50 mg progesterone, wherein administration of the pharmaceutical composition produces, in a plasma sample from the subject, one or more parameters selected from: (i) an area under the curve (AUC)(o-t) for estradiol that is from 140.3733 pg-hr/ml to 21 9.3333 pg-hr/ml;
  • administration of the pharmaceutical composition further produces, in a plasma sample from the subject, one or more parameters selected from: an AUC (0- t) for estrone that is from 909.6091 pg-hr/ml to 1421 .2642 pg-hr/ml; a C max for estrone that is from 42.6549 pg/ml to 66.6483 pg/ml; an AUC (0-t) for total estrone that is from 20.1752 ng-hr/ml to 31 .5238 ng-hr/ml; and a C max for total estrone that is from 3.5429 ng/ml to 5.5358 ng/ml.
  • the method comprises administering to the subject a
  • composition comprising about 0.25 mg estradiol and about 50 mg progesterone, wherein administration of the pharmaceutical composition produces, in a plasma sample from the subject, the following parameters:
  • the method comprises administering to the subject a
  • composition comprising about 0.50 mg estradiol and about 50 mg progesterone, wherein administration of the pharmaceutical composition produces, in a plasma sample from the subject, one or more parameters selected from:
  • administration of the composition to the subject further produces, in a plasma sample from the subject, one or more parameters selected from: an AUC (0- t) for estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml; a C max for estrone that is from 85.3098 pg/ml to 133.2966 pg/ml; an AUC (0-t) for total estrone that is from 40.3505 ng-hr/ml to 63.0476 ng-hr/ml; and a C max for total estrone that is from 7.0858 ng/ml to 11.0715 ng/ml.
  • the method comprises administering to the subject a
  • composition comprising about 0.50 mg estradiol and about 50 mg progesterone, wherein administration of the pharmaceutical composition produces, in a plasma sample from the subject, the following parameters:
  • estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml and (b) a C max for estradiol that is from 12.9580 pg/ml to 20.2469 pg/ml;
  • the method comprises administering to the subject a
  • composition comprising about 0.50 mg estradiol and about 100 mg progesterone, wherein administration of the pharmaceutical composition produces, in a plasma sample from the subject, one or more parameters selected from:
  • administration of the composition to the subject further produces, in a plasma sample from the subject, one or more parameters selected from: an AUC (0- t) for estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml; a C max for estrone that is from 85.3098 pg/ml to 133.2966 pg/ml; an AUC (0-t) for total estrone that is from 40.3505 ng-hr/ml to 63.0476 ng-hr/ml, and a C max for total estrone that is from 7.0858 ng/ml to 11.0715 ng/ml.
  • the method comprises administering to the subject a
  • composition comprising about 0.50 mg estradiol and about 100 mg progesterone, wherein administration of the pharmaceutical composition produces, in a plasma sample from the subject, the following parameters:
  • estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml and (b) a C max for estrone that is from 85.3098 pg/ml to 133.2966 pg/ml; and optionally
  • the method comprises administering to the subject a
  • composition comprising about 1 mg estradiol and about 100 mg progesterone, wherein administration of the pharmaceutical composition produces, in a plasma sample from the subject, one or more parameters selected from: (i) an area under the curve (AUC)(o-t) for estradiol that is from 561 .4933 pg-hr/ml to 877.3333 pg-hr/ml;
  • administration of the composition to the subject further produces, in a plasma sample from the subject, one or more parameters selected from: an AUC (0- t) for estrone that is from 3638.4363 pg-hr/ml to 5685.0567 pg-hr/ml; a C max for estrone that is from 170.6197 pg/ml to 266.5933 pg/ml; an AUC «j-t) for total estrone that is from 80.7010 ng-hr/ml to 126.0953 ng-hr/ml; and a C max for total estrone that is from 14.1716 ng/ml to 22.143 1 ng/ml.
  • the method comprises administering to the subject a
  • composition comprising about 1 mg estradiol and about 100 mg progesterone, wherein administration of the pharmaceutical composition produces, in a plasma sample from the subject, the following parameters:
  • estrone that is from 3638.4363 pg-hr/ml to 5685.0567 pg-hr/ml and (b) a C max for estrone that is from 170.6197 pg/ml to 266.5933 pg/ml; and optionally
  • Vasomotor symptoms To determine whether the TX-001HR given in a continuous fashion is effective at reducing the frequency and severity of moderate to severe vasomotor symptoms associated with menopause when compared with placebo treatment at weeks 4 and 12.
  • Endometrial hyperplasia To determine whether TX-001HR given in a continuous fashion is effective at achieving a ⁇ 1% incidence rate of endometrial hyperplasia following 12 months of therapy.
  • a subject MUST: (1) be a female between the ages of 40 and 65 years (at the time of randomization) who is willing to participate in the study, as documented by signing the informed consent form; (2) be a postmenopausal woman with an intact uterus and a Screening serum estradiol level of ⁇ 50 pg/mL.
  • Postmenopausal is defined herein as: (a) 12 ⁇ months of spontaneous amenorrhea, or (b) at least 6 months of spontaneous amenorrhea with a Screening serum FSH level of >40 mlU/ml, or (c) 6 ⁇ weeks postsurgical bilateral
  • oophorectomy (3) be seeking treatment or relief for vasomotor symptoms associated with menopause; (4) to participate in the VMS Substudy, a subject must also report 7 mod ⁇ erate to severe hot flushes per day, or 5 ⁇ 0 per week, at the baseline assessment during Screening;
  • the most recent 7 consecutive days of data prior to randomization (Day -7 to Day -1) will be used to determine the baseline number of mild, moderate and severe hot flushes for each subject.]; (5) have a Body Mass Index (BMI) less than or equal to 34 kg/m 2 (BMI values should be rounded to the nearest integer [e.g., 34.4 rounds down to 34, while 26.5 rounds up to 27]); (6) be willing to abstain from using products (other than study medication) that contain estrogen, progestin, or progesterone throughout study participation; (7) be judged by the principal or sub-investigator physician as being in otherwise generally good health based on a medical evaluation performed during the Screening period prior to the initial dose of study medication.
  • BMI Body Mass Index
  • the medical evaluation findings must include: (a) a normal or non-clinically significant physical examination, including vital signs (sitting blood pressure, heart rate, respiratory rate and temperature). Sitting systolic blood pressure must be ⁇ 140 mmHg and diastolic blood pressure must be ⁇ 90 mmHg at Screening. A subject may be taking up to two antihypertensive medications; (b) a normal or non- clinically significant pelvic examination; (c) a mammogram that shows no sign of significant disease (can be performed within previous 6 months prior to initial dose of study medication). Subjects must have a BI-RADS 1 or 2 to enroll in the study. An incomplete mammogram result, i.e. BI-RADS 0, is not acceptable.
  • the site must obtain a copy of the official report for the subject's study file, and it must be verified that the mammogram itself is available if needed for additional assessment; (d) a normal or non-clinically significant clinical breast examination.
  • An acceptable breast examination is defined as no masses or other findings identified that are suspicious of malignancy; (e) a normal Screening Papanicolaou (“Pap”) smear. (Subjects with findings of atypical glandular cells [AGC], AGUS, ASCUS with high risk HPV type upon reflex testing, LSIL, ASC-H, ITSIL, dysplastic cells, or malignant cells must be excluded from randomization.); (f) an acceptable result from an evaluable Screening endometrial biopsy.
  • the endometrial biopsy reports by the two central pathologists at Screening must each specify one of the following: proliferative endometrium; weakly proliferative endometrium; disordered proliferative pattern; secretory endometrium; endometrial tissue other (including benign, inactive or atrophic fragments of endometrial epithelium, glands, stroma, etc.); endometrial tissue insufficient for diagnosis; no endometrium identified; or no tissue identified.
  • at least one pathologist must identify sufficient tissue to evaluate the biopsy.
  • the endometrial biopsy reports by the two central pathologists of Other Findings at Screening must each specify one of the following: endometrial polyp not present; benign endometrial polyp; or polyp other. See Exclusion criteria #27 and #28; (g) a normal or non-clinically significant 12- lead ECG.
  • a subject To participate in the study, a subject must NOT: (1) be currently hospitalized; (2) have a history of thrombosis of deep veins or arteries or a thromboembolic disorder; (3) have a history of coronary artery or cerebrovascular disease (e.g., myocardial infarction, angina, stroke, TIA); (4) have a history of a chronic liver or kidney dysfunction/disorder (e.g., Hepatitis C or chronic renal failure); (5) have a history of a malabsorption disorder (e.g., gastric bypass, Crohn's disease); (6) have a history of gallbladder dysfunction/disorders (e.g., cholangitis, cholecystitis), unless gallbladder has been removed; (7) have a history of diabetes, thyroid disease or any other endocrinological disease.
  • a malabsorption disorder e.g., gastric bypass, Crohn's disease
  • immunologic, dermatologic, neurologic, psychological e.g., bipolar disorder, schizophrenia, major depressive disorder
  • musculoskeletal disease or disorder that is clinically significant in the opinion of the Principal Investigator or Medical Sub-Investigator; (16) have any of the following clinical laboratory values at Screening: (a) fasting triglyceride of 300 ⁇ mg/dL and/or total cholesterol of 3 ⁇ 00mg/dL; (b) positive laboratory finding for Factor V Leiden mutation; (c) AST or ALT ⁇ 1.5 times the upper limit of normal (ULN); (d) fasting glucose >125 mg/dL; (17) be known to be pregnant or have a positive urine pregnancy test.
  • a pregnancy test is not required for subjects who have had bilateral tubal ligation, bilateral oophorectomy, or are 55 years old or greater and have experienced cessation of menses for at least 1 year.); (18) have contraindication to estrogen and/or progestin therapy or allergy to the use of estradiol and/or progesterone or any components of the investigational drugs; (19) use 15 or more cigarettes per day or currently use any electronic cigarettes; (20) have a history of drug and/or alcohol abuse within one year of start of study; (21) have used, within 28 days prior to the initial dose of study medication at Visit 1, any medication known to induce or inhibit CYP3A4 enzyme activity that may affect estrogen and/or progestin drug metabolism; (22) have used, within 28 days prior to Screening, or plan to use during the study, any prescription or over-the-counter (OTC) medication (including herbal products, such as St.
  • OTC over-the-counter
  • vaginal nonsystemic hormonal products rings, creams, gels
  • vaginal systemic products e.g., FemRing
  • transdermal estrogen alone or estrogen/progestin products within 8 weeks prior to Screening
  • Oral estrogen and/or progestin therapy and/or SERM within 8 weeks prior to Screening
  • Progestational implants, estrogen or estrogen progestational injectable drug therapy within 3 months prior to Screening
  • estrogen pellet therapy or progestational injectable drug therapy within 6 months prior to Screening
  • oral, topic rings, creams, gels
  • vaginal systemic products e.g., FemRing
  • transdermal estrogen alone or estrogen/progestin products within 8 weeks prior to Screening
  • Oral estrogen and/or progestin therapy and/or SERM within 8 weeks prior to Screening
  • Progestational implants, estrogen or estrogen progestational injectable drug therapy within 3 months prior to Screening
  • SSRIs serotonin reuptake inhibitors
  • SNRIs serotonin and norepinephrine reuptake inhibitors
  • aldomet dopaminergic or antidopaminergic drugs, gabapentin, clonidine, or bellergal
  • (26) have any reason which, in the opinion of the Principal Investigator or Medical Sub-Investigator, would prevent the subject from safely participating in the study or complying with protocol requirements
  • (27) have a Screening endometrial biopsy sample that is found by both primary pathologists to have endometrial tissue insufficient for diagnosis, no endometrium identified, or no tissue identified.
  • progesterone other than study medication in the specified timeframes prior to Screening outlined in Section B.2 (Exclusion Criteria) nor during the study.
  • Subjects were instructed to report all concomitant medications, including over the counter (OTC) products and herbal or nutritional supplements/medications. Subject were also instructed to report any changes in concomitant medications; they are to be questioned by site personnel regarding concomitant medications at each site visit and, when appropriate, during contacts between visits.
  • OTC over the counter
  • a complete medical history including demographic data (age, sex, race and ethnicity), surgical and gynecological history (date of last menstrual period, date of bilateral oophorectomy, if applicable), and use of tobacco and alcohol history was recorded.
  • the medical history included a review of all past and current diseases. It also included the history of hot flushes. Any hormonal therapy taken within 6 months prior to this visit was recorded (using generic names, if known) with the corresponding indication.
  • the other medications to be recorded included prescription and OTC medications, dietary supplements, and all products taken within 30 days prior to the Screening visit.
  • a complete physical examination was conducted at Screening and Visit 7/End of Treatment.
  • the physical examination included, at a minimum, examination of the subject's general appearance, HEENT (head, eyes, ears, nose and throat), heart, lungs, musculoskeletal system, gastrointestinal (GI) system, neurological system, lymph nodes, abdomen and extremities.
  • the subject's height was measured at Screening only and body weight (while the subject is lightly clothed) was measured at Screening, Week 12, Month 6, and the End of Treatment. BMI was calculated.
  • a urine pregnancy test was performed at the very start of Screening. If the pregnancy test were positive, the subject was excluded from study participation. A pregnancy test was not required for subjects who had a bilateral tubal ligation, bilateral oophorectomy, or who are 55 years old or greater and have experienced cessation of menses for at least 1 year.
  • Blood Chemistry Sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), iron, albumin, total protein, aspartate aminotransferase (AST), alanine aminotransferase (ALT), amylase, alkaline phosphatase, serum creatinine, calcium, phosphate, uric acid, total bilirubin, glucose, triglycerides, total cholesterol, HDL, LDL (must be fasting a minimum of 8 hours).
  • CBC Complete blood count
  • WBC white blood cell count
  • RBC red blood cell
  • thromboplastin time APTT
  • fibrinogen a factor for thromboplastin
  • Protein C a factor for thromboplastin
  • Protein S a factor for thromboplastin
  • antithrombin III a factor for thromboplastin activity
  • Factor V Leiden a factor for thromboplastin time
  • FSH Follicle-stimulating hormone
  • TSH thyroid-stimulating hormone
  • Urine analysis Appearance, specific gravity, protein, pH.
  • Urine Pregnancy Test A pregnancy test was not required for subjects who had a bilateral tubal ligation, bilateral oophorectomy or are 55 ⁇ years old and have experienced cessation of menses for at least 1 year. A test could have been performed at any time during the study if a pregnancy was suspected.
  • Clinical laboratory tests could be repeated with prior approval of the Sponsor or designee only.
  • the Principal Investigator or a qualified and delegated Medical Sub-Investigator were responsible for interpreting the laboratory findings (i.e. , determining the clinical significance of any abnormal values indicated) and for signing and dating the laboratory report. Any clinically relevant changes requiring treatment, interruption or discontinuation of study medication occurring during the trial were reported as an adverse event.
  • Any authorized and qualified person was allowed to collect biological samples from the subject. The date and time of sample collection was recorded. A central laboratory was designated for this study to perform the analyses of blood and urine samples and to provide applicable kits, supplies, and instructions for the collection and handling of samples. Estradiol evaluations for screening inclusion criteria were conducted by a validated rapid chromatographic assay. All baseline and post-treatment estradiol, estrone, and progesterone were done by a validated bioanalytical assay. Sample collection and handling procedures for laboratory assessments were performed according to the procedures designated by the central laboratory. Contact information and relevant documentation regarding the central laboratory were provided separately.
  • Mammogram may have been performed within previous 6 months of first dose of study medication; the site must obtain a copy of the official report for the subject's study file, and it must be verified that the mammogram itself is available if needed for additional assessment. If the subject had not had a mammogram within the previous 6 months prior to the first dose of study medication or relevant documentation cannot be obtained, one was performed before the subject can be randomized).
  • Endometrial biopsies were performed by a board-certified gynecologist and the procedure, including instrument used, will be documented in the subject's source file.
  • the Screening endometrial biopsy was performed at various times during the screening period; however, it was suggested that it be performed last, after other screening assessments have indicated that the subject is otherwise an eligible candidate for the study to avoid performing unnecessary invasive procedures on subjects who screen fail for other reasons (preferably it was carried out around the middle of the Screening period, allowing for sufficient time to receive the pathologists' reports during the Screening window).
  • Biopsy specimens were processed by a central laboratory. To ensure uniformity in interpretation, a chartered Pathology Committee consisting of four independent pathologists who are experts in the field of endometrial pathology assessed endometrial biopsy samples in a blinded fashion. Instructions and other additional information regarding performing the endometrial biopsies, submission of samples and reporting were provided separately in the study Pathology Committee Charter.
  • the Screening endometrial biopsy could be repeated once when an initial endometrial biopsy was performed and both of the primary pathologists report endometrial tissue insufficient for diagnosis, no endometrium identified, or no tissue identified, and if the subject has met all other protocol-specified eligibility criteria to date.
  • End of Treatment or Early Termination biopsy was repeated once when all three of the pathologists report endometrial tissue insufficient for diagnosis, no endometrium identified, or no tissue identified. End of Treatment or Early Discontinuation endometrial biopsies that needed to be repeated per protocol were performed within 30 days of the final dose of study medication.
  • Hot Flush diary Upon completion of the initial screening procedures, all subjects who were determined to be eligible to continue screening were provided with a Hot Flush diary that was completed for the remainder of the Screening period. Subjects were instructed to complete the diary on a daily basis by recording the number and severity of vasomotor symptoms (hot flushes) in their diaries.
  • Substudy hot flush requirements were randomized into the non-Substudy portion of the trial until enrollment was completed.
  • MENQOL Menopause-specific quality of life questionnaire
  • MOS-Sleep The 1992 version of the Medical Outcomes Study-Sleep Questionnaire (MOS-Sleep), which is described by Hays, RD and Stewart, AL, Sleep Measures, in A.L. Stewart and .I.E. Ware (eds.), Measuring functioning and well-being: The Medical Outcomes Study approach (pp.235-259), Durham, NC: Duke University Press, 1992), was utilized to assess changes in sleep.
  • the MOS-Sleep questionnaire was conducted at Visits 1 , 4, 5 and 7.
  • the Screening Period began on the date that the subject signed the informed consent form. The prospective subjects visited the study center and were assessed by qualified and properly delegated study staff to verify eligibility and exclude any co-morbid conditions.
  • the screening evaluation period was completed within 60 days; however, the period may have been longer with the approval of the Medical Monitor. All Screening assessments were completed prior to randomization. Completion of Screening procedures typically required at least two clinic visits prior to randomization at Visit 1.
  • BP height and body weight measurements were taken, and BMI was calculated; a physical exam was carried out; 12-lead ECG was carried out; pelvic and breast examination was carried out; a pap smear was done; blood and urine samples were collected for blood chemistry, hematology and coagulations tests; blood samples were collected for measurements of FSH (subjects with ⁇ 12 months of spontaneous amenorrhea or bilateral oophorectomy were excluded), estradiol, estrone, progesterone, and TSH levels (note: if TSH was abnormal as per lab range, reflex testing of T3 and T4 was performed); a urine pregnancy test (subjects with history of tubal ligation, bilateral oophorectomy, or 5 ⁇ 5 years of age and amenorrheic for at least 1 year were excluded); mammogram was performed (if not completed within 6 months of Visit 1 or if a report was not available); endometrial biopsy was performed; dispensed Issue Treatment Hot Flush/Bleeding
  • the following procedures and evaluations were conducted at this visit: collection of vital signs (body temperature, HR, RR, and BP); blood collection for the monitoring of serum levels of estradiol and estrone; collection and review of completed subject diaries for the previous 4 weeks of treatment by site personnel; Issue Treatment Hot Flush/Bleeding and Spotting diaries were dispersed for the subsequent 4 weeks of treatment (with allowances for the visit window) and instructions for completion were reviewed, if necessary by site personnel; study medication was dispensed for the subsequent 4 weeks of treatment (with allowances for the visit window) and
  • CGI assessment 10 Global Impression assessment 10 was completed; and subjects were instructed to return to the study site in approximately 4 weeks (Day 56 ⁇ 3 days).
  • body temperature, HR, RR, and BP body weight measurements were taken; blood sample was collected for blood chemistry, hematology and coagulations tests; blood sample was collected for measurements of estradiol, estrone, and progesterone levels; a urine analysis was done;
  • Subjects were instructed to return to the study site in approximately 3 months (Month 6, Day 180 ⁇ 4 days). In addition, study subjects were notified that they may be contacted via telephone (or other means as appropriate) between visits. If contacted, subjects would be queried for treatment compliance, adverse events, and concomitant medications. If necessary, the subject will be re-instructed by site personnel on study medication self-administration and compliance with other study requirements (e.g., diary completion). All contacts with the subjects should have been documented in their source files.
  • Subjects enrolled in the VMS Substudy will continue their participation along with non-Substudy subjects after 12 weeks of evaluation.
  • Subjects were instructed to return to the study site in approximately 3 months (Month 9, Day 270 ⁇ 4 days). In addition, study subjects were notified that they may be contacted via telephone (or other means as appropriate) between visits. If contacted, subjects would be queried for treatment compliance, adverse events, and concomitant medications. If necessary, the subject will be re-instructed by site personnel on study medication self-administration and compliance with other study requirements (e.g., diary completion). All contacts with the subjects should have been documented in their source files.
  • Subjects were instructed to return to the study site in approximately 3 months (Month 12, Day 360 ⁇ 4 days). In addition, study subjects were notified that they may be contacted via telephone (or other means as appropriate) between visits. If contacted, subjects would be queried for treatment compliance, adverse events, and concomitant medications. If necessary, the subject will be re-instructed by site personnel on study medication self-administration and compliance with other study requirements (e.g., diary completion). All contacts with the subjects should have been documented in their source files.
  • Each subject who received study medication received a follow-up phone call, regardless of the duration of therapy, approximately 15 days following the last dose of study medication.
  • the follow-up generally took place after receipt of all safety assessments (e.g., endometrial biopsy and mammography results).
  • the follow-up phone call included: review of ongoing adverse events and any new adverse events that occurred during the 15 days following the last dose of study medication; review of ongoing concomitant medications and any new concomitant medications that occurred during the 15 days following the last dose of study medication;
  • TX-001HR is an oval, opaque, pink, soft gelatin formulation of a combination product comprising of 17 ⁇ -estradiol hemihydrate and micronized progesterone.
  • Study medication were dispensed to all eligible subjects at Visits 1 to 6. At Visits 2 to 7 subjects were instructed to return all used study medication containers and any unused study medication to study personnel in the original packaging, and were dispensed with the new medication for the subsequent period.
  • F.l.2 Primary Safety Endpoint Endometrial Hyperplasia •
  • the primary safety endpoint was the incidence rate of endometrial hyperplasia at 12 months (to demonstrate a hyperplasia rate that is ⁇ 1 percent with an upper bound of the one-sided 95 percent CI for that rate that does not exceed 4 percent) based on an a priori plan in which a consensus among two out of three pathologists is the final endometrial pathology diagnosis. When the two primary pathologists disagree on the presence of hyperplasia, the read of the third pathologist will be utilized.
  • Non-endometrial malignancy/non-hyperplasia- includes proliferative endometrium, weakly proliferative endometrium, disordered proliferative pattern, secretory endometrium, endometrial tissue (other) [i.e. , benign, inactive or atrophic fragments of endometrial epithelium, glands, stroma, etc.], endometrial tissue insufficient for diagnosis, no endometrium identified, no tissue identified, other.
  • Endometrial hyperplasia- includes simple hyperplasia with or without atypia and complex hyperplasia with or without atypia.
  • Secondary VMS SubStudy Endpoints include the following:
  • vasomotor symptoms from baseline at each week up to week 12.
  • a supplemental secondary analysis was performed.
  • the secondary endpoint was the incidence rate of endometrial hyperplasia at 12 months based on agreement of two of the three pathologists' reads. All biopsies were read by three blinded pathologists, and the results from the three pathologists were utilized. In this supplemental analysis, the final diagnosis was based on agreement of two of the three pathologist reads. Consensus was reached when two of the three pathologist readers agreed on any of the above categories. For example, any 2
  • Non-endometrial malignancy/non-hyperplasia was classified as “Category 1 : Non-endometrial malignancy/non-hyperplasia.” If all three readings were disparate (i.e., each falls into a different category- Category 1 , 2, or 3), the final diagnosis was based on the most severe of the three readings.
  • Subjects in the VMS Substudy were randomized within each study site to one of the treatment groups below in a 1 : 1 : 1 : 1 : 1 allocation ratio. Subjects not in the VMS Substudy were randomized to one of the active treatment groups in a 1 : 1 : 1 : 1 allocation ratio. Subjects were randomized to study medication within each site using a reproducible, computer- generated block randomization schedule. Randomization codes were generated and held with restricted access to decrease the chance of unblinding and to minimize bias.
  • the overall study sample size was based on the target that the combination therapy is effective at achieving a ⁇ 1 % incidence rate of endometrial hyperplasia following 12 months of therapy and that the upper bound of the 95% confidence interval of the estimated incidence rate is ⁇ 4%.
  • the VMS sub-study sample size was based on the expected changes in average weekly frequency and severity of vasomotor symptoms from baseline to weeks 4 and 12.
  • VMS Sub-study The primary method of analysis for both frequency counts and severity index was to account for missing information using imputation by last observation carried forward and a linear mixed effects covariance pattern model that treated subjects as a random effect and accounted for the repeated frequency and severity measures at baseline, week 4 and week 12. Each of the four active treatment groups and the 4 co-primary outcomes were compared to the placebo group in a hierarchical order to preserve the test level of significance for each comparison at 5% (two-sided). A two-group t-test was used to estimate sample size requirements.
  • Endometrial Hyperplasia All Treated subjects randomized to an active treatment group who remain on study treatment for 12 months, no major protocol violations, and have a biopsy at baseline and month 12 that can be evaluated for the presence of endometrial hyperplasia. In addition, if endometrial hyperplasia is diagnosed at a mid- study visit in a subject who had a definitive biopsy at baseline, the subject with the endometrial hyperplasia event will be counted in calculating the annual incidence.
  • VMS Sub-study Modified Intent-to-Treat All Treated subjects who qualify for the VMS Sub-study, had baseline measurement of frequency and severity of moderate to severe hot flushes, and had at least one week of reporting of frequency and severity of hot flushes following initiation of study treatment;
  • Efficacy analyses for endometrial hyperplasia will be performed using the EH population, efficacy analyses for VMS will be performed using the MITT and EE populations, and safety analyses will be performed using the All Treated/Safety population.
  • Concomitant Medications included any medication or health product taken during the active study treatment period.
  • Pre-trial medications included any medications taken within 30 days of randomization. The number of subjects and percent using medications were tabulated according to the medication's World Health Organization (WHO)Therapeutic Drug Class and Generic Term (2010 March dictionary or later) by treatment assignment for the All Treated population. There are separate tables for Pre-trial and Concomitant Medications. Subjects taking a medication more than once were only counted once for that medication.
  • WHO World Health Organization
  • Missing Data If there was missing data within a week of diary data, the following methods were used to estimate missing data.
  • the missing days of data within that week were estimated by the average of the non-missing days within that week. Once the missing values within the week hae been replaced with the average, the 7 days of values were used to calculate the score for that week.
  • a weekly severity score of zero (0) will be assigned for subjects reporting no hot flushes for a given assessment week.
  • the primary safety endpoint was the incidence rate of endometrial hyperplasia at 12 months (to demonstrate a hyperplasia rate that is ⁇ 1 percent with an upper bound of the onesided 95 percent CI for the rate that does not exceed 4 percent) based on an a priori plan in which a consensus among two out of three pathologists was the final endometrial pathology diagnosis. When the two primary pathologists disagreed on the presence of hyperplasia, the read of the third pathologist was utilized. [0389] For the primary endpoint, all endometrial biopsies were centrally read by three pathologists. Two pathologists, designated by the sponsor, were considered to be the primary pathologists (the pathologists were blinded to this designation).
  • Non-endometrial malignancy/non-hyperplasia includes proliferative endometrium, weakly proliferative endometrium, disordered proliferative pattern, secretory endometrium, endometrial tissue (other) [i.e., benign, inactive or atrophic fragments of endometrial epithelium, glands, stroma, etc.], endometrial tissue insufficient for diagnosis, no endometrium identified, no tissue identified, other.
  • Endometrial hyperplasia- includes simple hyperplasia with or without atypia and complex hyperplasia with or without atypia.
  • a confidence interval approach was used to determine if the hyperplasia incidence rate was acceptable. For each active treatment group, the incidence rate of hyperplasia at year 1 and the associated upper 95% 1 -sided confidence limit was calculated.
  • the primary analysis population for endometrium hyperplasia was endometrial hyperplasia (EH) population.
  • EH subject at year 1 is one who is randomly assigned and takes at least 1 dose of study medication, with no exclusionary protocol violation (as detailed at the Statistical Analysis Plan) and has a pretreatment endometrial biopsy and a biopsy at year 1 , or who has developed endometrial hyperplasia at any time during the study.
  • assessments were made for changes in frequency and severity of mild, moderate and severe vasomotor symptoms for each assessment week up to week 12. Two assessments were made with one including only moderate and severe vasomotor symptoms and one including mild, moderate and severe vasomotor symptoms. Severity scores were set to zero (0) for subjects reporting no moderate or severe flushes for the moderate and severe assessment, and set to zero (0) for subjects reporting no hot flushes for the mild moderate and severe assessments. Additionally, percent reductions from baseline and respective differences from placebo were reported.
  • the percent of treatment responders was identified within each treatment arm and compared (active treatments to placebo) at weeks 4, 8, and 12 by using the methodology described by Gerlinger et ah, supra, that combines subject self-assessment of satisfaction with treatment (using the CGI) and changes in reported moderate to severe flushes.
  • the Gerlinger approach first stratifies subjects' change from baseline in the number of moderate to severe hot flushes by their CGI response (7 levels ranging from "very much worse” to "very much better”); then discriminant analysis is applied to identify minimally clinically important reductions in the number of hot flushes that study subjects perceive as beneficial and that are then used to define a responder.
  • a second approach to identifying treatment responders was to calculate the percent of subjects with 50% and, separately, 75% reduction from baseline in moderate to severe vasomotor symptoms at each week up to week 12 and compare between active and placebo treatments.
  • a supplemental secondary analysis was performed. The results from the three pathologists were utilized. In this supplemental analysis the final diagnosis was based on agreement of two of the three pathologist reads. Consensus was reached when two of the three pathologist readers agreed on any of the above categories. For example, any 2 subcategories of "Non-endometrial malignancy/non-hyperplasia" was classified as "Category 1 : Non-endometrial malignancy/non-hyperplasia.” If all three readings were disparate (i.e., each fell into a different category - Category 1 , 2, or 3), the final diagnosis was based on the most severe of the three readings. G.6.2 Other Analyses
  • Percent amenorrhea Amenorrhea is defined as absence of bleeding or spotting. Within each treatment arm, the portion of subjects with cumulative amenorrhea from day 1 to day 364 was calculated and compared between active and placebo treatments.
  • Percent no bleeding No bleeding is defined as absence of bleeding. Within each treatment arm, the percent of subjects with no bleeding was calculated by cycle and for consecutive cycles and compared between active and placebo treatments.
  • MENQOL The menopause-specific quality of life questionnaire assesses changes in quality of life of study subjects over a one month period. It was self-administered and was measured at baseline and at week 12, month 6 and month 12 during the study. It is composed of 29 questions distributed across 4 domains: vasomotor, psychosocial, physical and sexual. There is no total score so domain scores were analyzed separately. Change in monthly scores were summarized and described within each treatment group.
  • MOS-Sleep The Medical Outcomes Study Sleep self-report questionnaire has 12 items that measure six dimensions of sleep over the past four weeks. It was self-administered and was measured at baseline and was measured at baseline and at week 12, month 6 and month 12 during the study. Change in scores over the past four weeks (total and subscales) was analyzed within each treatment.
  • Safety and tolerability were assessed by summarizing the incidence, relatedness, severity, and type of adverse events and treatment-emergent changes in safety evaluation criteria. Safety evaluation results were listed for all subjects and summaries will be tabulated by treatment. All safety and tolerability analyses were descriptive and used the All Treated/Safety population.
  • Adverse Events The number (percentage) of subjects with at least one treatment- emergent AE will be presented in a frequency table by MedDRA system-organ class and per MedDRA "preferred" term. A similar summary will be created for SAEs and AEs resulting in interruption of treatment or leading to discontinuation of study medication. Summaries will also be presented by severity and relationship to study medication.
  • TX-001HR estradiol 1 mg/progesterone 100 mg and TX-001HR estradiol 0.5
  • TX-001HR estradiol 0.5 mg/progesterone 50 mg and TX-001HR estradiol 0.25
  • mg/progesterone 50 mg were not statistically significant at all of the co-primary efficacy endpoints (see, Tables 26-29, below).
  • the estradiol 0.25 mg/progesterone 50 mg dose was included in the clinical trial as a non-effective dose to meet the requirement of the FDA guidance to identify the lowest effective dose. •
  • the incidence of consensus endometrial hyperplasia or malignancy was 0% across all four TX-001HR doses, meeting the recommendations as established by the U.S. Food and Drug Agency's (FDA) 12 draft guidance (see, Table 30, below).
  • the co-primary efficacy endpoints in the Replenish Trial were the change from baseline in the number and severity of hot flashes at weeks 4 and 12 as compared to placebo. 13
  • the primary safety endpoint was the incidence of endometrial hyperplasia with up to 12 months of treatment. General safety was also evaluated.
  • estradiol 1 mg/progesterone 100 mg and estradiol 0.5 mg/progesterone 100 mg were also associated with clinically meaningful and statistically significant improvements in secondary endpoints including:
  • MENQOL Menopause-Specific Quality of Life
  • CGI Clinical Global Impression
  • TX-001HR is the first bio-identical hormone therapy of estradiol in combination with natural progesterone to be evaluated in a large, well-controlled, randomized clinical trial.
  • the Replenish Trial demonstrated for the first-time safety and robust efficacy for the treatment of hot flashes of multiple doses of estradiol in combination with natural progesterone with a consistency of effect noted on the primary and secondary efficacy endpoints.
  • TX- 001HR establishes the FDA required endometrial safety for multiple doses of estradiol in combination with natural progesterone in continuous combined regimen.
  • a LOCF analysis was also -performed on the MITT- VMS population and the EE-VMS population.
  • the LOCF results were similar to those noted in the MMRM analyses for both populations.
  • the mean change in severity was statistically significantly different from placebo for the 1 mg E2/100 mg P, 0.5 mg E2/100 mg P, and 0.25 mg E2/50 mg P treatment groups.
  • results of the MMRM analysis of the change from Baseline to Weeks 4 and 12 in severity of moderate to severe VMS for the EE- VMS population and for Week 1 through Week 12 were also determined.
  • results were similar to the MITT- VMS population with the 1 mg E2/100 mg P, 0.5 mg E2/100 mg P, and 0.5 mg E2/50 mg P active treatment groups being statistically different from placebo.
  • Baseline values, mean changes from Baseline, and LS mean change from placebo in the weekly frequency of mild, moderate, and severe VMS at Weeks 4 and 12 are shown in Table 40. Data for Weeks 1 -12 were also collected. The mean change from Baseline for all groups are presented graphically in Figure 9.
  • M IT T-VMS modified intent to treat -vasomotor symptom
  • K2 - 1 7 ⁇ -estradiol P - progesterone
  • I ,S - least square SE - standard error
  • MMRM mixed model repeated measures
  • Results for the EE- VMS population are not different than those for the MITT- VMS population.
  • Baseline values, mean changes from Baseline, and LS mean change from placebo in the weekly frequency of mild, moderate, and severe VMS at Weeks 4 and 1 2 are shown in Table 41 and data for Weeks 1- 12 was also collected.
  • the mean change from Baseline for all groups are presented graphically in Figure 10.
  • MITT-VMS modified intent to treat -vasomotor symptom
  • E2 17 ⁇ -estradiol
  • P progesterone
  • LS least square
  • SE standard error
  • MMRM mixed model repeated measures
  • a responder was defined as a subject with 50% ⁇ reduction from Baseline in the number of
  • Weeks 4 and 12 are also shown graphically in Figure 11.

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