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WO2018136161A9 - Thérapies et formulations hormonales de substitution combinatoires naturelles - Google Patents

Thérapies et formulations hormonales de substitution combinatoires naturelles Download PDF

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Publication number
WO2018136161A9
WO2018136161A9 PCT/US2017/064788 US2017064788W WO2018136161A9 WO 2018136161 A9 WO2018136161 A9 WO 2018136161A9 US 2017064788 W US2017064788 W US 2017064788W WO 2018136161 A9 WO2018136161 A9 WO 2018136161A9
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WO
WIPO (PCT)
Prior art keywords
estradiol
subject
progesterone
pharmaceutical composition
administration
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2017/064788
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English (en)
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WO2018136161A1 (fr
Inventor
Julia M. Amadio
Brian A. Bernick
Sebastian MIRKIN
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TherapeuticsMD Inc
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TherapeuticsMD Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to CA3045024A priority Critical patent/CA3045024A1/fr
Priority to CN201780086119.7A priority patent/CN110290793A/zh
Priority to RU2019115913A priority patent/RU2019115913A/ru
Priority to AU2017394679A priority patent/AU2017394679A1/en
Priority to MX2019006513A priority patent/MX2019006513A/es
Priority to BR112019011655A priority patent/BR112019011655A2/pt
Priority to JP2019530027A priority patent/JP2020504093A/ja
Application filed by TherapeuticsMD Inc filed Critical TherapeuticsMD Inc
Priority to KR1020197019625A priority patent/KR20200018383A/ko
Priority to EP17893482.4A priority patent/EP3548036A4/fr
Publication of WO2018136161A1 publication Critical patent/WO2018136161A1/fr
Priority to IL267023A priority patent/IL267023A/en
Anticipated expiration legal-status Critical
Publication of WO2018136161A9 publication Critical patent/WO2018136161A9/fr
Ceased legal-status Critical Current

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Classifications

    • 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 repl acement 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 17p-estradiof 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. l7 -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 treatment of choice for most women with postmenopausal symptoms. Studies have shown that estrogen offers protection against osteoporosis. 2,3
  • Menopausal estrogen therapy is administered in a continuous daily dosage regimen or, alternatively, in a cyclic regimen.
  • the drugs are usually given once daily for 3 weeks followed by a 1 week hormone-free washout period, or once daily for 25 days followed by 5 hormone-free days, repeated as necessary.
  • 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
  • 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)co-t) or a Cma x for estradiol, progesterone, estrone, or total estrone as described herein, e.g., in Tables 18-21).
  • AUC area under the curve
  • compositions for co-administering estradiol and progesterone to a subject in need of natural hormone replacement therapies are provided.
  • the pharmaceutical composition is for co-administering estradiol and progesterone to a human subject having vasomotor symptoms associated with estrogen deficiency.
  • the pharmaceutical composition comprises 1 mg of estradiol and 100 mg of progesterone, and when administered to the subject, produces in a serum sample from the subject, one or more pharmacokinetic parameters selected from:
  • administration of the composition to the subject produces a steady state estradiol concentration that is from 42.29 pg/mL to 45.58 pg/mL. In some embodiments, administration of the composition to the subject produces both of a steady state estradiol concentration that is from 42.29 pg/mL to 45 58 pg/mL and a steady state progesterone concentration that is from 386.53 pg/mL to 547.83 pg/mL. In some embodiments, administration of the composition to the subject produces both of a steady state estradiol concentration that is
  • administration of the composition to the subject produces each of: (i) a steady state estradiol concentration that is from 42.29 pg/mL to 45.58 pg/mL; (ii) a steady state estrone concentration that is from 213.79 pg/mL to 241.57 pg/mL; and (iii) a steady state progesterone concentration that is from 386.53 pg/mL to 547.83 pg/mL.
  • the pharmaceutical composition comprises 0.5 mg of estradiol and 100 mg of progesterone, and when administered to the subject, produces in a serum sample from the subject, one or more pharmacokinetic parameters selected from:
  • administration of the composition to the subject produces a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL. In some embodiments, administration of the composition to the subject produces both of a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL and a steady state progesterone concentration that is from 386.53 pg/mL to 547.83 pg/mL.
  • administration of the composition to the subject produces both of a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL and a steady state estrone concentration that is from 113.59 pg/mL to 132.08 pg/mL.
  • administration of the composition to the subject produces each of: (i) a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL; (ii) a steady state estrone concentration that is from 113.59 pg/mL to 132.08 pg/mL; and (iii) a steady state progesterone concentration that is from 386.53 pg/mL to 547.83 pg/mL.
  • the pharmaceutical composition comprises 0.5 mg of estradiol and 50 mg of progesterone, and when administered to the subject, produces in a serum sample from the subject, one or more pharmacokinetic parameters selected from:
  • administration of the composition to the subject produces a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL. In some embodiments, administration of the composition to the subject produces both of a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL and a steady state progesterone concentration that is from 181.41 pg/mL to 247.17 pg/mL.
  • administration of the composition to the subject produces both of a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL and a steady state estrone concentration that is from 113.59 pg/mL to 132.08 pg/mL.
  • administration of the composition to the subject produces each of: (i) a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL; (ii) a steady state estrone concentration that is from 113.59 pg/mL to 132.08 pg/mL; and (iii) a steady state progesterone concentration that is from 181.41 pg/mL to 247.17 pg/mL.
  • the pharmaceutical composition comprises 0.25 mg of estradiol and 50 mg of progesterone, and when administered to the subject, produces in a serum sample from the subject, one or more pharmacokinetic parameters selected from:
  • administration of the composition to the subject produces a steady state estradiol concentration that is from 15.06 pg/mL to 18.50 pg/mL. ln some embodiments, administration of the composition to the subject produces both of a steady state estradiol concentration that is from 15.06 pg/mL to 18.50 pg/mL and a steady state progesterone concentration that is from 181.41 pg/mL to 247.17 pg/mL. In some embodiments, administration of the composition to the subject produces both of a steady state estradiol concentration that is
  • compositions to the subject produces each of: (i) a steady state estradiol concentration that is from 15.06 pg/mL to 18.50 pg/mL; (ii) a steady state estrone concentration that is from 69.02 pg/mL to 73.43 pg/mL; and (iii) a steady state progesterone concentration that is from 181.41 pg/mL to 247.17 pg/mL.
  • the pharmacokinetic parameters are measured after at least 4 weeks of daily administration of the pharmaceutical composition to the subject, e.g., after at least 6 weeks, 8 weeks, 10 weeks, 12 weeks, 16 weeks, 20 weeks, or 24 weeks of daily administration of the pharmaceutical composition to the subject.
  • the pharmaceutical composition comprises a solubilizing agent.
  • the pharmaceutical composition comprises solubilized estradiol.
  • the pharmaceutical composition comprises suspended progesterone.
  • each of the solubilized estradiol and the suspended progesterone are present in the solubilizing agent.
  • at least about 90% of the estradiol is solubilized in the solubilizing agent.
  • 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 CIO 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:
  • administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from: an AUC(o-t) for estrone that is from 909.6091 pg-hr/ml to 1421.2642 pg-hr/ml; and a Cmax 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 AUQo-t) f° r total estrone that is from 20.1752 ng-hr/ml to 31.5238 ng-hr/ml; and a Cmax 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:
  • estradiol that is from 140.3733 pg-hr/ml to 219.3333 pg-hr/ml and (b) a Cmax for estradiol that is from 6.4790 pg/ml to 10.1235 pg/ml, and
  • estrone that is from 909.6091 pg-hr/ml to 1421.2642 pg-hr/ml and (b) a Cmax 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:
  • estradiol (i) an AUC ( o-t) for estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml;
  • the method comprises administering to the subject a pharmaceutical composition comprising estradiol and progesterone as described herein (e.g., 1 mg of estradiol and 100 mg of
  • progesterone 0.5 mg of estradiol and 100 mg of progesterone; 0.5 mg of estradiol and 50 mg of progesterone; or 0.25 mg of estradiol and 50 mg of progesterone
  • administration of the pharmaceutical composition produces, in a sample (e.g., serum sample) from the subject, one or more pharmacokinetic parameters as described herein, e.g, a steady state concentration for one or more of estradiol, estrone, or progesterone.
  • administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from: an AUC(o-t) for estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml, and a Cmax 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 AUQo-o for total estrone that is from 40.3505 ng-hr/ml to 63.0476 ng-hr/ml, and a Cmax for total estrone that is from 7.0858 ng/ml to 1 1.0715 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 Cmax for estradiol that is from 12.9580 pg/ml to 20.2469 pg/ml;
  • estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml and (b) a Cmax 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 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 AUQo-t) for estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml, and a Cmax for estrone that is from 85.3098 pg/ml to 133.2966 pg/ml.
  • an AUQo-t for estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml
  • a Cmax 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 AUQo-t) for total estrone that is from 40.3505 ng-hr/ml to 63.0476 ng-hr/ml, and a Cmax for total estrone that is from 7.0858 ng/ml to 1 1.0715 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:
  • estrone that is from 1819.2181 pg-hr/ml5 to 2842.5283 pg-hr/ml and (b) a Cmax for estrone that is from 85.3098 pg/ml to 1 33.2966 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 AU o-t) for estrone that is from 3638.4363 pg-hr/ml to 5685.0567 pg-hr/ml, and a Cmax 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 AUQo- t) for total estrone that is from 80.7010 ng-hr/ml to 126.0953 ng-hr/ml, and a Cmax 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:
  • estradiol that is from 561.4933 pg-hr/ml to 877.3333 pg-hr/ml and (b) a Cmax for estradiol that is from 25.9161 pg/ml to 40.4939 pg/ml;
  • estrone that is from 3638.4363 pg-hr/ml to 5685.0567 pg-hr/ml and (b) a Cmax 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. 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 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 composition produces, in a plasma sample from the subject, one or more pharmacokinetic parameters as described herein.
  • the method comprises administering a pharmaceutical composition comprising estradiol at a dosage of about 0.05, 0.1, 0.125, 0.15,
  • 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.
  • administration of the composition to the subject further produces in the subject a reduction in the frequency and/or severity of one or more symptoms of menopause. In some embodiments, administration of the composition to the subject further produces in the subject a reduction in the frequency and/or severity of one or more moderate to severe vasomotor symptoms associated with menopause. In some embodiments, the vasomotor symptoms are selected from the group consisting of hot flashes or flushes, night sweats, sweating, sleep disturbances, and combinations thereof.
  • 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 AU o- t) for estrone that is from 909.6091 pg-hr/ml to 1421.2642 pg-hr/ml; a Cmax for estrone that is from 42.6549 pg/ml to 66.6483 pg/ml; an AUC ( o-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.
  • an AU o- t for estrone that is from 909.6091 pg-hr/ml to 1421.2642 pg-hr/ml
  • a Cmax 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:
  • 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 AUQo- t) for estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml; a Cmax 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 Cmax for total estrone that is from 7.0858 ng/ml to 1 1.0715 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:
  • estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml and (b) a Cmax 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 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 AUQo- t) for estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml; a Cmax for estrone that is from 85.3098 pg/ml to 133.2966 pg/ml; an AUQo-t) for total estrone that is from 40.3505 ng-hr/ml to 63.0476 ng-hr/ml, and a Cmax 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:
  • estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml and (b) a Cmax for estradiol that is from 12.9580 pg/ml to 20.2469 pg/ml; and
  • estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml and (b) a Cmax 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:
  • 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 AUQo- t) for estrone that is from 3638.4363 pg-hr/ml to 5685.0567 pg-hr/ml; a Cmax for estrone that is from 170.6197 pg/ml to 266.5933 pg/ml; an AUQo-t) for total estrone that is from 80.7010
  • 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:
  • estradiol that is from 561 .4933 pg-hr/ml to 877.3333 pg-hr/ml and (b) a Cmax for estradiol that is from 25.9161 pg/ml to 40.4939 pg/ml;
  • estrone that is from 3638.4363 pg-hr/ml to 5685.0567 pg-hr/ml and (b) a Cm ax for estrone that is from 170.6197 pg/ml to 266.5933 pg/ml; and optionally
  • the subject is female. In some embodiments, the subject is a woman having a uterus. In some embodiments, prior to treatment, the subject has a serum estradiol of ⁇ 10 pg/mL.
  • 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 AUQo-t) or Cmax 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 AUQo-t) or Cmax for estradiol, progesterone, estrone, or total estrone as described herein, e.g., as described in any of Tables 18-21).
  • compositions for use in a method of treating a disease or
  • INCORPORATED BY REFERENCE (RULE 20.6) 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.
  • F1G. 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.
  • the term“or” shall be understood to be defined as a logical disjunction (i.e., and/or) and shall not indicate an exclusive disjunction unless expressly indicated as such with the term“either,”“unless,” “alternatively,” and words of similar effect.
  • the term“or” is a logical disjunction (i.e., and/or) and does not indicate an exclusive disjunction unless expressly indicated as such with the terms“either,”“unless,” “alternatively,” and words of similar effect.
  • 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.
  • Cm ax 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
  • steady state concentration refers to the blood, plasma, or serum concentration of an active pharmaceutical ingredient (e.g., progesterone or estradiol) at the time when the rate of intake of the active pharmaceutical ingredient is in equilibrium with the rate of elimination of the active pharmaceutical ingredient.
  • an active pharmaceutical ingredient e.g., progesterone or estradiol
  • tmax 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, Cmax, and, optionally, Tmax 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, Cmax, or tma x 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
  • a pharmaceutical ingredient that is structurally identical to a hormone naturally or endogenously found in the human body (e.g., estradiol or progesterone).
  • the term“about” refers to ⁇ 10% of the noted value, unless otherwise specified, and unless the upper bound of the range would exceed 100% of the pharmaceutical composition, in which case the upper limit of the range is limited to 99.9%.
  • a pharmaceutical composition including about 10 weight percent of a given compound could have from 9 to 11 weight percent of the compound.
  • a pharmaceutical composition including about 10 weight percent of a given compound could have from 9 to 11 weight percent of the compound.
  • a pharmaceutical composition including about 10 weight percent of a given compound could have from 9 to 11 weight percent of the compound.
  • a pharmaceutical ingredient that is structurally identical to a hormone naturally or endogenously found in the human body (e.g., estradiol or progesterone).
  • API active pharmaceutical ingredient
  • An“active pharmaceutical ingredient” means the active compound or compounds used in formulating a drug product, such as l7P-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(3)-estra- 1 ,3, 5f 10)-triene-3, l7-diol. Estradiol is also interchangeably called l7p-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.
  • 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% 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 weight percent (wt %)).
  • estradiol 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,” as used herein, 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
  • 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
  • glycolide refers to an ester of glycerol (l,2,3-propanetriol) with acyl radicals of fatty acids and is also known as an acylglycerol. If only one position of the glycerol molecule is esterified with a fatty acid, 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-l, sn-2 and sn-3, with sn-2 being the middle carbon and sn-l 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). Other 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,
  • 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).
  • “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.
  • 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 (i.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). Tn 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
  • INCORPORATED BY REFERENCE (RULE 20.6) carbons including those that are C6-C14, C6-C12, C8-C14, C8-C12, C6-C10, C8-C10, 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.
  • the term“oil,” as used herein, 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.
  • the term“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. In some embodiments, 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.
  • 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.
  • 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-,
  • ECN equivalent carbon number
  • 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 com 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 monoglyceride ECN’s in the range of 6-14 contain mainly medium chain fatty acids
  • 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:
  • the ECN of the entire oil can be determined by calculating the ECN of each individual component (e.g., C8 monoglycerides, C8 di glycerides, C10 monoglycerides, and C10 di glycerides) and taking the sum of the relative percentage of the component multiplied by the ECN normalized to a monoglyceride for each component.
  • 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.
  • the terms“treat,”“treating,”“treatment,” and the like refer 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
  • the phrase“therapeutically 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.
  • the phrase“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, 5a-dihydroprogesterone, and estradiol.
  • the phrase“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.
  • the terms“treat,”“treating,” and“treatment” refer 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-C12 oil).
  • a pharmaceutical composition comprising estradiol, progesterone, and a solubilizing agent as described herein, when administered to a subject or a population of subjects, produces one or more AUC, Cmax, or Tmax 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 specifically embodiments that are: 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% soluble in a solubilizing agent. Solubility may be expressed as a mass fraction (% w/w, also referred to as wt %).
  • estradiol is micronized or partially micronized.
  • 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 X50 particle size value of less than about 15 microns, less than about 10 microns,
  • 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
  • Diffraction Particle Size Analyzer (the“Beckman Device”) may be used to determine particle size.
  • 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,
  • the medium chain fatty acids are C6, C8, C10, C12, C6-C 12, 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 C 12 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 ⁇ Cl), caprylic acid (C8), pelargonic acid (C9), capric acid (C10), undecylic acid (Cl l), 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.
  • 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).
  • MlGLYOLs® includes M1GLYOL® 810 (caprylic/capric triglyceride), M1GLYOL® 812 (caprylic/capric triglyceride), MIGLYOL® 816 (caprylic/capric triglyceride), and MIGLYOL® 829 (caprylic/capric/succinic triglyceride).
  • 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.
  • Other exemplary 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)
  • INCORPORATED BY REFERENCE (RULE 20.6) 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 l,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 (e.
  • CAPMUL® PG-2L EP/NF di ethylene glycol mono ester
  • di ethylene 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.
  • M1GLYOL® 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. However, it can also comprise small amounts of other fatty acids, e.g., less than about 5% of caproic (C6) acid, lauric (C12) acid, and myristic (C14) acid.
  • the pharmaceutical composition comprises about 20% to about 85% solubilizing agent by weight, e.g., about 60% to about 85% solubilizing agent by weight.
  • the composition comprises progesterone, e.g., dissolved and micronized,
  • the composition comprises estradiol from about 0.1 to about 0.8 wt %, e.g., about 0.15 to about 0.40 wt %.
  • the transdermal pharmaceutical compositions contain from about 10% (w/w) to about 30% (w/w).
  • the 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% (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% (w/w) to about 25% (w/w) medium-chain oil, or from about 25% (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 F/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 polyoxyl
  • 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) can be used herein as the surfactant.
  • 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
  • MIGLYOL® 812 GELUCIRE 50/13
  • MIGLYOL® 812 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 0.0l%-30.0%, about 0.1% to 10.0%, or about 1% to 10.0%, from 10% to 30%.
  • the pharmaceutical composition comprises about 10.0% surfactant by weight.
  • the pharmaceutical composition comprises about 15.0% surfactant by weight.
  • the pharmaceutical composition comprises about 0.1% to about 5.0% surfactant by weight, e.g., about 1 .0 wt %.
  • the pharmaceutical composition comprises about 5.0% to about 15.0% surfactant by weight.
  • 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 13.0%, less than 12.0%, less than 11.0%, less than 10.0%, 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 13.0%, less than 12.0%, less than 11.0%, less than 10.0%, less than 30.0%, less than 29.0%, less than 28.
  • INCORPORATED BY REFERENCE (RULE 20.6) 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% 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
  • INCORPORATED BY REFERENCE 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
  • 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 solubilizing agent
  • polyoxyglyceride as a 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 can be measured with respect to“estrone” amounts (excluding conjugates
  • estrone sulfate such as estrone sulfate
  • 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.
  • Cmax is well understood in the art as an abbreviation for the maximum drug concentration in blood, serum, or plasma of a subject.
  • Tmax is well understood in the art as an abbreviation for the time to maximum drug concentration in blood, serum, or plasma of a subject.
  • compositions of this disclosure can be characterized for 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.
  • pharmacokinetic parameters include steady state concentration, AUC, Cmax, and Tmax.
  • Steady state concentration is well understood in the art as the concentration (e.g ., blood, plasma, or serum concentration) of an active pharmaceutical ingredient (e.g., progesterone or estradiol) at the time when the rate of intake of the active pharmaceutical ingredient is in equilibrium with the rate of elimination of the active pharmaceutical ingredient.
  • 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.
  • Cm ax is well understood in the art as an abbreviation for the maximum drug concentration in blood, serum, or plasma of a subject.
  • Tmax 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, Cmax, or Tmax
  • estradiol In some embodiments, one or more pharmacokinetic parameters, e.g., AUC, Cmax, or Tmax, is measured for progesterone. In some embodiments, one or more pharmacokinetic parameters, e.g., AUC, Cmax, or Tmax, is measured for estrone. In some
  • one or more pharmacokinetic parameters e.g., AUC, Cmax, OG 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'
  • 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 Cmax, Tmax, or AUC. Timing can be adjusted based on the given circumstances (i.e., one formulation may cause a more rapid Cmax, in which case the initial times would be clustered closer together, closer to time zero, or both to ensure accurate measurement of Cmax, Tmax, and AUC).
  • the C max, Tmax, 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 levels of progesterone, estradiol, estrone, or total estrone are measured after a period of time of administering the composition comprising progesterone and estradiol to the subject.
  • the steady state concentration of progesterone, estradiol, estrone, or total estrone is measured after at least 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks,
  • the steady state concentration of progesterone, estradiol, estrone, or total estrone is measured after at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months of daily administration of the composition to the subject.
  • the values for Cmax, Tmax, 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, Cmax, or Tmax parameters, or one or more mean AUC, mean Cmax, or mean Tmax 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 or serum sample from the subject, one or more pharmacokinetic parameters selected from:
  • administration of the composition to the subject produces a steady state estradiol concentration that is from 15.06 pg/mL to 18.50 pg/mL. In some embodiments, administration of the composition to the subject produces both of a steady state estradiol concentration that is from 15.06 pg/mL to 18.50 pg/mL and a steady state progesterone concentration that is from 181.41 pg/mL to 247.17 pg/mL.
  • administration of the composition to the subject produces both of a steady state estradiol concentration that is from 15.06 pg/mL to 18.50 pg/mL and a steady state estrone concentration that is from 69.02 pg/mL to 73.43 pg/mL.
  • administration of the composition to the subject produces each of: (i) a steady state estradiol concentration that is from 15.06 pg/mL to 18.50 pg/mL; (ii) a steady state estrone concentration that is from 69.02 pg/mL to 73.43 pg/mL; and (iii) a steady state progesterone concentration that is from 181.41 pg/mL to 247.17 pg/mL.
  • 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(o-t) for estradiol that is from 140.3733 pg-hr/ml to 219.3333 pg-hr/ml, and a Cma x 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:
  • 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 Cmax 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 Tmax 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 Tmax 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
  • administering produces both parameters (iii) and (iv). In some embodiments, 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
  • 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 AUQo-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 AUQo-t) for estradiol that is from 140.3733 pg-hr/ml to 219.3333 pg-hr/ml, a mean Cmax for estradiol that is from 6.4790 pg/ml to 10.1235 pg/ml, and a mean Tmax 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(o-t) for progesterone that is from 24.0174 ng-hr/ml to 37.5272 ng-hr/ml, a mean Cmax for progesterone.
  • administration of the composition to a population of subject produces, in plasma samples from the subjects, one or more of a mean AUC(o-t) for estrone that is from 909.6091 pg-hr/ml to 1421.2642 pg-hr/ml, a mean Cmax for estrone that is from 42.6549 pg/ml to 66.6483 pg/ml, and a mean Tmax 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(o-t) for total estrone that is from 20. 1752 ng-hr/ml to 3 1 .5238 ng-hr/ml, a mean Cmax for total estrone that is from 3.5429 ng/ml to 5.5358 ng/ml, and a mean Tmax 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 0.25 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 AUQo- t) for estradiol that is from 140.3733 pg-hr/ml to 219.3333 pg-hr/ml; a Cmax for estradiol that is from 6.4790 pg/ml to 10.1235 pg/ml; a Tmax for estradiol that is from 7.2 hr to 11.3 hr; an AUQo- t) for progesterone that is from 24.0174 ng-hr/ml to 37.5272
  • 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, serum, or plasma samples) from the subjects administered the composition.
  • samples e.g., blood, serum, or plasma samples
  • administration of the composition to a population of subject produces, in samples (e.g., plasma or serum samples) from the subjects, one or more of a mean steady state estradiol concentration that is from 15.06
  • administration of the composition to a population of subject produces, in samples from the subjects, one or more of a mean steady state progesterone concentration that is from 181.41 pg/mL to 247.17 pg/m, a mean AUC(o- t) for progesterone that is from 24.0174 ng-hr/ml to 37.5272 ng-hr/ml, a mean Cmax for progesterone that is from 17.8444 ng/ml to 27.8819 ng/ml, and a mean Tmax for progesterone that is from 2.4 hr to 3.8 hr.
  • a mean steady state progesterone concentration that is from 181.41 pg/mL to 247.17 pg/m
  • a mean AUC(o- t) for progesterone that is from 24.0174 ng-hr/ml to 37.5272 ng-hr/ml
  • a mean Cmax for progesterone that is from 17.8444 ng
  • administration of the composition to a population of subject produces, in samples from the subjects, one or more of a mean steady state estrone concentration that is from 69.02 pg/mL to 73.43 pg/mL, a mean AUC ( o-t) for estrone that is from 909.6091 pg-hr/ml to 1421.2642 pg-hr/ml, a mean Cm ax for estrone that is from 42.6549 pg/ml to 66.6483 pg/ml, and a mean Tmax for estrone that is from 4.4 hr to 6.9 hr.
  • a mean steady state estrone concentration that is from 69.02 pg/mL to 73.43 pg/mL
  • a mean AUC ( o-t) for estrone that is from 909.6091 pg-hr/ml to 1421.2642 pg-hr/ml
  • administration of the composition to a population of subject produces, in samples from the subjects, one or more of a mean AUQo-t ) for total estrone that is from 20.1752 ng-hr/ml to 31.5238 ng-hr/ml, a mean Cmax for total estrone that is from 3.5429 ng/ml to 5.5358 ng/ml, and a mean Tmax 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 ln some embodiments, 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 sample (e.g., plasma or serum sample) from the subject, one or more parameters selected from: a steady state estradiol concentration that is from 15.06 pg/mL to 18.50 pg/mL; an AUQo-t ) for estradiol that is from 140.3733 pg-hr/ml to
  • INCORPORATED BY REFERENCE (RULE 20.6) is from 4.4 hr to 6.9 hr; an AUQo- t) for total estrone that is from 20.1752 ng-hr/ml to 31.5238 ng-hr/ml; a Cmax for total estrone that is from 3.5429 ng/ml to 5.5358 ng/ml; and a Tmax for total estrone that is from 2 hr to 3.1 hr.
  • 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 AUQo-t) for estradiol, a Cmax for estradiol, an AUC(o-t) for progesterone, a Cmax for progesterone, an AUQo-t) for estrone, a Cmax for estrone, an AUQo-t) for total estrone, and a Cmax for total estrone; wherein the presence of one or more of the following values is indicative of a therapeutically effective dose: an AUQo- t) for estradiol that is from 140.3733 pg-hr/ml to 219.3333 pg-hr/ml; a Cmax for estradiol that is from 6.47
  • a sample from the subject
  • 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. ln some embodiments, 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 more pharmacokinetic parameters selected from:
  • administration of the composition to the subject produces a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL. In some embodiments, administration of the composition to the subject produces both of a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL and a steady state progesterone concentration that is from 181.41 pg/mL to 247.17 pg/mL.
  • administration of the composition to the subject produces both of a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL and a steady state estrone concentration that is from 113.59 pg/mL to 132.08 pg/mL.
  • administration of the composition to the subject produces each of: (i) a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL; (ii) a steady state estrone concentration that is from 113.59 pg/mL to 132.08 pg/mL; and (iii) a steady state progesterone concentration that is from 181.41 pg/mL to 247.17 pg/mL.
  • 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:
  • administration of the composition to the subject produces both an AUC(o-t) for estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml, and a Cma x 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:
  • 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 Cmax 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 Tmax 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 Tmax 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:
  • estradiol that is from 12.9580 pg/ml to 20.2469 pg/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
  • administering produces both parameters (iii) and (iv). In some embodiments, 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
  • 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 AUQo-t) for 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 AUQo-t) for estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml, a mean Cmax for estradiol that is from 12.9580 pg/ml to 20.2469 pg/ml, and a mean Tmax for estradiol that is from 7.2 hr to 11.3 hr.
  • a mean AUQo-t for estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml
  • a mean Cmax for estradiol that is from 12.9580 pg/ml to 20.2469 pg/ml
  • a mean Tmax 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(o-t) for progesterone that is from 24.0174 ng-hr/ml to 37.5272 ng-hr/ml, a mean Cmax for progesterone.
  • administration of the composition to a population of subject produces, in plasma samples from the subjects, one or more of a mean AUC(o-t) for estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml, a mean Cmax for estrone that is from 85.3098 pg/ml to 133.2966 pg/ml, and a mean Tmax 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(o-t) for total estrone that is from 40.3505 ng-hr/ml to 63.0476 ng-hr/ml, a mean Cmax for total estrone that is from 7.0858 ng/ml to 1 1.0715 ng/ml, and a mean Tmax 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 AUQo- t) for estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml; a Cmax for estradiol that is from 12.9580 pg/ml to 20.2469 pg/ml; a Tmax for estradiol that is from 7.2 hr to 11.3 hr; an AUC(o- t) for progesterone that is from 24.0174 ng-hr/ml to 37.
  • a pharmaceutical composition comprising about 0.50 mg estradiol and about
  • 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, serum, or plasma samples) from the subjects administered the composition.
  • samples e.g., blood, serum, or plasma samples
  • administration of the composition to a population of subject produces, in samples (e.g., serum or plasma samples) from the subjects, one or more of a mean steady state estradiol concentration that is from 23.03
  • administration of the composition to a population of subject produces, in samples from the subjects, one or more of a mean steady state progesterone concentration that is from 181.41 pg/mL to 247.17 pg/mL; a mean AUQo- t) for progesterone that is from 24.0174 ng-hr/ml to 37.5272 ng-hr/ml, a mean Cmax for progesterone that is from 17.8444 ng/ml to 27.8819 ng/ml, and a mean Tmax for progesterone that is from 2.4 hr to 3.8 hr.
  • a mean steady state progesterone concentration that is from 181.41 pg/mL to 247.17 pg/mL
  • a mean AUQo- t) for progesterone that is from 24.0174 ng-hr/ml to 37.5272 ng-hr/ml
  • a mean Cmax for progesterone that is from 17.8444
  • administration of the composition to a population of subject produces, in samples from the subjects, one or more of a mean steady state estrone concentration that is from 1 13.59 pg/mL to 132.08 pg/mL; a mean AUQo-t) for estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml, a mean Cmax for estrone that is from 85.3098 pg/ml to 133.2966 pg/ml, and a mean Tm ax for estrone that is from 4.4 hr to 6.9 hr.
  • a mean steady state estrone concentration that is from 1 13.59 pg/mL to 132.08 pg/mL
  • a mean AUQo-t for estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml
  • administration of the composition to a population of subject produces, in samples from the subjects, one or more of a mean AUQo-t) for total estrone that is from 40.3505 ng-hr/ml to 63.0476 ng-hr/ml, a mean Cmax for total estrone that is from 7.0858 ng/ml to 11.0715 ng/ml, and a mean Tmax 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 serum or plasma sample from the subject, one or more parameters selected from: a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL; an AUQo-t ) for estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml; a Cmax for estradiol that is from 12.9580 pg/ml to 20.2469 pg/ml; a Tmax for estradiol that is from 7.2 hr to 1
  • 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 AUQo-t) for estradiol, a Cmax for estradiol, an AUC(o-t) for progesterone, a Cmax for progesterone, an AUQo-t) for estrone, a Cmax for estrone, an AUQo-t) for total estrone, and a Cmax for total estrone; wherein the presence of one or more of the following values is indicative of a therapeutically effective dose: an AUQo- t) for estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml; a Cmax for estradiol that is from
  • 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. ln some embodiments, 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 more pharmacokinetic parameters selected from:
  • administration of the composition to the subject produces a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL. In some embodiments, administration of the composition to the subject produces both of a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL and a steady state progesterone concentration that is from 386.53 pg/mL to 547.83 pg/mL.
  • administration of the composition to the subject produces both of a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL and a steady state estrone concentration that is from 113.59 pg/mL to 132.08 pg/mL.
  • administration of the composition to the subject produces each of: (i) a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL; (ii) a steady state estrone concentration that is from 113.59 pg/mL to 132.08 pg/mL; and (iii) a steady state progesterone concentration that is from 386.53 pg/mL to 547.83 pg/mL.
  • 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:
  • administration of the composition to the subject produces both an AUC(o-t) for estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml, and a Cma x 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:
  • administration of the composition to the subject produces both an AUC(o-t) for progesterone that is from 48.0348 ng-hr/ml to 75.0543 ng-hr/ml, and a Cmax 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 Tmax 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 Tmax 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:
  • estradiol that is from 12.9580 pg/ml to 20.2469 pg/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
  • administering produces both parameters (iii) and (iv). In some embodiments, 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, two, three 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 0.50 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 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 AU o- t) for estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml, a mean Cmax for estradiol that is from 12.9580 pg/ml to 20.2469 pg/ml, and a mean Tmax for estradiol that is from 7.2 hr to 11.3 hr.
  • administration of the composition produces, in plasma samples from the subjects, one or more of a mean AU o- t) for estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml, a mean Cmax for estradiol that is from 12.9580 pg/ml to 20.2469 pg/ml, and a mean Tmax for estradiol that is from 7.2 hr to
  • INCORPORATED BY REFERENCE (RULE 20.6) to a population of subject produces, in plasma samples from the subjects, one or more of a mean AUC(o-t) for progesterone that is from 48.0348 ng-hr/ml to 75.0543 ng-hr/ml, a mean Cmax for progesterone that is from 35.6889 ng/ml to 55.7639 ng/ml, and a mean Tmax 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 ( o-t) for estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml, a mean Cmax for estrone that is from 85.3098 pg/ml to 133.2966 pg/ml, and a mean Tm ax 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(o-t) for total estrone that is from 40.3505 ng-hr/ml to 63.0476 ng-hr/ml, a mean Cmax for total estrone that is from 7.0858 ng/ml to 11.0715 ng/ml, and a mean Tmax 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 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 AU o- t) for estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml; a Cmax for estradiol that is from 12.9580 pg/ml to 20.2469 pg/ml; a Tmax for estradiol that is from 7.2 hr to 11.3 hr; an AUC(o-t) for progesterone that is from 48.0348 ng-hr/ml to 75
  • a pharmaceutical composition comprising about 0.50 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, serum, and plasma samples) from the subjects administered the composition.
  • samples e.g., blood, serum, and plasma samples
  • administering produces, in samples (e.g ., serum or plasma samples) from the subjects, one or more of a mean steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL; a mean AUC(o-t) for estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml, a mean Cmax for estradiol that is from 12.9580 pg/ml to 20.2469 pg/ml, and a mean Tmax for estradiol that is from 7.2 hr to 11.3 hr.
  • a mean steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL
  • AUC(o-t) for estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml
  • administration of the composition to a population of subject produces, in samples from the subjects, one or more of a mean steady state progesterone concentration that is from 386.53 pg/mL to 547.83 pg/mL; a mean AUC(o-t) for progesterone that is from 48.0348 ng-hr/ml to 75.0543 ng-hr/ml, a mean Cmax for progesterone that is from 35 6889 ng/ml to 55.7639 ng/ml, and a mean Tmax for progesterone that is from 2.4 hr to 3.8 hr.
  • administration of the composition to a population of subject produces, in samples from the subjects, one or more of a mean steady state estrone concentration that is from 113.59 pg/mL to 132.08 pg/mL; a mean AUC(o-t) for estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml, a mean Cmax for estrone that is from 85.3098 pg/ml to 133.2966 pg/ml, and a mean Tmax for estrone that is from 4.4 hr to 6.9 hr.
  • administration of the composition to a population of subject produces, in samples from the subjects, one or more of a mean AUQo-t) for total estrone that is from 40.3505 ng-hr/ml to 63.0476 ng-hr/ml, a mean Cmax for total estrone that is from 7.0858 ng/ml to 11.0715 ng/ml, and a mean Tmax 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 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 serum or plasma sample from the subject, one or more parameters selected from: a steady state estradiol concentration that is from 23.03 pg/mL to 27.37 pg/mL; an AUC(o-t) for estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml; a Cm ax for estradiol that is from 12.9580 pg/ml to 20.2469 pg/ml; a Tm ax for estradiol that is from 7.2 h
  • 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 AUQo-t) for estradiol, a Cmax for estradiol, an AUQo-t) for progesterone, a Cmax for progesterone, an AUQo-t) for estrone, a Cmax for estrone, an AUQo-t) for total estrone, and a Cmax for total estrone; wherein the presence of one or more of the following values is indicative of a therapeutically effective dose: an AUQo-t) for estradiol that is from 280.7467 pg-hr/ml to 438.6667 pg-hr/ml; a Cmax for estradiol that is from 12.
  • a sample from the subject
  • 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.
  • administering produces, in a plasma sample from the subject, one or more pharmacokinetic parameters selected from:
  • administration of the composition to the subject produces a steady state estradiol concentration that is from 42.29 pg/mL to 45.58 pg/mL. In some embodiments, administration of the composition to the subject produces both of a steady state estradiol concentration that is from 42.29 pg/mL to 45.58 pg/mL and a steady state progesterone concentration that is from 386.53 pg/mL to 547.83 pg/mL.
  • administration of the composition to the subject produces both of a steady state estradiol concentration that is from 42.29 pg/mL to 45.58 pg/mL and a steady state estrone concentration that is from 213.79 pg/mL to 241 .57 pg/mL.
  • administration of the composition to the subject produces each of: (i) a steady state estradiol concentration that is from 42.29 pg/mL to 45.58 pg/mL; (ii) a steady state estrone concentration that is from 213.79 pg/mL to 241.57 pg/mL; and (iii) a steady state progesterone concentration that is from 386.53 pg/mL to 547.83 pg/mL.
  • 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:
  • administration of the composition to the subject produces both an AUC(o-t) for estradiol that is from 561 .4933 pg-hr/ml to 877.3333 pg-hr/ml, and a Cmax 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(o-t) for progesterone that is from 48.0348 ng-hr/ml to 75.0543 ng-hr/ml, and a Cmax 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,
  • 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, a T max for estradiol that is from 7.2 hr to 1 1 .3 hr. In some embodiments, administration of the composition to the subject further produces, in a plasma sample from the subject, a Tma x 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:
  • 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).
  • 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 (i) an AUC ( o-t) for estrone that is from 3638.4363 pg-hr/ml to 5685.0567 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 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.
  • samples e.g blood or plasma samples
  • a population of subject produces, in plasma samples from the subjects, one or more of a mean AUC(o-t) for estradiol that is from 561.4933 pg-hr/ml to 877.3333 pg-hr/ml, a mean Cmax for estradiol that is from 25.9161 pg/ml to 40.4939 pg/ml, and a mean Tmax for estradiol that is from 7.2 hr to 1 1.3 hr.
  • administration of the composition to a population of subject produces, in plasma samples from the subjects, one or more of a mean AUQo-t ) for progesterone that is from 48.0348 ng-hr/ml to 75.0543 ng-hr/ml, a mean Cmax for progesterone that is from 35.6889 ng/ml to 55.7639 ng/ml, and a mean Tmax 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 AUQo-t) for estrone that is from 3638.4363 pg-hr/ml to 5685.0567 pg-hr/ml, a mean Cmax for estrone that is from 170.6197 pg/ml to 266.5933 pg/ml, and a mean Tmax 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(o-t) for total estrone that is from 80.7010 ng-hr/ml to 126.0953 ng-hr/ml, a mean Cmax for total estrone that is from 14.1716 ng/ml to 22/1431 ng/ml, and a mean Tmax 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 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 AUQo-t) for estradiol that is from 561.4933 pg-hr/ml to 877.3333 pg-hr/m; a Cmax for estradiol that is from 25.9161 pg/ml to 40.4939 pg/ml; a Tmax for estradiol that is from 7.2 hr to 11.3 hr; an AUC ( o-t ) for progesterone that is from 48.0348 ng-hr/ml to 75.0543
  • 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, serum, or plasma samples) from the subjects administered the composition.
  • administration of the composition to a population of subject produces, in samples (e.g., serum or plasma samples) from the subjects, one or more of a mean steady state estradiol concentration that is from 42.29 pg/mL to 45.58 pg/mL; a mean AUQo-t) for estradiol that is from 561.4933 pg-hr/ml to 877.3333 pg-hr/ml, a mean Cmax for estradiol that is from 25.9161 pg/ml to 40.4939 pg/ml, and a mean Tmax for estradiol that is from 7.2 hr to 1 1.3 hr.
  • a mean steady state estradiol concentration that is from 42.29 pg/mL to 45.58 pg/mL
  • a mean AUQo-t for estradiol that is from 561.4933 pg-hr/ml to 877.3333 pg-hr/ml
  • administration of the composition to a population of subject produces, in samples from the subjects, one or more of a mean steady state progesterone concentration that is from 386.53 pg/mL to 547.83 pg/mL; a mean AUQo-t) for progesterone that is from 48.0348 ng-hr/ml to 75.0543 ng-hr/ml, a mean Cmax for progesterone that is from 35.6889 ng/ml to 55.7639 ng/ml, and a mean Tmax for progesterone that is from 2.4 hr to 3.8 hr.
  • a mean steady state progesterone concentration that is from 386.53 pg/mL to 547.83 pg/mL
  • a mean AUQo-t for progesterone that is from 48.0348 ng-hr/ml to 75.0543 ng-hr/ml
  • a mean Cmax for progesterone that is from 35
  • administration of the composition to a population of subject produces, in samples from the subjects, one or more of a mean steady state estrone concentration that is from 213.79 pg/mL to 241.57 pg/mL; a mean AUQo- t) for estrone that is from 3638.4363 pg-hr/ml to 5685.0567 pg-hr/ml, a mean Cmax for estrone that is from 170.6197 pg/ml to 266.5933 pg/ml, and a mean Tmax for estrone that is from 4.4 hr to 6.9 hr.
  • administration of the composition to a population of subject produces, in samples from the subjects, one or more of a mean AUQo-t) for total estrone that is from 80.7010 ng-hr/ml to 126.0953 ng-hr/ml, a mean Cmax for total estrone that is from 14.1716 ng/ml to 22/1431 ng/ml, and a mean Tmax 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 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 serum or plasma sample from the subject, one or more parameters selected from: a steady state estradiol concentration that is from 42.29 pg/mL to 45.58 pg/mL; an AUQo-t) for estradiol that is from 561.4933 pg-hr/ml to 877.3333 pg-hr/m; a Cmax for estradiol that is from 25.9161 pg/ml to 40.4939 pg/ml j a Tmax for estradiol that is from
  • 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 AUQo-t) for estradiol, a Cmax for estradiol, an AUQo-t) for progesterone, a Cmax for progesterone, an AUQo-t) for estrone, a Cmax for estrone, an AUQo-t) for total estrone, and a Cmax for total estrone; wherein the presence of one or more of the following values is indicative of a therapeutically effective dose: an AUQo-o for estradiol that is from 561.4933 pg-hr/ml to 877.3333 pg-hr/m; a Cmax for estradiol that is from 25.9161
  • 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:
  • estradiol (i) an AUC(o- t) for estradiol that is from 1 123 pg-h/ml to 1755 pg-h/ml; or
  • administration of the composition to the subject produces both an AUC ( o-t) for estradiol that is from 1123 pg-h/ml to 1755 pg-h/ml, and a Cmax 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:
  • administration of the composition to the subject produces both an AUC ( o-t) for progesterone that is from 96 ng-hr/ml to 150 ng-hr/ml, and a Cmax for 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,
  • estradiol (i) an AUC ( o-t ) for estradiol that is from 1 123 pg-h/ml to 1755 pg-h/ml;
  • administration of the composition to the subject further produces, in a plasma sample from the subject, a Tmax for estradiol that is from 7.2 hr to 1 1 .3 hr. In some embodiments, administration of the composition to the subject further produces, in a plasma sample from the subject, a Tmax 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:
  • estradiol that is from 52 pg/ml to 81 pg/ml;
  • administration of the pharmaceutical composition to the subject produces both parameters (i) and (ii). ln 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). ln 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
  • 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(o- t) for estradiol that is from 1123 pg-h/ml to 1755 pg-h/ml, a mean Cmax for estradiol that is from 52 pg/ml to 81 pg/ml, and a mean Tmax 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(o-t) for progesterone that is from 96 ng-hr/ml to 150 ng-hr/ml, a mean Cmax for progesterone that is from 71 ng/ml to 112 ng/ml, and a mean Tmax 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(o-t) for estrone that is from 7277 pg-hr/ml to 11370 pg-hr/ml, a mean Cmax for estrone that is from 341 pg/ml to 533 pg/ml, and a mean Tmax 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 AUQo- t) for total estrone that is from 161 ng-h/ml to 252 ng-h/ml, a mean Cmax for total estrone that is from 28 ng/ml to 44 ng/ml, and a mean Tmax 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 AUQo-t) for estradiol that is from 1123 pg-h/ml to 1755 pg-h/ml; a Cmax for estradiol that is from 52 pg/ml to 81 pg/ml ; a Tmax for estradiol that is from 7.2 hr to 11.3 hr; an AUQo-t) for progesterone that is from 96 ng-hr/ml to 150 ng-hr/ml; a Cmax for proge
  • 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 AUQo-t) for estradiol, a Cmax for estradiol, an AUQo-t) for progesterone, a Cmax for progesterone, an AUQo-t) for estrone, a Cmax for estrone, an AUQo-t) for total estrone, and a Cmax for total estrone; wherein the presence of one or more of the following values is indicative of a therapeutically effective dose: an AUQo-t) for estradiol that is from 1123 pg-h/ml to 1755 pg-h/ml; a Cmax for estradiol that is from 52 pg/ml to
  • 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 profde of Figure 1.
  • administration of the pharmaceutical composition results in the blood plasma progesterone concentration profde 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, intrastemal, 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”).
  • composition is selected based on the mode of administration
  • a pharmaceutical composition e.g., for oral administration or delivery by injection
  • 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.
  • 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
  • a binder such a starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose and derivatives thereof.
  • 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
  • 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 flash
  • 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 (N2).
  • 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.
  • Heat may be removed from the GELUC1RE® 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
  • the addition may occur all at once or may occur gradually over a period of time.
  • Micronized progesterone is then added and mixed until fully suspended.
  • 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. Eleat 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 fdl mass can be used for encapsulation.
  • a soft gelatin capsule contains a pharmaceutical composition having fully solubilized estradiol and partially solubilized progesterone comprising:
  • 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 17p-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.
  • 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 (Cmax, AUCo-t, and AUCo- ⁇ ) and secondary (Tmax, 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.
  • 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(o-t) for estrone that is from 909.6091 pg-hr/ml to 1421.2642 pg-hr/ml; and a Cmax 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 AUQo-t) f° r total estrone that is from 20.1752 ng-hr/ml to 31.5238 ng-hr/ml; and a Cmax 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:
  • estradiol that is from 140.3733 pg-hr/ml to 219.3333 pg-hr/ml and (b) a Cmax for estradiol that is from 6.4790 pg/ml to 10.1235 pg/ml, and
  • estrone that is from 909.6091 pg-hr/ml to 1421.2642 pg-hr/ml and (b) a Cmax 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:
  • estradiol (i) an 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 both parameters selected from: an AUQo-o for estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml, and a Cmax 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 AUQo-o for total estrone that is from 40.3505 ng-hr/ml to 63.0476 ng-hr/ml, and a Cmax 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 Cmax 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 AUQo-o for estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml, and a Cmax 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 AUQo-o for total estrone that is from 40.3505 ng-hr/ml to 63.0476 ng-hr/ml, and a Cmax 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, and administration of the composition to a subject produces, in a plasma sample from the subject, the following parameters:
  • 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 AUQo- t) for estrone that is from 3638.4363 pg-hr/ml to 5685.0567 pg-hr/ml, and a Cmax 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 AUQo-t) for total estrone that is from 80.7010 ng-hr/ml to 126.0953 ng-hr/ml, and a Cmax for total estrone that is from 14.1716 ng/ml to 22.1431 ng/ml.
  • an AUQo-t for total estrone that is from 80.7010 ng-hr/ml to 126.0953 ng-hr/ml
  • a Cmax 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:
  • estradiol that is from 561.4933 pg-hr/ml to 877.3333 pg-hr/ml and (b) a Cmax for estradiol that is from 25.9161 pg/ml to 40.4939 pg/ml;
  • estrone that is from 3638.4363 pg-hr/ml to 5685.0567 pg-hr/ml and (b) a Cmax 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. 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 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
  • 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 composition produces, in a plasma sample from the subject, one or more pharmacokinetic parameters as described herein.
  • the method comprises administering a pharmaceutical composition comprising estradiol at a dosage of about 0.05, 0.1, 0.125, 0.15,
  • 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:
  • estradiol that is from 140.3733 pg-hr/ml to 219.3333 pg-hr/ml;
  • administration of the pharmaceutical composition further produces, in a plasma sample from the subject, one or more parameters selected from: an AUQo- t) for estrone that is from 909.6091 pg-hr/ml to 1421 .2642 pg-hr/ml; a Cmax for estrone that is from 42.6549 pg/ml to 66.6483 pg/ml; an AUQo-t ) for total estrone that is from 20. 1752 ng-hr/ml to 3 1 .5238 ng-hr/ml; and a Cmax for total estrone that is from 3.5429 ng/ml to 5.5358 ng/ml.
  • an AUQo- t for estrone that is from 909.6091 pg-hr/ml to 1421 .2642 pg-hr/ml
  • a Cmax for estrone that is from 42.6549 pg/ml to 66.64
  • 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:
  • estradiol that is from 140.3733 pg-hr/ml to 219.3333 pg-hr/ml and (b) a Cmax for estradiol that is from 6.4790 pg/ml to 10.1235 pg/ml;
  • estrone that is from 909.6091 pg-hr/ml to 1421.2642 pg-hr/ml and (b) a Cmax 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 AUQo- t) for estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml; a Cma 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 Cmax for total estrone that is from 7.0858 ng/ml to 11.0715 ng/ml.
  • an AUQo- t) for estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml
  • a Cma for estrone that is from 85.3098 pg/ml to 133
  • 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 Cmax for estradiol that is from 12.9580 pg/ml to 20.2469 pg/ml; and
  • 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 AUQo- t) for estrone that is from 1819.2181 pg-hr/ml to 2842.5283 pg-hr/ml; a Cmax 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 Cmax 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:
  • the method comprises administering to the subject a
  • composition comprising about 1 mg estradiol and about 100 mg progesterone,
  • administration of the composition to the subject further produces, in a plasma sample from the subject, one or more parameters selected from: an AUQo- t) for estrone that is from 3638.4363 pg-hr/ml to 5685.0567 pg-hr/ml; a Cmax for estrone that is from 170.6197 pg/ml to 266.5933 pg/ml; an AUQo-t) for total estrone that is from 80.7010 ng-hr/ml to 126.0953 ng-hr/ml; and a Cmax 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:
  • estradiol that is from 561.4933 pg-hr/ml to 877.3333 pg-hr/ml and (b) a Cmax for estradiol that is from 25.9161 pg/ml to 40.4939 pg/ml;
  • estrone that is from 3638.4363 pg-hr/ml to 5685.0567 pg-hr/ml and (b) a Cmax 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.
  • Postmenopausal subjects with an intact uterus who met the study entry criteria were randomized to one of five treatment arms (four active and one placebo) and received blinded study medication for 12 months. During the Screening period, all subjects were provided with a diary to self-assess the frequency and severity of their vasomotor symptoms. Subjects experiencing a minimum daily frequency of >7 (or >50 per week) moderate to severe hot flushes participated in a VMS Substudy during the first 12 weeks of treatment. The Substudy subjects were stratified by treatment arm within the sites, and only Substudy subjects had the possibility of being randomized to placebo. Subjects who qualified for the study except for experiencing a
  • 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 moderate to severe hot flushes per day, or >50 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 Bl-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, HSIL, 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.
  • 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 coronary artery or cerebrovascular disease e.g., myocardial infarction, angina, stroke, TI
  • INCORPORATED BY REFERENCE (RULE 20.6) 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
  • SSRls 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. (With the approval of the Medical Monitor, the Screening endometrial biopsy may be repeated once.);
  • INCORPORATED BY REFERENCE (RULE 20.6) 1 central pathologist; (29) have contraindication to any planned study assessments (e.g., endometrial biopsy); (30) have participated in another clinical trial within 30 days prior to Screening, have received an investigational drug within the three months prior to the initial dose of study medication, or be likely to participate in a clinical trial or receive another investigational medication during the study; (31) currently use marijuana.
  • 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
  • the screening endometrial biopsy can be performed at any time during the screening period. It is suggested that is be performed last to avoid performing unnecessary invasive procedures on subjects who screen fail for other reasons.
  • H - A Pap smear is not required if one has been done ⁇ 5 months prior to early discontinuation.
  • the physical examination included, at a minimum, examination of the subject’s general appearance, HEENT (head, eyes, ears, nose and throat), heart, lungs, musculoskeletal5 system, gastrointestinal (GI) system, neurological system, lymph nodes, abdomen and
  • 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.
  • AST alanine aminotransferase
  • 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).
  • FSH Follicle-stimulating hormone
  • TSH secretory 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 (/.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.
  • a standard l2-lead ECG was obtained at Screening and Visit 7/End of Treatment and read locally. The investigator was responsible for reviewing the interpretation of the ECG and for retaining hardcopies.
  • 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.
  • 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.
  • 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.
  • Substudy hot flush requirements were randomized into the non-Substudy portion of the trial until enrollment was completed.
  • the study staff entered the subject diary data into the CRF promptly in order for the Sponsor to assess subject compliance with completion of the subject diaries. Subjects who did not complete the diary correctly or did not submit the diary despite repeated instructions could be discontinued for non-compliance after discussion with the Medical Monitor. If a subject forgot to return the diary to the site, the study staff made every reasonable attempt to collect the diary or any missing diary pages.
  • MENQOL Menopause-specific quality of life questionnaire
  • 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; l2-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 >55 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 lssue Treatment Hot Flush
  • MENQOL Menopause-specific quality of life questionnaire
  • MOS-Slccp The 1992 version of the Medical Outcomes Study-Sleep Questionnaire ( MOS-Slccp). which is described by Hays RD and Stewart, AL, Sleep Measures, in A.L. Stewart and J.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-Slccp questionnaire was conducted at Visits 1, 4, 5 and 7.
  • 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 lf 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. NOTE: 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 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;
  • Each subject was given a unique subject number at the start of Screening that was used to identify their clinical site and sequential number. In addition to the assigned subject number, subject initials were also used for identification.
  • Eligible subjects were randomized at Visit 1 (Week 0/Day 1).
  • the randomization code was created using a computer-generated randomization schedule prepared by a statistician prior to the start of the study.
  • TX-001HR is an oval, opaque, pink, soft gelatin formulation of a combination product comprising of l7p-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.
  • study personnel were responsible for recording the amount of study medication returned, the amount of study medication used by the subject, and the amount of study medication unused by the subject on a drug accountability log.
  • 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 Cl 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.
  • Tf all three readings are 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.
  • 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% l-sided confidence limit was be calculated. An observed incidence rate of 1 % or less with an upper 1 -sided 95% confidence limit of 4% or less was considered acceptably low.
  • Secondary VMS SubStudy Endpoints include the following:

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Abstract

L'invention concerne des compositions pharmaceutiques pour la co-administration d'estradiol et de progestérone à un sujet humain qui en a besoin. Dans certains modes de réalisation, la composition pharmaceutique comprend de l'estradiol solubilisé, de la progestérone en suspension, et un agent de solubilisation comprenant une huile à chaîne moyenne (C6-C12).
PCT/US2017/064788 2016-12-05 2017-12-05 Thérapies et formulations hormonales de substitution combinatoires naturelles Ceased WO2018136161A1 (fr)

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JP2019530027A JP2020504093A (ja) 2016-12-05 2017-12-05 天然配合ホルモン補充製剤及び治療法
RU2019115913A RU2019115913A (ru) 2016-12-05 2017-12-05 Природные комбинированные гормонозаместительные составы и способы терапии
AU2017394679A AU2017394679A1 (en) 2016-12-05 2017-12-05 Natural combination hormone replacement formulations and therapies
MX2019006513A MX2019006513A (es) 2016-12-05 2017-12-05 Formulaciones y terapias de reemplazo de hormonas de combinacion natural.
BR112019011655A BR112019011655A2 (pt) 2016-12-05 2017-12-05 fórmulas e terapias naturais combinadas para reposição
CA3045024A CA3045024A1 (fr) 2016-12-05 2017-12-05 Therapies et formulations hormonales de substitution combinatoires naturelles
CN201780086119.7A CN110290793A (zh) 2016-12-05 2017-12-05 天然组合激素替代制剂和治疗
EP17893482.4A EP3548036A4 (fr) 2016-12-05 2018-02-02 Thérapies et formulations hormonales de substitution combinatoires naturelles
KR1020197019625A KR20200018383A (ko) 2016-12-05 2018-02-02 천연 복합 호르몬 대체 제형 및 요법
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US6901278B1 (en) * 2002-01-29 2005-05-31 Morris Notelovitz Methods for reducing the risk of breast cancer in and improving the health of women
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