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WO2017100378A2 - Compositions pharmaceutiques à base d'œstradiol introduites par voie vaginale et procédés associés - Google Patents

Compositions pharmaceutiques à base d'œstradiol introduites par voie vaginale et procédés associés Download PDF

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Publication number
WO2017100378A2
WO2017100378A2 PCT/US2016/065466 US2016065466W WO2017100378A2 WO 2017100378 A2 WO2017100378 A2 WO 2017100378A2 US 2016065466 W US2016065466 W US 2016065466W WO 2017100378 A2 WO2017100378 A2 WO 2017100378A2
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WO
WIPO (PCT)
Prior art keywords
estradiol
vaginal
suppository
day
assessed
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
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PCT/US2016/065466
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English (en)
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WO2017100378A3 (fr
Inventor
Sebastian MIRKIN
Julia M. Amadio
Brian Bernick
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TherapeuticsMD Inc
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TherapeuticsMD Inc
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Publication date
Priority to JP2018529574A priority Critical patent/JP2018538290A/ja
Application filed by TherapeuticsMD Inc filed Critical TherapeuticsMD Inc
Priority to CA3007636A priority patent/CA3007636A1/fr
Priority to KR1020187019331A priority patent/KR20180100567A/ko
Priority to AU2016366200A priority patent/AU2016366200B2/en
Priority to EP16873806.0A priority patent/EP3386514A4/fr
Priority to MX2018006882A priority patent/MX384850B/es
Priority to BR112018011483A priority patent/BR112018011483A2/pt
Priority to US15/781,840 priority patent/US11266661B2/en
Publication of WO2017100378A2 publication Critical patent/WO2017100378A2/fr
Publication of WO2017100378A3 publication Critical patent/WO2017100378A3/fr
Priority to IL259884A priority patent/IL259884A/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
    • A61K9/025—Suppositories; Bougies; Bases therefor; Ovules characterised by shape or structure, e.g. hollow layered, coated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A61K9/4825—Proteins, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • 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
    • 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
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

Definitions

  • VVA vaginal atrophy
  • symptoms including, for example, vaginal dryness, vaginal odor, vaginal or vulvar irritation or itching, dysuria (pain, burning, or stinging when urinating), dyspareunia (vaginal pain associated with sexual activity), or vaginal bleeding associated with sexual activity.
  • symptoms include soreness; with urinary frequency and urgency; urinary discomfort and incontinence also occurring (“estrogen-deficient urinary state(s)").
  • vaginal atrophy is an increased vaginal pH, which creates an environment more susceptible to infections.
  • the mucosal epithelium of the VVA patients also reported to show signs of severe atrophy and upon cytological examination accompanied by an increased number of the parabasal cells and a reduced number of superficial cells.
  • VVA-related states manifest symptoms associated with decreased estrogenization of the vulvovaginal tissue, and can even occur in women treated with oral administration of an estrogen-based pharmaceutical drug product.
  • VVA is most common with menopausal women, it can occur at any time in a woman's life cycle. VVA symptoms also interfere with sexual activity and satisfaction. Women with female sexual dysfunction (FSD) are almost 4 times more likely to have VVA than those without FSD.
  • FSD Women with female sexual dysfunction
  • Estrogen treatment has proven to be very successful in controlling menopausal symptoms, including VVA and FSD.
  • Several studies have shown that the symptoms connected with vaginal atrophy are often relieved by estrogen treatment given either systemically or topically. The existing treatments have numerous problems, for example compliance issues with patients not completing or continuing treatment due to the problems associated with the form of treatment.
  • a new soft gel vaginal pharmaceutical composition and dosage form containing solubilized estradiol for the treatment of VVA has been designed to mitigate common limitations found with other vaginal forms of estradiol.
  • the soft gel vaginal pharmaceutical composition eases vaginal administration, provides improved safety of insertion, minimizes vaginal discharge following administration, and provides a more effective dosage form having improved efficacy, safety and patient compliance.
  • a soft gel vaginal pharmaceutical composition as a treatment for post-menopausal women suffering with moderate to severe symptoms of VVA is provided.
  • a suppository comprising: a) a therapeutically effective amount of estradiol; and b) a solubilizing agent comprising a medium chain oil.
  • the suppository includes about 1 ⁇ g to about 25 ⁇ g of estradiol.
  • the suppository can include about 1 ⁇ g to about 10 ⁇ g of estradiol; and about 10 ⁇ g to about 25 ⁇ g of estradiol.
  • the estradiol is solubilized.
  • the medium chain oil includes at least one C6-C12 fatty acid or a glycol, monoglyceride, diglyceride, or triglyceride ester thereof.
  • the solubilizing agent includes at least one ester selected from the group consisting of: an ester of caproic fatty acid, an ester of caprylic fatty acid, an ester of capric fatty acid, and combinations thereof.
  • the solubilizing agent can include a caprylic/capric triglyceride.
  • the suppository further includes a capsule.
  • the capsule can be a soft gelatin capsule.
  • a suppository comprising: a) a therapeutically effective amount of estradiol; b) a caprylic / capric triglyceride; c) a non-ionic surfactant comprising PEG-6 palmitostearate and ethylene glycol palmitostearate; and d) a soft gelatin capsule.
  • a suppository provided herein includes about 25 ⁇ g of estradiol, wherein administration of the suppository to a patient provides, in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (Cmax) of estradiol of about 19 pg*hr/mL to about 29 pg*hr/mL; and 2) a corrected geometric mean area under the curve (AUCV 24 of estradiol of about 75 pg*hr/mL to about 1 12 pg*hr/mL.
  • Cmax geometric mean peak plasma concentration
  • AUCV 24 corrected geometric mean area under the curve
  • a suppository provided herein includes about 25 ⁇ g of estradiol, wherein administration of the suppository to a patient provides, in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (Cmax) of estrone of about 9 pg*hr/mL to about 14 pg*hr/mL; and 2) a corrected geometric mean area under the curve (AUC)o-24 of estrone of about 43 pg*hr/mL to about 65 pg*hr/mL.
  • Cmax geometric mean peak plasma concentration
  • AUC corrected geometric mean area under the curve
  • a suppository provided herein includes about 25 ⁇ g of estradiol, wherein administration of the suppository to a patient provides, in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (Cmax) of estrone sulfate of about 416 pg*hr/mL to about 613 pg*hr/mL; and 2) a corrected geometric mean area under the curve (AUC)o-24 of estrone sulfate of about 3598 pg*hr/mL to about 5291 pg*hr/mL.
  • Cmax geometric mean peak plasma concentration
  • AUC corrected geometric mean area under the curve
  • a suppository provided herein includes about 10 ⁇ g of estradiol, wherein administration of the suppository to a patient provides, in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (Cmax) of estradiol of about 12 pg*hr/mL to about 18 pg*hr/mL; and 2) a corrected geometric mean area under the curve (AUCV 24 of estradiol of about 42 pg*hr/mL to about 63 pg*hr/mL.
  • the suppository further provides a corrected geometric mean time to peak plasma concentration (Tmax) of estradiol of about 1 hrs to about 3 hrs.
  • a suppository provided herein includes about 10 ⁇ g of estradiol, wherein administration of the suppository to a patient provides, in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (Cmax) of estrone of about 4 pg*hr/mL to about 7 pg*hr/mL; and 2) a corrected geometric mean area under the curve (AUC)o-24 of estrone of about 20 pg*hr/mL to about 31 pg*hr/mL.
  • Cmax geometric mean peak plasma concentration
  • AUC corrected geometric mean area under the curve
  • the suppository further provides a corrected geometric mean time to peak plasma concentration (Tmax) of estrone of about 4 hrs to about 8 hrs.
  • Tmax geometric mean time to peak plasma concentration
  • a suppository provided herein includes about 10 ⁇ g of estradiol, wherein administration of the suppository to a patient provides, in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (Cmax) of estrone sulfate of about 10 pg*hr/mL to about 16 pg*hr/mL; and 2) a corrected geometric mean area under the curve (AUC)o-24 of estrone sulfate of about 56 pg*hr/mL to about 84 pg*hr/mL.
  • Cmax geometric mean peak plasma concentration
  • AUC corrected geometric mean area under the curve
  • the suppository further provides a corrected geometric mean time to peak plasma concentration (Tmax) of estrone sulfate of about 4 hrs to about 7 hrs.
  • a suppository provided herein includes about 4 ⁇ g of estradiol, wherein administration of the suppository to a patient provides, in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (Cmax) of estradiol of about 4 pg*hr/mL to about 8 pg*hr/mL; and 2) a corrected geometric mean area under the curve (AUC)o-24 of estradiol of about 16 pg*hr/mL to about 26 pg*hr/mL.
  • the suppository further provides a corrected geometric mean time to peak plasma concentration (Tmax) of estradiol of about 0.25 hrs to about 2 hrs.
  • a suppository provided herein includes about 4 ⁇ g of estradiol, wherein administration of the suppository to a patient provides, in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (Cmax) of estrone of about 1 pg*hr/mL to about 3 pg*hr/mL; and 2) a corrected geometric mean area under the curve (AUC)o-24 of estrone of about 8 pg*hr/mL to about 13 pg*hr/mL.
  • Cmax geometric mean peak plasma concentration
  • AUC corrected geometric mean area under the curve
  • the suppository further provides a corrected geometric mean time to peak plasma concentration (Tmax) of estrone of about 1 hrs to about 4 hrs.
  • Tmax geometric mean time to peak plasma concentration
  • a suppository provided herein includes about 4 ⁇ g of estradiol, wherein administration of the suppository to a patient provides, in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (Cmax) of estrone sulfate of about 4 pg*hr/mL to about 7 pg*hr/mL; and 2) a corrected geometric mean area under the curve (AUC)o-24 of estrone sulfate of about 22 pg*hr/mL to about 34 pg*hr/mL.
  • the suppository further provides a corrected geometric mean time to peak plasma concentration (Tmax) of estrone sulfate of about 1 hrs to about 3 hrs.
  • a suppository comprising about 1 ⁇ g to about 25 ⁇ g of estradiol, wherein administration of the suppository to a patient provides a corrected geometric mean peak plasma concentration (C max ) of estradiol that is less than about 30 pg*hr/mL.
  • C max corrected geometric mean peak plasma concentration
  • administration of the suppository to a patient provides a corrected geometric mean peak plasma concentration (C max ) of estradiol that is less than about 18 pg*hr/mL.
  • a suppository comprising about 1 ⁇ g to about 25 ⁇ g of estradiol, wherein administration of the suppository to a patient provides a corrected geometric mean area under the curve (AUC)0-24 of estradiol that is less than about 112 pg*hr/mL.
  • administration of the suppository to a patient provides a corrected geometric mean area under the curve (AUC)0-24 of estradiol that is less than about 63 pg*hr/mL.
  • a suppository comprising about 1 ⁇ g to about 25 ⁇ g of estradiol, wherein administration of the suppository to a patient provides a corrected geometric mean peak plasma concentration (Cmax) of estrone that is less than about 14 pg*hr/mL.
  • C max corrected geometric mean peak plasma concentration
  • estrone that is less than about 7 pg*hr/mL.
  • a suppository comprising about 1 ⁇ g to about 25 ⁇ g of estradiol, wherein administration of the suppository to a patient provides a corrected geometric mean area under the curve (AUC)0-24 of estrone that is less than about 65 pg*hr/mL.
  • administration of the suppository to a patient provides a corrected geometric mean area under the curve (AUC)0-24 of estrone that is less than about 31 pg*hr/mL.
  • a suppository comprising about 1 ⁇ g to about 25 ⁇ g of estradiol, wherein administration of the suppository to a patient provides a corrected geometric mean peak plasma concentration (Cmax) of estrone sulfate that is less than about 613 pg*hr/mL.
  • administration of the suppository to a patient provides a corrected geometric mean peak plasma concentration (Cmax) of estrone sulfate that is less than about 16 pg*hr/mL.
  • a suppository comprising about 1 ⁇ g to about 25 ⁇ g of estradiol, wherein administration of the suppository to a patient provides a corrected geometric mean area under the curve (AUC)0-24 of estrone sulfate that is less than about 5291 pg*hr/mL.
  • administration of the suppository to a patient provides a corrected geometric mean area under the curve (AUC)0-24 of estrone sulfate that is less than about 84 pg*hr/mL.
  • a suppository comprising about 1 ⁇ g to about 25 ⁇ g of estradiol, wherein administration of the suppository to the proximal region of the vagina of a patient provides a therapeutically effective concentration of estradiol over 24 hours in the proximal region of the vagina.
  • This disclosure also provides a method of treating an estrogen-deficient state, the method comprising administering to a patient in need thereof, a suppository as provided herein.
  • a method of treating vulvovaginal atrophy is provided, the method comprising administering to a patient in need thereof, a suppository as provided herein.
  • treatment includes reducing the severity of one or more symptoms selected from the group consisting of: vaginal dryness, dyspareunia, vaginal or vulvar irritation, vaginal or vulvar burning, vaginal or vulvar itching, dysuria, and vaginal bleeding associated with sexual activity.
  • treatment includes reducing the vaginal pH of the patient.
  • treatment includes reducing the vaginal pH of the patient to a pH of less than about 5.0.
  • treatment includes a change in cell composition of the patient.
  • the change in cell composition includes reducing the number of parabasal vaginal cells or increasing the number of superficial vaginal cells.
  • the number of parabasal vaginal cells in the patient are reduced by at least about 35% (e.g., at least about 50%).
  • the number of superficial vaginal cells are increased by at least about 5% (e.g., at least about 35%).
  • a method for reducing vaginal discharge following administration of a suppository the method comprising administering to a patient in need thereof, a suppository provided herein, wherein the vaginal discharge following
  • administration of the suppository is compared to the vaginal discharge following
  • a method for treating female sexual dysfunction in a female subject in need thereof includes administering to the subject a vaginal suppository as described herein.
  • the method includes administering to the subject a vaginal suppository comprising: (a) a pharmaceutical composition comprising: a therapeutically effective amount of estradiol; a caprylic/capric triglyceride; a non-ionic surfactant comprising PEG-6 palmitostearate and ethylene glycol palmitostearate; and (b) a soft gelatin capsule; wherein the vaginal suppository includes from about 1 microgram to about 25 micrograms of estradiol; wherein estradiol is the only active hormone in the vaginal suppository.
  • the vaginal suppository does not include a hydrophilic gel-forming bioadhesive agent in the solubilizing agent.
  • treating female sexual dysfunction includes increasing the subject's desire, arousal, lubrication, satisfaction, and or/orgasms.
  • FIG. 1 is a flow diagram illustrating a process in accordance with various embodiments of the invention.
  • Fig. 2 illustrates a suppository in accordance with various embodiments of the invention;
  • Fig. 9 is a study schematic diagram.
  • Fig. 10 shows the percentage change in superficial cells at 12 weeks compared to placebo.
  • Fig. 11 shows the percentage change in superficial cells at week 2, week 6, week 8, and week 12 compared to placebo.
  • Fig. 12 shows percentage change in superficial cells per dose for each of week 2, week 6, week 8, and week 12 compared to placebo.
  • Fig. 13 shows the percentage change in parabasal cells at 12 weeks compared to placebo.
  • Fig. 14 shows the percentage change in parabasal cells at week 2, week 6, week 8, and week 12 compared to placebo.
  • Fig. 15 shows the percentage change in parabasal cells per dose for each of week 2, week 6, week 8, and week 12 compared to placebo
  • Fig. 16 shows the percentage change in pH at 12 weeks compared to placebo.
  • Fig. 17 shows the percentage change in pH at week 2, week 6, week 8, and week 12 compared to placebo.
  • Fig. 18 shows the percentage change in pH per dose for each of week 2, week 6, week 8, and week 12 compared to placebo.
  • Fig. 19A shows the change in visual assessments from baseline to week 12 in vaginal color in a modified itent to treat (MITT) population.
  • Fig. 19B shows the change in visual assessments from baseline to week 12 in vaginal epithelial integrity in a modified itent to treat (MITT) population.
  • Fig. 19C shows the change in visual assessments from baseline to week 12 in vaginal epithelial thickness a modified itent to treat (MITT) population.
  • Fig. 19D shows the change in visual assessments from baseline to week 12 in vaginal secretions in a modified itent to treat (MITT) population.
  • Fig. 20A shows the correlation between the total sum of four visual assessments and dyspareunia at week 12 in an intent to treat (ITT) population.
  • Fig. 20B shows the correlation between the total sum of four visual assessments and vaginal dryness at week 12 in an intent to treat (ITT) population.
  • Fig. 21 shows baseline adjusted estradiol serum concentration (pg/mL) assessed on Day 1 (squares) and Week 12 (diamonds) for four treatment artms.
  • Fig. 22 shows baseline adjusted estradiol serum concentration (pg/mL) assessed on Day 14 (squares) and Week 12 (diamonds) for four treatment artms.
  • Fig. 23 shows estradiol plasma levels measured in subjects following a supine period after administration of the estradiol formulation, compared with plasma levels measured in subjects following an ambulatory period after administration of the estradiol formulation.
  • Fig. 24 shows mean change from baseline in Total FSFI score at Week 12.
  • Fig. 25A shows the mean change from baseline to week 12 in the individual FSFI lubrication score.
  • Fig. 25B shows the mean change from baseline to week 12 in the individual FSFI arousal score.
  • Fig. 25C shows the mean change from baseline to week 12 in the individual FSFI satisfaction score.
  • Fig. 25D shows the mean change from baseline to week 12 in the individual FSFI desire score.
  • Fig. 25E shows the mean change from baseline to week 12 in the individual FSFI orgasm score.
  • Fig. 26A shows an estradiol softgel capsule held with the larger end between the fingers.
  • Fig. 26B shows insertion of an estradiol softgel capsule in a reclining position. The softgel is inserted into the lower third of the vagina with the smaller end up.
  • Fig. 26C shows insertion of an estradiol softgel capsule in a standing position. The softgel is inserted into the lower third of the vagina with the smaller end up.
  • API active pharmaceutical ingredient
  • co-administered means that two or more drug products are administered simultaneously or sequentially on the same or different days.
  • drug product means at least one active pharmaceutical ingredient in combination with at least one excipient and provided in unit dosage form.
  • 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.
  • Cmax 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
  • Tmax refers to the time that it takes for the blood concentration an active pharmaceutical ingredient (e.g., estradiol or progesterone), or a metabolite of the active pharmaceutical ingredient, to reach the maximum value.
  • an active pharmaceutical ingredient e.g., estradiol or progesterone
  • bioavailability refers to the rate and extent to which an API or active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.
  • bioavailability can be measured as the amount of API in the blood (serum or plasma) as a function of time.
  • Pharmacokinetic (PK) parameters such as AUC, Cmax, or may be used to measure and assess bioavailability.
  • bioavailability may be assessed by measurements intended to reflect the rate and extent to which the API or active ingredient or active moiety becomes available at the site of action.
  • bioequivalent refers to the absence of a significant difference in the rate and extent to which the API or active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical altematives 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 means hormones that match the chemical structure and effect of those that occur naturally or endogenously in the human body.
  • An exemplary natural estrogen is estradiol.
  • bio-identical hormone or "body-identical hormone” refers to an active pharmaceutical ingredient that is structurally identical to a hormone naturally or
  • estradiol refers to (17P)-estra-l,3,5(10)-triene-3,17-diol. Estradiol is also interchangeably called 17 -estradiol, oestradiol, or E2, and is found endogenously in the human body. As used herein, estradiol refers to the bio-identical or body-identical form of estradiol found in the human body having the structure:
  • Estradiol is supplied in an anhydrous or hemi -hydrate form.
  • the anhydrous form or the hemihydrate form can be substituted for the other by accounting for the water or lack of water according to well-known and understood techniques.
  • 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 wt%).
  • 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 bio-identical 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 agent(s) or the formulations disclosed herein.
  • the progesterone is "partially solubilized” with a portion of the progesterone being solubilized or dissolved in the solubilizing agent and a portion of the progesterone being suspended in the solubilizing agent.
  • Partially solubilized progesterone may include progesterone that is about 1 % solubilized, about 5% solubilized, about 10% solubilized, about 15% solubilized, about 20% solubilized, about 30% solubilized, about 40% solubilized, about 50% solubilized, about 60% solubilized, about 70% solubilized, about 80% solubilized, about 85% solubilized, about 90% solubilized or about 95% solubilized.
  • the progesterone is "fully solubilized” with all or substantially all of the progesterone being solubilized or dissolved in the solubilizing agent.
  • Fully solubilized progesterone may include progesterone that is about 97% solubilized, about 98% solubilized, about 99% solubilized or about 100% solubilized. Solubility can be expressed as a mass fraction (%w/w, which is also referred to as wt%).
  • micronized progesterone and micronized estradiol include micronized progesterone and micronized estradiol having an X50 particle size value below about 15 microns or having an X90 particle size value below about 25 microns.
  • X50 means that one-half of the particles in a sample are smaller in diameter than a given number.
  • micronized progesterone having an X50 of 5 microns means that, for a given sample of micronized progesterone, one-half of the particles have a diameter of less than 5 microns.
  • X90 means that ninety percent (90%) of the particles in a sample are smaller in diameter than a given number.
  • the term "glyceride” is an ester of glycerol (1,2,3-propanetriol) with acyl radicals of fatty acids and is also known as an acylglycerol.
  • a "monoglyceride” or “monoacylglycerol” is produced; if two positions are esterified, a “diglyceride” or “diacylglycerol” is produced; and if all three positions of the glycerol are esterified with fatty acids, a "triglyceride” or
  • triacylglycerol is produced.
  • a glyceride is “simple” if all esterified positions contain the same fatty acid; whereas a glyceride is “mixed” if the esterified positions contained different fatty acids.
  • the carbons of the glycerol backbone are designated sn-1, sn-2 and sn-3, with sn- 2 being in the middle carbon and sn-1 and sn-3 being the end carbons of the glycerol backbone.
  • 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 formulations 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 formulation.
  • excipients include, but are not limited to, surfactants, emulsifiers, thickeners, colorants, flavoring agents, 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 6 (C6) to 14 (C14) carbon atoms, 8 (C8) to 12 (C12) carbon atoms, or 8 (C8) to 10 (CIO) carbon atoms.
  • intermediate 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., having one or more double bonds between carbon atoms). In some embodiments, the aliphatic tails are saturated (i.e. , no double bonds between carbon atoms).
  • Medium chain fatty acids or medium chain fatty acid derivatives include those with aliphatic tails having 6-14 carbons, including those that are C6-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.
  • oil refers to any pharmaceutically acceptable oil, especially medium chain oils, and specifically excluding peanut oil, that can suspend or solubilize bioidentical progesterone or estradiol, including starting materials or precursors thereof, including micronized progesterone or micronized estradiol as described herein.
  • medium chain oil refers to an oil wherein the composition of the fatty acid fraction of the oil is substantially medium chain (i.e., C6 to C14) fatty acids, i.e., the composition profile of fatty acids in the oil is substantially medium chain.
  • substantially means that between 20% and 100% (inclusive of the upper and lower limits) of the fatty acid fraction of the oil is made up of medium chain fatty acids, i.e. , fatty acids with aliphatic tails (i.e. , carbon chains) having 6 to 14 carbons.
  • about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 85%, about 90% or about 95% of the fatty acid fraction of the oil is made up of medium chain fatty acids.
  • "predominantly” means that greater than or equal to 50% of the fatty acid fraction of the oil is made up of medium-chain fatty acids, i.e., fatty acids with aliphatic carbon chains having 6 to 14 carbon atoms.
  • medium chain oils suitable for use in the formulations 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 (C6-C12 alkyls). It will be understood by those of skill in the art that the medium chain oils suitable for use in the formulations disclosed herein are pharmaceutical grade (e.g., pharmaceutical grade medium chain oils).
  • medium chain oils include, for example and without limitation, medium chain fatty acids, medium chain fatty acid esters of glycerol (e.g., for example, mono-, di-, and triglycerides), medium chain fatty acid esters of propylene glycol, medium chain fatty acid derivatives of polyethylene glycol, and combinations thereof.
  • medium chain fatty acids include, for example and without limitation, medium chain fatty acids, medium chain fatty acid esters of glycerol (e.g., for example, mono-, di-, and triglycerides), medium chain fatty acid esters of propylene glycol, medium chain fatty acid derivatives of polyethylene glycol, and combinations thereof.
  • medium chain fatty acids include, for example and without limitation, medium chain fatty acids, medium chain fatty acid esters of glycerol (e.g., for example, mono-, di-, and triglycerides), medium chain fatty acid esters of propylene glycol, medium chain fatty acid derivatives of polyethylene glyco
  • ECN equivalent carbon number
  • ECN or "equivalent carbon number” means the sum of the number of carbon atoms in the fatty acid chains of an oil, and can be used to characterize an oil as, for example, a medium chain oil or a long-chain oil.
  • tripalmitin tripalmitic glycerol
  • Naturally occurring oils are frequently "mixed" with respect to specific fatty acids, but tend not to contain both long chain fatty acids and medium chain fatty acids in the same glycerol backbone.
  • triglycerides with ECN's of 21-42 typically contain predominantly medium chain fatty acids; while triglycerides with ECN's of greater than 43 typically contain predominantly long chain fatty acids.
  • the ECN of corn oil triglyceride in the USP would be in the range of 51-54.
  • Medium chain diglycerides with ECN's of 12-28 will often contain predominanty medium chain fatty chains, while diglycerides with ECN's of 32 or greater will typically contain predominanty long chain fatty acid tails.
  • Monoglycerides will have an ECN that matches the chain length of the sole fatty acid chain.
  • ECN's in the range of 6-14 contain mainly medium chain fatty acids, and monoglycerides with ECN's 16 or greater will contain mainly long chain fatty acids.
  • the average ECN of a medium chain triglyceride oil is typically 21-42.
  • medium chain triglycerides have the following composition as the exemplary oil set forth in the table below:
  • ECN of the exemplary medium chain triglycerides oil can also be expressed as a range (per the ranges set forth in the USP) of 24.9 - 27.0.
  • the ECN of the entire oil can be determined by calculating the ECN of each individual component (e.g., C8 monoglycerides, C8 diglycerides, CIO monoglycerides, and CIO monoglycerides) and taking the sum of the relative percentage of the component multiplied by the ECN normalized to a monoglyceride for each component.
  • the oil having C8 and CIO 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, and others used in formulating pharmaceutical products.
  • patient or “subject” refers to an individual to whom the pharmaceutical composition is administered.
  • composition refers to a pharmaceutical composition comprising at least a solubilizing agent and estradiol.
  • pharmaceutical compositions are delivered, for example via suppository (i.e., vaginal suppository), or absorbed vaginally.
  • progesterone means any natural or man-made substance that has pharmacological properties similar to progesterone.
  • 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.
  • VVA vaginal atrophy
  • vulvovaginal atrophy vaginal atrophy
  • VVA vaginal atrophy
  • sexual dysfunction refers to a condition having one or more symptoms of difficulty during any one or more stages. The dysfunction can prevent an individual from enjoying sexual activity.
  • symptoms of sexual dysfunction include: reduced sexual desire, reduced sexual pleasure, reduced sexual arousal and excitement, aversion to and avoidance of genital sexual contact, inability to attain or maintain arousal, and persistent or recurrent delay of, or absence of orgasm.
  • Sexual dysfunction may be lifelong (no effective performance ever) or acquired (after a period of normal function); generalized or limited to certain situations or certain partners; and total or partial.
  • sexual desire refers to the frequency of wanting to engage in sexual activity and/or the frequency of engaging in sexual activity as perceived by the individual.
  • sexual desire can be expressed, for example, in one or more cognitive activities, including the frequency of sexual thoughts, the extent of enjoyment of movies, books, music, etc. having sexual content and/or the extent of enjoyment or pleasure of thinking and fantasizing about sex as perceived by the individual.
  • arousal refers to the frequency of becoming sexually aroused, how readily sexual arousal occurs and/or if arousal is maintained, as perceived by the individual.
  • arousal can include factors such as increased desire for sexual activity and excitement related to sexual activity.
  • arousal can include increased blood flow to the genitals, causing clitoral engorgement, as well as vaginal lubrication.
  • lubrication refers to wetness in and around the vagina before, during, or after sexual activity. Increasing lubrication can include increasing the frequency of lubrication; decreasing the difficulty of becoming lubricated; and/or decreasing the difficulty in maintaining lubrication.
  • Satisfaction refers to one or more positive emotions (e.g., contentment, fulfillment, gratification, and the like) related to a sexual activity or sexual relationship. Satisfaction can include, for example, satisfaction with occurrence of sexual arousal or orgasm, satisfaction with the amount of closeness with a partner, and satisfaction with overall sex life.
  • orgasm refers to the highest point of sexual excitement characterized by a subjective experience of intense pleasure marked normally by vaginal contractions in females.
  • Increasing orgasm can include increasing the frequency, duration, and/or intensity of orgasms in a subject. Increasing orgasm can also include decreasing the difficulty of reaching orgasm.
  • compositions comprising solubilized estradiol designed to be absorbed vaginally.
  • the pharmaceutical compositions disclosed herein are designed to be absorbed and have their therapeutic effect locally, e.g., in vaginal or surrounding tissue. Further disclosed herein are data demonstrating efficacy of the pharmaceutical compositions disclosed, as well as methods relating to the pharmaceutical compositions.
  • the pharmaceutical compositions disclosed herein are useful in VVA, dyspareunia, and other indications caused by decrease or lack of estrogen.
  • Additional aspects and embodiments of this disclosure include: providing increased patient ease of use while potentially minimizing certain side effects from inappropriate insertion, minimizing incidence of vulvovaginal mycotic infection compared to incidence of vulvovaginal mycotic infection due to usage of other vaginally applied estradiol products; and, improved side effect profile (e.g., pruritus) compared to, for example, VAGIFEM ® (estradiol vaginal tablets, Novo Nordisk; Princeton, NJ).
  • side effect profile e.g., pruritus
  • the pharmaceutical compositions disclosed herein are alcohol-free or substantially alcohol-free.
  • the pharmaceutical compositions offer provide for improved patient compliance because of improvements over the prior offering.
  • the pharmaceutical compositions disclosed herein are encapsulated in soft gelatin capsules, which improve comfort during use.
  • the pharmaceutical compositions are substantially liquid, which are more readily absorbed in the vaginal tissue, and also are dispersed over a larger surface area of the vaginal tissue.
  • the pharmaceutical compositions disclosed herein are for vaginal insertion in a single or multiple unit dosage form.
  • the estradiol in the pharmaceutical compositions is at least about: 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% solubilized.
  • the estradiol is not 100% solubilized, the remaining estradiol is present in a micronized
  • estradiol is solubilized in a solubilizing agent during manufacturing process. According to embodiments, all or some of the estradiol is solubilized following administration (e.g., the micronized portion where the estradiol is not 100% solubilized is solubilized in a body fluid after administration).
  • the solubilizing agents taught herein, with or without additional excipients other than the solubilizing agents are liquid or semi-solid. To the extent the estradiol is not fully solubilized at the time of
  • the estradiol should be substantially solubilized at a body temperature (average of 37° C) and, generally, at the pH of the vagina (ranges from 3.8 to 4.5 in healthy patients; or 4.6 to 6.5 in VVA patients).
  • estradiol can be added to the pharmaceutical compositions disclosed herein as estradiol, estradiol hemihydrate, or other grade estradiol forms used in pharmaceutical compositions or formulations.
  • estradiol dosage strengths vary.
  • Estradiol (or estradiol hemihydrate, for example, to the extent the water content of the estradiol hemihydrate is accounted for) dosage strength of is from at least about 1 microgram ⁇ g or ⁇ g) to at least about 50 ⁇ g.
  • Specific dosage embodiments contain at least about: 1 ⁇ g, 2 ⁇ g, 3 ⁇ g, 4 ⁇ g, 5 ⁇ g, 6 ⁇ g, 7 ⁇ g, 8 ⁇ g, 9 ⁇ g, 10 ⁇ g, 11 ⁇ g, 12 ⁇ g, 13 ⁇ g, 14 ⁇ g, 15 ⁇ g, 16 ⁇ g, 17 ⁇ g, 18 ⁇ g, 19 ⁇ & 20 ⁇ & 21 ⁇ ⁇ , 22 ⁇ & 23 ⁇ ⁇ , 24 ⁇ ⁇ , 25 ⁇ ⁇ , 26 ⁇ ⁇ , 27 ⁇ & 28 ⁇ & 29 ⁇ & 30 ⁇ & 31 ⁇ & 32 ⁇ & 33 ⁇ & 34 ⁇ ⁇ , 35 ⁇ ⁇ , 36 ⁇ ⁇ , 37 ⁇ ⁇ , 38 ⁇ ⁇ , 39 ⁇ & 40 ⁇ & 41 ⁇ & 42 ⁇ & 43 ⁇ & 44 ⁇ & 45 ⁇ g, 46
  • the pharmaceutical compositions contain at least about 2.5 ⁇ g; 4 ⁇ g 6.25 ⁇ g, 7.5 ⁇ g, 12.5 ⁇ g, 18.75 ⁇ g of estradiol.
  • the pharmaceutical compositions contain from about 1 ⁇ g to about 10 ⁇ g, from 3 ⁇ g to 7 ⁇ g, from about 7.5 ⁇ g to 12.5 ⁇ g, from about 10 ⁇ g to about 25 ⁇ g, about 1 ⁇ g, about 2.5 ⁇ g, from about 23.5 ⁇ g to 27.5 ⁇ g, from about 7.5 ⁇ g to 22.5 ⁇ g, from 10 ⁇ g to 25 ⁇ g of estradiol.
  • estradiol dosage is about 4 ⁇ g. In one embodiment, the estradiol dosage is about 10 ⁇ g. In another embodiment, the estradiol dosage is about 25 ⁇ g.
  • the solvent system that solubilizes the estradiol are medium chain fatty acid based solvents, together with other excipients.
  • the solvent system includes non-toxic, pharmaceutically acceptable solvents, co-solvents, surfactants, and other excipients suitable for vaginal delivery or absorption.
  • oils having medium chain fatty acids as a majority component are used as solubilizing agents to solubilize estradiol.
  • the solubilizing agents comprise medium chain fatty acid esters (e.g., esters of glycerol, ethylene glycol, or propylene glycol) or mixtures thereof.
  • the medium chain fatty acids comprise chain lengths from C6 to C14. According to embodiments the medium chain fatty acids comprise chain lengths from C6 to CI 2. According to embodiments the medium chain fatty acids substantially comprise chain lengths from C8- C10. ECN's for medium chain oils will be in the range of 21-42 for triglycerides, 12-28 for diglycerides, and 6-14 for monoglycerides.
  • the medium chain fatty acids are saturated. According to embodiments, the medium chain fatty acids are predominantly saturated, i.e., greater than about 60% or greater than about 75% saturated.
  • estradiol is soluble in the solubilizing agent at room temperature, although it may be desirable to warm certain solubilizing agents during manufacture to improve viscosity.
  • the solubilizing agent is liquid at between room temperature and about 50 °C, at or below 50 °C, at or below 40 °C, or at or below 30 °C.
  • the solubility of estradiol in the medium chain oil, medium chain fatty acid, or solubilizing agent (or oil/surfactant) is at least about 0.01 wt%, 0.02 wt%, 0.05 wt%, 0.06 wt%, 0.08 wt%, 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1.0 wt%, or higher.
  • medium chain solubilizing agents include, for example and without limitation saturated medium chain fatty acids: caproic acid (C6), enanthic acid (C7), caprylic acid (C8), pelargonic acid (C9), capric acid (CIO), undecylic acid(Cl l), lauric acid (C12), tridecylic acid (C13), or myristic acid (C14).
  • the solubilizing agent includes 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 is selected from at least one of a solvent or co-solvent.
  • glycerin based solubilizing agents include: mono-, di-, or triglycerides and combinations and derivatives thereof.
  • Exemplary glycerin based solubilizing agents include MIGLYOLs ® , which are caprylic/capric triglycerides (SASOL Germany GMBH, Hamburg).
  • MIGLYOLs includes MIGLYOL 810 (caprylic/capric triglyceride), MIGLYOL 812 (caprylic/capric triglyceride), MIGLYOL 816 (caprylic/capric triglyceride), and MIGLYOL 829 (caprylic/capric/succinic triglyceride).
  • MIGLYOL 810 caprylic/capric triglyceride
  • MIGLYOL 812 caprylic/capric triglyceride
  • MIGLYOL 816 caprylic/capric triglyceride
  • 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; caprylic/capric/succinic triglycerides.
  • CAPMUL MCM medium chain mono- and di-glycerides
  • Other and triglycerides of fractionated vegetable fatty acids, and combinations or derivatives thereof can be the solubilizing agent, according to embodiments.
  • the solubilizing agent can be 1,2,3-propanetriol (glycerol, glycerin, glycerine) esters of saturated coconut and palm kernel oil and derivatives thereof.
  • Ethylene and propylene glycols which include polyethylene and polypropylene glycols solubilizing agents include: glyceryl mono- and di-caprylates; propylene glycol monocaprylate (e.g., CAPMUL ® PG-8 (the CAPMUL brands are owned by ABITEC, Columbus, Ohio)); propylene glycol monocaprate (e.g., CAPMUL PG-10); propylene glycol mono- and dicaprylates; propylene glycol mono- and dicaprate; diethylene glycol mono ester (e.g., TRANSCUTOL®, 2-(2-ethoxyethoxy)ethanol, GATTEFOSSE SAS); and diethylene glycol monoethyl ether.
  • glyceryl mono- and di-caprylates e.g., CAPMUL ® PG-8 (the CAPMUL brands are owned by ABITEC, Columbus, Ohio)
  • propylene glycol monocaprate e.g., CAPMUL PG-10
  • the solubilizing agent includes 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 solubilizing agent or as a surfactant.
  • 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 di esters of polyethylene glycol.
  • commercially available fatty acid glycerol and glycol ester solubilizing agents are often 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, for example.
  • an oil/solubilizing agent when described herein as a saturated Cg fatty acid mono- or diester of glycerol, the predominant component of the oil, i.e., >50 wt% (e.g., >75 wt%, >85 wt% or >90 wt%) is caprylic monoglycerides and caprylic diglycerides.
  • the Technical Data Sheet by ABITEC for 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% C IO, and ⁇ 1.5% C12 and higher.
  • MIGLYOL 812 is a solubilizing agent that is generally described as a C8-C 10 triglyceride because the fatty acid composition is at least about 80% triglyceride esters of caprylic acid (C8) and capric acid (CI O). However, it also includes small amounts of other fatty acids, e.g., less than about 5% of caproic acid (C6), lauric acid (C 12), and myristic acid (CI 4).
  • C6 caproic acid
  • C 12 lauric acid
  • CI 4 myristic acid
  • anionic or non-ionic surfactants may be used in pharmaceutical compositions containing solubilized estradiol. Ratios of solubilizing agent(s) to surfactant(s) vary depending upon the respective solubilizing agent(s) and the respective surfactant(s) and the desired physical characteristics of the resultant pharmaceutical composition. For example and without limitation, CAPMUL MCM and a non-ionic surfactant may be used at ratios including 65:35, 70:30, 75:25, 80:20, 85: 15 and 90: 10.
  • the pharmaceutical composition further includes a surfactant.
  • the surfactant can be a nonionic surfactant, cationic surfactant, anionic surfactant, or mixtures thereof.
  • Suitable surfactants include, for example, water-insoluble surfactants having a hydrophilic-lipophilic balance (HLB) value less than 12 and water-soluble surfactants having a HLB value greater than 12.
  • HLB hydrophilic-lipophilic balance
  • surfactants that have a high HLB and hydrophilicity aid the formation of oil-water droplets.
  • the surfactants are amphiphilic in nature and are capable of dissolving or solubilizing relatively high amounts of hydrophobic drug compounds.
  • Non-limiting examples include, Tween, Dimethylacetamide (DMA), Dimethyl sulfoxide (DMSO), Ethanol, Glycerin, N-methyl-2-pyrrolidone (NMP), PEG 300, PEG 400, Poloxamer 407, Propylene glycol, Phospholipids, Hydrogenated soy phosphatidylcholine (HSPC), Distearoylphosphatidylglycerol (DSPG), L-a-dimyristoylphosphatidylcholine (DMPC), L-a-dimyristoylphosphatidylglycerol (DMPG), Polyoxyl 35 castor oil
  • the non-ionic surfactant is selected from one or more of glycerol and polyethylene glycol esters of long chain fatty acids, for example, lauroyl macrogol-32 glycerides or lauroyl polyoxyl-32 glycerides, commercially available as GELUCIRE, including, for example, GELUCIRE 39/01 (glycerol esters of saturated C12- C18 fatty acids), GELUCIRE 43/01 (hard fat NF/JPE) and GELUCIRE 50/13 (stearoyl macrogol-32 glycerides EP, stearoyl polyoxyl-32 glycerides NF, stearoyl polyoxylglycerides (USA FDA IIG)).
  • GELUCIRE 39/01 glycerol esters of saturated C12- C18 fatty acids
  • GELUCIRE 43/01 hard fat NF/JPE
  • GELUCIRE 50/13 stearoyl macrogol-32 glycerides EP, stearoyl
  • surfactants may be used at concentrations greater than about 0.01%, and typically in various amounts of about 0.01%-10.0%, 10.1%-20%, and 20.1%-30%. In some embodiments, surfactants may be used at concentrations of about 1% to about 10% (e.g., about 1% to about 5%, about 2% to about 4%, about 3% to about 8%).
  • 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 (polysorbate 80) (Sigma Aldrich, St. Louis, MO).
  • Polysorbate 80 includes approximately 60%-70% oleic acid with the remainder comprising primarily linoleic acids, palmitic acids, and stearic acids. Polysorbate 80 may be used in amounts ranging from about 5 to 50%, and according to embodiments, about 30% of the pharmaceutical composition total mass.
  • the non-ionic surfactant includes PEG-6 palmitostearate and ethylene glycol palmitostearate, which are available commercially as TEFOSE ® 63 (GATTEFOSSE SAS, Saint-Priest, France), which can be used with, for example, CAPMUL MCM having ratios of MCM to TEFOSE 63 of, for example, 8:2 or 9: 1.
  • TEFOSE ® 63 GATTEFOSSE SAS, Saint-Priest, France
  • other solubilizing agents/non-ionic surfactants combinations include, for example, MIGLYOL 812:GELUCIRE 50/13 or MIGLYOL 812:TEFOSE 63.
  • the surfactant can be an anionic surfactant, for example: ammonium lauryl sulfate, dioctyl sodium sulfosuccinate, perfluoro-octane sulfonic acid, potassium lauryl sulfate, or sodium stearate.
  • anionic surfactant for example: ammonium lauryl sulfate, dioctyl sodium sulfosuccinate, perfluoro-octane sulfonic acid, potassium lauryl sulfate, or sodium stearate.
  • Cationic surfactants are also contemplated.
  • non-ionic or anionic surfactants can be used alone with at least one solubilizing agent or can be used in combination with other surfactants.
  • the pharmaceutical composition may be used to solubilize estradiol.
  • solubilizing agent e.g., surfactant, or any other excipient as set forth herein.
  • surfactant e.g., surfactant, or any other excipient as set forth herein.
  • the combination of solubilizing agent, surfactant, and other excipients should be designed whereby the estradiol is absorbed into the vaginal tissue.
  • the pharmaceutical composition will result in minimal vaginal discharge.
  • the pharmaceutical composition further includes at least one thickening agent. Generally, a thickening agent is added when the viscosity of the pharmaceutical composition results less than desirable absorption. According to
  • the surfactant(s) disclosed herein may also provide thickening of the pharmaceutical composition that, upon release, will aid the estradiol in being absorbed by the vaginal mucosa while minimizing vaginal discharge.
  • thickening agents include: hard fats; propylene glycol; a mixture of hard fat EP/NF/JPE, glyceryl ricinoleate, ethoxylated fatty alcohols (ceteth-20, steareth-20) EP/NF (available as OVUCIRE ® 3460, GATTEFOSSE, Saint-Priest, France); a mixture of hard fat EP/NF/JPE, glycerol monooleate (type 40) EP/NF (OVUCIRE WL 3264; a mixture of hard fat EP/NF/JPE, glyceryl monooleate (type 40) EP/NF (OVUCIRE WL 2944); a non-ionic surfactant comprising PEG- 6 stearate, ethylene glycol palmitostearate,
  • thickening agents such as the alginates, certain gums such as xanthan gums, agar-agar, iota carrageenans, kappa carrageenans, etc.
  • Several other compounds can act as thickening agents like gelatin, and polymers like HPMC, PVC, and CMC.
  • the viscosity of pharmaceutical compositions in accordance with various embodiments may comprise from about 50 cps to about 1000 cps at 25° C. A person of ordinary skill in the art will readily understand and select from suitable thickening agents.
  • the thickening agent is a non-ionic surfactant.
  • polyethylene glycol saturated or unsaturated fatty acid ester or diester is the non- ionic surfactant thickening agent.
  • the non-ionic surfactant includes a polyethylene glycol long chain (C16-C20) fatty acid ester and further includes an ethylene glycol long chain fatty acid ester, such as PEG-fatty acid esters or diesters of saturated or unsaturated C16-C18 fatty acids, e.g., oleic, lauric, palmitic, and stearic acids.
  • the non-ionic surfactant includes a polyethylene glycol long chain saturated fatty acid ester and further includes an ethylene glycol long chain saturated fatty acid ester, such as PEG- and ethylene gly col-fatty acid esters of saturated C16-C18 fatty acids, e.g., palmitic and stearic acids.
  • Such non-ionic surfactant can comprise PEG-6 stearate, ethylene glycol palmitostearate, and PEG-32 stearate, such as but not limited to TEFOSE 63.
  • TEFOSE 63 is used to provide additional viscosity and/or spreadability in the vagina so as to retard flow of the composition out of the vagina. While the pharmaceutical composition remains liquid, the viscosity of such a pharmaceutical composition causes the liquid to remain in the API absorption area whereby the
  • the pharmaceutical composition is substantially absorbed by the tissue.
  • an excipient to increase the viscosity and/or spreadability of the pharmaceutical compositions herein allows the administration of a pharmaceutical composition that is liquid at body temperature but does not excessively discharge from the vagina when the patient is standing, which allows the patients to be ambulatory after administration of the
  • the non-ionic surfactant used as a thickening agent is not hydrophilic and has good emulsion properties.
  • An illustrative example of such surfactant is TEFOSE 63, which has a hydrophilic-lipophilic balance (HLB) value of about 9-10.
  • the pharmaceutical composition further includes one or more mucoadherent agents to improve vaginal absorption of the estradiol by, for example, increasing the viscosity of of the pharmaceutical composition whereby flow out of the vagina is retarded.
  • the mucoadhesive agent causes the pharmaceutical composition to adhere to the vaginal tissue chemically or mechanically.
  • a mucoadherent agent can be present to aid the pharmaceutical composition with adherence to the mucosa upon activation with water.
  • polycarbophil is the mucoadherent agent.
  • other mucoadherent agents include, for example and without limitation: poly (ethylene oxide) polymers having a molecular weight of from about 100,000 to about 900,000; chitosans; carbopols including polymers of acrylic acid crosslinked with allyl sucrose or allyl pentaerythritol; polymers of acrylic acid and C10-C30 alkyl acrylate crosslinked with allyl pentaerythritol; carbomer homopolymer or copolymer that contains a block copolymer of polyethylene glycol and a long chain alkyl acid ester; and the like.
  • various hydrophilic polymers and hydrogels may be used as the mucoadherent agent.
  • the polymers or hydrogels can swell in response to contact with vaginal tissue or secretions, enhancing moisturizing and mucoadherent effects.
  • the selection and amount of hydrophilic polymer may be based on the selection and amount of solubilizing agent.
  • the pharmaceutical composition includes a hydrophilic polymer but optionally excludes a gelling agent.
  • having a hydrogel from about 5% to about 10% of the total mass may comprise the hydrophilic polymer.
  • hydrogels may be employed.
  • a hydrogel may comprise chitosan, which swell in response to contact with water.
  • a cream pharmaceutical composition may comprise PEG-90M.
  • a mucoadherent agent is present in the pharmaceutical formulation, in the soft gel capsule, or both.
  • the pharmaceutical compositions include one or more thermoreversible gels, typically of the hydrophilic nature including for example and without limitation, hydrophilic sucrose and other saccharide-based monomers (U. S. Pat. No.
  • the pharmaceutical composition further includes a lubricant.
  • a lubricant can be present to aid in formulation of a dosage form.
  • a lubricant may be added to ensure that capsules or tablets do not stick to one another during processing or upon storage.
  • Any suitable lubricant may be used.
  • lecithin which is a mixture of phospholipids, is the lubricant.
  • the pharmaceutical composition further includes an antioxidant. Any suitable anti-oxidant may be used. For example, butylated hydroxy toluene, butylated hydroxyanisole, and Vitamin E TPGS.
  • the pharmaceutical composition includes about 20% to about 80% solubilizing agent by weight, about 0.1% to about 5% lubricant by weight, and about 0.01% to about 0.1% antioxidant by weight.
  • excipient will depend on factors such as, for example, the effect of the excipient on solubility and stability.
  • Additional excipients used in various embodiments may include colorants and preservatives.
  • colorants include FD&C colors (e.g., blue No. 1 and Red No. 40), D&C colors (e.g., Yellow No. 10), and opacifiers (e.g., Titanium dioxide).
  • colorants comprise about 0.1% to about 2% of the pharmaceutical composition by weight.
  • preservatives in the pharmaceutical composition comprise methyl and propyl paraben, in a ratio of about 10: 1, and at a proportion of about 0.005% and 0.05% by weight.
  • solubilizing agents, excipients, other additives 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 maintain will result in the desired therapeutic effect when administered to a subject.
  • solubilizing agents comprising mixtures of medium chain fatty acid glycerides, e.g., C6-C12, Cg-C12, or Cg-CIO fatty acid mono- and diglycerides or mono-, di-, and triglycerides dissolve estradiol.
  • medium chain fatty acid glycerides e.g., C6-C12, Cg-C12, or Cg-CIO fatty acid mono- and diglycerides or mono-, di-, and triglycerides dissolve estradiol.
  • solubilizing agents that are predominantly a mixture of C8-C10 saturated fatty acid mono- and diglycerides, or medium chain
  • triglycerides e.g., MIGLYOL 810 or 812.
  • Longer chain glycerides appear to be not as well suited for dissolution of estradiol.
  • a solubilizing agent comprising propylene glycol monocaprylate (e.g., CAPRYOL) and 2-(2-Ethoxyethoxy)ethanol (e.g., TRANSCUTOL) solubilized estradiol well.
  • propylene glycol monocaprylate e.g., CAPRYOL
  • 2-(2-Ethoxyethoxy)ethanol e.g., TRANSCUTOL
  • the pharmaceutical composition is prepared via blending estradiol with a pharmaceutically acceptable solubilizing agent, including for example and without limitation, at least one medium chain fatty acid such as medium chain fatty acids consisting of at least one mono-, di-, or triglyceride, or derivatives thereof, or combinations thereof.
  • a pharmaceutically acceptable solubilizing agent including for example and without limitation, at least one medium chain fatty acid such as medium chain fatty acids consisting of at least one mono-, di-, or triglyceride, or derivatives thereof, or combinations thereof.
  • the pharmaceutical composition also includes at least one glycol or derivatives thereof or combinations thereof or combinations of at least one glyceride and glycol.
  • the glycol(s) may be used as solubilizing agents or to adjust viscosity and, thus, may be considered thickening agents, as discussed further herein.
  • other excipients including, for example and without limitation, antioxidants, lubricants, and the like.
  • the pharmaceutically acceptable solubilizing agent including for
  • composition includes sufficient solubilizing agent to fully solubilize the estradiol. It is expressly understood, however, the other volumes of solubilizing agent can be used depending on the level of estradiol solubilization desired. Persons of ordinary skill in the art will know and understand how to determine the volume of solubilizing agent and other excipients depending on the desired percent of estradiol to be solubilized in the
  • GELUCIRE 44/14 (lauroyl macrogol-32 glycerides EP, lauroyl polyoxyl-32 glycerides NF, lauroyl polyoxylglycerides (USA FDA IIG)) is heated to about 65 °C and CAPMUL MCM is heated to about 40 °C to facilitate mixing of the oil and non-ionic surfactant, although such heating is not necessary to dissolve the estradiol.
  • the capsules are soft capsules made of materials well known in the pharmaceutical arts, for example, gelatin.
  • the delivery vehicle is integral with the pharmaceutical composition (i.e., the pharmaceutical composition is the delivery vehicle).
  • the pharmaceutical compositions is a gel, cream, ointment, tablet, or other preparation that is directly applied and absorbed vaginally.
  • the capsules do not contain one or more of the following: a hydrophilic gel-forming bioadhesive agent, a lipophilic agent, a gelling agent for the lipophilic agent, and/or a hydrodispersible agent.
  • the capsules do not contain a hydrophilic gel-forming bioadhesive agent selected from: carboxy vinylic acid, hydroxypropylcellulose, carboxymethylcellulose, gelatin, xanthan gum, guar gum, aluminum silicate, and mixtures thereof.
  • the capsules do not contain a lipophilic agent selected from: a liquid triglyceride, a solid triglyceride (with a melting point of about 35 °C), camauba wax, cocoa butter, and mixtures thereof.
  • the capsules do not contain a hydrophobic colloidal silica gelling agent.
  • the capsules do not contain a hydrodispersible agent selected from: polyoxyethylene glycol, polyoxyethylene glycol 7-glyceryl-cocoate, and mixtures thereof.
  • the estradiol is formulated as a liquid composition consisting of a therapeutically effective amount of estradiol; a caprylic/capric triglyceride; and a non- ionic surfactant comprising PEG-6 palmitostearate and ethylene glycol palmitostearate.
  • a hydrophilic gel-forming bioadhesive agent in the liquid composition is contained with a gelatin capsule as described herein.
  • the capsule comprises gelatin and optionally one or more further components selected from the group consisting of gelatin, hydrolyzed gelatin, sorbitol-sorbitan solution, water, glycerin, titanium dioxide, FD&C Red #40, ethanol, ethyl acetate, propylene glycol, polyvinyl acetate phthalate, isopropyl alcohol, polyethylene glycol, and ammonium hydroxide.
  • the delivery vehicle is designed for ease of insertion.
  • the delivery vehicle is sized whereby it can be comfortably inserted into the vagina.
  • the delivery vehicle is prepared in a variety of geometries.
  • the delivery vehicle is shaped as a tear drop, a cone with frustoconical end, a cylinder, a cylinder with larger "cap” portion, or other shapes suitable for and that ease insertion into the vagina.
  • the delivery vehicle is used in connection with an applicator.
  • the delivery vehicle is inserted digitally.
  • a method for the treatment of VVA including dyspareunia, vaginal dryness, and estrogen-deficient urinary states (including urinary tract infections) wherein a composition for the treatment of VVA is digitally insert approximately two inches into the vagina or in the third of the vagina closest to the opening of the vagina and results in at least one of: improved compliance compared to other products for the treatment of VVA; improved user experience compared to other products for the treatment of VVA; and statistically significantly improved symptoms of VVA, compared to placebo or baseline within one of two, four, six, eight, ten, or twelve or more weeks after initiation of administration.
  • a method for the treatment of VVA including dyspareunia, vaginal dryness, and estrogen-deficient urinary states (including urinary tract infections) wherein a delivery vehicle containing a composition for the treatment of VVA and a tear drop shape as disclosed herein is insert approximately two inches into the vagina or in the third of the vagina closest to the opening of the vagina and results in at least one of: improved compliance compared to other products for the treatment of VVA; improved user experience compared to other products for the treatment of VVA; and statistically significantly improved symptoms of VVA, compared to placebo or baseline within one of two, four, six, eight, ten, or twelve or more weeks after initiation of administration.
  • delivery vehicle 200 includes pharmaceutical composition 202 and capsule 204.
  • Width 208 represents the thickness of capsule 204, for example about 0.108 inches.
  • the distance from one end of delivery vehicle 200 to another is represented by distance 206, for example about 0.690 inches.
  • the size of delivery vehicle 200 may also be described by the arc swept by a radius of a given length.
  • arc 210 which is defined by the exterior of gelatin 204, is an arc swept by a radius of about 0.189 inches.
  • Arc 212 which is defined by the interior of capsule 204, is an arc swept by a radius of about 0.0938 inches.
  • Arc 214 which is defined by the exterior of gelatin 204 opposite arc 210, is an arc swept by a radius of about 0.108 inches. Suitable capsules of other dimensions may be provided. According to embodiments, capsule 204 has dimensions the same as or similar to the ratios as provided above relative to each other.
  • the gelatin capsule further comprises one or more components selected from the group consisting of hydrolyzed gelatin, sorbitol-sorbitan solution, water, glycerin, titanium dioxide, FD&C Red #40, ethanol, ethyl acetate, propylene glycol, polyvinyl acetate phthalate, isopropyl alcohol, polyethylene glycol, and ammonium hydroxide.
  • the delivery vehicle is designed to remaining in the vagina until the pharmaceutical compositions are released.
  • delivery vehicle dissolves intravaginally and is absorbed into the vaginal tissue with the pharmaceutical composition, which minimizes vaginal discharge.
  • delivery mechanism is made from constituents that are non-toxic, for example, gelatin.
  • the pharmaceutical composition is designed to maximize favorable characteristics that lead to patient compliance (patients that discontinue treatment prior to completion of the prescribed course of therapy), without sacrificing efficacy.
  • Favorable characteristics include, for example, lack of or reduction of irritation relative to other hormone replacement pessaries, lack of or reduction in vaginal discharge of the pharmaceutical composition and delivery vehicle relative to other hormone replacement pessaries, lack of or reduction of pharmaceutical composition or delivery vehicle residue inside the vagina, ease of administration compared to other hormone replacement pessaries, or improved efficacy of drug product relative to otherwise similar pharmaceutical compositions.
  • the pharmaceutical composition is non-irritating or minimizes irritation.
  • Patient irritation includes pain, pruritus (itching), soreness, excessive discharge, swelling, or other similar conditions. Patient irritation results in poor compliance.
  • Non-irritating or reduced irritation pharmaceutical compositions are measured relative to competing hormone pessaries, including tablets, creams, or other intravaginal estrogen delivery forms.
  • the pharmaceutical compositions does not result in systemic exposure (e.g., blood circulation of estradiol), which improves safety.
  • the pharmaceutical compositions disclosed herein result in significantly reduced systemic exposure (e.g., blood circulation of estradiol) when compared to other vaginally administered drugs on the market for the treatment of VVA.
  • the administration of the pharmaceutical composition provides a mean concentration (Cav e ) value below 20.6 pg/mL on Day 1 of the treatment, and/or a C ⁇ e value below 19.4 pg/mL on Day 14 of the treatment, and/or a C ⁇ e value below 11.5 pg/mL on Day 83 of the treatment.
  • the administration of the pharmaceutical composition provides a mean concentration (C ave ) value below 10 pg/mL on Day 1 of the treatment, and/or a C ave value below 7.3 pg/mL on Day 14 of the treatment, and/or a Cave value below 5.5 pg/mL on Day 83 of the treatment.
  • the pharmaceutical composition does not leave residue inside the vagina. Rather, the pharmaceutical composition and delivery vehicle are substantially absorbed or dispersed without resulting in unabsorbed residue or unpleasant sensations of non-absorbed or non-dispersed drug product. Measurement of lack of residue is relative to other vaginally inserted products or can be measured obj ectively with inspection of the vaginal tissues. For example, certain other vaginally inserted products contain starch which can result in greater discharge from the vagina following administration than. In some embodiments, the pharmaceutical compositions provided herein provide a lower amount, duration, or frequency of discharge following administration compared to other vaginally inserted products (e.g., compressed tablets).
  • the pharmaceutical composition improves vaginal discharge compared to other pessaries, including pessaries that deliver hormones. Ideally, vaginal discharge is eliminated, minimized, or improved compared to competing products.
  • the pharmaceutical compositions disclosed herein are inserted digitally. According to embodiments, the pharmaceutical compositions are digitally inserted approximately two inches into the vagina without a need for an applicator.
  • the pharmaceutical compositions are designed to be also inserted with an applicator, if desired.
  • the pharmaceutical compositions disclosed herein are designed to be inserted in the proximal portion of the vagina.
  • the solubilizing agent was selected from at least one of a solvent or co-solvent.
  • Suitable solvents and co-solvents include any mono-, di- or triglyceride and glycols, and combinations thereof.
  • the pharmaceutical composition is delivered via a gelatin capsule delivery vehicle.
  • the pharmaceutical composition is a liquid pharmaceutical composition.
  • the delivery vehicle is a soft capsule, for example a soft gelatin capsule.
  • the pharmaceutical composition of such embodiments is encapsulated in the soft gelatin capsule or other soft capsule.
  • the pharmaceutical composition includes estradiol that is at least about 80% solubilized in a solubilizing agent comprising one or more C6 to C14 medium chain fatty acid mono-, di-, or triglycerides and, optionally, a thickening agent.
  • the pharmaceutical composition includes estradiol that is at least about 80% solubilized one or more C6 to C12 medium chain fatty acid mono-, di-, or triglycerides, e.g., one or more C6 to C14 triglycerides, e.g., one or more C6 to C12 triglycerides, such as one or more C8-C10 triglycerides.
  • estradiol being at least 80% solubilized.
  • these embodiments specifically contemplate the estradiol being at least 90% solubilized.
  • the estradiol being at least 95% solubilized.
  • the estradiol being fully solubilized.
  • liquid pharmaceutical compositions are liquid at room temperature or at body temperature.
  • a pharmaceutical composition provided herein is a liquid formulation contained within a soft gel capsule. Gels, hard fats, or other solid forms that are not liquid at room or body temperature are less desirable in embodiments of the pharmaceutical composition that are liquid.
  • the thickening agent serves to increase viscosity, e.g., up to about 10,000 cP (10,000 mPa-s), typically to no more than about 5000 cP, and more typically to between about 50 and 1000 cP.
  • the non-ionic surfactant e.g., GELUCIRE or TEFOSE
  • GELUCIRE or TEFOSE may be solid at room temperature and require melting to effectively mix with the solubilizing agent.
  • the resultant pharmaceutical composition remains liquid, albeit with greater viscosity, not solid.
  • the pharmaceutical composition includes estradiol, the medium chain solubilizing agent, and the thickening agent as the ingredients delivered via a soft capsule delivery vehicle.
  • Other ingredients e.g., colorants, antioxidants, preservatives, or other ingredients may be included as well.
  • the addition of other ingredients should be in amounts that do not materially change the solubility of the estradiol, the
  • pharmacokinetics of the pharmaceutical composition or efficacy of the pharmaceutical composition.
  • Other factors that should be considered when adjusting the ingredients of the pharmaceutical composition include the irritation, vaginal discharge, intravaginal residue, and other relevant factors, for example those that would lead to reduced patient compliance.
  • Other contemplated ingredients include: oils or fatty acid esters, lecithin, mucoadherent agents, gelling agents, dispersing agents, or the like.
  • the pharmaceutical compositions disclosed herein can be used for the treatment of VVA, including the treatment of at least one VVA symptom including: vaginal dryness, vaginal or vulvar irritation or itching, dysuria, dyspareunia, and vaginal bleeding associated with sexual activity, among others.
  • VVA symptom including: vaginal dryness, vaginal or vulvar irritation or itching, dysuria, dyspareunia, and vaginal bleeding associated with sexual activity, among others.
  • the methods of treatment are generally applicable to females.
  • the pharmaceutical compositions disclosed herein can be used for the treatment of estrogen-deficient urinary states. According to embodiments, the pharmaceutical compositions disclosed herein can be used for the treatment of dyspareunia, or vaginal bleeding associated with sexual activity.
  • treatment of the VVA, estrogen-deficient urinary states, and dyspareunia and vaginal bleeding associated with sexual activity occurs by administering the pharmaceutical compositions intravaginally.
  • the delivery vehicle is a capsule
  • the patient obtains the capsule and inserts the capsule into the vagina, where the capsule dissolves and the pharmaceutical composition is released into the vagina where it is absorbed into the vaginal tissue.
  • the pharmaceutical composition is completely absorbed into the vaginal tissue.
  • the pharmaceutical composition is substantially absorbed into the vaginal tissue (e.g., at least about 80% by weight, at least about 85% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, at least about 98% by weight, or at least about 99% by weight of the composition is absorbed).
  • the capsule is inserted about two inches into the vagina, however the depth of insertion is generally any depth that allows for adsorption of substantially all of the pharmaceutical composition.
  • the capsule can also be applied using an applicator that deposits the capsule at an appropriate vaginal depth as disclosed herein.
  • the capsule is insert into the lower third of the vagina (i.e., the third closest to the vaginal opening).
  • the softgel capsule can be held with the larger end between the fingers as shown in Fig. 26A.
  • the subject will select a position that is most comfortable (e.g., a reclining position as shown in Fig. 26B or a standing position as shown in Fig. 26C), and the subject will insert the softgel into the lower third of the vagina with the smaller end up.
  • the softgel capsule will dissolve rapidly.
  • the softgel can be inserted at any time of day and normal activities can be immediately resumed. According to embodiments, the same time of day for all insertions of of the softgel is used.
  • the pharmaceutical composition is a cream, gel, ointment, or other similar preparation
  • the pharmaceutical composition is applied digitally, as is well known and understood in the art.
  • estradiol Upon release of the pharmaceutical composition in the vagina, estradiol is locally absorbed.
  • estradiol is locally absorbed.
  • following administration of the suppository to the proximal region of the vagina of a patient provides a therapeutically effective concentration of estradiol over 24 hours in the proximal region of the vagina.
  • the timing of administration of the pharmaceutical composition of this disclosure may be conducted by any safe means as prescribed by an attending physician.
  • a patient will administer the pharmaceutical composition (e.g., a capsule) intravaginally each day for 14 days, then twice weekly thereafter.
  • the doses administered during the twice weekly dosing period are administered approximately 3-4 days apart.
  • doses administered during the twice weekly dosing period do not exceed more than twice in a seven day period.
  • the pharmaceutical compositions are vaginally administered with co-administration of an orally administered estrogen-based (or progestin- based or progestin- and estrogen-based) pharmaceutical drug product, or patch, cream, gel, spray, transdermal delivery system or other parenterally-administered estrogen-based pharmaceutical drug product, each of which can include natural, bio-similar, or synthetic or other derived estrogens or progestins.
  • modulation of circulating estrogen levels provided via the administration of the pharmaceutical compositions disclosed herein, if any, are not intended to be additive to any co-administered estrogen product and its associated circulating blood levels.
  • co-administrated estrogen products are intended to have an additive effect as would be determined by the patient physician.
  • a method for estrogenizing vaginal tissue includes administration of a (i.e., a suppository) or dosage as described herein.
  • Estrogenized vaginal tissue is typically characterized by one or more of the following properties: the presence clear secretions on vaginal walls; rogation and elasticity of the vaginal walls; intact vaginal epithelium; and pink tissue color.
  • estrogenizing vaginal tissue can include, increasing the level of vaginal secretions in a subject; increasing the number of vaginal rugae in the subject; and/or decreasing bleeding or petechiae in the subject.
  • a method for estrogenizing vaginal tissue including administering a suppository so as to provide an estradiol Cmax or AUC as described herein.
  • a method for estrogenizing vaginal tissue is provided, the method including administering a suppository so as to provide an estrone Cmax or AUC as described herein.
  • a method for estrogenizing the labia majora and labia minora (collectively "labia") is provided as described herein.
  • the pharmaceutical composition is inserted digitally into the vagina approximately two inches or inserted into the third of the vagina closest to the vaginal opening as shown in Figs. 26 A, 26B, and 26C.
  • the gelatin capsule containing the pharmaceutical composition dissolves, ruptures, or otherwise releases the pharmaceutical composition into the vagina, whereby the lower third of the vagina and labia are both reestrogenized.
  • the pharmaceutical composition is inserted digitally into the vagina approximately two inches or inserted into the third of the vagina closest to the vaginal opening as shown in Figs. 26 A, 26B, and 26C.
  • the gelatin capsule containing the pharmaceutical composition dissolves, ruptures, or otherwise releases the pharmaceutical composition into the vagina, whereby the lower third of the vagina and labia are both reestrogenized.
  • the pharmaceutical composition is inserted digitally into the vagina approximately two inches or inserted into the third of
  • composition is a liquid that partially flows to the labia and directly reestrogenizes the labia.
  • a method for estrogenizing the vulva is provided as described herein.
  • the pharmaceutical composition is inserted digitally into the vagina approximately two inches or inserted into the third of the vagina closest to the vaginal opening as shown in Figs. 26 A, 26B, and 26C.
  • the gelatin capsule containing the pharmaceutical composition dissolves, ruptures, or otherwise releases the pharmaceutical composition into the vagina, whereby the lower third of the vagina and vulva are both reestrogenized.
  • the pharmaceutical composition is a liquid that partially flows to the vulval tissue and directly reestrogenizes the vulva.
  • a method for treating vaginal dryness includes administration of a soft gel vaginal estradiol formulation (i.e., a suppository) or dosage as described herein.
  • Treating vaginal dryness according to the method disclosed herein can include, decreasing the severity of vaginal dryness by 1 %, 5%, 10%, 15%, 20%, 25%, 30%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%.
  • the decrease in severity can be obtained following 2 weeks of treatment, or 6 weeks of treatment, or 8 weeks of treatment, or 12 weeks of treatment.
  • vaginal dryness is assessed using a severity scale, ranging from 0 to 4 points wherein 0 indicates no dryness, 1 indicates mild dryness, 2 indicates moderate dryness, and 3 indicates severe dryness.
  • the method for treating vaginal dryness includes reducing the dryness severity score from 3, prior to treatment of a subject, to 2, after 2 weeks of treatment of the subject. In some embodiments, the method for treating vaginal dryness includes reducing the dryness severity score from 2, prior to treatment of a subject, to 1 , after 2 weeks of treatment of the subject. In some embodiments, the method for treating vaginal dryness includes reducing the dryness severity score from 1 , prior to treatment of subject, to 0, after 2 weeks of treatment of the subject. [0186] In some embodiments, the method for treating vaginal dryness includes reducing the dryness severity score from 3, prior to treatment of a subject, to 2, after 6 weeks of treatment of the subject.
  • the method for treating vaginal dryness includes reducing the dryness severity score from 2, prior to treatment of a subject, to 1, after 6 weeks of treatment of the subject. In some embodiments, the method for treating vaginal dryness includes reducing the dryness severity score from 1 , prior to treatment of subject, to 0, after 6 weeks of treatment of the subject.
  • the method for treating vaginal dryness includes reducing the dryness severity score from 3, prior to treatment of a subject, to 2, after 8 weeks of treatment of the subject. In some embodiments, the method for treating vaginal dryness includes reducing the dryness severity score from 2, prior to treatment of a subject, to 1 , after 8 weeks of treatment of the subject. In some embodiments, the method for treating vaginal dryness includes reducing the dryness severity score from 1 , prior to treatment of subject, to 0, after 8 weeks of treatment of the subject.
  • the method for treating vaginal dryness includes reducing the dryness severity score from 3, prior to treatment of a subject, to 2, after 12 weeks of treatment of the subject. In some embodiments, the method for treating vaginal dryness includes reducing the dryness severity score from 2, prior to treatment of a subject, to 1, after 12 weeks of treatment of the subject. In some embodiments, the method for treating vaginal dryness includes reducing the dryness severity score from 1 , prior to treatment of subject, to 0, after 12 weeks of treatment of the subj ect.
  • the method for treating vaginal dryness includes decreasing the severity of dryness after two weeks of treatment, wherein the severity is assessed on a scale of 0-3 points, and the average decrease ranges from a 0.5-point decrease to a 1.25-point decrease.
  • the average decrease can be determined by observing any suitable number of subjects. In some embodiments, the number of subjects is at least 100. In some
  • the number of subjects is at least 500. In some embodiments, the number of subjects ranges from 700 to 800. In some embodiments, the number of subjects ranges from 740 to 750. In some embodiments, the vaginal estradiol formulation contains 4 ⁇ g of estradiol. In some embodiments, the vaginal estradiol formulation contains 10 ⁇ g of estradiol. In some embodiments, the vaginal estradiol formulation contains 25 ⁇ g of estradiol. [0190] In some embodiments, the method for treating vaginal dryness includes decreasing the severity of dryness after six weeks of treatment, wherein the severity is assessed on a scale of 0-3 points, and the average decrease ranges from a 0.75-point decrease to a 1.5-point decrease. The average decrease can be determined by observing any suitable number of subjects. In some embodiments, the number of subjects is at least 100. In some
  • the number of subjects is at least 500. In some embodiments, the number of subjects ranges from 700 to 800. In some embodiments, the number of subjects ranges from 740 to 750. In some embodiments, the vaginal estradiol formulation contains 4 ⁇ g of estradiol. In some embodiments, the vaginal estradiol formulation contains 10 ⁇ g of estradiol. In some embodiments, the vaginal estradiol formulation contains 25 ⁇ g of estradiol.
  • the method for treating vaginal dryness includes decreasing the severity of dryness after eight weeks of treatment, wherein the severity is assessed on a scale of 0-3 points, and the average decrease ranges from a 0.9-point decrease to a 1.5-point decrease.
  • the average decrease can be determined by observing any suitable number of subjects. In some embodiments, the number of subjects is at least 100. In some
  • the number of subjects is at least 500. In some embodiments, the number of subjects ranges from 700 to 800. In some embodiments, the number of subjects ranges from 740 to 750. In some embodiments, the vaginal estradiol formulation contains 4 ⁇ g of estradiol. In some embodiments, the vaginal estradiol formulation contains 10 ⁇ g of estradiol. In some embodiments, the vaginal estradiol formulation contains 25 ⁇ g of estradiol. [0192] In some embodiments, the method for treating vaginal dryness includes decreasing the severity of dryness after twelve weeks of treatment, wherein the severity is assessed on a scale of 0-3 points, and the average decrease ranges from a 0.9-point decrease to a 1.5-point decrease.
  • the average decrease can be determined by observing any suitable number of subjects.
  • the number of subjects is at least 100. In some embodiments, the number of subjects is at least 500. In some embodiments, the number of subjects ranges from 700 to 800. In some embodiments, the number of subjects ranges from 740 to 750.
  • the vaginal estradiol formulation contains 4 ⁇ g of estradiol. In some embodiments, the vaginal estradiol formulation contains 10 ⁇ g of estradiol. In some embodiments, the vaginal estradiol formulation contains 25 ⁇ g of estradiol.
  • the method for treating vaginal dryness includes administering a suppository so as to provide an estradiol Cmax or AUC as described herein.
  • a method for treating vaginal dryness is provided, the method including administering a suppository so as to provide an estrone Cmax or AUC as described herein.
  • a method for treating vulvar and/or vaginal itching or irritation includes administration of a soft gel vaginal estradiol formulation (i.e., a suppository) or dosage as described herein.
  • Treating vulvar and/or vaginal itching or irritation according to the method disclosed herein can include, decreasing the severity of vulvar and/or vaginal itching or irritation by 1%, 5%, 10%, 15%, 20%, 25%, 30%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%.
  • the decrease in severity can be obtained following 2 weeks of treatment, or 6 weeks of treatment, or 8 weeks of treatment, or 12 weeks of treatment.
  • vulvar and/or vaginal itching or irritation is assessed using a severity scale, ranging from 0 to 4 points wherein 0 indicates no itching or irritation, 1 indicates mild itching or irritation, 2 indicates moderate itching or irritation, and 3 indicates severe itching or irritation.
  • the method for treating vulvar and/or vaginal itching or irritation includes reducing the itching/irritation severity score from 3, prior to treatment of a subject, to 2, after 2 weeks of treatment of the subject.
  • the method for treating vulvar and/or vaginal itching or irritation includes reducing the itching/irritation severity score from 2, prior to treatment of a subject, to 1, after 2 weeks of treatment of the subject.
  • the method for treating vulvar and/or vaginal itching or irritation includes reducing the itching/irritation severity score from 1, prior to treatment of subject, to 0, after 2 weeks of treatment of the subject.
  • the method for treating vulvar and/or vaginal itching or irritation includes reducing the itching/irritation severity score from 3, prior to treatment of a subject, to 2, after 6 weeks of treatment of the subject. In some embodiments, the method for treating vulvar and/or vaginal itching or irritation includes reducing the itching/irritation severity score from 2, prior to treatment of a subject, to 1, after 6 weeks of treatment of the subject. In some embodiments, the method for treating vulvar and/or vaginal itching or irritation includes reducing the itching/irritation severity score from 1, prior to treatment of subject, to 0, after 6 weeks of treatment of the subject.
  • the method for treating vulvar and/or vaginal itching or irritation includes reducing the itching/irritation severity score from 3, prior to treatment of a subject, to 2, after 8 weeks of treatment of the subject. In some embodiments, the method for treating vulvar and/or vaginal itching or irritation includes reducing the itching/irritation severity score from 2, prior to treatment of a subject, to 1, after 8 weeks of treatment of the subject. In some embodiments, the method for treating vulvar and/or vaginal itching or irritation includes reducing the itching/irritation severity score from 1, prior to treatment of subject, to 0, after 8 weeks of treatment of the subject.
  • the method for treating vulvar and/or vaginal itching or irritation includes reducing the itching/irritation severity score from 3, prior to treatment of a subject, to 2, after 12 weeks of treatment of the subject. In some embodiments, the method for treating vulvar and/or vaginal itching or irritation includes reducing the itching/irritation severity score from 2, prior to treatment of a subject, to 1, after 12 weeks of treatment of the subject. In some embodiments, the method for treating vulvar and/or vaginal itching or irritation includes reducing the itching/irritation severity score from 1, prior to treatment of subject, to 0, after 12 weeks of treatment of the subject.
  • the method for treating vulvar and/or vaginal itching or irritation includes decreasing the severity of itching/irritation after two weeks of treatment, wherein the severity is assessed on a scale of 0-3 points, and the average decrease ranges from a 0.3-point decrease to a 0.6-point decrease.
  • the average decrease can be determined by observing any suitable number of subjects.
  • the number of subjects is at least 100.
  • the number of subj ects is at least 500.
  • the number of subjects ranges from 700 to 800.
  • the number of subjects ranges from 740 to 750.
  • the vaginal estradiol formulation contains 4 ⁇ g of estradiol.
  • the vaginal estradiol formulation contains 10 ⁇ g of estradiol.
  • the vaginal estradiol formulation contains 25 ⁇ g of estradiol.
  • the method for treating vulvar and/or vaginal itching or irritation includes decreasing the severity of itching/irritation after six weeks of treatment, wherein the severity is assessed on a scale of 0-3 points, and the average decrease ranges from a 0.5-point decrease to a 0.7-point decrease.
  • the average decrease can be determined by observing any suitable number of subjects.
  • the number of subjects is at least 100.
  • the number of subj ects is at least 500.
  • the number of subjects ranges from 700 to 800.
  • the number of subjects ranges from 740 to 750.
  • the vaginal estradiol formulation contains 4 ⁇ g of estradiol.
  • the vaginal estradiol formulation contains 10 ⁇ g of estradiol.
  • the vaginal estradiol formulation contains 25 ⁇ g of estradiol.
  • the method for treating vulvar and/or vaginal itching or irritation includes decreasing the severity of itching/irritation after eight weeks of treatment, wherein the severity is assessed on a scale of 0-3 points, and the average decrease ranges from a 0.5-point decrease to a 0.8-point decrease.
  • the average decrease can be determined by observing any suitable number of subjects.
  • the number of subjects is at least 100.
  • the number of subj ects is at least 500.
  • the number of subjects ranges from 700 to 800.
  • the number of subjects ranges from 740 to 750.
  • the vaginal estradiol formulation contains 4 ⁇ g of estradiol.
  • the vaginal estradiol formulation contains 10 ⁇ g of estradiol. In some embodiments, the vaginal estradiol formulation contains 25 ⁇ g of estradiol.
  • the method for treating vulvar and/or vaginal itching or irritation includes decreasing the severity of itching/irritation after twelve weeks of treatment, wherein the severity is assessed on a scale of 0-3 points, and the average decrease ranges from a 0.5-point decrease to a 1.0-point decrease. The average decrease can be determined by observing any suitable number of subjects. In some embodiments, the number of subjects is at least 100. In some embodiments, the number of subjects is at least 500. In some embodiments, the number of subjects ranges from 700 to 800.
  • the number of subjects ranges from 740 to 750.
  • the vaginal estradiol formulation contains 4 ⁇ g of estradiol. In some embodiments, the vaginal estradiol formulation contains 10 ⁇ g of estradiol. In some embodiments, the vaginal estradiol formulation contains 25 ⁇ g of estradiol.
  • the method for treating vulvar and/or vaginal itching or irritation includes administering a suppository so as to provide an estradiol Cmax or AUC as described herein.
  • a method for treating vulvar and/or vaginal itching or irritation is provided, the method including administering a suppository so as to provide an estrone Cmax or AUC as described herein.
  • a method for treating dyspareunia includes administration of a suppository or dosage as described herein. Treating dyspareunia according to the method disclosed herein can include, decreasing the severity of dyspareunia by 1%, 5%, 10%, 15%, 20%, 25%, 30%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%. The decrease in severity can be obtained following 2 weeks of treatment, or 6 weeks of treatment, or 8 weeks of treatment, or 12 weeks of treatment.
  • dyspareunia is assessed using a severity scale, ranging from 0 to 4 points wherein 0 indicates no pain associated with sexual activity (with vaginal penetration), 1 indicates mild pain associated with sexual activity (with vaginal penetration), 2 indicates moderate pain associated with sexual activity (with vaginal penetration), and 3 indicates severe pain associated with sexual activity (with vaginal penetration).
  • the method for treating dyspareunia includes reducing the dyspareunia severity score from 3, prior to treatment of a subject, to 2, after 2 weeks of treatment of the subject. In some embodiments, the method for treating dyspareunia includes reducing the dyspareunia severity score from 2, prior to treatment of a subject, to 1, after 2 weeks of treatment of the subject. In some embodiments, the method for treating dyspareunia includes reducing the dyspareunia severity score from 1 , prior to treatment of subject, to 0, after 2 weeks of treatment of the subject.
  • the method for treating dyspareunia includes reducing the dyspareunia severity score from 3, prior to treatment of a subject, to 2, after 6 weeks of treatment of the subject. In some embodiments, the method for treating dyspareunia includes reducing the dyspareunia severity score from 2, prior to treatment of a subject, to 1 , after 6 weeks of treatment of the subject. In some embodiments, the method for treating dyspareunia includes reducing the dyspareunia severity score from 1 , prior to treatment of subject, to 0, after 6 weeks of treatment of the subject.
  • the method for treating dyspareunia includes reducing the dyspareunia severity score from 3, prior to treatment of a subject, to 2, after 8 weeks of treatment of the subject. In some embodiments, the method for treating dyspareunia includes reducing the dyspareunia severity score from 2, prior to treatment of a subject, to 1 , after 8 weeks of treatment of the subject. In some embodiments, the method for treating dyspareunia includes reducing the dyspareunia severity score from 1 , prior to treatment of subject, to 0, after 8 weeks of treatment of the subject.
  • the method for treating dyspareunia includes reducing the dyspareunia severity score from 3, prior to treatment of a subject, to 2, after 12 weeks of treatment of the subject. In some embodiments, the method for treating dyspareunia includes reducing the dyspareunia severity score from 2, prior to treatment of a subject, to 1 , after 12 weeks of treatment of the subject. In some embodiments, the method for treating dyspareunia includes reducing the dyspareunia severity score from 1 , prior to treatment of subject, to 0, after 12 weeks of treatment of the subject.
  • the method for treating dyspareunia includes decreasing the severity of dyspareunia after two weeks of treatment, wherein the severity is assessed on a scale of 0-3 points, and the average decrease ranges from a 0.9-point decrease to a 1.1 -point decrease.
  • the average decrease can be determined by observing any suitable number of subjects. In some embodiments, the number of subjects is at least 100. In some
  • the number of subjects is at least 500. In some embodiments, the number of subjects ranges from 700 to 800. In some embodiments, the number of subjects ranges from 740 to 750. In some embodiments, the vaginal estradiol formulation contains 4 ⁇ g of estradiol. In some embodiments, the vaginal estradiol formulation contains 10 ⁇ g of estradiol. In some embodiments, the vaginal estradiol formulation contains 25 ⁇ g of estradiol.
  • the method for treating dyspareunia includes decreasing the severity of dyspareunia after six weeks of treatment, wherein the severity is assessed on a scale of 0-3 points, and the average decrease ranges from a 1.3-point decrease to a 1.5-point decrease.
  • the average decrease can be determined by observing any suitable number of subjects. In some embodiments, the number of subjects is at least 100. In some
  • the number of subjects is at least 500. In some embodiments, the number of subjects ranges from 700 to 800. In some embodiments, the number of subjects ranges from 740 to 750. In some embodiments, the vaginal estradiol formulation contains 4 ⁇ g of estradiol. In some embodiments, the vaginal estradiol formulation contains 10 ⁇ g of estradiol. In some embodiments, the vaginal estradiol formulation contains 25 ⁇ g of estradiol.
  • the method for treating dyspareunia includes decreasing the severity of dyspareunia after eight weeks of treatment, wherein the severity is assessed on a scale of 0-3 points, and the average decrease ranges from a 1.5-point decrease to a 1.8-point decrease.
  • the average decrease can be determined by observing any suitable number of subjects. In some embodiments, the number of subjects is at least 100. In some
  • the number of subjects is at least 500. In some embodiments, the number of subjects ranges from 700 to 800. In some embodiments, the number of subjects ranges from 740 to 750. In some embodiments, the vaginal estradiol formulation contains 4 ⁇ g of estradiol. In some embodiments, the vaginal estradiol formulation contains 10 ⁇ g of estradiol. In some embodiments, the vaginal estradiol formulation contains 25 ⁇ g of estradiol.
  • the method for treating dyspareunia includes decreasing the severity of dyspareunia after twelve weeks of treatment, wherein the severity is assessed on a scale of 0-3 points, and the average decrease ranges from a 1.5-point decrease to a 1.8-point decrease.
  • the average decrease can be determined by observing any suitable number of subjects. In some embodiments, the number of subjects is at least 100. In some
  • the number of subjects is at least 500. In some embodiments, the number of subjects ranges from 700 to 800. In some embodiments, the number of subjects ranges from 740 to 750. In some embodiments, the vaginal estradiol formulation contains 4 ⁇ g of estradiol, In some embodiments, the vaginal estradiol formulation contains 10 ⁇ g of estradiol, In some embodiments, the vaginal estradiol formulation contains 25 ⁇ g of estradiol.
  • the method for treating dyspareunia includes administering a suppository so as to provide an estradiol Cmax or AUC as described herein.
  • a method for treating dyspareunia is provided, the method including administering a suppository so as to provide an estrone Cmax or AUC as described herein.
  • urinary tract infection refers to an infection of the kidneys, ureters, bladder and urethra by a microorganism such as Escherichia coli,
  • the method for treating urinary tract infections generally includes administering a soft gel vaginal estradiol formulation (i.e., a suppository) as described herein.
  • the method further includes decreasing urethral discomfort, frequency or urination, hematuria, dysuria, and/or stress incontinence.
  • a method for treating urinary tract infections is provided, the method including administering a suppository as described herein and decreasing vaginal pH from above 4.5 to between 3.5 and 4.5 (inclusive).
  • the method can be particularly effective for treating urinary tract infections in elderly subjects (e.g., subjects older than 65 years, or older than 75 years, or older than 85 years).
  • a method for treating urinary tract infections is provided, the method including administering a suppository so as to provide an estradiol Cmax or AUC as described herein.
  • a method for treating urinary tract infections is provided, the method including administering a suppository so as to provide an estrone Cmax or AUC as described herein.
  • a method for treating sexual dysfunction is provided.
  • a method for treating sexual dysfunction generally refers to pain or discomfort during sexual intercourse, diminished vaginal lubrication, delayed vaginal engorgement, increased time for arousal, diminished ability to reach orgasm, diminished clitoral sensation, diminished sexual desire, and/or diminished arousal.
  • a method for treating sexual dysfunction is provided, the method including administering a suppository so as to provide an estradiol Cmax or AUC as described herein.
  • a method for treating sexual dysfunction is provided, the method including administering a suppository so as to provide an estrone Cmax or AUC as described herein.
  • FSFI Female Sexual Function Index
  • Rosen R, Brown C, Heiman J, et al. The Female Sexual Function Index (FSFI): A Multidimensional Self-Report Instrument for the Assessment of Female Sexual Function.” Journal of Sex & Marital Therapy 2000. 26: p.191-208).
  • the FSFI is useful for assessing various domains of sexual functioning (e.g. sexual desire, arousal, orgasm, satisfaction and pain).
  • the method for treating sexual dysfunction as provided herein can include administering a vaginal soft gel formulation to a subject and increasing a subject's full-scale FSFI score, FSFI-desire score, FSFI-arousal score, FSFI-lubrication score and/or FSFI-orgasm score.
  • FSFI Female Sexual Function Index
  • the method for treating sexual dysfunction includes administering estradiol to the subject and increasing the FSFI-desire score by at least about 20%, or at least about 25%, or at least about 30% as compared to baseline.
  • the method for treating sexual dysfunction includes administering estradiol to the subject and increasing the FSFI-arousal score by at least about 30%, or at least about 40%, or at least about 50% as compared to baseline.
  • the method for treating sexual dysfunction includes administering estradiol to the subject and increasing the FSFI-lubrication score by at least about 85%, or at least about 95%, or at least about 115% as compared to baseline.
  • the method for treating sexual dysfunction includes administering estradiol to the subject and increasing the FSFI-orgasm score by at least about 40%, or at least about 60% as compared to baseline.
  • the method for treating sexual dysfunction includes administering estradiol to the subject and increasing the total FSFI score by at least about 50%, or at least about 55%, or at least about 70% as compared to baseline.
  • Examples of other metrics for assessment of sexual function include, but are not limited to, Changes in Sexual Function Questionnaire ("CSFQ”; Clayton et al, Psychopharmacol Bull. 33(4):731-45 (1997) and Clayton et al, Psychopharmacol. Bull. 33(4):747-53 (1997)); the Derogatis Interview for Sexual Functioning-Self-Report (“DISF- SR”; Derogatis, J SexMarital Ther. 23:291-304 (1997)); the Golombok-Rust Inventory of Sexual Satisfaction (“GRISS”; Rust et al., Arch. Sex Behav. 15: 157-165 (1986)); the Sexual Function Questionnaire ("SFQ”; Quirk et al.
  • CSFQ Changes in Sexual Function Questionnaire
  • DISF- SR Derogatis Interview for Sexual Functioning-Self-Report
  • GRISS Golombok-Rust Inventory of Sexual Satisfaction
  • GRISS Rust et al., Arch. Sex Behav
  • a measure of sexual dysfunction function is increased when the score in the appropriate domain, subscale or subtest is indicative of sexual dysfunction, as established for that questionnaire. For instance, a female's sexual interest is considered reduced, when assessed using the CSFQ, if the subscale for sexual interest score is less than or equal to 9. Conversely, sexual dysfunction is considered improved when the score in the appropriate domain, subscale or subtest is indicative of higher (e.g., normal or desired) sexual function.
  • sexual dysfunction may be assessed in comparison to a previous point in time for the patient and/or in comparison to a patient's peers with respect to age, gender, sexual experience, and health, or may also be determined via a validated questionnaire administered by the clinician.
  • the efficacy and safety of the pharmaceutical compositions described herein in the treatment of the symptoms of VVA may be determined.
  • the size, effect, cytology, histology, and variability of the VVA may be determined using various endpoints to determine efficacy and safety of the pharmaceutical compositions described herein or as otherwise accepted in the art, at present or as further developed.
  • One source of endpoints is with the US Food and Drug
  • a method of treating VVA including dyspareunia, vaginal dryness, and estrogen-deficient urinary states (including urinary tract infections), is provided that allows a subject to be ambulatory immediately or within minutes after a gelatin capsule containing the pharmaceutical compositions disclosed herein are administered.
  • a gelatin capsule containing a pharmaceutical composition as disclosed herein is administered by digitally inserting the gelatin capsule containing the pharmaceutical composition into the vagina approximately two inches or inserting into the third of the vagina closest to the vaginal opening as shown in Figs. 26A, 26B, and 26C.
  • the gelatin capsule adheres to the vaginal tissue and dissolves, ruptures, or otherwise disintegrates soon after being inserted into the vagina thereby releasing the pharmaceutical composition.
  • the pharmaceutical composition spreads onto the vaginal tissue and is rapidly absorbed.
  • the gelatin capsule is also fully absorbed by the vaginal tissue.
  • a viscosity enchancer such as TEFOSE 63 provides increased viscosity to ensure the pharmaceutical composition stays within the desired absorption area, thereby estrogenizing the vagina, labia, and/or vulva.
  • the combination of high viscosity, bioadhesion, and rapid absorption prevents the need for subjects to remain supine after administration to allow the tissue to absorb the estradiol, thereby allowing subjects to be ambulatory immediately or almost immediately after administration.
  • a method for treating VVA including dyspareunia, vaginal dryness, and estrogen-deficient urinary states (including urinary tract infections), without causing non-natural discharge (e.g., discharge of a pharmaceutical composition or a component thereof) is provided.
  • a soft gelatin capsule is administered containing a liquid pharmaceutical composition that is able to be fully absorbed by the vaginal tissue.
  • the pharmaceutical composition itself is fully absorbed by the vaginal tissue.
  • the pharmaceutical composition and gelatin capsule are administered in a volume and size, respectively, that allows a subject's vaginal tissue to fully absorb the pharmaceutical composition. According to embodiments, such absorption will occur contemporaneously with the subject being ambulatory.
  • the gelatin capsule and liquid pharmaceutical composition are fully absorved by the vaginal tissue, wherein the only discharge that occurs after estrogenizing the vagina is natural discharge that a woman would have experienced prior to menopause.
  • Natural vaginal discharge refers to a small amount of fluid that flows out of the vagina each day, carrying out old cells that have lined the vagina. Natural discharge is usually clear or milky. Non-natural discharge can refer to discharge that is higher in volume than natural discharge, different in color than natural discharge, or different in consistency than natural discharge. Non-natural discharge can also refer to the discharge (e.g., leaking) of a pharmaceutical composition from the vagina.
  • a method of treating VVA including dyspareunia, vaginal dryness, and estrogen-deficient urinary states (including urinary tract infections), using a liquid pharmaceutical composition.
  • a soft gelatin capsule containing a liquid composition for treating VVA is provided to a subject.
  • the subject inserts the soft gelatin capsule containing the liquid composition for treating VVA into their vagina either digitally or with an applicator, wherein the soft gelatin capsule dissolves, ruptures, or disintegrates and the liquid composition is released into the vagina.
  • the liquid composition for treating VVA is a pharmaceutical composition disclosed herein.
  • the subject inserts the gelatin capsule about two inches into the vagina, or in the third of the vagina closest to the vaginal opening.
  • the subject is ambulatory immediately after or soon after administration.
  • a method for treating VVA comprising improving the symptoms of VVA, compared to placebo or baseline, within two weeks by vaginally administering a composition for the treatment of VVA.
  • a composition for the treatment of VVA is a liquid pharmaceutical composition as disclosed herein.
  • the composition for the treatment of VVA is a liquid containing from 1 ⁇ g to 25 ⁇ g of estradiol.
  • the method of administration is a method disclosed herein, including the insertion method shown in Figs. 26A, 26B, and 26C.
  • the estradiol is not detected systemically when measured using standard pharmaceutical pharmacokinetic parameters,
  • a method for treating VVA comprising improving the symptoms of VVA, compared to placebo or baseline, within four weeks by vaginally administering a composition for the treatment of VVA.
  • a composition for the treatment of VVA is a liquid pharmaceutical composition as disclosed herein.
  • the composition for the treatment of VVA is a liquid containing from 1 ⁇ g to 25 ⁇ g of estradiol.
  • the method of administration is a method disclosed herein, including the insertion method shown in Figs. 26A, 26B, and 26C.
  • the estradiol is not detected systemically when measured using standard pharmaceutical pharmacokinetic parameters, such as AUC and C max .
  • a method for treating VVA comprising improving the symptoms of VVA, compared to placebo or baseline, within eight weeks by vaginally administering a composition for the treatment of VVA.
  • the composition for the treatment of VVA is a liquid pharmaceutical composition as disclosed herein.
  • the composition for the treatment of VVA is a liquid containing from 1 ⁇ g to 25 ⁇ g of estradiol.
  • the method of administration is a method disclosed herein, including the insertion method shown in Figs. 26A, 26B, and 26C. According to
  • the estradiol is not detected systemically when measured using standard pharmaceutical pharmacokinetic parameters, such as AUC and C max .
  • a method for treating VVA comprising improving the symptoms of VVA, compared to placebo or baseline, within ten weeks by vaginally administering a composition for the treatment of VVA.
  • the composition for the treatment of VVA is a liquid pharmaceutical composition as disclosed herein.
  • the composition for the treatment of VVA is a liquid containing from 1 ⁇ g to 25 ⁇ g of estradiol.
  • the method of administration is a method disclosed herein, including the insertion method shown in Figs. 26A, 26B, and 26C. According to
  • the estradiol is not detected systemically when measured using standard pharmaceutical pharmacokinetic parameters, such as AUC and C max .
  • a method for treating VVA including dyspareunia, vaginal dryness, and estrogen-deficient urinary states (including urinary tract infections), comprising administering a composition containing estradiol for the treatment of VVA is provided, wherein the method improves the symptoms of VVA, compared with baseline or placebo, in at least one of two weeks, four weeks, six weeks, eight weeks, or twelve weeks, wherein the estradiol is not detected systemically using standard pharmaceutical
  • the composition containing estradiol is a liquid composition as disclosed herein.
  • the copomosition contains 1 ⁇ g to 25 ⁇ g of estradiol.
  • a method for reestrogenizing the vagina, labia, or vulva comprises administering a composition containing estradiol for the treatment of VVA, wherein the composition is a liquid containing estradiol or a synthetic estrogen, and wherein the liquid spreads over a surface area of the vagina, labia, or vulva which is larger than the area covered by a solid composition.
  • the liquid can spread over a surface area ranging from about 50 cm 2 to about 120 cm 2 (e.g., from about
  • the subject inserts a liquid composition into her vagina in a capsule, such as a hard or soft gelatin capsule, that then dissolves, ruptures, disintegrates, or otherwise releases the liquid in the vagina.
  • a capsule such as a hard or soft gelatin capsule
  • the liquid contains at least one of a bio-adhesive or viscosity enhancer to prevent the liquid from discharging from the vagina before the estradiol or synthetic estrogen can be absorbed into the vaginal tissue in a dose sufficient to effect reestrongenization of the vagina.
  • the vagina will be statistically significantly
  • the vagina will be statistically significantly reestrogenized within four weeks of administration compared to baseline or placebo levels.
  • the vagina will be statistically significantly
  • the vagina will be statistically significantly reestrogenized within six weeks of administration compared to baseline or placebo levels. According to embodiments, the vagina will be statistically significantly reestrogenized within eight weeks of administration compared to baseline or placebo levels. According to embodiments, the vagina will be statistically significantly reestrogenized within ten weeks of administration compared to baseline or placebo levels. According to embodiments, the vagina will be statistically significantly reestrogenized within twelve or more weeks of
  • VVA vaginal wall
  • VVA vaginal wall
  • Such symptoms include, without limitations, an increase in vaginal pH; reduction of vaginal epithelial integrity, vaginal secretions, or epithelial surface thickness; pruritus; vaginal dryness; dyspareunia (pain or bleeding during sexual intercourse); urinary tract infections; or a change in vaginal color.
  • efficacy is measured as a reduction of vulvar and vaginal atrophy in a patient back to premenopausal conditions.
  • the change is measured as a reduction in the severity of one or more atrophic effects measured at baseline (screening, Day 1) and compared to a measurement taken at Day 15 (end of treatment).
  • One of the symptoms of VVA is increased vaginal pH.
  • treatment with the pharmaceutical compositions described herein resulted in a decrease in vaginal pH.
  • a decrease in vaginal pH is measured as a decrease from the vaginal pH at baseline (screening) to the vaginal pH at Day 15, according to embodiments.
  • a pH of 5 or greater may be associated with VVA.
  • pH is measured using a pH indicator strip placed against the vaginal wall.
  • a change in vaginal pH is a change in a patient's vaginal pH to a pH of less than about pH 5.0.
  • a subject's vaginal pH may be less than about pH 4.9, pH 4.8, pH 4.7, pH 4.6, pH 4.5, pH 4.4, pH 4.3, pH 4.2, pH 4.1 , pH 4.0, pH 3.9, pH 3.8, pH 3.7, pH 3.6, or pH 3.5.
  • a change in cell composition is measured as the change in percent of composition or amount of parabasal vaginal cells, intermediate cells, and superficial vaginal cells, such as a change in the composition or amount of parabasal vaginal cells compared with or, relative to, a change in superficial vaginal cells.
  • a subject having VVA symptoms often has an increased number of parabasal cells and a reduced number of superficial cells (e.g., less than about 5%) compared with women who do not suffer from VVA.
  • a subject having decreasing VVA symptoms, or as otherwise responding to treatment may demonstrate an improvement in the Maturation Index, specifically a decrease in the amount of parabasal cells or an increase in the amount of superficial cells compared to baseline (screening).
  • a decrease in parabasal cells is measured as a reduction in the percent of parabasal cells; the percent reduction may be at least about an 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15% or 10% reduction in the number of parabasal cells.
  • a percent reduction may be at least about a 54% reduction in the number of parabasal cells.
  • an increase in superficial cells is measured as an increase in the percent of superficial cells; the percent increase in superficial cells may be at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% increase in the number of superficial cells. In further embodiments, a percent increase may be at least about a 35% increase in the number of superficial cells.
  • an improvement in the Maturation Index is assessed as a change over time. For example, as a change in cell composition measured at a baseline
  • the change in cell composition may also be assessed as a change in the amount of parabasal cells over time, optionally in addition to measuring changes in parabasal cells and superficial cells as described above.
  • Such cells may be obtained from the vaginal mucosal epithelium through routine gynecological examination and examined by means of a vaginal smear.
  • treatment with the pharmaceutical compositions described herein resulted in any of: an increase in superficial cells; a decrease in parabasal cells; and an increase in intermediate cells.
  • samples may be collected to determine hormone levels, in particular, estradiol levels.
  • blood samples may be taken from a subject and the level of estradiol measured (pg/mL).
  • estradiol levels may be measured at 0 hours (for example, at time of first treatment), at 1 hour (for example, post first treatment), at 3 hours, and at 6 hours.
  • samples may be taken at day 8 (for example, post first treatment) and at day 15 (for example, one day post the last treatment on day 14).
  • descriptive statistics of plasma estradiol concentrations at each sampling time and observed and T max values may be measured and the AUC calculated.
  • a suppository can comprise about 25 ⁇ g of estradiol.
  • administration of the suppository to a patient can provide, in a plasma sample from the patient, parameters including one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (Cmax) of estradiol of about 19 pg*hr/mL to about 29 pg*hr/mL (e.g., 19.55 pg*hr/mL to about 28.75 pg*hr/mL); or 2) a corrected geometric mean area under the curve (AUC)o-24 of estradiol of about 75 pg*hr/mL to about 112 pg*hr/mL (e.g., 75.82 pg*hr/mL to about 111.50).
  • Cmax geometric mean peak plasma concentration
  • AUC corrected geometric mean area under the curve
  • administration of the suppository to a patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (Cmax) of estrone of about 9 pg*hr/mL to about 14 pg*hr/mL (e.g., 9.17 pg*hr/mL to about 13.49 pg*hr/mL); and 2) a corrected geometric mean area under the curve (AUC)o-24 of estrone of about 43 pg*hr/mL to about 65 pg*hr/mL (e.g., 43.56 pg*hr/mL to about 64.06 pg*hr/mL).
  • Cmax geometric mean peak plasma concentration
  • AUC corrected geometric mean area under the curve
  • administration of the suppository to a patient provides, in a plasma sample from the patient, provides one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (C max ) of estrone sulfate of about 416 pg*hr/mL to about 613 pg*hr/mL (e.g., 416.53 pg*hr/mL to about 612.55 pg*hr/mL); and 2) a corrected geometric mean area under the curve (AUC)o-24 of estrone sulfate of about 3598 pg*hr/mL to about 5291 pg*hr/mL (e.g., 3598.04 pg*hr/mL to about 5291.24 pg*hr/mL).
  • C max corrected geometric mean peak plasma concentration
  • AUC corrected geometric mean area under the curve
  • a suppository includes about 25 ⁇ g of estradiol.
  • administration of the suppository to a patient can provide, in a plasma sample from the patient, parameters including one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (Cmax) of estradiol ranging from about 20.9 pg/mL to about 32.8 pg/mL (e.g., 20.96 pg/mL to about 32.75 pg/mL); 2) a corrected geometric mean area under the curve (AUC)o-24 of estradiol ranging from about 104.3 pg*hr/mL to about 163.1 pg*hr/mL (e.g., 104.32 pg*hr/mL to about 163.0 pg*hr/mL); and 3) an average concentration (Cavg) of estradiol ranging from about 4.3 pg/mL to about 6.8 pg/mL (Cmax) of estradiol ranging from about
  • administration of a suppository comprising about 25 ⁇ g of estradiol to a patient can provide, in a plasma sample from the patient, parameters including one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (Cmax) of estradiol of about 26.2 pg/mL; 2) a corrected geometric mean area under the curve (AUC)o-24 of estradiol of about 130 pg*hr/mL; and 3) an average
  • administration of a suppository comprising about 25 ⁇ g of estradiol to a patient can provide, in a plasma sample from the patient, parameters including one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (Cmax) of estradiol ranging from about 9.5 pg/mL to about 15.1 pg/mL (e.g., 9.60 pg*hr/mL to about 15.00 pg/mL); 2) a corrected geometric mean area under the curve (AUC)o-24 of estradiol ranging from about 67.6 pg*hr/mL to about 105.8 pg*hr/mL (e.g., 67.68 pg*hr/mL to about 105.75 pg*hr/mL); and 3) an average concentration (Cav ) of estradiol ranging from about 2.7 pg/mL to about 4.4 pg/mL (e.g.,
  • administration of a suppository comprising about 25 ⁇ g of estradiol to a patient can provide, in a plasma sample from the patient, parameters including one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (Cmax) of estradiol of about 12.0 pg/mL; 2) a corrected geometric mean area under the curve (AUC)o-24 of estradiol of about 84.6 pg*hr/mL; and 3) an average concentration (Cavg) of estradiol of about 3.5 pg/mL, as assessed at day 14.
  • Cmax corrected geometric mean peak plasma concentration
  • AUC corrected geometric mean area under the curve
  • Cavg average concentration
  • administration of a suppository comprising about 25 ⁇ g of estradiol to a patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (Cmax) of estrone conjugates ranging from about 158.8 pg/mL to about 248.3 pg/mL (e.g., 158.88 hr/mL to about 248.25 pg*hr/mL); and 2) a corrected geometric mean area under the curve (AUC)o-24 of estrone conjugates ranging from about 1963.1 pg*hr/mL to about 3067.6 pg*hr/mL (e.g., 1963.20 pg*hr/mL to about 3067.50 pg*hr/mL) as assessed at day 1.
  • Cmax geometric mean peak plasma concentration
  • AUC corrected geometric mean area under the curve
  • administration of a suppository comprising about 25 ⁇ g of estradiol to a patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (Cmax) of estrone conjugates of about 198.6 pg/mL; and 2) a corrected geometric mean area under the curve (AUC)o-24 of estrone conjugates of about 2454 pg*hr/mL as assessed at day 1.
  • Cmax corrected geometric mean peak plasma concentration
  • AUC corrected geometric mean area under the curve
  • administration of a suppository comprising about 25 ⁇ g of estradiol to a patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) an unadjusted arithmetic mean area under the curve (AUC)o-24 of estradiol ranging from about 173.5 pg*hr/mL to about 271.3 pg*hr/mL (e.g., from 173.60 pg*hr/mL to about 271.25 pg*hr/mL; or about 217 pg*hr/mL), as assessed at day 1 ; 2) a corrected arithmetic mean peak plasma concentration (C av [o-24]) of estradiol ranging from about 7.2 pg/mL to about 11.4 pg/mL (e.g., from 7.25 pg/mL to about 1 1.33 pg/mL; or about 9.06 pg/mL), as assessed at day
  • AUC unadjust
  • administration of a suppository comprising about 25 ⁇ g of estradiol to a patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) an unadjusted arithmetic mean area under the curve (AUC)o-24 of estrone ranging from about 335.1 pg*hr/mL to about 523.8 pg*hr/mL (e.g., from 335.20 pg*hr/mL to about 523.75 pg*hr/mL; or about 419 pg*hr/mL), as assessed at day 1 ; 2) a corrected arithmetic mean peak plasma concentration (C av [o-24]) of estrone ranging from about 13.9 pg/mL to about 21.9 pg/mL (e.g., from 14.00 pg/mL to about 21.88 pg/mL; or about 17.5 pg/mL), as assessed at day
  • AUC unadjust
  • estrone ranging from about 14.3 pg/mL to about 22.4 pg/mL (e.g., from 14.32 pg/mL to about 22.38 pg/mL; or about 17.9 pg/mL), as assessed at day 14.
  • administration of a suppository comprising about 25 ⁇ g of estradiol to a patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) an unadjusted arithmetic mean area under the curve (AUC)o-24 of estrone conjugates ranging from about 7,300.7 pg*hr/mL to about 1 1 ,407.6 pg*hr/mL (e.g., from 7,300.80 pg*hr/mL to about 1 1,407.50 pg*hr/mL; or about 9, 126 pg*hr/mL), as assessed at day 1 ; 2) a corrected arithmetic mean peak plasma concentration (Cav g [o- 2 4]) of estrone conjugates ranging from about 303.9 pg/mL to about 475.1 pg/mL (e.g., from 304.00 pg/mL to about 475.00 pg/mL;
  • AUC unadjust
  • a suppository can comprise about 10 ⁇ g of estradiol.
  • administration of the suppository to a patient can provide, in a plasma sample from the patient, one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (Cmax) of estradiol of about 12 pg*hr/mL to about 18 pg*hr/mL (e.g., 12.22 pg*hr/mL to about 17.98 pg*hr/mL); 2) a corrected geometric mean area under the curve (AUC)o-24 of estradiol of about 42 pg*hr/mL to about 63 pg*hr/mL (e.g., 42. 18 pg*hr/mL to about 62.02 pg*hr/mL); and 3) a corrected geometric mean time to peak plasma
  • administration of the suppository to a patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (C max ) of estrone of about 4 pg*hr/mL to about 7 pg*hr/mL (e.g., 4.38 pg*hr/mL to about 6.44 pg*hr/mL); 2) a corrected geometric mean area under the curve (AUC)o-24 of estrone of about 20 pg*hr/mL to about 31 pg*hr/mL (e.g., 20.60 pg*hr/mL to about 30.30 pg*hr/mL); and 3) a corrected geometric mean time to peak plasma concentration (Tmax) of estrone of about 4 hrs to about 8 hrs (e.
  • C max corrected geometric mean peak plasma concentration
  • AUC corrected geometric mean area under the curve
  • administration of the suppository to a patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (Cmax) of estrone sulfate of about 10 pg*hr/mL to about 16 pg*hr/mL (e.g., 10.34 pg*hr/mL to about 15.20 pg*hr/mL); 2) a corrected geometric mean area under the curve (AUC)o-24 of estrone sulfate of about 56 pg*hr/mL to about 84 pg*hr/mL (e.g., 56.61 pg*hr/mL to about 83.25 pg*hr/mL); and 3) a corrected geometric mean time to peak plasma concentration (Tmax) of estrone sulfate of about 4 hrs to about 7 hrs (e.g., 4.67 hrs to about 6.86 hrs).
  • Cmax corrected geometric mean peak plasma concentration
  • a suppository includes about 10 ⁇ g of estradiol.
  • administration of the suppository to a patient can provide, in a plasma sample from the patient, a corrected geometric mean peak plasma concentration (Cmax) of estradiol ranging from about 4.7 pg/mL to about 7.6 pg/mL (e.g., 4.80 pg*hr/mL to about
  • administration of a suppository comprising about 10 ⁇ g of estradiol to a patient can provide, in a plasma sample from the patient, a corrected geometric mean peak plasma concentration (Cmax) of estradiol ranging from about 2.3 pg*hr/mL to about 3.8 pg*hr/mL (e.g., 2.40 pg*hr/mL to about 3.75 pg*hr/mL) of estradiol as assessed at day 14.
  • Cmax geometric mean peak plasma concentration
  • administration of a suppository comprising about 10 ⁇ g of estradiol to a patient provides, in a plasma sample from the patient, a corrected geometric mean peak plasma concentration (Cmax) of estradiol of about 6.0 pg/mL, as assessed at day 1.
  • administration of a suppository comprising about 10 ⁇ g of estradiol to a patient can provide, in a plasma sample from the patient, a corrected geometric mean peak plasma concentration (Cmax) of estradiol of about 3.0 pg/mL, as assessed at day 14.
  • administration of a suppository comprising about 10 ⁇ g of estradiol to a patient provides, in a plasma sample from the patient, a corrected geometric mean area under the curve (AUCV 24 of estradiol ranging from about 17.5 pg/mL to about 27.4 pg/mL (e.g., 17.52 pg*hr/mL to about 27.37 pg*hr/mL), as assessed at day 1.
  • AUCV 24 of estradiol ranging from about 17.5 pg/mL to about 27.4 pg/mL (e.g., 17.52 pg*hr/mL to about 27.37 pg*hr/mL), as assessed at day 1.
  • administration of a suppository comprising about 10 ⁇ g of estradiol to a patient can provide, in a plasma sample from the patient, a corrected geometric mean area under the curve (AUC)o-24 of estradiol ranging from about 10.9 pg*hr/mL to about 17.2 pg*hr/mL (e.g., 10.96 pg*hr/mL to about 17. 13 pg*hr/mL) of estradiol as assessed at day 14.
  • AUC geometric mean area under the curve
  • administration of a suppository comprising about 10 ⁇ g of estradiol to a patient provides, in a plasma sample from the patient, a corrected geometric mean area under the curve (AUCV24 of estradiol of about 21.9 pg*hr/mL, as assessed at day 1.
  • administration of a suppository comprising about 10 ⁇ g of estradiol to a patient can provide, in a plasma sample from the patient, a corrected geometric mean area under the curve (AUCV 24 of estradiol of about 13.7 pg*hr/mL, as assessed at day 14.
  • administration of a suppository comprising about 10 ⁇ g of estradiol to a patient provides, in a plasma sample from the patient, an average concentration (C av g) of estradiol ranging from about 0.6 pg/mL to about 1.1 pg/mL (e.g., 0.64 pg/mL to about 1.0 pg/mL), as assessed at day 1.
  • C av g average concentration
  • administration of a suppository comprising about 10 ⁇ g of estradiol to a patient can provide, in a plasma sample from the patient, an average concentration (Cavg) of estradiol ranging from about 0.1 pg/mL to about 0.3 pg/mL (e.g., 0.16 pg/mL to about 0.25 pg/mL) of estradiol as assessed at day 14.
  • Cavg average concentration
  • administration of a suppository comprising about 10 ⁇ g of estradiol to a patient provides, in a plasma sample from the patient, an average concentration (Cav ) of estradiol of about 0.8 pg/mL, as assessed at day 1.
  • administration of a suppository comprising about 10 ⁇ g of estradiol to a patient can provide, in a plasma sample from the patient, an average concentration (C avg ) of estradiol of about 0.2 pg/mL, as assessed at day 14.
  • administration of a suppository comprising about 10 ⁇ g of estradiol to a patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (Cmax) of estrone conjugates ranging from about 72.1 pg/mL to about 112.8 pg/mL (e.g., 72.16 pg/mL to about 112.75 pg/mL); and 2) an average concentration (C avg ) of estrone conjugates ranging from about 6.3 pg/mL to about 10.1 pg/mL (e.g., 6.40 pg/mL to about 10.00 pg/mL) as assessed at day 1.
  • Cmax geometric mean peak plasma concentration
  • Cmax corrected geometric mean peak plasma concentration
  • estrone conjugates ranging from about 72.1 pg/mL to about 112.8 pg/mL (e.g., 72.16 pg/mL to about 112.75 pg/m
  • administration of a suppository comprising about 10 ⁇ g of estradiol to a patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (Cmax) of estrone conjugates of about 90.2 pg/mL; and 2) an average concentration (C avg ) of estrone conjugates of about 8.0 pg/mL, as assessed at day 1.
  • Cmax geometric mean peak plasma concentration
  • C avg an average concentration of estrone conjugates of about 8.0 pg/mL
  • administration of a suppository comprising about 10 ⁇ g of estradiol to a patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) an unadjusted arithmetic mean area under the curve (AUC)o-24 of estradiol ranging from about 110.3 pg*hr/mL to about 172.6 pg*hr/mL (e.g., from 110.40 pg*hr/mL to about 172.50 pg*hr/mL; or about 138 pg*hr/mL), as assessed at day 1 ; 2) a corrected arithmetic mean peak plasma concentration (C av [o-24]) of estradiol ranging from about 4.6 pg/mL to about 7.8 pg/mL (e.g., from 4.61 pg/mL to about 7.20 pg/mL; or about 5.76 pg/mL), as assessed at day
  • AUC unadjust
  • administration of a suppository comprising about 10 ⁇ g of estradiol to a patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) an unadjusted arithmetic mean area under the curve (AUC)o-24 of estrone ranging from about 370.3 pg*hr/mL to about 578.8 pg*hr/mL (e.g., from 370.40 pg*hr/mL to about 578.75 pg*hr/mL; or about 463 pg*hr/mL), as assessed at day 1 ; 2) a corrected arithmetic mean peak plasma concentration (C av [o-24]) of estrone ranging from about 15.4 pg/mL to about 24.2 pg/mL (e.g., from 15.44 pg/mL to about 24.13 pg/mL; or about 19.3 pg/mL), as assessed
  • administration of a suppository comprising about 10 ⁇ g of estradiol to a patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) an unadjusted arithmetic mean area under the curve (AUC)o-24 of estrone conjugates ranging from about 4,745.5 pg*hr/mL to about 7,414.9 pg*hr/mL (e.g., from 4,745.60 pg*hr/mL to about 7,415.00 pg*hr/mL; or about 5,932 pg*hr/mL), as assessed at day 1; 2) a corrected arithmetic mean peak plasma concentration (Cav [o-24]) of estrone conjugates ranging from about 197.5 pg/mL to about 308.8 pg/mL (e.g., from 197.60 pg/mL to about 308.75 pg/mL; or about 247 pg/
  • AUC unadjust
  • a suppository can comprise about 4 ⁇ g of estradiol.
  • administration of the suppository to a patient can provide, in a plasma sample from the patient, one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (Cmax) of estradiol of about 4 pg*hr/mL to about 8 pg*hr/mL; 2) a corrected geometric mean area under the curve (AUC)o-24 of estradiol of about 16 pg*hr/mL to about 26 pg*hr/mL; and 3) a corrected geometric mean time to peak plasma concentration (Tmax) of estradiol of about 0.25 hrs to about 2 hrs.
  • Cmax corrected geometric mean peak plasma concentration
  • AUC corrected geometric mean area under the curve
  • administration of the suppository to a patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (Cmax) of estrone of about 1 pg*hr/mL to about 3 pg*hr/mL; 2) a corrected geometric mean area under the curve (AUCV 24 of estrone of about 8 pg*hr/mL to about 13 pg*hr/mL; and 3) a corrected geometric mean time to peak plasma concentration (Tmax) of estrone of about 1 hrs to about 4 hrs.
  • Cmax corrected geometric mean peak plasma concentration
  • AUCV 24 of estrone of about 8 pg*hr/mL to about 13 pg*hr/mL
  • Tmax corrected geometric mean time to peak plasma concentration
  • administration of the suppository to a patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (C max ) of estrone sulfate of about 4 pg*hr/mL to about 7 pg*hr/mL; 2) a corrected geometric mean area under the curve (AUC)o-24 of estrone sulfate of about 22 pg*hr/mL to about 34 pg*hr/mL; and 3) a corrected geometric mean time to peak plasma concentration (Tmax) of estrone sulfate of about 1 hrs to about 3 hrs.
  • C max corrected geometric mean peak plasma concentration
  • AUC corrected geometric mean area under the curve
  • Tmax corrected geometric mean time to peak plasma concentration
  • a suppository includes about 4 ⁇ g of estradiol.
  • administration of the suppository to a patient can provide, in a plasma sample from the patient, one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (Cmax) of estradiol ranging from about 2.0 pg/mL to about 3.3 pg/mL (e.g., 2.08 pg*hr/mL to about 3.25 pg*hr/mL); and 2) a corrected geometric mean area under the curve (AUCV 24 of estradiol ranging from about 9.5 pg*hr/mL to about 15.1 pg*hr/mL (e.g., ; 9.60 pg*hr/mL to about 15.0 pg*hr/mL), as assessed at day 1.
  • Cmax corrected geometric mean peak plasma concentration
  • AUCV 24 of estradiol ranging from about 9.5 pg*hr/mL to about 15.1 pg*hr/m
  • administration of a suppository comprising about 4 ⁇ g of estradiol to a patient can provide, in a plasma sample from the patient, one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (C max ) of estradiol ranging from about 1.0 pg*hr/mL to about 1.7 pg*hr/mL (e.g., 1.04 pg*hr/mL to about 1.63 pg*hr/mL) of estradiol, and 2) a corrected geometric mean area under the curve (AUC)o-24 of estradiol ranging from about 5.7 pg*hr/mL to about 9.1 pg*hr/mL (e.g., 5.76 pg*hr/mL to about 9.0 pg*hr/mL).
  • C max corrected geometric mean peak plasma concentration
  • AUC corrected geometric mean area under the curve
  • administration of a suppository comprising about 4 ⁇ g of estradiol to a patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (Cmax) of estradiol of about 2.6 pg/mL; and 2) a corrected geometric mean area under the curve (AUC)o-24 of estradiol of about 12 pg*hr/mL, as assessed at day 1.
  • Cmax corrected geometric mean peak plasma concentration
  • AUC corrected geometric mean area under the curve
  • administration of a suppository comprising about 10 ⁇ g of estradiol to a patient can provide, in a plasma sample from the patient, one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (Cmax) of estradiol of about 1.3 pg/mL; 2) a corrected geometric mean area under the curve (AUC)o-24 of estradiol of about 7.2 pg*hr/mL, as assessed at day 14.
  • Cmax corrected geometric mean peak plasma concentration
  • AUC corrected geometric mean area under the curve
  • administration of a suppository comprising about 4 ⁇ g of estradiol to a patient provides, in a plasma sample from the patient, a corrected geometric mean peak plasma concentration (Cmax) of estrone conjugates ranging from about 0.3 pg/mL to about 0.5 pg/mL (e.g., 0.32 pg/mL to about 0.5 pg/mL) as assessed at day 1.
  • Cmax geometric mean peak plasma concentration
  • administration of a suppository comprising about 4 ⁇ g of estradiol to a patient provides, in a plasma sample from the patient, a corrected geometric mean peak plasma concentration (Cmax) of estrone conjugates of about 0.4 pg/mL as assessed at day 1.
  • Cmax geometric mean peak plasma concentration
  • administration of a suppository comprising about 4 ⁇ g of estradiol to a patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) an unadjusted arithmetic mean area under the curve (AUC)o-24 of estradiol ranging from about 73.3 pg*hr/mL to about 1 14.7 pg*hr/mL (e.g., from 73.36 pg*hr/mL to about 1 14.63 pg*hr/mL; or about 91.7 pg*hr/mL), as assessed at day 1 ; 2) a corrected arithmetic mean peak plasma concentration (C av [o-24]) of estradiol ranging from about 3.
  • AUC unadjusted arithmetic mean area under the curve
  • estradiol 1 pg/mL to about 4.8 pg/mL (e.g., from 3.14 pg/mL to about 4.90 pg/mL; or about 3.92 pg/mL), as assessed at day 1 ; 3) an unadjusted arithmetic mean area under the curve (AUC)o- 24 of estradiol ranging from about 69.7 pg*hr/mL to about 108.9 pg*hr/mL (e.g., from 69.76 pg*hr/mL to about 109.00 pg*hr/mL; or about 87.2 pg*hr/mL), as assessed at day 14; and 4) a corrected arithmetic mean peak plasma concentration (C av [o-24]) of estradiol ranging from about 2.8 pg/mL to about 4.6 pg/mL (e.g., from 2.90 pg/mL to about 4.54
  • administration of a suppository comprising about 4 ⁇ g of estradiol to a patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) an unadjusted arithmetic mean area under the curve (AUC)o-24 of estrone ranging from about 231.9 pg*hr/mL to about 362.4 pg*hr/mL (e.g., from 232.00 pg*hr/mL to about 362.50 pg*hr/mL; or about 290 pg*hr/mL), as assessed at day 1 ; 2) a corrected arithmetic mean peak plasma concentration (C av [o-24]) of estrone ranging from about 10.3 pg/mL to about 16.3 pg/mL (e.g., from 10.40 pg/mL to about 16.25 pg/mL; or about 13 pg/mL), as assessed at day 1 ;
  • AUC unadjuste
  • administration of a suppository comprising about 4 ⁇ g of estradiol to a patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) an unadjusted arithmetic mean area under the curve (AUC)o-24 of estrone conjugates ranging from about 4,062.3 pg*hr/mL to about 6,347.6 pg*hr/mL (e.g., from 4,062.40 pg*hr/mL to about 6,347.50 pg*hr/mL; or about 5,078 pg*hr/mL), as assessed at day 1 ; 2) a corrected arithmetic mean peak plasma concentration (Cav [o-24]) of estrone conjugates ranging from about 172.7 pg/mL to about 270.1 pg/mL (e.g., from 172.80 pg/mL to about 270.00 pg/mL; or about 216 p
  • AUC unadjust
  • a pharmaceutical composition provided herein can result in substantially local delivery of estradiol.
  • plasma concentrations of estradiol, estrone, and estrone sulfate measured in the plasma of a patient following administration of a pharmaceutical composition as provided herein be statistically similar to those measured following administration of a placebo formulation (i.e., a similar formulation lacking the estradiol).
  • the plasma concentrations of estradiol, estrone, or estrone sulfate measured following administration of a pharmaceutical composition provided herein may be low compared to RLD formulations.
  • a suppository can include about 1 ⁇ g to about 25 ⁇ g of estradiol.
  • a plasma sample from the patient can provide a corrected geometric mean peak plasma concentration (Cmax) of estradiol that is less than about 30 pg*hr/mL.
  • Cmax corrected geometric mean peak plasma concentration
  • administration of the suppository to a patient provides a corrected geometric mean peak plasma concentration (Cmax) of estradiol that is less than about 18 pg*hr/mL.
  • administration of the suppository to a patient provides a corrected geometric mean area under the curve (AUC)0-24 of estradiol that is less than about 112 pg*hr/mL.
  • administration of the suppository to a patient provides a corrected geometric mean area under the curve (AUC)0-24 of estradiol that is less than about 63 pg*hr/mL.
  • administration of the suppository to a patient provides a corrected geometric mean peak plasma concentration (Cmax) of estrone that is less than about 14 pg*hr/mL.
  • C max corrected geometric mean peak plasma concentration
  • administration of the suppository to a patient provides a corrected geometric mean peak plasma concentration (C max ) of estrone that is less than about 7 pg*hr/mL.
  • administration of the suppository to a patient provides a corrected geometric mean area under the curve (AUC)0-24 of estrone that is less than about 65 pg*hr/mL.
  • administration of the suppository to a patient provides a corrected geometric mean area under the curve (AUC)0-24 of estrone that is less than about 31 pg*hr/mL.
  • administration of the suppository to a patient provides a corrected geometric mean peak plasma concentration (Cmax) of estrone sulfate that is less than about 613 pg*hr/mL.
  • administration of the suppository to a patient provides a corrected geometric mean peak plasma concentration (Cmax) of estrone sulfate that is less than about 16 pg*hr/mL.
  • administration of the suppository to a patient provides a corrected geometric mean area under the curve (AUC)0-24 of estrone sulfate that is less than about 5291 pg*hr/mL.
  • administration of the suppository to a patient provides a corrected geometric mean area under the curve (AUC)0-24 of estrone sulfate that is less than about 84 pg*hr/mL.
  • capsule disintegration may be determined.
  • delivery vehicle disintegration or absorption presence or absence of the delivery vehicle after administration at day 1 of treatment (for example, at 6 hours post first treatment) and at day 15 (for example, one day post the last treatment on day 14).
  • compositions can be formulated as described herein 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 estradiol in the subject.
  • a pharmaceutical composition as described herein produces desirable pharmacokinetic parameters for one or more metabolites of estradiol in the subject, for example, estrone or total estrone.
  • estradiol is typically converted reversibly to estrone, and both estradiol and estrone can be converted to the metabolite estriol.
  • a significant proportion of circulating estrogens exist as sulfate conjugates, especially estrone sulfate.
  • estrone can be measured with respect to “estrone” amounts (excluding conjugates such as estrone sulfate) and “total estrone” amounts (including both free, or unconjugated, estrone and conjugated estrone such as estrone sulfate).
  • compositions of this disclosure can be characterized for one or more pharmacokinetic parameters of estradiol or a metabolite thereof following
  • 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.
  • one or more pharmacokinetic parameters e.g., AUC, Cmax, C av g, or Tmax
  • estradiol e.g., one or more pharmacokinetic parameters, e.g., AUC, Cmax, C av , or Te
  • estrone e.g., one or more pharmacokinetic parameters, e.g., AUC, Cmax, C av , or Tmax
  • any pharmacokinetic parameter can be a "corrected" parameter, wherein the parameter is determined as a change over a baseline level.
  • any of a variety of methods can be used for measuring the levels of estradiol, estrone, or total estrone in a sample, including immunoassays, mass spectrometry (MS), high performance liquid chromatography (HPLC) with ultraviolet fluorescent detection, liquid chromatography in conjunction with mass spectrometry (LC-MS), tandem mass spectrometry (MS/MS), and liquid chromatography -tandem mass spectrometry (LC-MS/MS).
  • the levels of 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. Statistical Measurements
  • pharmacokinetics of the pharmaceutical composition disclosed herein are measured using statistical analysis.
  • Analysis of Variance (“ANOVA") or Analysis of CoVariance (“ANCOVA”) are used to evaluate differences between a patient receiving treatment with a pharmaceutical composition comprising an active pharmaceutical composition (for example, a pharmaceutical composition comprising estradiol) and a patient receiving treatment with a placebo (for example, the same pharmaceutical composition but without estradiol) or a reference drug.
  • a person of ordinary skill in the art will understand how to perform statistical analysis of the data collected. VIII. EXAMPLES
  • estradiol is procured and combined with one or more
  • estradiol is purchased as a pharmaceutical grade ingredient, often as micronized estradiol, although other forms can also be used.
  • the pharmaceutical composition includes estradiol in a dosage strength of from about 1 ⁇ g to about 50 ⁇ g. In embodiments, the pharmaceutical composition includes 10 ⁇ g of estradiol. In embodiments, the pharmaceutical composition includes 25 ⁇ g of estradiol.
  • the estradiol is combined with pharmaceutically acceptable solubilizing agents, and, optionally, other excipients, to form a pharmaceutical composition.
  • the solubilizing agent is one or more of CAPMUL MCM, MIGLYOL 812, GELUCIRE 39/01, GELUCIRE 43/01, GELUCIRE 50/13, and TEFOSE 63.
  • GELUCIRE 39/01 and GELUCIRE 43/01 each have an HLB value of 1.
  • GELUCIRE 50/13 has an HLB value of 13.
  • TEFOSE 63 has an HLB value of between 9 and 10.
  • Table 1 Capmul MCM ("MCM”). Gelucire 39/01 ("39/01”). Gelucire 43/01 ("43/01").
  • Tefose 63 Tefose
  • compositions appearing in Table 1 that were solid at room temperature were assessed at 37 °C to determine their melting characteristics.
  • the viscosity of the gels can be important during encapsulation of the formulation. For example, in some cases, it is necessary to warm the formulation prior to filing of the gelatin capsules.
  • the melting characteristics of the composition can have important implications following administration of the formulation into the body. For example, in some
  • the formulation will melt at temperatures below about 37° C.
  • Pharmaceutical Composition 11 (Capmul MCM/Tefose 63), for example, did not melt at 37 °C or 41 °C.
  • a dispersion assessment of the pharmaceutical compositions appearing in Table 1 was performed. The dispersion assessment was performed by transferring 300 mg of each vehicle system in 100 mL of 37 °C water, without agitation, and observing for mixing characteristics. Results varied from formation of oil drops on the top to separation of phases to uniform, but cloudy dispersions. Generally speaking, it is believed that formulations able to readily disperse in aqueous solution will have better dispersion characteristics upon administration. It was surprisingly found, however, as shown below in Examples 7-9, that formulations that did not readily disperse in aqueous solution (e.g., Formulation 13) and instead formed two phases upon introduction to the aqueous solution were found to be the most effective when administered to the human body.
  • aqueous solution e.g., Formulation 13
  • the pharmaceutical composition is delivered in a gelatin capsule delivery vehicle.
  • the gelatin capsule delivery vehicle includes, for example, gelatin (e.g., Gelatin, NF (150 Bloom, Type B)), hydrolyzed collagen (e.g., GELITA ® , GELITA AG, Eberbach, Germany), glycerin, sorbitol special, or other excipients in proportions that are well known and understood by persons of ordinary skill in the art. Sorbitol special may be obtained commercially and may tend to act as a plasticizer and humectant.
  • a variety of delivery vehicles were developed, as show in Table 2, Gels A through F. In Table 2, each delivery vehicle A through F differs in the proportion of one or more components.
  • Each delivery vehicle A through F was prepared at a temperature range from about 45 °C to about 85 °C. Each molten delivery vehicle A through F was cast into a film, dried, and cut into strips. The strips were cut into uniform pieces weighing about 0.5 g, with about 0.5 mm thickness. Strips were placed into a USP Type 2 dissolution vessel in either water or pH 4 buffer solution and the time for them to completely dissolve was recorded (see Table 2) Delivery vehicle A had the fastest dissolution in both water and pH 4 buffer solution.
  • EXAMPLE 3 Pharmaceutical Compositions and Delivery Vehicle
  • each aliquot of the pharmaceutical compositions of Table 3 about 300 mg to about 310 mg. Batch size was as listed in Table 3.
  • each 300 mg to about 310 mg pharmaceutical composition aliquot was encapsulated in about 200 mg of the gelatin capsule delivery vehicle.
  • the pharmaceutical composition denoted by MCM:39/01 was encapsulated in gelatin capsule delivery vehicle A for a total encapsulated weight of about 500 mg to about 510 mg.
  • the aliquot size is arbitrary depending on the concentration of the estradiol and the desired gelatin capsule delivery vehicle size. Artisans will readily understand how to adjust the amount of estradiol in the pharmaceutical composition to accommodate a given size of delivery vehicle, when the delivery vehicle encapsulates the pharmaceutical composition.
  • solubilizing agents were tested to determine whether they were able to solubilize 2 mg of estradiol for a total pharmaceutical composition weight of 100 mg.
  • the solubilizing agents were considered suitable if estradiol solubility in the solubilizing agent was greater than or equal to about 20 mg/g.
  • Initial solubility was measured by dissolving micronized estradiol into various solubilizing agents until the estradiol was saturated (the estradiol/solubilizing agent equilibrated for three days), filtering the undissolved estradiol, and analyzing the resulting pharmaceutical composition for estradiol concentration by HPLC.
  • composition 1 10 ⁇ £ estradiol
  • composition 2 10 ⁇ 3 ⁇ 4 estradiol
  • composition 3 25 ⁇ 3 ⁇ 4 estradiol
  • estradiol is equivalent to 1.03 mg estradiol hemihydrate
  • composition 4 4 ⁇ £ estradiol
  • estradiol is equivalent to 1.03 mg estradiol hemihydrate
  • Pharmaceutical Composition 5 10 ⁇ 3 ⁇ 4 estradiol
  • estradiol is equivalent to 1.03 mg estradiol hemihydrate
  • composition 6 25 ⁇ 3 ⁇ 4 estradiol
  • estradiol is equivalent to 1.03 mg estradiol hemihydrate
  • composition 7 Placebo
  • TX-004HR is Pharmaceutical Compositions 4, 5, and 6 (TX-004HR 4 ⁇ g, TX-004HR 10 ⁇ g, and TX-004HR 25 ⁇ g) compared to Pharmaceutical Composition 7.
  • EXAMPLE 6 Process
  • Fig. 1 illustrates an embodiment of a method making pharmaceutical composition comprising estradiol solubilized in CapmulMCM/Gelucire solubilizing agent encapsulated in a soft gelatin delivery vehicle 100.
  • the CapmulMCM is heated to 40 °C ⁇ 5 °C. Heating may be accomplished through any suitable means. The heating may be performed in any suitable vessel, such as a stainless steel vessel.
  • Other pharmaceutical compositions can be made using the same general method by substituting various excipients, including the solubilizing agent.
  • GELUCIRE is mixed with the CapmulMCM to form the finished solubilizing agent.
  • any form of GELUCIRE may be used in operation 104.
  • GELUCIRE 39/01, GELUCIRE 43/01, GELUCIRE 50/13 may be used in operation 104.
  • Mixing is performed as would be known to persons of ordinary skill in the art, for example by impeller, agitator, stirrer, or other like devices used to mix pharmaceutical compositions.
  • Operation 104 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas.
  • Mixing may be performed in any vessels that are known to persons of ordinary skill in the art, such as a stainless steel vessel or a steel tank.
  • estradiol is mixed into the solubilizing agent.
  • the estradiol in micronized when mixed into the solubilizing agent.
  • the estradiol added is in a non-micronized form.
  • Mixing may be facilitated by an impeller, agitator, stirrer, or other like devices used to mix pharmaceutical compositions.
  • Operation 106 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas.
  • the addition of estradiol may be performed prior to operation 104.
  • operations 104 and 106 are interchangeable with respect to timing or can be performed contemporaneously with each other.
  • the gelatin delivery vehicle is prepared. Any of the gelatin delivery vehicles described herein may be used in operation 110.
  • gelatin, hydrolyzed collagen, glycerin, and other excipients are combined at a temperature range from about 45 °C to about 85 °C and prepared as a film. Mixing may occur in a steel tank or other container used for preparing gelatin delivery vehicles.
  • Operation 110 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas.
  • the gelatin delivery vehicle mixture is degassed prior to being used to encapsulate the pharmaceutical composition.
  • the gelatin delivery vehicle encapsulates the pharmaceutical composition, according to protocols well known to persons of ordinary skill in the art.
  • a soft gelatin capsule delivery vehicle is prepared by combining the pharmaceutical composition made in operation 106 with the gelatin delivery vehicle made in operation 110. The gelatin may be wrapped around the material, partially or fully
  • operation 112 is completed in a suitable die to provide a desired shape.
  • Vaginal soft gel capsules may be prepared in a variety of geometries.
  • vaginal soft gel capsules may be shaped as a tear drop, a cone with frustoconical end, a cylinder, a cylinder with larger "cap” portion as illustrated in Fig. 2, or other shapes suitable for insertion into the vagina.
  • the resulting pharmaceutical composition encapsulated in the soft gelatin delivery vehicle may be inserted digitally or with an applicator.
  • EXAMPLE 7 Study of Estradiol Pharmaceutical composition on the Improvement of Vulvovaginal Atrophy (VVA) [0303]
  • the objective of this study was designed to evaluate the efficacy and safety of a pharmaceutical composition comprising 10 ⁇ g estradiol (i.e., Pharmaceutical Composition 2) in treating moderate to severe symptoms of VVA associated with menopause after 14 days of treatment, and to estimate the effect size and variability of vulvovaginal atrophy endpoints.
  • the systemic exposure to estradiol from single and multiple doses of the pharmaceutical composition was investigated.
  • This study was a phase 1, randomized, double-blind, placebo-controlled trial to evaluate safety and efficacy of the pharmaceutical composition in reducing moderate to severe symptoms of vaginal atrophy associated with menopause and to investigate the systemic exposure to estradiol following once daily intravaginal administrations of a pharmaceutical composition for 14 days.
  • Postmenopausal subjects who met the study entry criteria were randomized to one of two treatment groups (pharmaceutical composition or placebo). During the screening period subjects were asked to self-assess the symptoms of VVA, including vaginal dryness, vaginal or vulvar irritation or itching, dysuria, vaginal pain associated with sexual activity, and vaginal bleeding associated with sexual activity. Subjects with at least one self-assessed moderate to severe symptom of VVA identified by the subject as being most bothersome to her were eligible to participate in the study.
  • Visit 1 Randomization/Baseline (day 1);
  • Visit 3 End of the treatment (day 15).
  • Eligible subjects were randomized in a 1 : 1 ratio to receive either pharmaceutical composition comprising estradiol 10 ⁇ g or a matching placebo vaginal softgel capsule, and self-administered their first dose of study medication at the clinical facility under the supervision of the study personnel.
  • Serial blood samples for monitoring of estradiol level were collected at 0.0, 1.0, 3.0, and 6.0 hours relative to first dose administration on day 1.
  • Subjects remained at the clinical site until completion of the 6-hour blood draw and returned to clinical facility for additional single blood draws for measurement of estradiol concentration on day 8 (before the morning dose) and day 15.
  • Subjects were provided with enough study medication until the next scheduled visit and were instructed to self-administer their assigned study treatment once a day intravaginally at approximately the same time ( ⁇ 1 hour) every morning. Each subject was provided with a diary in which she was required to daily record investigational drug dosing dates and times. Subjects returned to clinical facility on day 8 for interim visit and on day 15 for end of treatment assessments and post study examinations. Capsule disintegration state was assessed by the investigator at day 1 (6 hours post-dose) and day 15.
  • Criteria of inclusion in the study included self-identification of at least one moderate to severe symptom of VVA, for example, vaginal dryness, dyspareunia, vaginal or vulvar irritation, burning, or itching, dysuria, vaginal bleeding associated with sexual activity, that was identified by the subject as being most bothersome to her; ⁇ 5% superficial cells on vaginal smear cytology; vaginal pH>5.0; and estradiol level ⁇ 50 pg/mL. Subject who were judged as being in otherwise generally good health on the basis of a pre-study physical examination, clinical laboratory tests, pelvic examination, and mammography were enrolled.
  • Treatment A The pharmaceutical composition of Example 5 (Pharmaceutical Composition 2: 10 ⁇ g estradiol); or
  • Treatment B Placebo vaginal softgel capsule, containing the same formulation as Treatment A, except for the 10 ⁇ g of estradiol.
  • estradiol formulation was a tear drop shaped light pink soft gel capsule.
  • Treatment B had the same composition, appearance, and route of administration as the Treatment A, but contained no estradiol. Duration of Treatment
  • vaginal bleeding associated with sexual activity Change from baseline (randomization) to day 15 in severity of the most bothersome symptoms: (1) vaginal dryness; (2) vaginal or vulvar irritation, burning, or itching; (3) dysuria; (4) dyspareunia; (5) vaginal bleeding associated with sexual activity. Data for this endpoint are shown in Tables 13 and 15.
  • Vaginal cytology data was collected as vaginal smears from the lateral vaginal walls according to standard procedures to evaluate vaginal cytology at screening and Visit 3— End of treatment (day 15).
  • the change in the Maturation Index was assessed as a change in cell composition measured at Visit 1— Baseline (day 1) compared to the cell composition measured at Visit 3— End of treatment (day 15).
  • the change in percentage of superficial, parabasal, and intermediate cells obtained from the vaginal mucosal epithelium from a vaginal smear was recorded. Results from these assessments are presented in Tables 6, 7, and 8.
  • Vaginal pH was measured at Screening and Visit 3— End of treatment (day 15). The pH measurement was obtained by pressing a pH indicator strip against the vaginal wall. The subjects entering the study were required to have a vaginal pH value greater than 5.0 at screening. pH values were recorded on the subject's case report form. The subjects were advised not to have sexual activity and to refrain from using vaginal douching within 24 hours prior to the measurement. Results from these assessments are presented in Table 9. Table 9: Primary Efficacy Analysis Results of Change from Baseline (Screening) to Day 15 in Vaginal pH
  • ANOVA model contained a fixed effect for treatment.
  • ANCOVA added baseline as a covariate to the model.
  • estradiol level For the purpose of monitoring the estradiol level during the study blood samples were collected at 0.0, 1.0, 3.0, and 6.0 hours relative to dosing on day 1; prior to dosing on day 8; and prior to dosing on day 15. Efforts were made to collect blood samples at their scheduled times. Sample collection and handling procedures for measurement of estradiol blood level was performed according to procedure approved by the sponsor and principal investigator. All baseline and post-treatment plasma estradiol concentrations were determined using a validated bioanalytical (UPLC-MS/MS) methods. These data are shown in Tables 16 and 17.
  • Serum hormone level data was collected to measure the serum concentrations of estradiol. These data were used for screening inclusion and were determined using standard clinical chemistry methods.
  • ANCOVA ANCOVA
  • the 90% confidence intervals on the differences between estradiol 10 ⁇ g and placebo endpoint means were determined to evaluate the effect size.
  • the change from baseline in vaginal bleeding associated with sexual activity was evaluated in terms of the proportion of subjects who had treatment success or failure. Any subject reporting bleeding at baseline who did not report bleeding at Day 15 was considered to have been successfully treated. Any subject reporting bleeding at day 15 was considered a treatment failure, regardless of whether they reported baseline bleeding or not. Subjects reporting no bleeding at both baseline and day 15 were classified as no-change and were excluded from the statistical evaluation.
  • the difference in the proportion of subjects with success between the two treatment groups was statistically evaluated using Fisher's Exact Test. Results of this difference in proportion are presented in Table 10.
  • Subjects were required to complete a diary in order to record treatment compliance. Diaries were reviewed for treatment compliance at day 8 and day 15 visits. A total of 45 subjects (21 subjects in the estradiol 10 ⁇ g group and 24 subjects in the placebo group) were 100% compliant with the treatment regimen.
  • estradiol 10 ⁇ g capsules showed no statistically detectable difference in regard to reduction of severity from baseline according to the investigator's assessment of vaginal color or vaginal epithelial surface thickness.
  • a pharmaceutical composition comprising estradiol 10 ⁇ g outperformed placebo treatment in regard to improvement in the Maturation Index, reduction in vaginal pH, reduction in the atrophic effects on epithelial integrity and vaginal secretions.
  • the lack of statistical significance between the two treatments in regard to reduction of severity for the most bothersome symptom, and the individual vaginal atrophy symptoms of dryness, irritation, pain associated with sexual activity, and pain/burning/stinging during urination, is not unexpected given the small number of subjects in the study and the short duration of therapy. Too few subjects in the study had vaginal bleeding associated with sexual activity to permit any meaningful evaluation of this vaginal atrophy symptom.
  • estradiol 10 ⁇ g was well tolerated when administered intravaginally in once daily regimen for 14 days.
  • EXAMPLE 8 PK Study (25 ug formulation)
  • Table 23 Statistical Summary of the Comparative Bioavailability Data for Unsealed Average BE studies of Estradiol. Least Square Geometric Means of Estradiol. Ratio of Means and 90% Confidence Intervals. Fasting/Fed Bioeauivalence Study (Study No. : ESTR-1K-500-
  • baseline adjusted PK data illustrates that the formulations disclosed herein unexpectedly show a 54% decrease in Cmax and a 31% decrease in the AUC relative to the RLD. This result is desirable because the estradiol is intended only for local absorption. These data suggest a decrease in the circulating levels of estradiol relative to the RLD. Moreover, it is noteworthy to point out that the Cmax and AUC levels of estradiol relative to placebo are not statistically differentiable, which suggests that the formulations disclosed herein have a negligible systemic effect. As shown in Table 24, there was no significant difference between the test and reference products due to sequence and period effects. However, there was a significant difference due to treatment effect for both and AUC.
  • Table 25 Statistical Summary of the Comparative Bioavailability Data for Unsealed Average BE studies of Estrone. Least Square Geometric Means. Ratio of Means and 90% Confidence Intervals. Fasting/Fed Bioeauivalence Study (Study No.: ESTR-1K-500-12); Dose 25 ig
  • PK for circulating total estrone sulfate is shown in Table 27. These data show that the total circulating estrone sulfate for the pharmaceutical compositions disclosed herein resulted in a 33% decrease in the C max and a 42% decrease in the AUC for circulating estrone sulfate.
  • a PK study was undertaken to compare the 10 ⁇ g formulation disclosed herein (Pharmaceutical Composition 2) to the RLD.
  • the results of the PK study for estradiol are summarized in Table 29-40, and Figs. 9-14.
  • a PK study was undertaken to compare pharmaceutical compositions disclosed herein having 10 ⁇ g of estradiol to the RLD.
  • the results of the PK study for estradiol are summarized in Tables 29-34, which demonstrate that the pharmaceutical compositions disclosed herein more effectively prevented systemic absorption of the estradiol.
  • Table 35 shows that the pharmaceutical compositions disclosed herein had a 28% improvement over the RLD for systemic blood concentration Cmax and 72% AUC improvement over the RLD.
  • the PK data for total estrone likewise demonstrated reduced systemic exposure when compared to the RLD.
  • Table 33 shows the pharmaceutical compositions disclosed herein reduced systemic exposure by 25% for Cmax and 49% for AUC.
  • Table 35 Geometric Mean of Test Product (T) and Reference product (R) of Estrone -
  • Table 36 Statistical Results of Test product (T) versus Reference product (R) for Estrone -
  • the PK data for estrone sulfate likewise demonstrated reduced systemic exposure when compared to the RLD.
  • Table 37 shows the pharmaceutical compositions disclosed herein reduced systemic exposure by 25% for C max and 42% for AUC.
  • Table 37 Summary of Pharmacokinetic Parameters of Test product (T) of Estrone Sulfate -
  • EXAMPLE 10 Randomized, double-blind, placebo-controlled multicenter study of Estradiol Vaginal Softgel Capsules for Treatment of VVA.
  • the study was a randomized, double-blind, placebo-controlled multicenter study design. Postmenopausal subjects who meet the study entry criteria will be randomized in a 1: 1 : 1 :1 ratio to receive Estradiol Vaginal Softgel Capsule 4 ⁇ g, Estradiol Vaginal Softgel Capsule 10 ⁇ g, Estradiol Vaginal Softgel Capsule 25 ⁇ g, or matching placebo.
  • Subjects will be asked to self-assess the symptoms of vulvar or vaginal atrophy including vaginal pain associated with sexual activity, vaginal dryness, vulvar or vaginal itching or irritation by completing the VVA symptom self-assessment questionnaire and identification of her MBS at screening visit 1A to determine eligibility for the study.
  • the VVA symptom Self- Assessment Questionnaire, vaginal cytology, vaginal pH, and vaginal mucosa will be assessed at screening visit IB. These assessments will determine continued eligibility and will be used as the baseline assessments for the study. Randomized subjects will then complete the Questionnaire during visits 3, 4, 5, and 6.
  • the safety endpoints for the study included: (1) Adverse events; (2) Vital signs; (3) Physical examination findings; (4) Gynecological examination findings; (5) Clinical laboratory tests; (6) Pap smears; and (7) Endometrial biopsy.
  • Subjects were assigned to one of four treatment groups: (1) 4 ⁇ g formulation; (2) 10 ⁇ g formulation; (3) 25 ⁇ g formulation; and (4) placebo. [0360] Most subjects participated in the study for 20-22 weeks. This included a 6 to 8 week screening period (6 weeks for subjects without an intact uterus and 8 weeks for subjects with an intact uterus), 12 weeks on the investigational product, and a follow-up period of approximately 15 days after the last dose of investigational product. Some subjects' involvement lasted up to 30 weeks when an 8-week wash-out period was necessary. Subjects who withdrew from the study were not replaced regardless of the reason for withdrawal.
  • FSH follicle stimulating hormone
  • the subject inclusion criteria also included: (2) ⁇ 5% superficial cells on vaginal cytological smear; (3) Vaginal pH > 5.0; (4) Moderate to severe symptom of vaginal pain associated with sexual activity considered the most bothersome vaginal symptom by the subject at screening visit 1A; (5) Moderate to severe symptom of vaginal pain associated with sexual activity at screening visit IB; (6) Onset of moderate to severe dyspareunia in the postmenopausal years; (7) Subjects were sexually active (i.e., had sexual activity with vaginal penetration within approximately 1 month of screening visit 1A); and (8) Subjects anticipated having sexual activity (with vaginal penetration) during the conduct of the trial
  • the subject inclusion criteria also included: (9) subjects had an acceptable result from an evaluable screening endometrial biopsy.
  • the endometrial biopsy reports by the two central pathologists at screening specified one of the following: 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; endometrial hyperplasia; endometrial malignancy; or other findings (endometrial polyp not present, benign endometrial polyp, or other endometrial polyp). Identification of sufficient tissue to evaluate the biopsy by at least one pathologist was required.
  • BMI Body Mass Index
  • the exclusion criteria included: (1) use of oral estrogen-, progestin-, androgen-, or SERM-containing drug products within 8 weeks before screening visit 1A (entry of washout was permitted); use of transdermal hormone products within 4 weeks before screening visit 1A (entry of washout was permitted); use of vaginal hormone products (rings, creams, gels) within 4 weeks before screening visit 1A (entry of washout was permitted); use of intrauterine progestins within 8 weeks before screening visit 1A (entry of washout was permitted); use of progestin implants/injectables or estrogen pellets/injectables within 6 months before screening visit 1 A (entry of washout was not permitted); or use of vaginal lubricants or moisturizers within 7 days before the screening visit IB vaginal pH assessment.
  • the exclusion criteria also included: (2) a history or active presence of clinically important medical disease that might confound the study or be detrimental to the subject, including, for example: hypersensitivity to estrogens; endometrial hyperplasia; undiagnosed vaginal bleeding; a history of a chronic liver or kidney dysfunction/disorder (e.g., Hepatitis C or chronic renal failure); thrombophlebitis, thrombosis, or thromboembolic disorders; cerebrovascular accident, stroke, or transient ischemic attack; myocardial infarction or ischemic heart disease; malignancy or treatment for malignancy, within the previous 5 years, with the exception of basal cell carcinoma of the skin or squamous cell carcinoma of the skin (a history of estrogen dependent neoplasia, breast cancer, melanoma, or any gynecologic cancer, at any time, excluded the subject); and endocrine disease (except for controlled hypothyroidism or controlled non-insulin dependent diabetes mell
  • the exclusion criteria also included: (3) recent history of known alcohol or drug abuse; (4) history of sexual abuse or spousal abuse that was likely to interfere with the subject's assessment of vaginal pain with sexual activity; (5) current history of heavy smoking (more than 15 cigarettes per day) or use of e-cigarettes; (6) use of an intrauterine device within 12 weeks before screening visit 1A; (7) use of an investigational drug within 60 days before screening visit 1A; (8) any clinically important abnormalities on screening physical exam, assessments, electrocardiogram (ECG), or laboratory tests; (9) known pregnancy or a positive urine pregnancy test; and (10) current use of marijuana. [0370] In this study, if a subject discontinued or was withdrawn, the subject was not replaced.
  • each subject was given a unique subject number that identified their clinical site and sequential number. In addition to the assigned subject number, subject initials were used for identification.
  • the clinical trial was performed in compliance with standard operating procedures as well as regulations set forth by FDA, ICH E6 (Rl) guidelines, and other relevant regulatory authorities. Compliance was achieved through clinical trial-specific audits of clinical sites and database review.
  • estradiol vaginal softgel capsules (4 ⁇ g, 10 ⁇ g, and 25 ⁇ g) when compared to placebo on vaginal superficial cells, vaginal parabasal cells, vaginal pH, and on the symptom of moderate to severe dyspareunia (vaginal pain associated with sexual activity) as the MBS at week 12.
  • estradiol vaginal softgel capsules 4 ⁇ g, 10 ⁇ g, and 25 ⁇ g
  • Table 41 provides the effect sizes, power, and sample size determinations for each of the primary endpoints.
  • subjects in the study met all inclusion/exclusion criteria and had moderate to severe dyspareunia as their most bothersome symptom of VVA. Based on the power analysis and the design considerations, approximately 175 subjects per treatment arm were enrolled.
  • ITT intent-to-treat
  • MTT Modified intent-to-treat
  • the efficacy-evaluable (EE) population was defined as all MITT subjects who completed the clinical trial, were at least 80% compliant with investigational product, had measurements for all primary efficacy endpoints, and were deemed to be protocol compliant, with no significant protocol violations.
  • the safety population included all ITT subjects.
  • ANCOVAs Primary and secondary efficacy endpoints were measured at baseline and at 2, 6, 8, and 12 weeks. The analysis examined change from baseline. Therefore, ANCOVAs were based on a repeated measures mixed effects model (MMRM) where the random effect was subject and the two fixed effects were treatment group and visit (2, 6, 8, and 12 weeks). Baseline measures and age were used as covariates. ANCOVAs were therefore not calculated independently for each study collection period. The analyses started with the full model but, interaction terms for visit (week 2, 6, 8, and 12) with treatment only remained where statistically significant (p ⁇ 0.05).
  • MMRM mixed effects model
  • hyperplasia- includes simple hyperplasia with or without atypia and complex hyperplasia with or without atypia
  • category 3 malignancy - endometrial malignancy.
  • the final diagnosis was based on agreement of two of the three reads. Consensus was reached when two of the three pathologist readers agreed on any of the above categories. For example, any 2 subcategories of "not hyperplasia/not malignancy” were classified as "Category 1 : not hyperplasia/not malignancy.” If all three readings were disparate (i.e., each fell into a different category - category 1, 2, or 3), the final diagnosis was based on the most severe of the three readings.
  • the analysis population for endometrium hyperplasia was the endometrial hyperplasia (EH) population.
  • EH endometrial hyperplasia
  • An EH subject at week 12 was one who was randomly assigned and took at least 1 dose of investigational product, with no exclusionary protocol violation (as detailed at the Statistical Analysis Plan), and had a pretreatment endometrial biopsy and a biopsy on therapy.
  • Investigational product was dispensed to all eligible subjects at visit 2. Each subject was provided a total of 30 soft gel capsules of investigational product in a labeled bottle, allowing for extra capsules for accidental loss or damage. A second bottle was dispensed at Visit 5. Each subject was trained by the clinical site to self-administer intravaginally one capsule daily at approximately the same hour for 2 weeks (14 days). The drug administration instructions included: "Remove vaginal capsule from the bottle; find a position most comfortable for you; insert the capsule with the smaller end up into vaginal canal for about 2 inches.” Starting on Day 15, each subject administered 1 capsule twice weekly for the remaining 10 weeks. Twice weekly dosing was approximately 3-4 days apart, and generally did not exceed more than twice in a seven day period.
  • the investigational estradiol vaginal softgel drug products used in the study are pear-shaped, opaque, light pink softgel capsules.
  • the capsules contain the solubilized estradiol pharmaceutical compositions disclosed herein as Pharmaceutical Compositions 4-7.
  • the softgel capsules come in contact with the vaginal mucosa, the soft gelatin capsule releases the pharmaceutical composition, into the vagina. In embodiments, the soft gelatin capsule completely dissolves.
  • the placebo used in the study contained the excipients in the investigational estradiol vaginal softgel capsule without the estradiol (see, e.g., Pharmaceutical Composition 7).
  • the packaging of the investigational products and placebo were identical to maintain adequate blinding of investigators. Neither the subject nor the investigator was able to identify the treatment from the packaging or label of the investigational products.
  • a subject was required to use at least 80% of the investigational product to be considered compliant with investigational medication administration. Capsule count and diary cards were be used to determine subject compliance at each study visit. Subjects were randomly assigned in a 1 : 1 : 1 ratio to receive Estradiol Vaginal Softgel Capsule 4 ⁇ g (Pharmaceutical Composition 4), Estradiol Vaginal Softgel Capsule 10 ⁇ g (Pharmaceutical Composition 5), Estradiol Vaginal Softgel Capsule 25 ⁇ g (Pharmaceutical Composition 6), or placebo (Pharmaceutical Composition 7).
  • Concomitant medications/treatments were used to treat chronic or intercurrent medical conditions at the discretion of the investigator. The following medications were prohibited for the duration of the study: investigational drugs other than the investigational Estradiol Vaginal Softgel Capsule; estrogen-, progestin-, androgen (i.e., DHEA) or SERM- containing medications other than the investigational product; medications, remedies, and supplements known to treat vulvar/vaginal atrophy; vaginal lubricants and moisturizers (e.g., Replens) be discontinued 7 days prior to Visit IB vaginal pH assessment; and all medications excluded before the study.
  • Vaginal cytological smears were collected from the lateral vaginal walls according to standard procedures and sent to a central laboratory to evaluate vaginal cytology. The percentage of superficial, parabasal, and intermediate cells was determined. All on- therapy/early termination vaginal cytology results were blinded to the Sponsor, Investigators, and subjects.
  • Vaginal pH was determined at screening Visit IB and visits 3, 4, 5, and 6/end of treatment. Subjects were not allowed to use vaginal lubricants or moisturizers within 7 days of the screening vaginal pH assessment or at any time afterwards during the study.
  • a pH indicator strip was applied to the lateral vaginal wall until it became wet, taking care to avoid cervical mucus, blood or semen that are known to affect vaginal pH. The color of the strip was compared immediately with a colorimetric scale and the measurement was recorded.
  • Vaginal normal clear superficial coating of scant not covering none, inflamed, secretions secretions noted on secretions, difficulty the entire vaginal ulceration noted, vaginal walls with speculum vault, may need need lubrication with insertion lubrication with speculum insertion to speculum insertion prevent pain to prevent pain
  • Vaginal normal vaginal surface vaginal surface vaginal surface has epithelial bleeds with scraping bleeds with light petechiae before integrity contact contact and bleeds with light contact
  • the VVA symptom self-assessment questionnaire is an instrument for subjects to self-assess their symptoms of vulvar or vaginal atrophy, including vaginal pain associated with sexual activity, vaginal dryness, vulvar or vaginal itching, or irritation.
  • screening visit 1 A subjects were asked to complete the questionnaire and identify their most bothersome symptoms, and the results of the survey were used to determine initial eligibility for the study.
  • visit 1A subjects were also asked to indicate which moderate or severe symptoms bothered them most.
  • the questionnaire was administered again at screening visit IB and used to determine continued eligibility for the study.
  • the Female Sexual Function Index is a brief, multidimensional scale for assessing sexual function in women (see, Rosen, 2000, supra 26: p.191-208, incorporated by reference herein).
  • the scale consists of 19 items that assess sexual function over the past 4 weeks and yield domain scores in six areas: sexual desire, arousal, lubrication, orgasm, satisfaction, and pain. Further validation of the instrument was conducted to extend the validation to include dyspareunia/vaginismus (pain), and multiple sexual dysfunctions (see, Weigel, M., et al. "The Female Sexual Function Index (FSFI): Cross-Validation and Development of Clinical Cutoff Scores. " Journal of Sex & Marital Therapy, 2005. 31 : p. 1— 20, incorporated by reference herein).
  • the FSFI was conducted at Visits 2 and 6. Subjects participating in the PK substudy were not assessed using FSFI.
  • a complete medical history including demographic data (age and race/ethnicity) gynecological, surgical, and psychiatric history and use of tobacco and alcohol was recorded at the washout/screening visit 1 A prior to any washout period; this history included a review of all past and current diseases and their respective durations as well as any history of amenorrhea.
  • a complete physical examination was conducted at screening visit 1A and visit 6/end of treatment.
  • the physical examination included, at a minimum, examination of the subject's general appearance, HEENT (head, eyes, ears, nose, and throat), heart, lungs, musculoskeletal system, gastrointestinal (GI) system, neurological system, lymph nodes, abdomen, and extremities.
  • the subject's height was measured at washout/screening visit 1A only and body weight (while the subject is lightly clothed) was be measured at
  • BMI washout/screening visit 1A and end of treatment.
  • BMI was calculated at washout/screening visit 1A.
  • Vital signs body temperature, heart rate [HR], respiration rate [RR], and sitting blood pressure [BP]) were measured at all visits after the subject had been sitting for >10 minutes. If the initial BP reading was above 140 mmHg systolic or 90 mmHg diastolic, the option for a single repeat assessment performed 15 minutes later was provided.
  • a standard 12-lead ECG was obtained at screening visit 1A and visit 6 or early termination.
  • Subjects were required to have a pelvic examination and Pap smear performed during the screening visit IB and visit 6 or early termination.
  • the Pap smear was required for all subjects with or without an intact uterus and cervix.
  • the Pap smear was obtained by sampling the apex of the vaginal cuff. All subjects were required to have a Pap smear done during screening, regardless of any recent prior assessment.
  • Subjects who discontinued the study after 2 weeks of investigational product were required to have an end of treatment Pap smear.
  • Subjects had a breast examination performed during screening visit 1A and at visit 6 or early termination.
  • Endometrial biopsies were performed by a board-certified gynecologist at screening and at visit 6/end of treatment. Unscheduled endometrial biopsies were performed during the study, when indicated for medical reasons. The screening biopsy was performed at screening visit IB, after the subject's initial screening visit assessments indicated that the subject was otherwise an eligible candidate for the study.
  • endometrial biopsies were read centrally by two pathologists. A candidate subject was excluded from the study if at least one pathologist assessed the endometrial biopsy as endometrial hyperplasia, endometrial cancer, proliferative
  • endometrium weakly proliferative endometrium, or disordered proliferative partem, or if at least one pathologist identified an endometrial polyp with hyperplasia, glandular atypia of any degree (e.g., atypical nuclei), or cancer. Additionally, identification of sufficient tissue to evaluate the biopsy by at least one pathologist was required for study eligibility. The option for one repetition of the screening endometrial biopsy was made available when an initial endometrial biopsy was performed and both of the primary pathologists reported endometrial tissue insufficient for diagnosis, no endometrium was identified, or no tissue was identified, and if the subj ect had met all other protocol-specified eligibility criteria to date. The visit 6 (or early termination) endometrial biopsies and on treatment unscheduled biopsies were assessed by three pathologists.
  • a urine pregnancy test was conducted at screening visit 1A unless the subject had a history of tubal ligation, bilateral oophorectomy, or was >55 years of age and had experienced cessation of menses for at least 1 year.
  • Blood samples for blood chemistry, hematology, coagulation tests, and hormone levels and urine samples for urine analysis were collected and sent to a central laboratory.
  • Blood Chemistry sodium, potassium, chloride, total cholesterol, blood urea nitrogen (BUN), iron, albumin, total protein, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, creatinine, calcium, phosphorous, uric acid, total bilirubin, glucose and triglycerides (must be fasting minimum of 8 hours).
  • a fasting glucose of > 125 mg/dL will require a HgAlC) was monitored.
  • CBC complete blood count
  • FSH follicle-stimulating hormone
  • the last PK sample (approximately day 84) was obtained 4 days following the last insertion of investigational product.
  • Blood samples were analyzed to characterize area under the curve (AUC), time of maximum concentration (tmax), minimum concentration (Cmi n ), and maximum concentration (Cmax). Blood samples were also analyzed to measure the levels of estradiol, estrone, and estrone conjugates. No fasting requirements were applied. Sex hormone binding globulin (SHBG) levels were obtained at pre-treatment baseline (day 1 , visit 2), and day 14 at the Oh and on the day 84 final hormone blood draw.
  • AUC area under the curve
  • tmax time of maximum concentration
  • Cmi n minimum concentration
  • Cmax maximum concentration
  • SHBG Sex hormone binding globulin
  • a copy of the diary was made at each visit and re-dispensed to the subject.
  • a dosing diary was dispensed at visit 2 and at visit 3 and subjects were be instructed on completion. Subjects recorded investigational product usage and sexual activity. The dosing diary dispensed at visit 3 was re-dispensed at visits 4 and 5. A copy of the diary was made at each visit prior to re-dispensing to the subj ect.
  • Visit 1A Visit IB Visit 2: Visit 3:
  • Washout Period Visit (if applicable; Weeks -14 to -6). The purpose of this visit was to discuss the study with a potential subject and obtain informed consent that is signed and dated before any procedures, including washout are performed. Subjects who agreed to discontinue current treatment began washout after the consent form was signed. A symptoms/complaints and medication diary was dispensed at this visit and the subject was instructed in how to complete the diary. Once the washout period was completed, the subject will return to the site for visit 1A.
  • the activities and assessments conducted during the visit included: informed consent; demographics; medical/gynecological history; collection of prior and concomitant medication information; height, body weight measurement and BMI calculation; collection of vital signs (body temperature, HR, RR, and BP); dispensation of symptoms/complaints diary and instruction in how to complete the diary
  • Screening Period Visits (Visits 1A and IB). Subjects not requiring washout begin screening procedures at visit 1 A as described above for the washout period. With the exception of vital signs, procedures performed at washout will not be repeated at screening visit 1A. In general, screening visits 1A and IB were completed within 6 weeks (42 days) for subjects without a uterus or within 8 weeks (56 days) for subjects with a uterus. All screening assessments were completed prior to randomization. The investigators reviewe d the results from all screening procedures and determined if the subjects were eligible for enrollment into the study.
  • Visit 1A (approximately Week -6 to 0). Visit 1 A was conducted after the wash-out period (if applicable) or after the subject provided informed consent. The subject was advised to fast for 8 hours prior to the visit for blood draws.
  • Visit 1A the VVA symptom self-assessment questionnaire was conducted and most bothersome symptoms were identified, with the subject self-identifying moderate or severe pain with sexual activity as her MBS to continue screening.
  • the symptoms/complaints and medications diary was dispensed, and subjects were instructed in how to complete the diary. Subjects were instructed to refrain from use of vaginal lubricants for 7 days and sexual intercourse/vaginal douching for 24 hours prior to the vaginal pH assessment to be done at visit IB.
  • Visit IB (approximately Week -4 to Week 0). Visit IB was conducted after the subject's initial screening visit and after the other screening results indicated that the subject was otherwise an eligible candidate for the study (preferably around the middle of the screening period).
  • VVA symptom self- assessment questionnaire the subject having indicated moderate to severe pain with sexual activity with vaginal penetration in order to continue screening; collection of vital signs (body temperature, HR, RR, and BP); pelvic examination; investigator assessment of vaginal mucosa as described above; assessment of vaginal pH (sexual intercourse or vaginal douching within 24 hrs prior to the assessment being prohibited, and a subject's vaginal pH being >5.0 to continue screening); Pap smear; vaginal cytological smear (one repetition being permitted during screening if no results were obtained from the first smear); endometrial biopsy performed as described above; review of the symptoms/complaints and medications diary with the subject.
  • Visit 2 (Week 0; Randomization/Baseline). Subjects who met entry criteria were randomized to investigational product at this visit. Procedures and evaluations conducted at the visit included: self-administration of FSFI by subjects not participating in the PK substudy; review of the symptoms/complaints and medications diary with the subject; review of evaluations performed at screening visits and verification of present of all inclusion criteria and the absence of all exclusion criteria; collection of vital signs (body temperature, HR, RR, and BP); randomization, with subjects meeting all entry criteria being randomized and allocated a bottle number; dispensation of investigational product and instruction in how to insert the capsule vaginally, with subjects receiving their first dose of investigational product under supervision; dispensation of dosing diary and instruction on completion of the treatment diary, including recording investigational product usage and sexual activity.
  • Visit 3 (Week 2, Day 14 ⁇ 3 days). Procedures and evaluations conducted at the visit included: completion of the VVA symptom self-assessment questionnaire; review of the symptoms/complaints and medications diaries with the subject; collection of vital signs (body temperature, HR, RR, and BP); Assessment of vaginal mucosa; assessment of vaginal pH (with sexual intercourse or vaginal douching within 24 hrs prior to the assessment being prohibited); vaginal cytological smear; collection of unused investigational product and bottle for assessment of compliance/accountability; re-dispensation of investigational product and re-instruction in how to insert the capsule vaginally if necessary; review of the completed dosing diary with the subject.
  • Visit 4 (Week 6, Day 42 ⁇ 3 days). Procedures and evaluations conducted at the visit included: completion of the VVA symptom self-assessment questionnaire; review of the symptoms/complaints and medications diary with the subject; collection of vital signs (body temperature, HR, RR, and BP); assessment of vaginal mucosa as described above; vaginal cytological smear; assessment of vaginal pH (with sexual intercourse or vaginal douching within 24 hrs prior to the assessment being prohibited); collection of unused investigational product for assessment of compliance/accountability; re-dispensation of investigational product and re-instruction in how to insert the capsule vaginally if necessary; review of the completed dosing diary with the subject.
  • Visit 5 (Week 8, Day 56 ⁇ 3 days). Procedures and evaluations conducted at the visit included: completion of the VVA symptom self-assessment questionnaire; review of the symptoms/complaints and medications diary with the subject; collection of vital signs (body temperature, HR, RR, and BP); assessment of vaginal mucosa as described above; vaginal cytological smear; assessment of vaginal pH (with sexual intercourse or vaginal douching within 24 hrs prior to the assessment being prohibited); collection of unused investigational product for assessment of compliance/accountability; re-dispensation of investigational product and re-instruction in how to insert the capsule vaginally if necessary; review of the completed dosing diary with the subject.
  • Visit 6 (Week 12, Day 84 ⁇ 3 days or early termination). This visit was performed if a subject withdraws from the study before visit 6. Procedures performed at this visit included: completion of the VVA symptom self-assessment questionnaire; review of the subject the dosing diary, symptoms/complaints, and medications diaries with the subject; collection of blood and urine sample collection for blood chemistry (minimum fast of 8 hrs), hematology, and urinalysis; collection of vital signs (body temperature, HR, RR, and BP) and weight; performance of 12-lead-ECG; collection of unused investigational product and container for assessment of compliance/accountability; physical examination; breast exam; assessment of vaginal mucosa as described above; assessment of vaginal pH (with sexual intercourse or vaginal douching within 24 hrs prior to the assessment being prohibited); vaginal cytological smear; Pap smear; endometrial biopsy; self-administration of FSFI by subjects not participating in the PK
  • investigational product Each subject who received investigational product received a follow-up phone call, regardless of the duration of therapy, approximately 15 days following the last dose of investigational product.
  • the follow-up generally took place after receipt of all safety assessments (e.g., endometrial biopsy and mammography results).
  • the follow-up included: review of ongoing adverse events and any new adverse events that occurred during the 15 days following the last dose of investigational product; review of ongoing concomitant medications and any new concomitant medications that occurred during the 15 days following the last dose of investigational product; and discussion of all end of study safety assessments and determination if further follow up or clinic visit is required.
  • Visit 2 (Week 0, Day 1).
  • activities in the PK substudy also included collection of serum blood sample obtained prior to the administration of investigational product (timepoint Oh) for baseline assessment of estradiol, estrone, estrone conjugates, and SHBG.
  • the investigational product was self- administered by the subject after the pre-treatment blood sample has been taken.
  • serum blood samples were obtained at 2h, 4h, 6h, lOh, and 24h timepoints for estradiol, estrone, and estrone conjugates (serum samples were generally taken within +/- 5 minutes at 2h and 4h, within +/- 15 minutes at 6h, and within +/- lh at lOh and 24h).
  • the subject was released from the site after the 10 hour sample and instructed to return to the site the next morning for the 24 hour blood draw. The subject was instructed not to self-administer the day 2 dose until instructed by the site personnel to dose at the clinical site. The subject was released from the clinical site following the 24 hour blood sample and administration of the day 2 dose.
  • Visit 3 (Week 2, Day 14). The visit must occurred on day 14 with no visit window allowed.
  • the PK substudy included collection of a serum blood sample prior to the administration of day 14 dose (timepoint Oh) for SHBG and PK assessments. The subject self-administered the day 14 dose at the clinical site, and serum blood samples were obtained at 2h, 4h, 6h, lOh, and 24h timepoints for estradiol, estrone, and estrone conjugates. The subject was released from the site after the 10 hour sample and instructed to return to the site the next morning for the 24 hour blood draw. The subject was instructed not to self-administer the day 15 dose until instructed by the site personnel to dose at the clinical site.
  • the subject was released from the clinical site following the 24 hour blood sample and administration of the day 15 dose.
  • the subject was be instructed to administer the next dose of study drug on day 18 or day 19 and continue dosing on a bi-weekly basis at the same time of day for each dose.
  • Visit 6 (Week 12, Day 84 ⁇ 3 days, or at early termination). The visit took place 4 days after last IP dose or early termination. A serum sample for estradiol, estrone, and estrone conjugates and SHBG was drawn in addition to the procedures described above.
  • PK sub-study visits were typically conducted so as to include the activities outlined in Table 44.
  • Visit 4 Visit 5: of treatment Telephone
  • Visit 4 Visit 5: of treatment Telephone
  • An Adverse Event in the study was defined as the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered casually related to the product.
  • An AE could occur from overdose of investigational product.
  • an AE can include an undesirable medical condition occurring at any time, including baseline or washout periods, even if no study treatment has been administered.
  • the investigators determined the relationship to the investigational product for each AE (Not Related, Possibly Related, or Probably Related).
  • the degree of "relatedness" of the adverse event to the investigational product was described as follows: not related— no temporal association and other etiologies are likely the cause; possible— temporal association, but other etiologies are likely the cause. However, involvement of the investigational product cannot be excluded; probable— temporal association, other etiologies are possible but unlikely. The event may respond if the investigational product is discontinued.
  • EXAMPLE 11 Efficacy results of randomized, double-blind, placebo-controlled multicenter study.
  • Each of the three doses showed statistical significance compared with placebo for the primary endpoints.
  • Each of the three doses showed statistical significance compared with placebo for the secondary endpoints.
  • Table 45 shows the statistical significance of the experimental data for each of the four co-primary endpoints.
  • Each of the dosages met each of the four co-primary endpoints at a statistically significant level.
  • the 25 meg dose of TX- 004HR demonstrated highly statistically significant results at the p ⁇ 0.0001 level compared to placebo across all four co-primary endpoints.
  • the 10 meg dose of TX-004HR The 25 meg dose of TX- 004HR
  • Vaginal cytology data was collected as vaginal smears from the lateral vaginal walls according to procedures presented above to evaluate vaginal cytology at screening and Visit 6— End of treatment (day 84).
  • the change in the Maturation Index was assessed as a change in cell composition measured at Visit 1— Baseline (day 1) compared to the cell composition measured at Visit 3— End of treatment (day 84).
  • the change in percentage of superficial, parabasal, and intermediate cells obtained from the vaginal mucosal epithelium from a vaginal smear was recorded. Results from these assessments for superficial cells are presented in Table 46 and Table 47, as well as Fig. 10, Fig. 11, and Fig. 12. Results from these assessments for parabasal cells are presented in Table 48 and Table 49, as well as Fig. 13, Fig. 14, and Fig. 15.

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Abstract

L'invention concerne, entre autres choses, une composition pharmaceutique vaginale à enveloppe molle et une forme galénique contenant de l'œstradiol solubilisé pour le traitement de l'atrophie vulvovaginale (AVV) et de la dysfonction sexuelle féminine (DSF).
PCT/US2016/065466 2012-12-21 2016-12-07 Compositions pharmaceutiques à base d'œstradiol introduites par voie vaginale et procédés associés Ceased WO2017100378A2 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
US15/781,840 US11266661B2 (en) 2012-12-21 2016-12-07 Vaginal inserted estradiol pharmaceutical compositions and methods
CA3007636A CA3007636A1 (fr) 2015-12-07 2016-12-07 Compositions pharmaceutiques a base d'ƒstradiol introduites par voie vaginale et procedes associes
KR1020187019331A KR20180100567A (ko) 2015-12-07 2016-12-07 질 삽입식 에스트라디올 약제학적 조성물 및 방법
AU2016366200A AU2016366200B2 (en) 2015-12-07 2016-12-07 Vaginal inserted estradiol pharmaceutical compositions and methods
EP16873806.0A EP3386514A4 (fr) 2015-12-07 2016-12-07 Compositions pharmaceutiques à base d' stradiol introduites par voie vaginale et procédés associés
JP2018529574A JP2018538290A (ja) 2015-12-07 2016-12-07 膣挿入エストラジオール医薬組成物および方法
BR112018011483A BR112018011483A2 (pt) 2015-12-07 2016-12-07 métodos e composições farmacêuticas com estradiol vaginalmente inserido
MX2018006882A MX384850B (es) 2015-12-07 2016-12-07 Composiciones farmacéuticas de estradiol insertadas por vía vaginal y métodos.
IL259884A IL259884A (en) 2015-12-07 2018-06-07 Medicinal estradiol compositions for vaginal insertion and methods of using them

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US201562264309P 2015-12-07 2015-12-07
US62/264,309 2015-12-07
US201662296552P 2016-02-17 2016-02-17
US62/296,552 2016-02-17
US201662324838P 2016-04-19 2016-04-19
US62/324,838 2016-04-19
US201662329940P 2016-04-29 2016-04-29
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Cited By (1)

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Publication number Priority date Publication date Assignee Title
EP4051203A4 (fr) * 2019-10-31 2023-10-25 R.P. Scherer Technologies, LLC Capsule de suppositoire

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KR102696460B1 (ko) 2021-01-20 2024-08-22 주식회사 바이올렛드림 질 내 수용성 겔 조성물

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FR2739558B1 (fr) * 1995-10-05 1997-11-28 Innothera Lab Sa Forme galenique unitaire pour hormonotherapie locale de la secheresse vaginale
US6117446A (en) * 1999-01-26 2000-09-12 Place; Virgil A. Drug dosage unit for buccal administration of steroidal active agents
AP2365A (en) * 2004-10-20 2012-02-20 Endorech Inc Sex steroid precursors alone or in combination with a selective estrogen receptor modulator and/or with estrogens and/or a type 5 CGMP phosphodiesterase inhibitor for the prevention and treatment of vaginal dryness and sexual dysfunction in postmenopausal women.
BR112014031914B1 (pt) * 2012-06-18 2021-12-14 Therapeuticsmd, Inc Formulação farmacêutica encapsulada para liberação intravaginal compreendendo estradiol e uso da mesma para o tratamento de atrofia vulvovaginal e de um sistoma associado, bem como de um estado urinário deficiente em estrogênio
US10806697B2 (en) * 2012-12-21 2020-10-20 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US9180091B2 (en) * 2012-12-21 2015-11-10 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4051203A4 (fr) * 2019-10-31 2023-10-25 R.P. Scherer Technologies, LLC Capsule de suppositoire

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JP2018538290A (ja) 2018-12-27
AU2016366200A1 (en) 2018-06-28
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MX384850B (es) 2025-03-14
BR112018011483A2 (pt) 2018-12-04
IL259884A (en) 2018-07-31
EP3386514A2 (fr) 2018-10-17
WO2017100378A3 (fr) 2018-02-22
EP3386514A4 (fr) 2019-07-24
MX2018006882A (es) 2019-05-16
KR20180100567A (ko) 2018-09-11
CA3007636A1 (fr) 2017-06-15

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