WO2013192248A1

WO2013192248A1 - Progesterone formulations

Info

Publication number: WO2013192248A1
Application number: PCT/US2013/046442
Authority: WO
Inventors: Janice Louise Cacace; Peter H.R. PERISCANER
Original assignee: Therapeuticsmd, Inc.
Priority date: 2012-06-18
Filing date: 2013-06-18
Publication date: 2013-12-27
Also published as: US10639375B2; EP3560500A1; BR112014031837A2; AU2018222947B2; AU2018222947A1; EP2861233A1; EP2861234B1; JP6298460B2; MX2014015900A; JP2015520236A; CA2876964A1; AU2013277235B2; EP3560500B1; US20130338122A1; WO2013192250A1; BR112014031824A2; JP6342389B2; EP2861234A1; BR112014031837B1; AU2013277233A1

Abstract

Pharmaceutical formulations for oral use in hormone replacement therapy comprising ultra-micronized progesterone are disclosed, wherein the ultra-micronized progesterone is combined with a suitable excipient. The preferred excipients comprise medium chain fatty acid-glycol esters and a nonionic surfactant comprising a polyethylene glycol fatty acid ester. In some embodiments C8 to C18 fatty acid esters of glycerol and polyethylene glycol are the preferred nonionic surfactants.

Description

PROGESTERONE FORMULATIONS CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to the following U.S. Patent Applications: U.S. Provisional Application Serial No. 61 /661 ,302, entitled "ESTRADIOL FORMULATIONS," which was filed on June 18, 2012; U.S. Provisional

Application Serial No. 61 /662,265, entitled "PROGESTERONE

FORMULATIONS," which was filed on June 20, 2012; U.S. Patent Application Serial No. 13/684,002, entitled "NATURAL COMBINATION HORMONE

REPLACEMENT FORMULATIONS AND THERAPIES," which was filed

November 21 , 2012; U.S. Patent Application Serial No. PCT/US2013/023309, entitled "TRANSDERMAL HORMONE REPLACEMENT THERAPIES," which was filed January 25, 2013; and U.S. Patent Application Serial No. 13/843,362, entitled "TRANSDERMAL HORMONE REPLACEMENT THERAPIES," which was filed March 15, 2013. All aforementioned applications are hereby incorporated by reference herein in their entirety.

Field

The disclosure relates to progesterone formulations. Various

progesterone formulations may be used in hormone therapies for menopausal, peri-menopausal and post-menopausal females, for example, to mitigate side effects from estrogen replacement therapy. In addition, various progesterone formulations may be used to prevent preterm delivery in pregnant women having a shortened cervix.

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61186.00816 Background

Hormone replacement therapy (HRT) is a medical treatment that involves the use of one or more of a group of medications designed to supplement hormone levels in women who lack adequate hormone production. It can mitigate and prevent symptoms caused by diminished circulating estrogen and progesterone hormones.

HRT is available in various forms. One therapy involves administration of low dosages of one or more estrogen(s) or one or more chemical analogues. Another involves administration of progesterone or one or more chemical analogues. Among other effects, progesterone administration acts to mitigate certain undesirable side effects from estradiol administration or naturally- occurring elevated blood levels including endometrial hyperplasia (thickening) and prevention or inhibition of endometrial cancer. Progesterone is a C-21 steroidal sex hormone involved in the female menstrual cycle, pregnancy (supports gestation) and embryogenesis of humans and other species.

Progesterone belongs to a class of hormones called progestogens, and is the major naturally occurring human progestogen. Like other steroids, progesterone consists of four interconnected cyclic hydrocarbons. Progesterone is

hydrophobic, having a reported aqueous solubility of 0.007±0.0 mg/ml.

Progesterone is poorly absorbed when administered orally.

Conventional progesterone therapeutics include the administration of

PROMETRIUM (progesterone, USP) (Abbott Laboratories, Chicago, IL).

PROMETRIUM is an FDA-approved drug, formulated in a peanut oil-based medium, containing micronized progesterone, but with a relatively large particle size fraction.

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61186.00816 The active ingredient is considered to be structurally identical to naturally occurring progesterone produced by a woman's body (also known as a

"bioidentical).

Clinical trials involving PROMETRIUM have shown significant patient variability. For example, a clinical trial involving postmenopausal women who were administered PROMETRIUM once a day for five days resulted in the mean pharmacokinetic parameters listed in Table 1 (see Table 1 , package insert for PROMETRIUM).

TABLE 1 . Pharmacokinetic Parameters of PROMETRIUM Capsules

The unusually high variability in the Cmax and AUC, as evidenced by the large reported standard deviation, indicates that a significant percentage of patients are overdosed or receive a sub-optimal dose.

The presence of peanut oil in the formulation excludes patients who are allergic to peanut oil. Peanut oil, like other peanut products, may act as an allergen. Indeed, there is a portion of the population that has severe reactions to

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61186.00816 peanut oil. Peanut allergies are becoming a significant health concern. Food allergies are a leading cause of anaphylaxis, with approximately 200 deaths occurring annually in the United States. While incidence and prevalence are not entirely known, it is suspected that about 6% of children and 4% of adults in North America are affected by food allergies. Many food allergies experienced by children are generally outgrown in adulthood with the exception of peanut allergies.

Progesterone and its analogues can be used to treat a variety of medical conditions, including acute diseases or disorders, as well as chronic diseases and disorders associated with long-term declines of natural progesterone levels.

Accordingly, improved formulations of progesterone would be

advantageous.

SUMMARY

Various pharmaceutical formulations are disclosed herein. For example, pharmaceutical formulations are disclosed comprising ultra-micronized progesterone. Moreover, pharmaceutical formulations are disclosed comprising formulations of ultra-micronized progesterone, wherein the ultra-micronized progesterone is combined with a suitable excipient.

Thus, in various illustrative embodiments, the invention comprises an encapsulated liquid pharmaceutical formulation for orally administering progesterone to a mammal in need thereof, said formulation comprising:

progesterone, as the sole active pharmaceutical ingredient, in micronized form, in solubilized form, or in micronized and partially soluble form in a carrier that comprises a medium chain fatty acid-glycol ester or mixtures thereof and a non- ionic surfactant comprising a polyethylene glycol fatty acid ester. In some such

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61186.00816 embodiments the progesterone is ultra-micronized. In some such embodiments, at least about 80 wt% of the total progesterone is micronized. The fatty acids can be predominantly (>50 wt%): C6 to C12 fatty acids, C6 to C10 fatty acids, C8 to C12 fatty acids, or C8 to C10 fatty acids, the esters can be mono-, di-, or triesters or mixtures thereof, and the glycols can be glycerol, polyethylene glycol or propylene glycol or mixtures thereof. Some embodiments comprise a non-ionic surfactant that comprises C8 to C18 fatty acid esters of glycerol and polyethylene glycol.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings are included to provide a further

understanding of the disclosure and are incorporated in and constitute a part of this specification, illustrate embodiments of the disclosure, and together with the description serve to explain the principles of the disclosure.

Figure 1 illustrates a process to produce fill material in accordance with various embodiments;

Figure 2 illustrates a process to produce softgel capsules in accordance with various embodiments;

Figure 3 illustrates a process to produce softgel capsules in accordance with various embodiments; and

Figure 4 illustrates a dissolution study of a formulation in accordance with various embodiments.

Figure 5 illustrates a graph of the particle distribution obtained in Example

10.

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61186.00816 Figure 6 illustrates a dissolution study of a formulation in accordance with various embodiments of the invention.

DETAILED DESCRIPTION OF THE ILLUSTRATED EMBODIMENTS

According to various embodiments, a pharmaceutical formulation comprising ultra-micronized progesterone is provided. As described in detail here, various carriers, lubricants, and other excipients may be included. In further embodiments, ultra-micronized progesterone formulations provide improved bioavailability and other pharmacokinetic improvements.

DEFINITIONS

Unless otherwise specified, the following definitions apply.

The term "ultra-micronized progesterone," as used herein, includes micronized progesterone having an X50 value below about 20 microns and/or having an X90 value below about 25 microns.

A chemical structure of progesterone is depicted below:

The term "administer," "administration," "deliver" or "delivery" (collectively "administration"), as used herein, means administration to the body via, without limitation, tablets, capsules, softgel capsules, injections, transdermal patches, creams, gels, vaginal suppositories including gelcaps or other mechanisms known in the art or hereinafter developed. The term "administration" may also

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61186.00816 mean direct application of softgel contents into the vagina, such as by accessing the softgel contents opening or rupturing the softgel capsule to liberate the contents therein.

The term "X50," as used herein, means that half of the particles in a sample are smaller in diameter than a given number. For example, ultra- micronized progesterone having an X50 of 5 microns means that, for a given sample of ultra-micronized progesterone, half of the particles have a diameter of less than 5 microns. In that regard, similar terms, in the form XYY mean that YY percent of the particles in the sample are smaller in diameter than a given number. For example, X90 means that ninety percent of the particles in a sample are smaller in diameter than a given number.

The term "medium chain," as used herein means any medium chain carbon-contain substance, including C4-C18, and including C6-C12 substances, fatty acid esters of glycerol, fatty acids, and mono-, di-, and tri-glycerides of such substances. For further illustration, C6-C14 fatty acids, C6-C12 fatty acids, and C8-C10 fatty acids are all medium chain fatty acids and may be used in instances in which this specification calls for use of medium chain fatty acids, e.g., medium chain fatty acid esters of glycerol or other glycols.

The term "uniform distribution" means at least one of uniform dispersion, solubility, or lack of agglomeration of progesterone in gastric juices compared to PROMETRIUM.

The term "gastric juices" means the watery, acidic digestive fluid that is secreted by various glands in the mucous membrane of the stomach and consists chiefly of hydrochloric acid, pepsin, rennin, and mucin.

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61186.00816 The term, "API," as used herein, refers to active pharmaceutical ingredient.

In formulations, the API is progesterone.

The term "excipients," as used herein, refers to non-API substances such as carriers, solvents, lubricants and others used in formulating pharmaceutical products. They are generally safe for administering to humans according to established governmental standards, including those promulgated by the United States Food and Drug Administration.

The term "carrier," as used herein, means any substance or mixture of substances that may be mixed with or contain an API (e.g., ultra-micronized progesterone).

The term "capsule," as used herein, refers to a generally safe, readily dissolvable enclosure for carrying certain pharmaceutical products, and includes hard or soft shell capsules.

The term "softgel," includes soft shell capsules, including soft-gelatin capsules and soft vegetable-based capsules, and soft capsules made from other materials providing the composition of such soft capsules are compatible with the formulations of the various embodiments described herein. A softgel may comprise two primary phases: a gel or vegetable-based capsule and a fill material of the pharmaceutical formulation as described herein.

The term "bioavailability," as used herein means the concentration of an active ingredient (e.g., progesterone) in the blood (serum or plasma). The relative bioavailability may be measured as the concentration in the blood (serum or plasma) versus time. Other pharmacokinetic (PK) indicators may be used to measure and assess bioavailability, determined by suitable metrics including AUC, Cmax and optionally T_max.

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61186.00816 The terms "pharmacokinetics" and "pharmacokinetic measurements" include assessments and determinations to study absorption, distribution, metabolism, and excretion of a drug.

The term "AUC," as used herein, refers to the area under the curve that represents changes in blood concentration of progesterone over time.

The term, "C_max" as used herein, refers to the maximum value of blood concentration shown on the curve that represents changes in blood

concentrations of progesterone over time.

The term, "T_max" as used herein, refers to the time that it takes for progesterone blood concentration to reach the maximum value.

Optionally, the term, "Ti/₂" as used herein, refers to the time that it takes for progesterone blood concentration to decline to one-half of the maximum level.

Collectively AUC, C_max, and optionally T_max and T½, are the principle pharmacokinetic parameters that can characterize the pharmacokinetic responses of a particular drug product such as progesterone in an animal or human subject.

DESCRIPTION

Generally, the pharmaceutical formulations described herein are prepared and administered as filled capsules, typically soft capsules of one or more materials well known in the art including, for example and without limitation, soft gelatin capsules. Micronized progesterone, as described herein, may also be prepared for administration in tablets or other well-known orally administered dosage forms using standard techniques.

Another aspect of the present disclosure includes a pharmaceutical formulation of micronized progesterone, micronized progesterone with partially

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61186.00816 solubilized progesterone, and fully solubilized progesterone, wherein said formulation may provide increased progesterone bioavailability in a treated subject compared to the bioavailability provided by Prometrium® when administered at equal dosage strengths.

In illustrative embodiments, total progesterone, i.e., dissolved and micronized, is 20 to 50 wt%, e.g., 30 to 35 wt%, based on the weight of the entire fill, i.e., the liquid pharmaceutical formulation.

Other embodiments disclosed herein further provide: more uniform dissolution of progesterone, and reduced intra- and inter-patient blood level variability in formulations of progesterone of the present disclosure, when compared to equal dosages of PROMETRIUM. Blood level variability is also compared at equal sampling times following administration.

According to the PROMETRIUM prescribing information, clinical trials have shown significant patient variability. For example, a clinical trial involving postmenopausal women who were administered PROMETRIUM once a day for five days resulted in the mean PK parameters listed in the following table:

In particular illustrative aspects and embodiments of this invention, it is possible, though not necessary, to reduce the standard deviations in one or more of these PK parameters.

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61186.00816 More uniform dissolution of progesterone in a formulation of the present disclosure compared to the dissolution of PROMETRIUM at equal dosage strengths and using the same USP apparatus can be determined using standard techniques established for API dissolution testing, including that which is described in the examples below.

Reduced intra- and inter-patient variability of progesterone formulated pursuant to the present disclosure compared to PROMETRIUM can be demonstrated via a fed bio-study such as that described below.

Other aspects of the present disclosure include the use of formulations as described herein wherein progesterone is at least one API in said formulation for the treatment of an animal, especially a mammal, including humans: for endometrial hyperplasia; for secondary amenorrhea; as a method of treatment for preterm birth, when said animal has a shortened cervix, and other disease states or conditions treated with supplemental progesterone (collectively, "Progesterone-deficient States") in a subject in need of treatment, and with a non- toxic effective amount of said formulations. As used herein, the term "treatment", or a derivative thereof, contemplates partial or complete inhibition of the stated disease state when a formulation as described herein is administered

prophylactically or following the onset of the disease state for which such formulation is administered. For the purposes of the present disclosure,

"prophylaxis" refers to administration of the active ingredient(s) to an animal especially a mammal, to protect the animal from any of the disorders set forth herein, as well as others.

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61186.00816 Exemplary dosage strengths for progesterone for use in the formulations described herein include, without limitation, 25, 50, 75, 100, 125, 150, 175, 200 mg, 250 mg, 300 mg, 350 mg and 400 mg.

Progesterone active pharmaceutical ingredient may be micronized via any one of the multiple methods typically utilized by the ordinarily skilled artisan.

Particle size may be determined in any suitable manner. For example, a

Beckman Coulter LS 13 320 Laser Diffraction Particle Size Analyzer (the

"Beckman Device") may be used to determine particle size. Particle size may be represented by various metrics, for example, through an X50 particle size, and/or X90 particle size, or similar descriptions of particle size.

The Beckman Device may be used with various modules for introducing a sample for analysis. The Beckman Device may be used with the LS 13 320 Universal Liquid Module ("ULM"). The ULM is capable of suspending samples in the size range of 0.017 μιη to 2000 μιη. The ULM is a liquid based module that allows for delivery of the sample to the sensing zone. The ULM recirculates the sample through the Beckman Device. The ULM comprises two hoses, one for fluid delivery and another for waste. The total volume used may be 125 mL or less. A sample mass of from about 1 mg to about 10g may be used. The ULM may interact with the Beckman Device via pins that fit into slots on the ULM. The ULM may use a variety of suspension fluids, for example, water, butonol, ethanol, chloroform, heptanes, toluene, propanol, COULTER Type 1 B Dispersant

("Coulter 1 B"), and a variety of other suspension fluids. Surfactants may also be used, though pump speed should be adjusted to prevent excessive bubbling. Coulter 1 B may comprise one or more of acetaldehyde, ethylene oxide, and/or

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61186.00816 1 ,4-dioxane. The Beckman Device may be configured to use a variety of optical theories, including the Fraunhofer optical model and the Mie Theory.

The Beckman Device may comprise software to control the Beckman Device while the ULM is in use. The software may control, for example, pump speed, use of de-bubble routine, rinse routine, sonicate routine, and fill routine, among others. Parameters regarding the sample run may also be configured. For example, run length may be set. Though any suitable run length may be used, in various embodiments, a time period of 30 seconds to 120 seconds, and preferably between 30 seconds and 90 seconds may be used.

The Beckman Device may be used with the LS 13 320 Micro Liquid Module ("MLM"). The MLM is capable of suspending samples in the size range of 0.4 μιη to 2000 μιη. The MLM is a liquid based module that allows for delivery of the sample to the sensing zone. The MLM includes a stirrer. The total volume used may be 12 mL or less. The MLM may use a variety of suspension fluids, both aqueous and non-aqueous.

In various embodiments, ultra-micronized progesterone has an X50 value of less than about 15 microns, less than about 10 microns, less than about 5 microns and/or less than about 3 microns; and an X90 value of less than about 25 microns, less than about 20 microns, and/or less than about 15 microns.

In various embodiments, ultra-micronized progesterone is formulated with peanut and peanut-oil free excipients.

In various embodiments, the carrier is selected to enhance dissolution and suspension properties of progesterone. In further various embodiments, the carrier is selected to enhance absorption of the API by cells of a mammal. For example, certain carriers may be selected to enhance absorption of the other

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61186.00816 formulation components, including the API. Absorption may comprise absorption into any cell and particularly absorption into digestive system cells, such as intestinal cells, and cells of the female reproductive system, such as the vagina and the cervix. Selected mono/di/triglyercides are particularly suited to aid in cellular absorption

In various embodiments, the carrier may comprise medium chain fatty acids. Suitable carriers include caproic fatty acid; caprylic fatty acid;capric fatty acid; lauric acid; myristic acid; linoleic acid; succinic acid; glycerin; propylene glycol; caprylic/capric triglycerides; caproic/caprylic/capric/lauric triglycerides; caprylic/capric/linoleic triglycerides; caprylic/capric/succinic triglycerides;

polyethylene glycol; propylene glycol dicaprylate/dicaprate; and combinations and derivatives thereof.

Suitable carriers further include esters of saturated coconut and palm kernel oil and derivatives thereof, including fractionated coconut oils and palm kernel oils thereof; and triglycerides of fractionated vegetable fatty acids, and derivatives thereof and combinations thereof. In further various embodiments, the carrier may comprise one or more monoglycerides, diglycerides, triglycerides, and combinations thereof. Such a suitable carrier is available commercially under the trademark M IGLYOL (caprylic/capric triglyceride) (Sasol Germany, GmbH). MIGLYOL products comprise esters of saturated coconut and palm kernel oil-derived caprylic and capric fatty acids, glycerin and/or propylene glycol. Suitable M IGLYOL products include MIGLYOL 810 (Caprylic / Capric

Triglyceride)MIGLYOL 812 (Caprylic / Capric Triglyceride), MIGLYOL 818 (Caprylic / Capric/Linoleic Triglyceride) and M IGLYOL 829 (Caprylic /

Capric/Succinic Triglyceride).

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61186.00816 Additional examples include a polyethylene glycol glyceride (Gelucire®;

GATTEFOSSE SAS, Saint-Priest, France); a propylene glycol; a

caproic/caprylic/capric/lauric triglyceride; a caprylic/capric/linoleic triglyceride; a caprylic/capric/succinic triglyceride; propylene glycol monocaprylate; propylene glycol monocaprate; (Capmul® PG-8 and 10; the CAPMUL brands are owned by ABITEC, Columbus Ohio); propylene glycol dicaprylate; propylene glycol dicaprylate; medium chain mono- and di-glycerides (CAPMUL MCM); a diethylene glycol mono ester (including 2-(2-Ethoxyethoxy)ethanol: Transcutol); diethylene glycol monoethyl ether; esters of saturated coconut and palm kernel oil and derivatives thereof; triglycerides of fractionated vegetable fatty acids, and combinations and derivatives thereof. In other aspects and embodiments, progesterone is fully solubilized using, for example and without limitation, sufficient amounts of: TRANSCUTOL (Diethylene glycol monoethyl ether)and MIGLYOL; TRANSCUTOL, MIGLYOL and CAPMUL PG-8 (Propylene Glycol Monocaprylate) and/or CAPMUL PG-10 (Propylene Glycol Monocaprate);

CAPMUL MCM (Medium Chain Mono- and Diglycerides); CAPMUL MCM and a non-ionic surfactant; and CAPMUL MCM and GELUCIRE (a polyethylene glycol glyceride).

Various ratios of these oils can be used for suspension and/or

solubilization of progesterone. CAPMUL MCM and a non-ionic surfactant, e.g., GELUCIRE 44/14 (LauroyI macrogol-32 glycerides EP LauroyI polyoxyl-32 glycerides NF LauroyI polyoxylglycerides (USA FDA IIG)) , can be used at ratios of about 99:1 to 2:1 , including, for example and without limitation: 60:40, 65:35, 70:30, 75:25, 80:10, 80:15, 85:20, 90: 10, and 98:1 . The ratios of oil (e.g., medium chain fatty acid esters of monoglycerides and diglycerides) to non-ionic surfactant

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61186.00816 can be significantly higher. For example, in certain examples, below, CAPMUL MCM and GELUCIRE were used in ratios of up to about 65:1 , e.g., 8: 1 , 22:1 , 49:1 , 65:1 and 66:1 . Thus, useful ratios can be, e.g., 8:1 or greater, e.g., 60 to 70:1 .

Combinations of these oils can produce partially solubilized progesterone, depending upon the desired unit dosage amount of progesterone. The greater the amount of progesterone per unit dosage form, the less progesterone may be solubilized. The upward limit of dosage strength per unit dose it generally limited only by the practical size of the final dosage form.

In illustrative embodiments, oils used to suspend, partially solubilize, or fully solubilize progesterone include medium chain fatty acid esters, (e.g., esters of glycerol, polyethylene glycol, or propylene glycol) and mixtures thereof. In illustrative embodiments, the medium chain fatty acids are C6 to C14 or C6 to C12 fatty acids. In illustrative embodiments, the medium chain fatty acids are saturated, or predominantly saturated, e.g., greater than about 60% or greater than about 75% saturated. In illustrative embodiments, progesterone is soluble in the oils at room temperature, although it may be desirable to warm certain oils initially during manufacture to improve viscosity. In illustrative embodiments, the oil or oil/surfactant is liquid at between room temperature and about 50°C, e.g., at or below 50°C, at or below 40°C, or at or below 50°C. In illustrative

embodiments, GELUCIRE 44/14 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 or progesterone.

In illustrative embodiments, the solubility of estradiol in the oil (or oil/surfactant) is at least about 0.5 wt%, e.g., 0.8 wt% or higher, or 1 .0 wt% or

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61186.00816 higher. Illustrative examples of mono- and diglycerides of medium chain fatty acids include, among others, CAPMUL MCM, CAPMUL MCM C10 (Glyceryl Monocaprate) , CAPMUL MCM C8 (Glyceryl Monocaprylate), and CAPMUL MCM C8 EP (Glyceryl Monocaprylate). These oils are C8 and C10 fatty acid mono- and diglycerides. Illustrative examples of oils that are triglycerides of medium chain fatty acids include, among others, MIGLYOL 810 and MIGLYOL 812.

Illustrative examples of oils that are medium chain fatty acid esters of propylene glycol include, among others, CAPMUL PG-8, CAPMUL PG-2L EP/NF (Propylene Glycol Dilaurate), CAPMUL PG-8 NF (Propylene Glycol

Monocaprylate), CAPMUL PG-12 EP/NF (Propylene Glycol Monolaurate)and CAPRYOL (Propylene glycol monocaprylate (type II) NF). Other illustrative examples include M IGLYOL 840 (Propylene Glycol Dicaprylate / Dicaprate).

Illustrative examples of oils that are medium chain fatty acid esters of polyethylene glycol include, among others, GELUCIRE 44/14 (PEG-32 glyceryl laurate EP), which is polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol. Without intending to be bound to any particular mechanism, it appears that at least in formulations comprising small amounts of GELUCIRE, e.g., 10 wt% or less, the primary function of this oil is as a non-ionic surfactant.

These illustrative examples comprise predominantly medium chain length, saturated, fatty acids, specifically predominantly C8 to C12 saturated fatty acids.

It will be understood that commercially available fatty acid esters of glycerol and other glycols are often prepared from natural oils and therefore may comprise components additional to the fatty acid esters that comprise the

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61186.00816 predominant (by weight) component(s) and that therefore are used to

characterize the product. Such other components may be, e.g., other fatty acid triglycerides, mono- and diesters, free glycerol, or free fatty acids. So, for example, when an oil/solubilizing agent is described herein as a saturated C8 fatty acid mono- or diester of glycerol, it will be understood that the predominant component of the oil, i.e., >50 wt% (e.g., >75 wt%, >85 wt% or >90 wt%) are caprylic monoglycerides and caprylic diglycerides. For example, 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% C10, and <= 1 .5% C12 and higher.

By way of further example, MIGLYOL 812 is generally described as a C8- C10 triglyceride because the fatty acid composition is at least about 80% caprylic (C8) acid and capric (C10) acid. However, it can also comprise small amounts of other fatty acids, e.g., less than about 5% of caproic (C6) acid, lauric (C12) acid, and myristic (C14) acid.

Specifically, a product information sheet for MIGLYOL by SASOL provides the composition of fatty acids as follows:

Tests 810 812 818 829 840

Caproic acid max. 2,0 max. 2,0 max. 2 max. 2 max. 2

Caprylic acid 65,0 - 80,0 50,0 - 65,0 45 - 65 45 - 55 65 - 80

Capric acid 20,0 - 35,0 30,0 - 45,0 30 - 45 30 - 40 20 - 35

Laurie acid max. 2 max. 2 max. 3 max. 3 max. 2

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61186.00816 Myristic acid max. 1 ,0 max. 1 ,0 max. 1 max. 1 max. 1 (C14:0)

Linoleic acid 2 - 5

(C18:2)

Succinic acid - - 15 - 20 -

Where certain embodiment of this invention are described as comprising (or consisting essentially of) a capsule shell, estradiol solubilized in C8-C10 triglycerides, and a thickening agent, it will be understood that the fatty acid esters component of the formulation may be, e.g., MIGLYOL 812 or a similar product.

By way of further illustration, GELUCIRE 44/14 is generally described as lauroyl polyoxyl-32 glycerides, i.e., polyoxyethylene 32 lauric glycerides (which is a mixture of mono-, di-, and triesters of glycerol and mono- and diesters of PEGs) because the fatty acid composition is 30 to 50 % lauric acid and smaller amounts of other fatty acids, e.g., up to 15 % caprylic acid, up to 12% capric acid, up to 25% myristic acid, up to 25% palmitic acid, and up to 35% stearic acid. The product may also contain small amounts of non-esterified glycols. Where certain embodiment of this invention are described as comprising (or consisting essentially of) a capsule shell, estradiol solubilized in triglycerides, and a thickening agent that is a non-ionic surfactant comprising C8 to C18 fatty acid esters of glycerol and polyethylene glycol, it will be understood that the thickening agent component of the formulation may be, e.g., GELUCIRE 44/14 or a similar product.

Similarly, where certain embodiment of this invention are described as comprising (or consisting essentially of) a capsule shell, estradiol solubilized in

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61186.00816 triglycerides, and a thickening agent that is a non-ionic surfactant comprising

PEG-6 stearate, ethylene glycol palmitostearate, and PEG-32 stearate, it will be understood that the thickening agent component of the formulation may be, e.g., TEFOSE 63 (PEG-6 palmitostearate and ethylene glycol palmitostearate) or a similar product.

In illustrative embodiments of the invention, the selected oil does not require excessive heating in order to solubilize progesterone. For example, when the formulation comprises medium chain fatty acid mono- and diglycerides (e.g., CAPMUL MCM) and polyethylene glycol glycerides (e.g., GELUCIRE) as a surfactant, the oil and/or the surfactant can be warmed up, e.g., to about 65 C in the case of the surfactant and less in the case of the oil, to facilitate mixing of the oil and surfactant. The progesterone can be added as the mixture cools, e.g., to below about 40 C or to below about 30 C, even down to room temperature.

In certain embodiments, an anionic and/or a non-ionic surfactant is used. Exemplary non-ionic surfactants may include one or more of glycerol and polyethylene glycol esters of fatty acids, for example, lauroyl macrogol-32 glycerides and/or lauroyl polyoxyl-32 glycerides, commercially available as GELUCIRE, including, for example, GELUCIRE 44/1 1 and GELUCIRE 44/14. These 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 certain examples, below, GELUCIRE 44/14 is used as a surfactant in amounts of 1 to 10 wt%. See, Tables below. Other non-ionic surfactants include, e.g., LABRASOL (CaprylocaproyI macrogol-8 glycerides EP CaprylocaproyI polyoxyl-8 glycerides NF PEG-8 Caprylic/Capric Glycerides (USA FDA IIG))(Gattefosse) and LABARAFIL ( corn/apricot oil PEG-6 esters) (Gattefosse).

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61186.00816 In various embodiments, a lubricant is used. Any suitable lubricant may be used, such as, for example and without limitation, lecithin, and in various embodiments, a mixture of polyethylene glycol ("PEG") esters, glycerides, and PEG, such as is commercially available under the trade name GELUCIRE (Gattefosse, FR) may also be used as a lubricant. Suitable lubricants may also comprise calcium stearate, ethyl oleate, ethyl laureate, glycerin, glyceryl palmitostearate, hydrogenated vegetable oil, magnesium, oxide, magnesium stearate, poloxamer, glycols, and phospholipid mixtures. In particular, a mixture of polyethylene glycol esters, glycerides, and PEG such as GELUCIRE 44/14, may be used as a lubricant. GELUCIRE 44/14 is a non-ionic water dispersible surfactant, also known as lauroyl macrogol-32 glycerides EP and lauroyl polyoxyl-32 glycerides NF. In various embodiments, GELUCIRE 44/14 acts as a suspension agent.

In various embodiments, an antioxidant is used. Any suitable antioxidant may be used, such as, for example and without limitation, butylated

hydroxytoluene. Butylated hydroxytoluene, a derivative of phenol, is lipophilic and is thus suited to being intermixed with ultra-micronized progesterone and carriers disclosed or contemplated herein.

For example, in various embodiments, a pharmaceutical formulation comprises about 20% to about 80% carrier by weight, about 0.1 % to about 5% lubricant by weight, and about 0.01 % to about 0.1 % antioxidant by weight.

The choice of excipient will, to a large extent, depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Excipients used in various embodiments may include colorants, flavoring agents, preservatives and taste-

21

61186.00816 masking agents. Colorants, for example, may comprise about 0.1 % to about 2% by weight. Preservatives may comprise methyl and propyl paraben, for example, in a ratio of about 10:1 , and at a proportion of about 0.005% and 0.05% by weight.

As is with all oils, solubilizers, excipients and any other additives used in the formulations described herein, each is to be non-toxic and pharmaceutically acceptable.

As referenced above, the formulations of the present disclosure are generally orally administered, typically via, for example, capsules such as soft capsules. The present formulations can also be used to form transdermal patches using standard technology known in the art. Solubilized formulations of the present invention can also be formulated for intraperitoneal administration using techniques well known in the art.

Thus, an illustrative embodiment of a pharmaceutical composition of the invention comprises progesterone, at least 75% of the progesterone being solubilized (the balance being micronized as discussed elsewhere herein), and an oil, wherein the oil is medium chain fatty acid mono- and diesters of one or more glycols, with or without surfactant. In certain embodiments, a specification for progesterone is set at >80% solubilized, <20% micronized or >85%

solubilized, <15% micronized.

Pharmaceutical formulations in accordance with various embodiments comprise ultra-micronized progesterone. In further embodiments, a

pharmaceutical formulation comprises ultra-micronized progesterone, a carrier, and a lubricant. In still further embodiments a pharmaceutical formulation comprises ultra-micronized progesterone, a carrier, a lubricant, and optionally an antioxidant. In still further embodiments, a pharmaceutical formulation comprises

22

61186.00816 ultra-micronized progesterone, and a medium chain triglyceride as a carrier. In still further embodiments, a pharmaceutical formulation comprises ultra- micronized progesterone, and monoglycerides/diglycerides/triglycerides of caprylic/capric acid as a carrier. Various further embodiments also comprise lecithin and optionally butylated hydroxytoluene.

In additional embodiments, a pharmaceutical formulation comprises ultra- micronized progesterone and at least one carrier, a lubricant, optionally an antioxidant, and other pharmaceutically acceptable excipients. For example, in various embodiments, a pharmaceutical formulation comprises about 20% to about 80% carrier by weight, about 0.1 % to about 5% lubricant by weight, and about 0.01 % to about 0.1 % antioxidant by weight.

The choice of excipient will, to a large extent, depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Excipients used in various embodiments may include colorants, flavoring agents, preservatives and taste- masking agents. Colorants, for example, may comprise about 0.1 % to about 2% by weight. Preservatives may comprise methyl and propyl paraben, for example, in a ratio of about 10:1 , and at a proportion of about 0.005% and 0.05% by weight.

Formulations in accordance with various embodiments may be

administered alone or combination with one or more other drugs (or as any combination thereof). For example, formulations in accordance with various embodiments may also comprise estradiol.

In various embodiments, ultra-micronized progesterone is administered in a capsule. Capsules may be prepared using one or more film forming polymers.

23

61186.00816 Suitable film forming polymers include natural polymers, such as gelatin, and synthetic film forming polymers, such as modified celluloses. Suitable modified celluloses include, but are not limited to, hydroxypropyl methyl cellulose, methyl cellulose.

Hard or soft shell capsules can be used to administer the API. In certain embodiments, capsules may be prepared by forming the two capsule halves, filling one of the halves with the fill solution, and then sealing the capsule halves together to form the finished capsule.

Hard shell capsules may be prepared by combining the "Body" and the "Cap". The "Body" of the capsule is filled with the "fill mass" and then closed with the "Cap". The "Body'V'Cap" interface is then sealed/banded.

Soft gelatin capsules may be prepared using a rotary die encapsulation process, as further described below.

Suitable shell additives, for either a hard or soft shell capsules, may include plasticizers, opacifiers, colorants, humectants, preservatives, flavorings, and buffering salts and acids, and combinations thereof. The main ingredients of the capsule shell is primarily gelatin (or a gelatin substitute for non-gelatin capsules), plasticizer, and purified water. Hard shell and soft shell capsules differ primarily in the amount of plasticizer present that is used in the capsule shell.

Plasticizers are chemical agents added to gelatin to make the material softer and more flexible. Suitable plasticizers include, but are not limited to, glycerin, sorbitol solutions which are mixtures of sorbitol and sorbitan, and other polyhydric alcohols such as propylene glycol and maltitol or combinations thereof.

24

61186.00816 Opacifiers are used to opacify the capsule shell when the encapsulated active agents are light-sensitive. Suitable opacifiers include titanium dioxide, zinc oxide, calcium carbonate and combinations thereof.

Colorants can be used for marketing and product

identification/differentiation purposes. Suitable colorants include synthetic and natural dyes and combinations thereof.

Flavorings can be used to mask unpleasant odors and tastes of fill formulations. Suitable flavorings include synthetic and natural flavorings. The use of flavorings can be problematic due to the presence of aldehydes which can cross-link gelatin. As a result, buffering salts and acids can be used in conjunction with flavorings that contain aldehydes in order to minimize cross- linking of the gelatin.

In accordance with various embodiments, a softgel dosage form is used. A softgel comprises two primary phases: a gel capsule and a fill material. The softgel may comprise a gelatin material in a relatively solid or stiff form. The softgel may define an inner volume that may contain the fill material. Dissolution of the softgel may commence at various points, such as along the digestive tract (mouth, esophagus, stomach and intestines), or other body cavities, such as the vaginal cavity.

As the softgel dissolves, the inner volume may come into fluid

communication with the digestive system, allowing the fill material to leach outside the softgel. A softgel may also be punctured, cut, or otherwise opened outside a body. The fill material may then be poured or squeezed outside the gel capsule and applied on or in the body, such as within the vaginal cavity.

25

61186.00816 Humectants can be used to suppress the water activity of the softgel.

Suitable humectants include glycerin and sorbitol, which are often components of the plasticizer composition. Due to the low water activity of dried, properly stored softgels, the greatest risk from microorganisms comes from molds and yeasts. For this reason, preservatives can be incorporated into the capsule shell. Suitable preservatives include alkyl esters of p-hydroxy benzoic acid such as methyl, ethyl, propyl, butyl and heptyl esters (collectively known as "parabens") or combinations thereof.

The fill material may comprise a liquid, such as an oil, a solution, a suspension, or other acceptable forms. The active ingredient or active ingredient may be contained within the liquid.

Formulations in accordance with various embodiments may be

administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.

Ultra-micronized progesterone in accordance with various embodiments may be formulated as a vaginal suppository or vaginal cream for administration onto the vulva or into the vagina, cervix, or uterus of a human. Capsules (e.g., softgels) containing ultra-micronized progesterone also may be administered vaginally, including insertion of a capsule directly into the vaginal cavity or delivery of such capsule contents into the vaginal cavity. Ultra-micronized progesterone, in accordance with various embodiments, may be formulated for intraperitoneal administration, and atomization, such as with nasal mist administration.

26

61186.00816 In accordance with various embodiments, enhanced bioavailability of progesterone is provided, such as over conventional progesterone formulations wherein it is well known that commercially available formulations of progesterone are poorly or inconsistently absorbed. While not bound by theory, the elements of the present formulation provide the enhanced performance characteristics as further described herein, including, for example and without limitation, improved bioavailability and the potential to be able to reduce the administered dosage strength compared to presently available progesterone formulations.

Bioavailability comparisons to commercially available forms, such as tablet forms, may be determined by standard pharmacokinetic techniques

In accordance with various embodiments, food effects are reduced, e.g., relative to comparative progesterone products.

In accordance with various embodiments, formulations do not include peanut oil. The lack of peanut oil obviates the risk posed to those having peanut- based allergies.

Capsules may be arranged in blisters or cartridges or bottles.

According to various embodiments, a 28-day or monthly regimen of capsules can be packaged in a single kit (e.g., a blister pack) having delivery days identified to improve compliance and reduce associated symptoms, among others. One or more of the capsules may contain no estradiol, for example, and/or no progesterone. Capsules that comprise no API or hormone (e.g., progesterone) may be referred to as placebos. A blister pack can have a plurality of scores or perforations separating blister pack into 28 days. Each day may further comprise a single blister or a plurality of blisters. In various embodiments, each dose (e.g.., each softgel) may contain ultra-micronized progesterone in

27

61186.00816 amounts of 100 mg, 150 mg, 200 mg, and 250 mg, though other dose ranges are contemplated herein. In addition, kits having other configurations are also contemplated herein. For example, without limitation, kits having such blister packs may contain any number of capsules.

Formulations in accordance with various embodiments may be used to treat or prevent preterm delivery in pregnant women, including in certain women having a shortened cervix. In various embodiments, a capsule, for example a softgel capsule, may be opened and the fill material applied in or around the vagina. However, in various embodiments the capsules are taken orally.

Formulations in accordance with various embodiments may be used to treat or prevent endometrial hyperplasia.

Formulations in accordance with various embodiments may be used to treat or prevent secondary amenorrhea.

Formulations in accordance with various embodiments may be used to mitigate or treat the effects of estradiol supplementation. In particular,

formulations in accordance with various embodiments may be co-administered with estradiol and/or co-formulated with estradiol.

Formulations in accordance with various embodiments may be used to treat menopause-related symptoms, including vasomotor symptoms, for example, in relation to treatment of hypoestrogenism related symptoms including hot flashes and night sweats (vasomotor symptoms), sleep disturbances, mood changes, vulvo-vaginal atrophy; and osteoporosis and endometrial hyperplasia reduction.

Additional objects of the present disclosure include: providing increased patient compliance secondary to ease of use; providing increased physician

28

61186.00816 adoption secondary to ease of use/instruction with less worry of side effects from inappropriate usage; providing decreased side-effects from erroneous use (decreased irregular bleeding); providing better efficacy/control of symptoms secondary to appropriate use; reducing the metabolic and vascular side effects of the commonly used synthetic progestins when administered alone or in combination with an estrogen (norethindrone acetate, medroxyprogesterone acetate, etc.) including, for example, stroke, heart attacks, blood clots and breast cancer.

Specific Embodiments

Through extensive trial-and-error testing of various fatty acid esters of glycerol and other glycols, embodiments of the invention have been invented that have one or more favorable characteristics for development as a human drug product. Such favorable characteristics include those described above, e.g., improved PK and reduced variability.

Such embodiments include an encapsulated liquid pharmaceutical formulation for orally administering progesterone to a mammal in need thereof, said formulation comprising: progesterone, as the sole active pharmaceutical ingredient, in micronized form suspended in a carrier that comprises a medium chain fatty acid-glycol ester or mixtures thereof and a non-ionic surfactant comprising a polyethylene glycol fatty acid ester.

A more specific such embodiment is such formulation wherein the progesterone is ultramicronized.

In certain such embodiments, the progesterone is suspended and/or solubilized in one or more C6 to C12 fatty acid mono-, di-, or triesters of glycerol, e.g., one or more C6 to C14 triglycerides, e.g., one or more C6 to C12

29

61186.00816 triglycerides, such as one or more C8-C10 triglycerides. An example of a carrier that provides beneficial properties is C8, C10, or C8 and C10 saturated triglycerides, such as but not limited to M IGLYOL, e.g., MIGLYOL 812.

In such general and more specific embodiments, the non-ionic surfactant is a polyethylene glycol saturated or unsaturated fatty acid ester or diester. In certain such embodiments, the non-ionic surfactant comprises C8 to C18 fatty acid esters of glycerol and polyethylene glycol. An example of a non-ionic surfactant that provides beneficial properties is GELUCIRE, e.g., GELUCIRE 44/14.

In certain such embodiments, the non-ionic surfactant has a HLB value of about 15. An illustrative example of such surfactant is GELUCIRE 44/14.

As noted above, such formulations are liquid at room temperature, not gels, hard fats, or any other solid form. The non-ionic surfactant serves to increase viscosity. In some such embodiments, the non-ionic surfactant, e.g., GELUCIRE or TEFOSE, may be solid at room temperature and require melting to effect mixing with the estradiol solubilized in fatty acid-glycol esters but the resultant formulation is advantageously liquid, not solid.

The formulation of such embodiments is typically encapsulated in a soft gelatin capsule or other soft capsule.

Typically, such formulations do not comprise a bioadhesive (i.e., muco- adhesive) agent, a gelling agent, or a dispersing agent, or, at least, do not comprise one or two of such components.

In more specific such formulations, the capsule shell, the active pharmaceutical ingredient, the fatty acid esters and the non-ionic surfactant are the only essential ingredients. Non-essential ingredients, e.g., colorants,

30

61186.00816 antioxidants or other preservatives, etc., may, of course, be included but other ingredients in amounts that would materially change the solubility of the progesterone, the PK of the encapsulated formulation, or other clinically relevant properties, e.g., other oils or fatty acid esters, lecithin, muco-adherent agents, gelling agents, dispersing agents, or the like would not be included. Such embodiments of the invention may be described as consisting essentially of the capsule shell, the active pharmaceutical ingredient, the fatty acid esters and the non-ionic surfactant, as described in the immediately preceding paragraphs describing illustrative embodiments discovered to have favorable characteristics.

As an example of such embodiments discovered to have such favorable characteristics is mentioned the product identified in Example 2, Table 3, below.

EXAMPLES

Example 1

In an exemplary embodiment, a capsule is provided containing a fill material comprising:

TABLE 2

31

61186.00816 referred to as "BHT^") ; | ;

The above formulation is prepared as follows: MIGLYOL is heated to about 45°C. GELUCIRE 44/14 is added and mixed until dissolved. BHT is added and mixed until dissolved. Progesterone is suspended and passed through a colloid mill. The resultant fill mass can be used for encapsulation.

Example 2

TABLE 3

In various embodiments, amounts of MIGLYOL may be present in a range from about 35-95% by weight; GELUCIRE 44/14 from about 0.5-30% by weight; and BHT from about 0.01 -0.1 % by weight.

Example 3

Progesterone Solubility

In various embodiments, both estradiol and progesterone may be dissolved in a solvent. In various embodiments, the solubility of both estradiol and progesterone will be such that a therapeutically effective dose may be obtained in a reasonably sized mass, generally considered to be between 1 mg

32

61186.00816 and 1200mg, preferably suitable for encapsulation in a size 3 to 22 oval or oblong capsule. For example, in various embodiments, 50mg to 100mg of progesterone may be dissolved in a volume of solvent; i.e., the solubility would be 50mg to 100 mg per capsule. MIGLYOL was attempted, and while it can be considered a good carrier for progesterone, it alone did not provide a desirable level of solubilization of estradiol (e.g., solubility of 12 mg/g may be desirable in various embodiments). Thus, MIGLYOL, including without limitation M IGLYOL 812, may be used in embodiments comprising a suspension of progesterone.

As can be seen in Table 9, the solubility of progesterone in CAPMUL MCM is -73 mg/g. Therefore, by suspending 200 mg progesterone in 400 mg of solvent, part of the dose (-14%) is already dissolved and the remaining is still a suspension. In some aspects and embodiments, it is desired to minimize the partial solubility of progesterone in the formulation in order to minimize the possibility of recrystallization.

Based on 73 mg/g solubility, the capsule size required to make a capsule of 50 mg solubilized progesterone would be 685 mg.

TABLE 4

33

61186.00816 GELUCIRE 44/14 (6:3)

In addition, it has been found that the solubility of progesterone in a solvent of CAPMUL MCM in combination with GELUCIRE 44/14 in a 9:1 ratio increases the solubility to approximately 86 mg/g. Therefore, in various embodiments, progesterone and/or estradiol may be dissolved in a CAPMUL MCM and GELUCIRE 44/14 system, wherein the ratio of CAPMUL MCM to GELUCIRE 44/14 is 9:1 .

TABLE 5

Example 4

In an exemplary embodiment, a capsule is provided containing a fill material having suspended progesterone comprising:

TABLE 6

34

61186.00816 (M IGLYOL 812 or

equivalent)

Lecithin Liquid 1 .63 I 0.25 Lubricant/

Emulsifier

Butylated 0.13 I 0.02 Antioxidant

Hydroxytoluene (also

referred to as "BHT")

The above formulation is prepared as follows: MIGLYOL is heated to about 45°C. GELUCIRE 44/14 is added and mixed until dissolved. BHT is added and mixed until dissolved. Progesterone is suspended and passed through a colloid mill. The resultant fill mass can be used for encapsulation. In an exemplary embodiment, a capsule is provided containing a fill material having partially solubilized progesterone comprising:

TABLE 7

Ingredient Qty/Caps % w/w Qty/Capsule I Amount/Batch ule (mg) (mg) (kg)

Micronized 200.00 33.33 Active I 2.0

Progesterone, USP

Monoglycerides/digly 394.0 65.67 Carrier I 3.94 cerides/triglycerides

of ca pry lie/cap e acid

(CAPMUL MCM)

Lauroyl polyoxyl-32- 6.0 1 Lubricant/ I 0.06

35

61186.00816

For suspensions of progesterone and partially solubilized progesterone, GELUCIRE 44/14 may be added at 1 % to 2% w/w to increase viscosity. The above formulation is prepared as follows: CAPMUL MCM is heated to about 65°C. GELUCIRE 44/14 is added and mixed until dissolved. Heat is removed. Progesterone is added and the mixture is passed through a colloid mill. The resultant fill mass can be used for encapsulation.

EXAMPLE 5

TABLE 8

36

61186.00816 j Butylated Hydroxytoluene j 0.03 j 1 .95 Antioxidant j

Total j 100 I 650

EXAMPLE 6

Bioavailability Assessment - Fasted

A randomized single-dose oral bioequivalence study comparing 200 mg ultra-micronized progesterone capsule test product (T) and 200 mg

PROMETRIUM® (progesterone) capsules (Abbott Laboratories, Abbott Park, IL) reference product (R) is conducted. Subjects are administered a single 200 mg dose of either test product (T) or the reference product (R) under fasting conditions, for example, subjects fasted at least 10.0 hours prior to dosing. Blood is collected pre-dose and post-dose. Pre-dose samples are collected at approximately -01 .00, -00.50, and 00.00 hours. Post-dose samples are collected at approximately 01 .00, 02.00, 03.00, 04.00, 05.00, 06.00, 07.00, 08.00, 09.00, 10.00, 12.00, 18.00, 24.00, 36.00 and 48.00 hours. Standard meals are provided at 04.00, 09.00, 13.00, 25.00, 29.00, 33.00 and 37.00 hours post-dose.

Pharmacokinetic measurements are assessed including C_max, AUC and optionally T_max. Comparative bioavailability of the test product (T) and reference product are assessed.

Example 7

Bioavailability Assessment - Fed

37

61186.00816 The procedures for determining bioavailability under fasted conditions are repeated except that subjects are administered a single 200 mg dose of either test product (T) or reference product (R) immediately following a high fat meal, for example, within 30 minutes of dosing. Blood is collected pre-dose and post- dose. Pre-dose samples are collected at approximately -01 .00, -00.50, and 00.00 hours. Post-dose samples are collected at approximately 01 .00, 02.00, 03.00, 04.00, 05.00, 06.00, 07.00, 08.00, 09.00, 10.00, 12.00, 18.00, 24.00, 36.00 and 48.00 hours. Standard meals are provided at 04.00, 09.00, 13.00, 25.00, 29.00, 33.00 and 37.00 hours post-dose. Pharmacokinetic measurements are assessed including C_max, AUC and optionally T_max. Bioavailability of the test product (T) in reference to the reference product is assessed. The effect of food on the comparative bioavailability of the test product (T) and the reference product (R) are also assessed.

Example 8

Method of manufacture in accordance with various embodiments are shown in Figures 1 -3. With reference to Figure 1 , method of fill material, i.e. fill mass, preparation 100 is shown. Step 102 comprises mixing a carrier, a lubricant, and an antioxidant as described herein. For example, lecithin and butylated hydroxytoluene may be mixed with one or more medium chain mono-, di- or triglycerides, or combinations thereof. Mixing may be facilitated by an impellor, agitator, or other suitable means. Step 102 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N₂. Mixing may be performed in any suitable vessel, such as a stainless steel vessel.

Step 104 may comprise mixing ultra-micronized progesterone into the mixture of the carrier, the lubricant, and the antioxidant. A pasty substance is

38

61186.00816 thus formed. Mixing may occur in a steel tank or vat. Mixing may be facilitated by an impellor, agitator, or other suitable means. Step 104 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N₂. Step 106 comprises degasing. The resulting mixture from step 106 may comprise a fill material suitable for production into a softgel capsule.

With reference to Figure 2, softgel capsule, i.e. gel mass, production 200 is shown. Step 202 comprises mixing glyercin with water. The water used in step 202 may be purified by any suitable means, such as reverse osmosis, ozonation, filtration (e.g., through a carbon column) or the like. Mixing may be facilitated by an impellor, agitator, or other suitable means. Step 202 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N₂. Heating may be performed until the temperature reaches 80°±5°C.

Step 204 comprises the addition of gelatin to the glycerin water mixture. Mixing may be facilitated by an impellor, agitator, or other suitable means. Step 204 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N₂. A vacuum may be drawn in step 204 to de-aerate.

Step 206 comprises addition of a coloring agent such as a dye. A coloring agent may comprise products sold under the trademark OPATINT or other suitable agent. Step 206 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N₂. Step 208 comprises degasing. The resulting mixture from step 208 may comprise a gel capsule material suitable for use as a gel capsule in production of a softgel capsule.

With reference to Figure 3, softgel capsule assembly process 300 is shown. Step 302 comprises heating the fill material. The fill material may be heated to any suitable temperature. In various embodiments, the fill material is

39

61186.00816 heated to 30°C +/- 3°C. Fill material maybe heated in a fill hopper. A fill hopper may comprise a device configured to hold a volume of the fill material and/or to dispense the fill material in controlled volumes.

Step 304 comprises filling a gel mass. A gel mass may be taken from the gel capsule material produced in step 208 of Figure 2. Filling may be performed by injecting, placing, or otherwise disposing the fill material within a volume defined by the gel capsule material. The filling may occur in an encapsulator. The spreader boxes may be a temperature of 55°C +/- 10°C. The wedge temperature may be 38°C +/- 3°C. The drum cooling temperature may be 4°C +/- 2°C. The encapsulator may be lubricated using M IGLYOL 812. Step 304 thus produces one or more softgel capsules. Filling may comprise producing a ribbon of thickness 0.85±0.05 mm using spreader box knobs. The fill material may be injected into the gel to produce a fill weight having target weight ± 5% (i.e., 650±33 mg and 325±16.3 mg).

Step 306 comprises drying the softgel capsules. Drying may be performed in a tumble dryer, tray dryer, or combinations thereof. For example, drying may be performed in a tumble drying basket for between about 10 minutes and about 120 minutes. Drying may continue in a drying room for about 24 hours to about 72 hours. Polishing may be performed with isopropyl alcohol.

Example 9

Stability Study

In accordance with various embodiments, formulations in accordance with various embodiments have an exemplary shelf life of 3 months with storage at 25±2°C/60±5%RH in 75 cc HDPE white, opaque bottles with a 38/400 mm white child resistant cap.

40

61186.00816 Packaging during testing comprises a 75cc round HDPE bottle and 33mm cap. A Brasken FPT 300F resin is associated with the cap. Testing criteria include visual appearance, assay of progesterone, dissolution, content uniformity and microbial limits testing.

Three test groups are created. Test group 1 comprises a test at

40°C/75%RH. Test group 2 comprises a test at 30°C/65%RH. Test group 3 comprises a test at 25°C/60%RH. Test group 1 is tested for visual appearance, assay of ultra-micronized progesterone, and dissolution at months 1 , 2, 3, and 6. Test group 2 is tested for visual appearance, assay of ultra-micronized

progesterone, and dissolution at months 0, 1 , 2, 3, 6, and 12. Test group 3 is tested for visual appearance, assay of ultra-micronized progesterone, and dissolution at months 0, 1 , 2, 3, 6, 12 and 24.

Example 10

A particle size analysis is conducted by using a Beckman Coulter LS 13 320 Laser Diffraction Particle Size Analyzer (the "Beckman Device"). The Beckman Device uses laser diffraction to determine particle size. A sample of a formulation in accordance with various embodiments is provided. The Beckman Device particle sensor yields that the sample has an X50 of 6.67 μιη, an X75 of 14.78 m, and an X25 of 2.193 μιη.

Example 1 1

A dissolution study was performed using a formulation in accordance with various embodiments. The results of the dissolution study are shown in Figure 4.

The dissolution study was performed using a United States

Pharmacopoeia dissolution apparatus 3 (reciprocating cylinder) ("USP Apparatus 3"). The USP Apparatus 3 was set to 30 dips per minute. Two hundred fifty mL

41

61186.00816 (250 mL) of a solution of.1 N HCL with 3% sodium lauryl sulfate was used at 37°C.

Figure 4 shows dissolution percentage in the y axis over time in minutes on the x axis. A formulation in accordance with various embodiments is shown having circular dots, and is labeled formulation 402. An existing commercial pharmaceutical product containing progesterone is shown having square dots and is labeled existing product 404. As shown in Figure 4, formulation 402 reaches a higher level of dissolution in a shorter time than existing product 404.

Example 12

For the purposes of this Example, a particle size analysis is conducted by using the Beckman Device. A sample API comprising micronized progesterone in accordance with various embodiments is provided for analysis.

Approximately 0.01 g of a sample API in accordance with various embodiments was combined with Coulter 1 B and 10 mL of deionized water. Sonication was performed for 15 seconds. The Beckman Device, equipped with a ULM, performed analysis for 90 seconds. The Beckman Device was configured to use the Fraunhofer optical model. The Beckman Device yielded that the sample has an X50 of 4.279 μιη, an X75 of 7.442 μιη, and an X25 of 1 .590 μιη. The Beckman Device also yielded that the mean particle size is 4.975 μιη, the median particle size is 4.279 μιη, the mode particle size is 6.453 μιη, and the standard deviation is 3.956 μιη. A graph of the particle distribution obtained is shown in Figure 5.

EXAMPLE 13

Study 352 - Progesterone and Estradiol Combination Study under Fed Conditions. This following study protocol was used to establish bio-availability and

42

61186.00816 bio-equivalence parameters for a combination product of the present disclosure comprising progesterone (200 mg) and estradiol (2.0 mg) as prepared via the process described in Example 14 and compared to 200 mg of PROMETRIUM® (Catalent Pharmaceuticals, St. Petersburg, FL (and 2.0 mg of ESTRACE

(estradiol vaginal cream, USP, 0.01 %) (Bristol-Myers Squibb Co. Princeton, NJ), administered to twenty-four (24) normal healthy, adult human post-menopausal female subjects under fed conditions.

The pharmaceutical formulation of the invention used in these PK studies had substantially the following formula:

The Study Design: An open-label, balanced, randomized, two-treatment, two-period, two-sequence, single-dose, two-way crossover study.

The subjects were housed in the clinical facility from at least 1 1 .00 hours pre-dose to at least 48.00 hours post-dose in each period, with a washout period of at least 14 days between the successive dosing days.

Subjects were fasted for at least about 10.00 hours before being served a high-fat, high-calorie breakfast, followed by dosing, then followed by a 04.00 hour, post-dose additional period of fasting.

43

61186.00816 Standard meals were provided at about 04.00, 09.00, 13.00, 25.00, 29.00,

34.00 and 38.00 hours post-dose, respectively.

Water was restricted at least about 01 hour prior to dosing until about 01 hour post-dose (except for water given during dosing). At other times, drinking water was provided ad libitum.

Subjects were instructed to abstain from consuming caffeine and/or xanthine containing products (i.e. coffee, tea, chocolate, and caffeine-containing sodas, colas, etc.) for at least about 24.00 hours prior to dosing and throughout the study, grapefruit and\or its juice and poppy containing foods for at least about 48.00 hours prior to dosing and throughout the study.

Subjects remained seated upright for about the first 04.00 hours post-dose and only necessary movements were allowed during this period. Thereafter subjects were allowed to ambulate freely during the remaining part of the study. Subjects were not allowed to lie down (except as directed by the physician secondary to adverse events) during restriction period.

Subjects were instructed not to take any prescription medications within 14 days prior to study check in and throughout the study. Subjects were instructed not to take any over the counter medicinal products, herbal medications, etc. within 7 days prior to study check-in and throughout the study.

After overnight fasting of at least about 10.00 hours, a high-fat high-calorie breakfast was served about 30 minutes prior to administration of investigational product(s). All subjects were required to consume their entire breakfast within about 30 minutes of it being served, a single dose of either test product (T) of Progesterone 200 mg & Estradiol 2 mg tablets or the reference product (R) PROMETRIUM® (Progesterone) soft gel Capsule 200 mg and ESTRACE®

44

61186.00816 (Estradiol) Tablets 2 mg (according to the randomization schedule) were administered with about 240 mL of water under fed condition, at ambient temperature in each period in sitting posture. A thorough mouth check was done to assess the compliance to dosing.

All dosed study subjects were assessed for laboratory tests at the end of the study or as applicable.

In each period, twenty-three (23) blood samples were collected. The pre- dose (10 mL) blood samples at -01 .00, -00.50, 00.00 hours and the post-dose blood samples (08 mL each) were collected at 00.25, 00.50, 00.67, 00.83, 01 .00, 01 .33, 01 .67, 02.00, 02.50, 03.00, 04.00, 05.00, 06.00, 07.00, 08.00, 10.00, 12.00, 18.00, 24.00 and 48.00 hours in labeled K2EDTA - vacutainers via an indwelling cannula placed in one of the forearm veins of the subjects. Each intravenous indwelling cannula was kept in situ as long as possible by injecting about 0.5 mL of 10 IU / mL of heparin in normal saline solution to maintain the cannula for collection of the post-dose samples. In such cases blood samples were collected after discarding the first 0.5 mL of heparin containing blood. Each cannula was removed after the 24.00 hour sample was drawn or earlier or if blocked.

At the end of the study, the samples were transferred to the bio-analytical facility in a box containing sufficient dry ice to maintain the integrity of the samples. These samples were stored at a temperature of -70°C ± 20°C in the bio-analytical facility until analysis.

Progesterone (Corrected and Uncorrected) and Estradiol (unconjugated) and estrone (total) in plasma samples is assayed using a validated LC-MS/MS method.

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61186.00816 The pharmacokinetic parameters Cmax, AUCO-t & AUC0-∞ were calculated on data obtained from 24 subjects for the test product and reference product. In general, bioavailability of progesterone and estradiol were similar but bioequivalence was not established.

Corrected pharmacokinetic profile summaries are presented in Table 9, below, for progesterone.

Table 9: Summary of Primary Pharmacokinetic Profile of Test Product (T) versus Reference Product (R) for Progesterone (Corrected)

*Estimate of Least Square Mean used to calculate Geometric

Mean

Study 351 - Progesterone and Estradiol Combination Study under Fasting Conditions.

Fasted studies using the above protocol and test and reference products were also conducted. However, rather than the high-fat meal prior to administration of the test and reference drug, each subject fasted for a period of at least twelve (12) hours prior to dose administration.

The pharmacokinetic parameters Cmax, AUCO-t & AUC0-∞ were calculated on data obtained from 23 subjects under fasting conditions for the test

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61186.00816 product and reference product. In general, bioavailability of progesterone and estradiol were similar but bioequivalence was not established.

Corrected pharmacokinetic profile summaries are presented in Table 10, below for progesterone.

Table 10: Summary of Primary Pharmacokinetic Profile of Test Product (T) versus Reference Product (R) for Progesterone (Corrected)

*Estimate of Least Square Mean used to calculate Geometric

Mean

The data indicate good (i.e., low) inter-patient and intra-patient variability relative to PROMETRIUM. EXAMPLE 14 Dissolution

Dissolution studies were performed using a formulation of this invention comparing the dissolution of progesterone to the dissolution of PROMETRIUM and comparing the dissolution of estradiol to the dissolution of Estrace. In one study, a formulation of the invention in capsules comprising 200 mg of progesterone and 2 mg estradiol was used. In a second study, a formulation of the invention in capsules comprising 50 mg of progesterone and 2 mg estradiol was used. The two formulations comprised:

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61186.00816 The dissolution study was performed using a USP dissolution apparatus

(reciprocating cylinder) ("USP Apparatus 3"). The apparatus was set to 30 dips per minute. 250 mL of a solution of 0.1 N HCI with 3% sodium lauryl sulfate was used at 37 C.

In both studies, progesterone was dissolved faster, and with smaller standard deviations, from the capsules of the invention than from PROMETRIUM. Dissolution of estradiol was comparable but marginally slower from the capsules of the invention than from Estrace. For illustrative purposes, a graph showing progestrone dissolution from the 200 mg progesterone capsule of the invention and from PROMETRIUM is attached as Figure 6.

Both capsules of the invention were stable on storage in white HDPE bottles. Positive stability data were obtained with the 200 mg progesterone formulation over 6 months (>6 months data unavailable) and with the 50 mg progesterone formulation over 3 months (>3 months data unavailable).

It will be apparent to those skilled in the art that various modifications and variations can be made in the present disclosure without departing from the spirit or scope of the disclosure. Thus, it is intended that the present disclosure cover the modifications and variations of this disclosure provided they come within the scope of the appended claims and their equivalents.

Likewise, numerous characteristics and advantages have been set forth in the preceding description, including various alternatives together with details of the structure and function of the devices and/or methods. The disclosure is intended as illustrative only and as such is not intended to be exhaustive. It will be evident to those skilled in the art that various modifications may be made, especially in matters of structure, materials, elements, components, shape, size

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61186.00816 and arrangement of parts including combinations within the principles of the disclosure, to the full extent indicated by the broad, general meaning of the terms in which the appended claims are expressed. To the extent that these various modifications do not depart from the spirit and scope of the appended claims, they are intended to be encompassed therein.

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61186.00816

Claims

WHAT IS CLAIMED IS:

1 . An encapsulated liquid pharmaceutical formulation for orally administering progesterone to a mammal in need thereof, said formulation comprising:

progesterone, as the sole active pharmaceutical ingredient, in micronized form, in solubilized form, or in micronized and partially soluble form in a carrier that comprises a medium chain fatty acid-glycol ester or mixtures thereof and a non- ionic surfactant comprising a polyethylene glycol fatty acid ester.

2. The formulation of claim 1 , wherein the progesterone is ultra-micronized.

3. The formulation of claim 1 , comprising micronized progesterone and partially solubilized progesterone.

4. The formulation of claim 2 which comprises micronized progesterone and partially solubilized progesterone and wherein at least about 80 wt% of the total progesterone is micronized and suspended.

5. The formulation of claim 3 or 4 wherein the fatty acids are predominantly (>50 wt%):

C6 to C12 fatty acids,

C6 to C10 fatty acids,

C8 to C12 fatty acids, or

C8 to C10 fatty acids.

6. The formulation of claim 5 wherein the progesterone is in:

one or more C6 to C14 fatty acid mono-, di-, or triesters of glycerol; or one or more C6 to C12 fatty acid mono-, di-, or triesters of glycerol; or one or more C6 to C14 fatty acid triesters of glycerol; or

one or more C6 to C12 fatty acid triesters of glycerol; or

one or more C8 to C10 fatty acid triesters of glycerol.

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61186.00816

7. The formulation of claim 4, wherein the non-ionic surfactant comprises C8 to C18 fatty acid esters of glycerol and polyethylene glycol.

9. The formulation of any of the preceding claims wherein the non-ionic surfactant comprises C8 to C18 fatty acid esters of glycerol and polyethylene glycol and has a HLB value of about 15.

10. The formulation of any of the preceding claims wherein the capsule is a soft gelatin capsule or other soft capsule.

1 1 . The formulation of any of the preceding claims that does not comprise at least one of a bioadhesive agent, a gelling agent, or a dispersing agent.

12. The encapsulated pharmaceutical formulation or any of the preceding claims that provides one or more of the following advantages:

increased bioavailability, compared to micronized progesterone suspended in peanut oil, more uniform distribution of progesterone in gastric juices, compared to micronized progesterone suspended in peanut oil, improved pharmacokinetics, compared to micronized progesterone suspended in peanut oil, reduced food effect, compared to micronized progesterone suspended in peanut oil, and provides more uniform distribution of progesterone in gastric juices, compared to micronized progesterone suspended in peanut oil.

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61186.00816

13. A method for preventing endometrial hyperplasia in a subject having a uterus, comprising administering to the subject a pharmaceutical formulation of any one of claims 1 through 1 1 .

14. A method for treating secondary amenorrhea in a subject, comprising administering to the subject pharmaceutical formulation of any one of claims 1 through 1 1 .

15. A method for preventing preterm birth in a pregnant subject, comprising administering to the subject a pharmaceutical formulation of any one of claims 1 through 1 1 .

16. A method of claim 15, wherein the pregnant subject has a shortened cervix.

17. A method for treating menopause-related symptoms, including vasomotor symptoms comprising administering to the subject a pharmaceutical formulation of any one of Claims 1 through 1 1 .

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61186.00816