EP3122364A1 - Formulations de progestérone - Google Patents

Formulations de progestérone

Info

Publication number
EP3122364A1
EP3122364A1 EP15768772.4A EP15768772A EP3122364A1 EP 3122364 A1 EP3122364 A1 EP 3122364A1 EP 15768772 A EP15768772 A EP 15768772A EP 3122364 A1 EP3122364 A1 EP 3122364A1
Authority
EP
European Patent Office
Prior art keywords
progesterone
pharmaceutical composition
solubilized
capsule
formulation
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.)
Withdrawn
Application number
EP15768772.4A
Other languages
German (de)
English (en)
Other versions
EP3122364A4 (fr
Inventor
Janice Cacace
Peter Persicaner
Thorsteinn Thorsteinsson
Frederick Sancilio
Julia Amadio
Brian Bernick
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
TherapeuticsMD Inc
Original Assignee
TherapeuticsMD Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by TherapeuticsMD Inc filed Critical TherapeuticsMD Inc
Publication of EP3122364A1 publication Critical patent/EP3122364A1/fr
Publication of EP3122364A4 publication Critical patent/EP3122364A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • A61P15/06—Antiabortive agents; Labour repressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • 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
    • A61P5/34—Gestagens

Definitions

  • progesterone formulations Various progesterone form u lations may be used in homione therapies for menopausal, peri -m enopau sal and postmenopausal females, for example, to mitigate side effects from estrogen replacement therapy.
  • various progesterone formulations may be used to prevent preterm delivery in pregnant women having a shortened cervix. Progesterone can likewise be used to treat endometrial hyperplasia and amenorrhea.
  • vaginal dryness vaginal odor
  • vulvar irritation itching
  • dysuria pain, burning or stinging when urinating
  • dysparuenia vaginal pain associated with sexual activity
  • vaginal bleeding associated with sexual activity it is not uncommon for pre -menopausal, peri -menopausal, menopausal, or postmenopausal females, to experience vaginal dryness, vaginal odor, vulvar irritation and itching, dysuria (pain, burning or stinging when urinating), dysparuenia (vaginal pain associated with sexual activity), or vaginal bleeding associated with sexual activity.
  • estrogens including estradiol
  • estradiol may lead to the symptoms and disorders previously mentioned.
  • progesterone administration is often a prophylactic method or prescribed treatment to prevent the negative effects of estrogens such as endometrial hyperplasias and related disorders.
  • HRT hormone replacement therapy
  • HRT Hormone replacement therapy
  • 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.
  • 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 embi ogenesis of humans and other species.
  • Progesterone belongs to a class of hormones called progestogens, and is the major naturally occurring human progestogen.
  • progesterone Like other steroids, progesterone consists of four interconnected cyclic hydrocarbons. Progesterone is hydrophobic, having a reported aqueous solubility of 0.007 ⁇ 0.0 mg/rnl. Progesterone is poorly absorbed when administered orally.
  • PROMETRIUM progesterone, USP
  • PROMETRIUM is an FDA-approved drug, formulated in a peanut oil-based medium, containing micronized progesterone, but with a relatively large particle size fraction.
  • the active ingredient in PROMETRIUM is considered to be structurally identical to naturally occurring progesterone produced by a woman's body (also known as a "bioidentical").
  • 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 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.
  • a new softgel progesterone pharmaceutical composition containing solubilized or partially solubilized progesterone, suspended progesterone, a soiubilizing agent, and a non-ionic surfactant.
  • compositions comprising ultra-mi cronized progesterone.
  • pharmaceutical formulations comprising formulations of ultra- micronized progesterone, wherein the ultra-micronized progesterone is combined with a suitable excipient.
  • the invention comprises an encapsulated liquid pharmaceutical formulation for oral ly administering progesterone to a mammal in need thereof, said formulation comprising: progesterone, as the sole active pharmaceutical ingredient.
  • the progesterone can be fully solubilized, or, more typically, partially solubilized, in a solubilizing agent, with any insoluble progesterone being suspended in the soiubilizing agent.
  • the solubilizing agent can comprise a medium chain fatty acid- polyolester or a mixture of medium chain fatty acid-polyol esters.
  • the polyol can be, for example, a glycol such as ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, etc.
  • the polyol can be a triol such as glycerol.
  • the glycol can be mono- or di-esterified with a given fatty acid (simple) or can be a mixed di-ester using different medium chain fatty acids.
  • the polyol is glycerol
  • the glycerol can be mono-, di-, or tri-esterified giving a monoglyceride, diglyceride, or triglyceride.
  • Typical di- and triglycerides are simple triglycerides, though in certain embodiments, the di- and triglycerides can be mixed.
  • the solubilizing agent can comprise a simple, mixed, or combination simple and mixed glycol di- ester.
  • the solubilizing agent can be a simple, mixed, or combination simple and mixed triglyceride.
  • the solubilizing agent can comprise an oil having simple and mixed triglycerides prepared from predominantly C8 and CIO fatty acids.
  • An example of such a triglyceride is MIGLYOL® 812.
  • the formulation can further comprise a non-ionic surfactant.
  • the non-ionic surfactant can compriseGELUQRE 44/14.
  • the progesterone is micronized or ultra-micronized. In certain 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 CIO fatty acids, C8 to C12 fatty acids, or C8 to CIO fatty acids.
  • Some embodiments comprise a non-ionic surfactant that comprises C8 to CI 8 fatty acid esters of glycerol and polyethylene glycol.
  • a softgel progesterone pharmaceutical composition as a hormone replacement therapy (HRT), or as a prophylactic method or a prescribed treatment to mitigate the associated symptoms associated with irregular or inadequate hormone levels is provided.
  • HRT hormone replacement therapy
  • 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.
  • 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.
  • Figure 6 illustrates a dissolution study of a formulation in accordance with various embodiments of the invention.
  • Figure 9 illustrates a graph that is a Linear Plot of Mean Plasma Progesterone (Uncorrected) Concentrations Versus Time (N ::: 62)
  • Figure 10 illustrates a graph that is a Semi-logarithmic Plot of Mean Plasma Pro esterone (Uncorrected) Concentrations Versus Time (NTM62)
  • a pharmaceutical formulation comprising progesterone and a solubilizing agent.
  • a pharmaceutical formulation comprising ultra- mi cronized progesterone is provided.
  • various solubilizing agents, lubricants, and other excipients may be included.
  • ultra- micronized progesterone formulations provide improved bioavailability and other pharmacokinetic improvements.
  • active pharmaceutical ingredient means the active compound(s) used in formulating a drag product.
  • the API is progesterone.
  • bioequivalent has the meaning prescribed in 21 CFR ⁇ 320.1(e), e.g. the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. Where there is an intentional difference in rate (e.g., in certain extended release dosage forms), certain pharmaceutical equivalents or alternatives may be considered bioequivalent if there is no significant difference in the extent to which the active ingredient or moiety from each product becomes available at the site of drug action.
  • bioidenticai or “natural” used in conjunction with the hormones disclosed herein, means hormones that are identical to or match the chemical stracture and effect of those that occur naturally or endogenously in the human bod)'.
  • An exemplary natural estrogen is estradiol.
  • drag product means at least one API in combination with at least one excipient, wherein the API and at least one excipient are provided in unit dosage form.
  • estradiol means generally the different hormone types of estrogen, synthetically or naturally occurring, including estradiol, estriol, and estrone.
  • estradiol means (17f3)-estra-l,3,5(10)-trieiie-3,17-diol, Estradiol is also called 17B-estradiol, oestradioL or E2 and is found endogenousiy in the human body, irrespective of the what it is called, estradiol refers to the bio-identical form of estradiol found in the human body having the structure:
  • Estradiol is supplied in an anhydrous or a hemi-hydrate form; for the purposes of this disclosure, 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.
  • equivalent dosage form refers to a dosage form that is identical to a reference dosage form in composition (e.g. identical solubi!izing agent(s), non- ionic surfactant(s), and API), but differs from the reference dosage form in the amount of API present or in the ratio of the various components in the reference dosage form.
  • composition e.g. identical solubi!izing agent(s), non- ionic surfactant(s), and API
  • ultra-micronized progesterone refers to rmcronized progesterone having an X50 particle size value below about 20 microns or having an X90 value below about 25 microns.
  • X50 means that half of the particles in a sample are smaller in diameter than a given number.
  • 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.
  • X90 means that ninety percent of the particles in a sample are smaller in diameter than a given number.
  • administer means oral administration of the formulation disclosed herein, preferably in a soft gelatin capsule.
  • glycolide is an ester of glycerol (1,2,3-propanetriol) with acyl radicals of fatty acids and is also known as an acvlglycerol. If only one position of the glycerol molecule is esterified with a fatty acid, a “monoglyceride” is produced; if two positions are esterified, a “diglyceride” is produced; and if all three positions of the glycerol are esterified with fatty acids, a "triglyceride” or “triacylglycerol” is produced, A giyceride is "simple” if all esterified positions contain the same fatty acid; whereas a giyceride 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.
  • 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 (CI 4) carbon atoms, 8 (C8) to 12 (CI 2) 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 carboxyiic 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 (one or more double bonds between carbon atoms).
  • 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, capryiic 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 and/or soiubilize bioidentical progesterone and/or estradiol, including starting materials and/or precursors thereof, including mieronized progesterone and/or micronized estradiol as described herein.
  • medium chain oi l refers to an oil wherein the composition of the fatty acid fraction of the oil is predominantly medium chain (i.e., C6 to C14) fatty acids, i.e., the composition profile of fatty acids in the oil is predominantly medium chain.
  • “predominantly” 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.
  • fatty acid- fraction of the oil is made up of medium chain fatty acids.
  • alkyl content or “alkyl distribution” of an oil can be used in place of the term "fatty acid fraction" of an oil in characterizing a given oil or soiubilizmg agent, and these terms are used interchangeable herein.
  • medium chain oils suitable for use in the formulations disclosed herein include medium chain oils wherein the fatty acid fraction of the oil is predominantly medium chain fatty acids, or medium chain oils wherein the alkyl content or alkyl distribution of the oi l 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.
  • ECN equivalent carbon number
  • ECN or "equivalent carbon number” means the sum of the number of carbon atoms in the fatty acid chains of an oil, and can be used to characterize an oil as, for example, a medium chain oil or a long-chain oil.
  • tripalmitin tripalmitic glycerol
  • Naturally occurring oils are frequently "mixed" with respect to specific fatty acids, but tend not to contain both long chain fatty acids and medium chain fatty acids in the same glycerol backbone.
  • triglycerides with ECN's of 21 -42 typically contain predominately medium chain fatty acids; while triglycerides with ECN's of greater than 43 typically contain predominantly long chain fatty acids.
  • the ECN of corn oil triglyceride in the USP would be in the range of 51-54.
  • Medium chain diglycerides with ECN's of 12-28 will often contain predominately medium chain fatty chains, while diglycerides with ECN's of 32 or greater will typically contain predominately long chain fatty acid tails.
  • onoglycerides will have an ECN that matches the chain length of its sole fatty acid chain.
  • monoglyceride 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.
  • USP US Pharmacopeia
  • the 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 EC of each individual component (e.g., C8 monoglycerics, 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.
  • patient refers to a human individual who has received, who might receive, or is receiving health or pharmaceutical care, or is under the supervision and care of a physician, pharmacist, or medically trained professional. This individual may be expecting this care, may be currently receiving it, or may have already received it.
  • progesterone refers to pregn-4 ⁇ ene-3,2Q-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, or 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. In particular embodiments, the progesterone is less than about 20%) solubilized. Solubility can be expressed as a mass fraction (%w/w, which is also referred to as wt%).
  • composition refers to a composition comprising at least a solubilizing agent and progesterone.
  • pharmaceutical compositions are delivered, for example via oral administration.
  • pharmaceutical composition and “formulation” are used interchangeably.
  • uniform distribution means at least one of uniform dispersion, solubility, or lack of agglomeration of progesterone in gastric juices compared to PROMETRIUM.
  • 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.
  • excipients refers to non-API substances such as solubilizing agents, anti -oxidants, oils, 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.
  • carrier means any substance or mixture of substances thai- may be mixed with or contain an API (e.g., ultra-micronized progesterone).
  • API e.g., ultra-micronized progesterone
  • carrier is interchangeable with solubilizing agent.
  • capsule refers to a generally safe, readily dissolvable enclosure for carrying certain pharmaceutical products, and includes hard or soft shell capsules.
  • 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 weight of the fill material does not exceed 500 mg, i.e. the fill material weighs less than 500 mg, less than 450 mg, less than 400 mg, less than 350 mg, less than 300 mg, less than 250 mg, less than 200 mg, or less than 150 mg.
  • bioavailability has the meaning prescribed in 21 CFR ⁇ 320.1(a): the rate and extent to which the active ingredient or active moiety is absorbed from a drag product and becomes available at the site of action.
  • bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.
  • bioavailability can be measured as the amoun t of API in the blood (serum or plasma) as a function of time.
  • Pharmacokinetic (PK) indicators such as AUC, Cnax, or T max may be used to measure and assess bioavailability.
  • Absorption as used in this definition can include absorption in the stomach, intestines, or other tissue that help facili tate absorption of the A PI into the bloodstream.
  • co-administered means that two drag products are administered simultaneously or sequentially on the same or different days.
  • PK parameters refers to parameters or measures used to assess bioavailability such as AUG, C max , or T max include assessments and determinations to study absorption, distribution, metabolism, and excretion of a drug.
  • RTD reference listed drug product
  • PROMETRIUM progesterone, USP
  • PROMETRIUM is an FDA- approved drug, formulated in a peanut oil-based medium, containing micronized progesterone, but with a relatively large particle size fraction.
  • secretory activity refers to complete and partial secretory activity of the endometrium as is well understood in the art and as is discussed at length in Noyes, R.W., Hertig, A.T. and Rock, J. (1950), Dating the endometrial biopsy. Fert.il. Steril., 1 , 3-25, which is incorporated herein by reference. See also, Deliqdisch, L., (1993), Effects of hormone therapy on the endometrium. Mod Pathol. January, vol. 6(1), pp 94-106, which is incorporated herein by reference, Noyes et al., is also referenced for additional information regarding endometrial biopsies.
  • Solubility and percent solubility are expressed herein as a mass fraction (mg/g) or (% w/w, also referred to as wt. %).
  • 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 examples 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).
  • subject refers to both human and non-human animal subjects who are administered the pharmaceutical composition of this disclosure. Specifically intended are mammalian subjects. More specifically intended are human subjects.
  • AUC area under the curve
  • AUCW is the area under the concentration-time curve extrapolated to infinity following the administration of a dose.
  • AlJCo-t is the area under the concentration-time curve from time zero to time t following the administration of a dose, wherein t is the last time point with a measurable concentration.
  • C max refers to the maximum value of blood concentration shown on the curve that represents changes in blood concentrations of an active pharmaceutical ingredient (e.g., progesterone), or a metabolite of the active pharmaceutical ingredient, over time.
  • an active pharmaceutical ingredient e.g., progesterone
  • T, nax refers to the time that it takes for the blood concentration of 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
  • T1/2 refers to the time that it takes for progesterone blood concentration to decline to one -half of the maximum level.
  • AUC, C max , and optionally T max and T 1 ⁇ 2 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.
  • oral pharmaceutical compositions comprising solubilized or partially solubilized progesterone. Further disclosed herein are data demonstrating the efficacy of these pharmaceutical compositions, as well as methods of using the described pharmaceutical compositions. Generally, the pharmaceutical compositions disclosed herein can be useful in mitigating the symptoms and effects of increased, decreased, or irregular estrogen levels.
  • Additional aspects and embodiments of this disclosure include: providing increased patient ease of use while potentially minimizing certain side effects from erroneous use, providing reduced metabolic and vascular side effects of commonly used synthetic progesterone, providing reduced food and allergy effects, providing improved bioavailability of progesterone as compared to the PROMETRIUM®, and in some embodiments providing for improved bioavailability of progesterone or a bioequivalent progesterone product at a reduced dose of API compared to the RLDs.
  • Various embodiments are improvements over exiting progesterone formulations, treatments, and methods of using these formulations and treatments.
  • the elements of the pharmaceutical compositions of this disclosure provide improved bioavailability, improved pharmacokinetics, bioequivalent pharmaceutical compositions, and the potential to reduce the administered dosage strength. Bioavailability comparisons to commercially available forms, such as tablet and capsule forms, may be determined by standard pharmacokinetic techniques.
  • progesterone is solubilized or partially solubilized (partially suspended) when administered.
  • the type of progesterone used, the form of that progesterone (i.e., solubilized or suspended), the different solubilizing agent used, the different excipients used, and the administration under proper conditions (i.e. fed, absence of concomitant medications, etc) contribute, in part, to the improvements over existing progesterone compositions, methods, and treatments.
  • the pharmaceutical compositions do not include peanut oil.
  • the API is progesterone, which is solubilized or partially solubilized (partially suspended).
  • progesterone is the sole API.
  • the pharmaceutical formulations described herein are prepared and administered as filled capsules, typically soft capsules or softgels of one or more materials well known in the art including, for example and without limitation, soft gelatin capsules.
  • Ultra-micronized progesterone, as described herein, may also be prepared for administration in tablets or other well-known orally administered dosage forms using standard techniques.
  • total progesterone i.e., dissolved and suspended progesterone
  • inventions disclosed herein further provide more uniform dissolution of progesterone and reduced intra- and inter-patient P parameters when compared to equal dosages of PROMETRIUM.
  • Dissolution uniformity of progesterone in a formulation of this disclosure compared to 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.
  • progesterone absorption is highly variable from patient to patient and within the same patient.
  • 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:
  • 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.
  • progesterone-deficient States supplemental progesterone
  • treat refers to any indicia of success in the treatment or amelioration of an injury, disease, or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, disease, or condition more tolerable to the patient; slowing in the rate of degeneration or decline; or improving a patient's physical or mental well-being.
  • the treatment or amelioration of symptoms can be based on objective or subject parameters, including the results of a physical examination, neuropsychiatric examinations, or psychiatric evaluation.
  • progesterone refers to administration of the progesterone, to an animal, especially a mammal, and in particular a human, to protect the animal from any of the disorders set forth herein, as well as others, before or after the disorder has occurred in the subject.
  • Exemplary dosage strengths for progesterone for use in the formulations described herein include, without limitation, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 350 mg and 400 mg.
  • progesterone dosage strength is from at least 25 mg to at least 200 mg.
  • Specific dosage embodiments contain at least: 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg 46 mg, 47 mg, 48 mg,
  • the pharmaceutical compositions can contain at least about
  • the pharmaceutical compositions contain from about 25 mg to about 50 mg, from about 75 mg to 100 mg, from about 50 mg to about 100 mg, about 75 mg, about 150 mg, about 200 mg, from about 100 mg to 150 mg, from about 150 mg to 200 mg, from 100 mg to 200 mg of progesterone.
  • the lowest clinically effective dose of progesterone is used for treatment symptoms occurring due to irregular or inadequate hormone production, or for estrogen HRT patients.
  • the progesterone dosage is about 75 mg.
  • the progesterone dosage is about 150 mg.
  • the progesterone dosage is about 200 nig.
  • the dosage is 75 mg, 150 mg, or 200 mg.
  • compositions of this disclosure can be formulated for administration using techniques disclosed herein, and also using techniques well known in the art.
  • an illustrative embodiment of a pharmaceutical composition of the invention comprises progesterone, at least 75% of the progesterone being solubilized (the balance being suspended/uitra-micronized as discussed elsewhere herein), and an oil, wherein the oil is medium chain fatty acid mono- and di- esters of one or more glycols, with or without surfactant.
  • the progesterone in the pharmaceutical compositions is not more than about 20% solubilized, not more than about 19% solubilized, not more than about 18% solubilized, not more than about 17% solubilized, not more than about 16% solubilized, not more than about 15% solubilized, not more than about 14% solubilized, not more than about 13% solubilized, not more than about 12% solubilized, not more than about 11% solubilized, not more than about 10% solubilized, not more than about 9% solubilized, not more than about 8% solubilized, not more than about 7% solubilized, not more than about 6% solubilized, or not more than about 5% solubilized, with the balance being suspended in the formulation as discussed elsewhere herein.
  • the suspended/uitra-micronized progesterone is absorbable by the body and retains biological functionality despite not being soluble in the formulation, in a particular embodiment, the progesterone is about 15% solubilized in the formulation, with balance (about 85%) being suspended/uitra-micronized. In another embodiment, the progesterone is about 5% solubilized in the formulation, with balance (about 95%) being suspended/uitra-micronized.
  • progesterone solubility in various solubilizing agents ranges from 27 mg/g to 95 mg/g. More specifically, in certain embodiments, progesterone 's solubility in solubilizing agents is from 27.8 mg/g, 57.4 mg/g, 70.5 mg/g, 73.4 mg/g, 86.4 mg/g, to 95 mg/g.
  • Progesterone may be micronized/ultra-micromzed 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 may be used to determine particle size. Particle size may be represented by various metrics, for example, through an X50 particle size, 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 ⁇ to 2000 ⁇ .
  • 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 img to about l Og may be used.
  • the ULM may interact with the Beckman Device via pins that fit into slots on the ULM.
  • the LILM may use a variety of suspension fluids, for example, water, butonol, ethanol, chloroform, heptanes, toluene, propanoL COULTER Type IB Dispersaiit ("Coulter IB"), and a variety of other suspension fluids. Surfactants may also be used, though pump speed should be adjusted to prevent excessive bubbling.
  • Coulter IB may comprise one or more of acetaldehyde, ethylene oxide, or 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").
  • MLM is capable of suspending samples in the size range of 0.4 ⁇ to 2000 ⁇ .
  • 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.
  • ultra-micronized progesterone has an X50 value of less than about 15 microns, less than about 10 microns, less than about 5 microns or less than about 3 microns; and an X90 value of less than about 25 microns, less than about 20 microns, or less than about 15 microns.
  • ultra-micronized progesterone is formulated with peanut and peanut-oil free excipients.
  • a solvent system solubiliz.e s one or more APIs, and in particular, progesterone.
  • the solvent system is a mixture of solubilizmg agents, together with co-solvents, surfactants, or other excipients.
  • the solvent system comprises non-toxic, pharmaceutically acceptable solvents (alternatively referred to as "carriers"), co-solvents, surfactants, and excipients suitable for oral administration or absorption.
  • oils having medium chain fatty acids as a predominant or majority component are used as solubilizmg agents/carriers to solubilize the one or more APIs.
  • the solubilizmg 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 CI 4.
  • the medium chain fatty acids comprise chain lengths from C6 to CI 2.
  • the medium chain fatty acids are mono-, di-, or triglycerides predominately with chain lengths from C8 to CI O.
  • the medium chain fatty acids can be saturated. In certain embodiments, the medium chain fatty acids are predominantly saturated, i.e., greater than about 60%, greater than about 70%, greater than about 75%, greater than about 80%. greater than about 85%. greater than about 90%, or greater than about 95%o saturated.
  • the solubilizmg agent comprises a mixed triglyceride predominantly comprising C8 and CIO fatty acids.
  • the soiubilizing agent comprises both simple and mixed triglycerides predominately comprising C8 and CI O fatty acids.
  • the soiubilizing agent comprises a mixed triglyceride predominantly comprising saturated C8 and CIO fatty acids.
  • the soiubilizing agent comprises both simple and mixed triglycerides predominately comprising saturated C8 and C10 fatty acids.
  • the soiubilizing agent/carrier is selected to enhance dissolution or suspension of progesterone.
  • the soiubi lizing agent/carrier is selected to enhance absorption of the API by cells of a mammal.
  • certain carriers may be selected to enhance absorption of the other 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-, or triglyercides are particularly suited to aid in cellular absorption.
  • a surfactant is used to aid in solubilizing, partially solubilizing, or suspending progesterone in the solubilizing agent.
  • a surfactant such as GELUCIRE 44/14
  • GELIJCIRE 44/14 may be heated to approximately 45-50°C.
  • the surfactant is completely melted, it is added to an appropriate container that contains the solubilizing agent.
  • the solubilizing agent and surfactant are mixed.
  • the progesterone is added, thus, solubilizing, partially solubilizing, or suspending progesterone.
  • 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 solubilizing agent/carrier can be an oil having medium chain fatty acids as a majority or predominant component.
  • Suitable medium chain fatty acids include caproic acid (C6), enanthic acid (C7), caprylic acid (C8), peiargo ic acid (C9), capric acid (CIO), undecylie acid (CI 1), lauric acid (CI 2), trideeyiic acid (CI 3), and myristie acid (CI 4).
  • these fatty acids are predominantly saturated (e.g., greater than 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90%, or greater than about 95%, or about 100% ⁇ ).
  • predominantly C6 to C12 saturated fatty acids are contemplated.
  • piedominatelyCS to CIO saturated fatty adds are axitemplated.
  • these fatty acids may be bound to glycerin, propylene glycol, ethylene glycol, or polyethylene glycol.
  • the solubilizing agent is selected from at least one of a solvent or co- solvent.
  • the solubilizing agent can comprise a mixture of capryiic/ ' capric triglycerides; caproic/capiylic/capric/Iauric triglycerides; caprylic/capric/Iinoleic triglycerides; caprylic/capric/succimc triglycerides; propylene glycol dicapryiate/dicaprate; and combinations and derivatives thereof.
  • the solubilizing agent in addition to the various mixtures of the specified triglycerides, can further include polyethylene glycol.
  • Suitable carriers/solubilizing agents further include esters of saturated coconut and palm kernel oil and derivatives thereof, including fractionated coconut oils and palm kernel oils; and triglycerides of fractionated vegetable fatty acids, and derivatives thereof and combinations thereof.
  • the carrier/solubilizing agent may comprise one or more monoglycerides, diglycerides, triglycerides, and combinations thereof having predominately C6-C12 fatty acid esters.
  • the solvent are mono-, di-, and triglycerides of saturated C8-C 10 (caprylic/capric) fatty acids.
  • Exemplary glycerin based solubilizing agents include MIGLYOLs ® , which are caprylic/capric triglycerides (SASOL Germany GMBH, Hamburg).
  • MIGLYOLs includes M IGLYOL 810 (caprylic/capric triglyceride), MIGLYOL 812 (caprylic/capric triglyceride), MIGLYOL 816 (caprylic/capric triglyceride), and MIGLYOL 829 (caprylic/capric/succmic triglyceride).
  • caprylic/capric triglyceride solubilizing agents are likewise contemplated, including, for example: caproic/caprylic/capric/lauric triglycerides; caprylic/capric/iinoleic triglycerides; caprylic/capric/succinic triglycerides.
  • CAPMUL MCM medium chain mono- and di-glycerides of caprylic/capric fatty acids
  • CAPMUL PG-8 Propylene Glycol Monocaprylate
  • CAPMUL PG-10 Propylene Glycol Monocaprate
  • Triglycerides of fractionated vegetable fatty acids, and combinations or derivatives thereof can be the solubilizing agent, in certain embodiments.
  • solubilizing agents include a polyethylene glycol giyceride (Gelucire®; GATTEFOSSE SAS, Saint-Priest, France); a propylene glycol; a caproic/caprylic/capric/lauric triglyceride; a caprylic/capric/linoleic triglyceride; a capiylic/capric/succinic triglyceride; propylene glycol monocaprylate; propylene glycol monocaprate; (Capmul® PG-8 and 10; the CAPMUL brands are owned by AB1TEC, Columbus Ohio); propylene glycol dicapryiate; propylene glycol dieapryiate; a diethylene glycol mono ester (including 2-(2- Ethoxyethoxy)ethanol (also referred to as TRANSCUTOL®); diethylene glycol monoethyl ether; esters of saturated coconut and palm kernel oil and derivatives thereof; triglycerides of fractionated vegetable fatty acid
  • progesterone is fully solubilized using, for example and without limitation, sufficient amounts of: TRANSCUTOL and MIGLYOL; TRANSCUTOL, MIGLYOL and CAPMUL PG-8 or CAPMUL PG-10; CAPMUL MCM (Medium Chain Mono- and Diglycerides); CAPMUL MCM and a non-ionic surfactant; and CAPMUL MCM and GELUCIRE.
  • the solubilizing agent comprises combinations of mono- and di- esters of propylene glycol or ethylene glycol or mono-, di-, and triglyceride combinations.
  • polyethylene glycol giyceride (GELUCIRE ® , GATTEFOSSE SAS, Saint-Priest, France) can be used as the solubilizing agent or as a surfactant.
  • GELUCIRE 44/14 can be used.
  • GELUCIRE 44/14 is a non-ionic water dispersible surfactant, also known as lauroyl macrogol-32 glycerides EP and lauroyl polyoxyl-32 glycerides NF.
  • a non-ionic surfactant is selected from one or more of glycerol and polyethylene glycol esters of long chain fatty acids, such GELUCIRE 44/14 (discussed previously herein), GELUCIRE 44/11, 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 polyoxyl-32 glycerides NF, and stearoyl polyoxylglycerides (USA FDA II G)).
  • GELUCIRE 44/14 discussed previously herein
  • GELUCIRE 44/11 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 polyoxy
  • these surfactants may be used at concentrations between 0.01 wt. % to 5.00 wt. %.
  • 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 can comprise polyethylene sorbitol esters, such as polysorbate 80, which is commercially available under the trademark TWEEN® 80 (polysorbate 80) (Sigma Aldrich, St. Louis, MO).
  • Polysorbate 80 comprises approximately 60%-70% oleic acid with the remainder comprising primarily linoleic acids, palmitic acids, and stearic acids.
  • Polysorbate 80 may be used in amounts ranging from about 5 to 50% of the pharmaceutical composition by mass, and in particular embodiments, about 30% of the pharmaceutical composition total mass.
  • non-ionic surfactants is PEG-6 paimitostearate and ethylene glycol pal itostearate, which is 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 so lubilizing agents/non-ionic surfactants combinations include, for example, MIGLYOL 812:GELUCIRE 50/13 or MIGLYOL 8I2: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.
  • the non-ionic or anionic surfactant(s) can be used alone with at least one solubi.liz.ing agent or can be used in combination with other surfactants. Accordingly, such surfactants, or any other excipient as set forth herein, may be used to solubilize one or more APIs.
  • the API is progesterone. The combination of solubilizing agent, surfactant, and other excipients should be designed whereby the one or more APIs are delivered to the target tissue and result the intended effect of the API.
  • CAPMUL MCM and a non-ionic surfactant e.g., GELUCIRE 44/14 (Lauroyl macrogol-32 glycerides EP Lauroyl polyoxyl-32 glycerides NF Lauroyl polyoxylglycerides (USA FDA IIG)), can be used at ratios of about 9:1, 7:3, 6:4, and 6:3 when progesterone is the sole API and at ratios of 65:35, 70:30, 75:25, 80:20, 85: 15 and 90: 10 with estradiol as the sole API.
  • GELUCIRE 44/14 Liauroyl macrogol-32 glycerides EP Lauroyl polyoxyl-32 glycerides NF Lauroyl polyoxylglycerides (USA FDA IIG)
  • CAPMUL MCM and GELUCIRE 44/14 used in ratios including, for example, and without limitation, 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;
  • CAPMUL MCM and GELUCIRE 39/01 can be used in ratios including, for example and without limitation, 6:4, 7:3, and 8:2 (one or more API composition);
  • CAPMUL MCM and GELUCIRE 43/01 can be used in ratios including, for example and without limitation, 7:3, and 8:2 (one or more API composition);
  • CAPMUL MCM and GELUCIRE 50/13 can be used in ratios including, for example and without limitation, 7:3, and 8:2, and 9:1.
  • 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.
  • useful ratios can be, e.g., 8: 1 or greater, e.g., 60 to 70: 1.
  • Combinations of these solubilizing agents can produce solubiiized or partially solubiiized progesterone, depending upon the desired unit dosage amount of progesterone.
  • the upward limit of dosage strength per unit dose it generally limited only by the practical size of the final dosage form.
  • solubilizing agents used to suspend, partially solubilize, or fully solubilize progesterone include medium chain fatty acid esters, (e.g., esters of glycerol, ethylene glycol, polyethylene glycol, or propylene glycol) and mixtures thereof.
  • the medium chain fatty acids are C6 to C14 or C6 to C12 fatty acids.
  • the medium chain fatty acids are saturated, or predominantly saturated, e.g., greater than about 60% or greater than about 75% saturated.
  • progesterone is soluble in the oils at room temperature, although it may be desirable to warm certain oils initially during manufacture to improve viscosity.
  • 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 30°C.
  • 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.
  • the solubility of estradiol in the soiubilizing agent or combination of soiubilizing agents is at least about 0,5 wt%, e.g., 0.8 wt% or higher, or 1.0 wt% or higher.
  • mono- and diglycerides of medium chain fatty acids include, among others, CAPMUL MCM, CAPMUL MCM CI O (Glyceryl Monocaprate) , CAPMUL MCM C8 (Glyceryl Monocaprylate), and CAPMUL MCM C8 EP (Glyceryl Monocaprylate).
  • These oils are C8 and CIO fatty acid mono- and diglycerides.
  • oils that are triglycerides of medium chain fatty acids include, among others, MIGLYOL 810 and MIGLYOL 812.
  • Other illustrative examples include MIGLYOL 840 (Propylene Glycol Dicaprylate / Dicaprate).
  • GELUCIRE 44/14 PEG-32 glyceryl laurate EP
  • GELUCIRE 44/14 PEG-32 glyceryl laurate EP
  • GELUCIRE 44/14 PEG-32 glyceryl laurate EP
  • These illustrative examples comprise predominantly medium chain length, saturated, fatty acids, specifically predominantly C8 to CI 2 saturated fatty acids.
  • the predominantly €8 to C12 saturated fatty acids comprise not less than 50 wt%, not less than 75 wt%, not less than 85 wt%, not less than 90 wt%, or not less than 95 wt% of the soiubilizing agent.
  • 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 predominant (by weight) components) 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.
  • an oil/solubilizmg agent is described herein as a saturated C8 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 t%) are caprylic monoglycerides and eaprylic diglyeerides.
  • MIGLYOL 812 is generally described as a C8- CIO triglyceride because the fatty acid composition is at least about 80% caprylic (C8) acid and capric (CIO) acid. However, it can also comprise small amounts of other fatty acids, e.g., less than about 5% of caproic (C6) acid, lauric (CI 2) acid, and myristic (C 14 ⁇ acid.
  • a product information sheet for MIGLYOL by SASOL provides the composition of fatty acids as follows:
  • fatty acid esters component of the formulation may be, e.g., MIGLYOL 812 or a similar product.
  • GELUCIRE 44/14 is generally described as lauroyl poIyoxyl-32 giycerides, 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.
  • the thickening agent component of the formulation may be, e.g., TEFOSE 63 (PEG-6 palmitostearate and ethylene glycol palmitostearate) or a similar product.
  • the selected soiubilizmg agent does not require excessive heating in order to solubilize progesterone.
  • the formulation comprises medium chain fatty acid mono- and diglycerides (e.g., CAPMUL VI ( ' VI ; and polyethylene glycol glycerides (e.g., GELUCIRE) as a surfactant
  • the oil or the surfactant can be warmed up, e.g., to about 65 C 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.
  • 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.
  • PEG polyethylene glycol
  • GELUCIRE GELUCIRE
  • Suitable lubricants may also comprise calcium stearate, ethyl oleate, ethyl laureate, glycerin, glyceryl palmitostearate, hydrogenated
  • GELUCIRE 44/14 is a non-ionic water dispersible surfactant, also known as lauroyl macrogol-32 glycerides EP and lauroyl polyoxyl-32 glycerides NF.
  • GELUCI RE 44/14 acts as a suspension agent.
  • an antioxidant is used. Any suitable antioxidant may be used, such as, for example and without limitation, butylated hydroxyto!uene, also commercially referred to as BHT. 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.
  • a pharmaceutical formulation comprises 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.
  • the pharmaceutical composition further comprises at least one thickening agent.
  • a thickening agent is added when the viscosity of the pharmaceutical composition provides less than desirable absorption following administration.
  • thickening agents include: hard fats; propylene glycol; a mixture of hard fat EP NF/JPE, glyceryl rieinoleate, 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 monooieate (type 40) EP/NF (OVUCIRE WL 3264; a mixture of hard fat EP/NF/JPE, glyceryle monooieate (type 40) EP/NF (OVUCIRE WL 2944); and a mixture of various hard fats (WITEPSOL®, Sasoi Germany GmbH, Hamburg, Germany).
  • the viscos include: hard fats; propy
  • 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 comprises a polyethylene glycol long chain (C16-C20) fatty acid ester and further comprises 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 comprises a polyethylene glycol long chain saturated fatty acid ester and further comprises an ethylene glycol long chain saturated fatty acid ester, such as PEG- and ethylene glycol-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.
  • 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 hydrophiiic-lipophilie balance (HLB) value of about 9-10.
  • the selection and amount of hydrophilic polymer may be based on the selection and amount of solubiiizing agent.
  • the pharmaceutical composition can include a hydrophilic polymer but optionally excludes a gelling agent. In embodiments having a hydrogel, from about 5% to about 10% of the total mass may comprise the hydrophilic polymer. In further embodiments, hydrogels may be employed. A hydrogel may comprise chitosan, which swell in response to contact with water. In various embodiments, a cream pharmaceutical composition may comprise PEG-90M,
  • compositions described herein can include one or more thermoreversible gels, typically of the hydrophilic nature including for example and without limitation, hydrophilic sucrose and other sacchari de-based monomers (U.S. Pat. No. 6,018,033, which is incorporated herein by reference).
  • 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, flavoring agents, taste -masking agents and preservatives. In certain embodiments, colorants, comprise about 0.1% to about 2% of the pharmaceutical composition by weight. In certain embodiments, 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.
  • the solubiiizing 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 phamiaceutical 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.
  • 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. As is with all oils, solubiiizers, excipients and any other additives used in the formulations described herein, each is to be non-toxic and pharmaceutically acceptable.
  • formulations of this disclosure are generally orally administered, typically via, for example, capsules such as soft capsules.
  • a pharmaceutical composition of this disclosure comprises progesterone, (with about 15% or less, and in particular embodiments, about 5% or less of the progesterone being solubilized -the balance being ltra-micromzed/suspended 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 wi thout surfactant.
  • compositions in accordance with various embodiments comprise ultra- rnicronized progesterone.
  • a pharmaceutical formulation comprises ultra-micronized progesterone, a carrier, and a lubricant.
  • a pharmaceutical formulation comprises ultra-micronized progesterone, a carrier, a lubricant, and optionally an antioxidant.
  • a pharmaceutical formulation comprises ultra-micronized progesterone, and a medium chain triglyceride as a carrier.
  • a pharmaceutical formulation comprises ultra-micronized progesterone, and mono-, di-, or triglycerides of caprylic/capric acid as a carrier.
  • Various further embodiments also comprise lecithin and optionally butylated hydroxytoiuene.
  • a pharmaceutic ai formulation comprises ultra-micronized progesterone and at least one carrier, a lubricant, optionally an antioxidant, and other pharmaceutically acceptable excipients.
  • a pharmaceutical formulation comprises about 20% to about 80% carrier by weight, about Q.1% to about 5% lubricant by weight, and about 0.01% to about 0.1% antioxidant by weight.
  • a pharmaceutical formulation comprises ultra-micronized progesterone, at least one carrier, and a non-ionic surfactant.
  • 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 parabeii, for example, in a ratio of about 10: 1, and at a proportion of about 0.005% and 0.05% by weight.
  • ultra-micronized progesterone is administered in a capsule.
  • Capsules may be prepared using one or more film forming polymers.
  • 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 cel lulose, methyl cellulose.
  • the pharmaceutical composition is prepared by blending progesterone 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 comprises 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.
  • Other excipients can optionally be included, including, for example and without limitation, anti-oxidants, lubricants, and the like.
  • the pharmaceutical composition includes sufficient solubilizing agent(s) to fully solubilize the progesterone. It is expressly understood, however, that other volumes of solubilizing agent can be used depending on the level of progesterone 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 progesterone to be solubiiized in the pharmaceutical composition.
  • GELUCIRE 44/14 (lauroyl macrogol-32 glycerides
  • lauroyl polyoxyl-32 glycerides NF lauroyl polyoxyl glycerides (USA FDA II G)) is heated to about 45-65 °C and CAPMUL MCM or M1GLYOL 812 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 progesterone.
  • the pharmaceutical compositions described herein can be delivered orally inside of a delivery vehicle, for example a capsule.
  • the capsules are soft capsules made of materials well known in the pharmaceutical arts such as gelatin.
  • the delivery vehicle is integral with the pharmaceutical composition (i .e., the pharmaceutical composition is the delivery vehicle).
  • Hard or soft shell capsules can be used to administer the API.
  • capsules may be prepared by forming the two capsule halves, filling one of the halves with a 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 (“softgel”) capsules may be prepared using a rotary die encapsulation process, as further described below.
  • Softgel capsules may contain the formulation disclosed herein as a "fill material.”
  • the soft gelatin capsule do not contain one or more of the following as the fill material: hydrophilic gel-forming bioadhesive (e.g., mucoadhesive) agents; a lipophilic agent and a gelling agent for the lipophilic agent, or a hydrodispersible agent.
  • the hydrophilic gel -forming bioadhesive agent is carboxyvinylic acid; hydroxypropyicelluiose; carboxymethylcellulose; gelatin; xanthane gum; guar gum; aluminum silicate; or mixtures thereof.
  • the lipophilic agent is a liquid triglyceride; solid triglyceride (e.g., with a melting point of about 35 °C); carnauba wax; cocoa butter; or a mixture thereof.
  • the gelling agent is a hydrophobic colloidal silica.
  • the hydrodispersible agent can be polyoxyethylene glycol; polyoxyethylene glycol 7-glyceryl-cocoate; or a mixture thereof.
  • the softgel capsule itself may comprise a gelatin material in a relatively solid or stiff form.
  • the gel capsule defines an inner volume that contains the fill material. Dissolution of the gelatin material may commence at various points after administration, such as in the digestive tract (mouth, esophagus, stomach and intestines), or in another body cavity, such as the vaginal tract.
  • Gel capsules may be prepared using one or more film forming polymers.
  • Suitable film forming polymers include, but are not limited to, natural polymers, such as gelatin, and synthetic film forming polymers, such as modified celluloses.
  • Suitable modified celluloses include, but are not limited to, hydroxypropyi methyl cellulose, methyl cellulose.
  • 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.
  • 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.
  • buffering salts and acids can be used in conjunction with flavorings that contain aldehydes in order to minimize cross-linking of the gelatin.
  • a softgel dosage form is used.
  • 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.
  • Humectants can be used to suppress the water activity of the softgel. Suitable humectants include glycerin, sorbitol, propylene glycol, macrocrystalline cellulose, silica, mineral oil, and combinations thereof which are often components of the plasticizer composition. Regulated water activity in pharmaceutical compositions and dosage forms, such as capsules, can improve the compatibility and stability of the compositions and forms. This is because when hydrolosis is regulated chemical degradation caused by water is also regulated (or slowed, as is desirable in the present case). Thus, by regulating water in the present compositions, the capsule shells are less likely to soften, dissolve, break, or leak during storage.
  • 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.
  • Hard and softgei capsules can be manufactured according to various techniques known in the art.
  • softgei capsules can be prepare using a rotary die encapsulation process.
  • An exemplary process is disclosed in Wilkinson, P. K. et al, 1990, "Softgels: manufacturing considerations.” In: Specialized Drug Delivery Systems, P. Tyle (Ed.), pp.409-449. Marcel Dekker, Inc., New York, the entirety of which is hereby incorporated by reference.
  • softgels can be prepared according to the process disclosed in
  • Hard shell capsules can also be used as the delivery vehicle. These capsules may be prepared by forming the two capsule halves, filling one half with the fill material, and then sealing the halves together to form the finished capsule. In other embodiments, hard shell capsules may be prepared by combining a "body” and a "cap.” The "body” of the capsule is filled with the fill material and then closed with the cap. The body/cap interface is then sealed or banded.
  • Operation 102 comprises mixing a solubilizing agent, a surfactant (i.e. lubricant), and an antioxidant as described herein.
  • a solubilizing agent i.e. lubricant
  • an antioxidant i.e. lubricant
  • 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. Operation 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.
  • Operation 104 may comprise mixing progesterone (progesterone) into the mixture of the solubilizing agent, the surfactant (i.e. lubricant), and the antioxidant. A pasty substance is thus formed. Mixing may occur in a steel tank or vat. Mixing may be facilitated by an impellor, agitator, or other suitable means. Operation 104 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N 2 . Operation 106 comprises degasing. The resulting mixture from operation 106 may comprise a pharmaceutical composition suitable for production into a softgel capsule.
  • Operation 202 comprises mixing glyercin with water.
  • the water used in operation 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.
  • Operation 202 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N 2 . Heating may be performed until the temperature reaches 80° ⁇ 5°C.
  • Operation 204 comprises the addition of gelatin to the glycerin water mixture. Mixing may be facilitated by an impellor, agitator, or other suitable means. Operation 204 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N 2 . A vacuum may be drawn in operation 204 to de-aerate.
  • N 2 nitrogen gas
  • Operation 206 comprises addition of an excipient (i.e. coloring agent) such as a dye.
  • a coloring agent may comprise products sold under the trademark OPATINT or the suitable agent.
  • Operation 206 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N2.
  • Operation 208 comprises degasing.
  • the resulting mixture from operation 208 may comprise a gel capsule material suitable for use as a gel capsule in production of a softgel capsule.
  • softgel capsule assembly process 300 is shown. Operation
  • the 302 comprises heating the fill material.
  • the pharmaceutical composition may be heated to any suitable temperature.
  • the pharmaceutical composition is heated to 30°C +/- 3°C.
  • pharmaceutical composition maybe heated in a fill hopper.
  • a fill hopper may comprise a device configured to hold a volume of the pharmaceutical composition or to dispense the pharmaceutical composition in controlled volumes.
  • Operation 304 comprises filling a gel mass.
  • a gel mass may be taken from the gel capsule material produced in operation 208 of Figure 2.
  • Filling may be performed by injecting, placing, or otherwise disposing the pharmaceutical composition 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 MIGLYOL 812. Operation 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 pharmaceutical composition 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).
  • Operation 306 comprises drying the softgei 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.
  • the pharmaceutical composition is designed to maximize API solubility, and other favorable characteristics without sacrificing efficacy, while simultaneously improving bioavailability in subjects.
  • Other favorable characteristics, besides improving bioavailability as compared to the RLD, include, for example, bioavailability that is bioequivalent to the RLD, improved subject compliance (i.e., ability to easily take the right capsule during the correct period), reducing food and allergy effects due to administration, and reducing required prescribed dosage levels in order to achieve efficacy of the drug product.
  • progesterone is fully or partially solubilized.
  • the form of the API i.e., being in solution
  • other factors and conditions may account for the increased bioavailabilty of progesterone as compared to the RLD.
  • the pharmaceutical composition is delivered via a gelatin capsule delivery vehicle.
  • the pharmaceutical composition is a liquid pharmaceutical composition.
  • the pharmaceutical composition of such embodiments is encapsulated in the gelatin capsule. The inclusion of the capsules in blister packs, as described elsewhere herein, ensures that subjects will receive the right dosage during the correct period of time.
  • the gelatin capsules are softgels.
  • Other forms of adm istration i.e. injection, intra-muscular, etc.
  • Softgels eliminate these problems, while minimizing adverse tastes.
  • Softgels can be administered orally or can be administered locally. In some embodiments, the softgei is administered orally.
  • 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 solubilizing agent was selected from one or more C6 to C12 fatty acid mono-, di-, or triesters of glycerol, e.g., one or more C6 to CI.4 triglycerides, e.g., one or more C6 to C12 triglycerides, such as one or more C8-C10 triglycerides.
  • the pharmaceutical composition comprises progesterone that is at least about 75% solubilized in a solubilizing agent comprising one or more C6 to C14 medium chain fatty acid mono-, di-, or triglycericdes and, optionally, a thickening agent.
  • the pharmaceutical composition comprises progesterone that is at least about 75% 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 C 12 triglycerides, such as one or more C8-C10 triglycerides.
  • progesterone being at least 85% solubilized, at least 90% solubilized, at least 95% solubilized, and in certain instances, 100% solubilized.
  • estradiol or a combination of progesterone and estradiol is included in the pharmaceutical compositions as the one or more APIs.
  • liquid pharmaceutical compositions are preferably liquid at room temperature. Accordingly, 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.
  • a non-ionic surfactant such as GELUCIRE or TEFOSE to increase viscosity
  • the non-ionic surfactant may be solid at room temperature. In those situations, the non-ionic surfactant may require melting to mix with one or more APIs solubilized in a fatty acid-glycol ester.
  • the resultant composition is advantageously liquid, not solid. However, in these embodiments, the resultant pharmaceutical composition remains liquid, albeit with greater viscosity, although it is still not a solid.
  • the pharmaceutical composition comprises progesterone, a medium chain solubilizing agent, and a thickening agent as the only essential ingredients delivered via a softgel deliver vehicle.
  • Non-essential ingredients e.g., colorants, antioxidants, preservatives, or other excipients may be included as well.
  • Other embodiments comprise one or more APIs.
  • Additional ingredients can be incorporated in amounts that do not materially change the solubility of the progesterone, the pharmacokinetics of the pharmaceutical composition, or the efficacy of the pharmaceutical composition.
  • Other factors that should be considered when adjusting the ingredients of the pharmaceutical composition include taste, water regulation, and other relevant factors, for example those that would lead to reduced patient compliance.
  • mucoadhesive agents In softgel embodiments, mucoadhesive agents, gelling agents, dispersing agents, or the like would not be included because of effects some of these ingredients may have on bioavailability of the API(s) in the digestive system .
  • compositions in different embodiments may be administered alone or combination with one or more other drugs (or as any combination thereof).
  • compositions in accordance with embodiments including one or more other drugs may also comprise estradiol.
  • estradiol is also an API
  • the pharmaceutical composition disclosed herein can be administered orally in a softgel.
  • the inner volume may come into fluid communication with the digestive system such that the progesterone present in the pharmaceutical composition can be absorbed systemically.
  • Oral administration may involve swallowing, so that the pharmaceutical composition enters the gastrointestinal tract.
  • buccal or sublingual administration may be employed such that the pharmaceutical composition enters the bloodstream directly from the mouth.
  • the method of administration is typically oral.
  • Hard capsules or softgels may be arranged in blisters or cartridges or bottles.
  • 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 subject compliance.
  • a single kit e.g., a blister pack
  • One or more of the capsules may contain no progesterone.
  • 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.
  • each dose e.g., each softgel
  • kits having other configurations are also contemplated herein.
  • kits having such blister packs may contain any number of capsules.
  • progesterone is formulated for intraperitoneal, percutaneous, subcutaneous, mtra-rnuscu!ar, and atomization administration (i.e. such as with nasal mist administration).
  • the pharmaceutical compositions are administered according to other techniques known to those skilled in the art, which may include, but are not limited to: tablets, film-coated tablets, prolonged-release tablets, modified- released tablets, effervescent tablets, orodispersible tablets, sachets, dr powders used to form suspension; or liquid dosage forms.
  • compositions in accordance with the various embodiments disclosed herein may be used to treat or prevent endometrial hyperplasia, prevent secondary amenorrhea, or mitigate or treat the effects of estradiol supplementation.
  • compositions comprising progesterone may be co-administered with estradiol or co-formulated with estradiol.
  • 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.
  • 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 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, vulvovaginal atrophy; and osteoporosis and endometrial hyperplasia reduction.
  • vasomotor symptoms including hot flashes and night sweats (vasomotor symptoms), sleep disturbances, mood changes, vulvovaginal atrophy; and osteoporosis and endometrial hyperplasia reduction.
  • formulation in accordance with various embodiments may be used to treat amenorrhea.
  • Additional objects of this disclosure include: providing increased patient compliance secondary to ease of use; providing increased physician 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 secondar ⁇ ' 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.
  • the formulations disclosed herein provide enhanced bioavailability of progesterone when compared to conventional progesterone formulations. As a result of this improved bioavailability, certain embodiments of the formulations disclosed herein allow for a reduction in the quantity of progesterone administered to a person in need thereof while still providing the providing the benefits of a dosage form containing the greater amount of progesterone.
  • a formulation of this disclosure can include less than 200 mg of progesterone while still having an acceptable P profile.
  • the formulation can include about 175 mg of progesterone, about 170 mg of progesterone, about 165 mg of progesterone, about 160 mg of progesterone, about 159 mg of progesterone, about 158 mg of progesterone, about 157 mg of progesterone, about 156 mg of progesterone, about 155 mg of progesterone, about 154 mg of progesterone, about 153 mg of progesterone, about 152 mg of progesterone, about 151 mg of progesterone, about 150 mg of progesterone, about 149 mg of progesterone, about 148 mg of progesterone, about 147 mg of progesterone, about 146 mg of progesterone, about 145 mg of progesterone, about 170 mg of progesterone, about 140 mg of progesterone, about 135 mg
  • this disclosure provides a formulation including less than 200 mg of progesterone having an AUCo- ⁇ i (ng/ml)*hr of from about 5 to about 500, from about 5 to about 400, from about 5 to about 300, from about 5 to about 270, from about 20 to about 200, from about 25 to about 150, or from about 25 to about 140.
  • the formulation including less than 200 mg progesterone can have an AUC 0 . ⁇ of about 137 (ng/ml)*hr ⁇ 95%.
  • the formulation can have about 150 or exactly 150 mg progesterone.
  • this disclosure provides a formulation including less than 200 mg of progesterone having an AUCo-t in (ng/ml.)*hr of from about 5 to about 500, from about 5 to about 400, from about 5 to about 300, from about 5 to about 240, from about 20 to about 200, from about 25 to about 150, or from about 25 to about 140.
  • the formulation including less than 200 mg progesterone can have an AUCo-i of about 120 (ng/ml)*hr ⁇ 95%.
  • the formulation can have about 150 or exactly 150 mg progesterone.
  • this disclosure provides a formulation including less than 200 mg of progesterone having a C max in ng/ml of from about 3 to about 350, from about 3 to about 325, from about 3 to about 300, from about 3 to about 250, from about 3 to about 240, and from about 3 to about 230.
  • the formulation including less than 200 mg progesterone can have a C max of about 75 ng/ml ⁇ 95%.
  • the formulation can have about 150 or exactly 150 mg progesterone.
  • the amount of progesterone is typically less than 200 mg, in certain embodiments, the amount of progesterone can be about 300 mg.
  • the formulation can have the following PK parameters upon administration:
  • this disclosure provides a formulation including about 300 mg of progesterone having an AUC 0 . ⁇ in (ng/ml) *hr of from about 0 to about 1000, from about 10 to about 800, from about 10 to about 600, from about l Oto about 540, from about 40 to about 400, from about 50 to about 300, or from about 50 to about 280.
  • the formulation including about 300 mg progesterone can have an AUCo - ⁇ of about 274 (ng/ml)*hr ⁇ 95%.
  • this disclosure provides a formulation including about 300 mg of progesterone having an AUC 0-t in (ng ml)*hr of from about 10 to about 1000, from about 10 to about 800, from about 10 to about 600, from about 10 to about 480, from about 40 to about 400, from about 50 to about 300, or from about 50 to about 280.
  • the formulation including about 300 mg progesterone can have an ⁇ . ' ( ' ;, . of about 240 (ng/ml)*hr ⁇ 95%.
  • this disclosure provides a formulation including about 300 mg of progesterone having a C max in ng/ml of from about 6 to about 700, from about 6 to about 650, from about 6 to about 600, from about 6 to about 500, from about 6 to about 480, and from about 6 to about 460.
  • the formulation including about 300 mg progesterone can have a C ma> ; of about 150 ng/ml ⁇ 95%.
  • Bioavailability comparisons to commercially available forms, such as tablet forms, may be determined by standard pharmacokinetic techniques
  • food effects are reduced, e.g., relative to comparative progesterone products.
  • formulations do not include peanut oil.
  • the lack of peanut oil obviates the risk posed to those having peanut-based allergies. Measurement of Efficacy
  • Efficacy can be measured using standard techniques known in the art. However in certain embodiments, subjects are administered progesterone. After administration of the progesterone, endometrial biopsies can be performed by a board-certified gynecologist. Procedures, instruments used, and observations are documented in the subject's file.
  • the resulting biopsy specimens can then processed by a central laboratory.
  • the central laboratory includes a chartered pathology committee of independent pathologists who are experts in the field of endometrial pathology to assess all endometrial biopsy sample.
  • treatment with the pharmaceutical compositions described herein resulted in complete and partial secretor ⁇ ' activity.
  • complete secretory activity subjects experienced 1) glands with secretory changes, and 2) stromal predecidual changes.
  • stromal predecidual changes In cases of partial secretory activity, subjects experienced 1) glands with secretory changes, or 2) stromal predecidual changes.
  • subjects are administered pharmaceutical compositions as described herein, while other subjects are administered placebos.
  • Exemplary test scenarios are described in the Example section, below.
  • secretory activity is measured as a proportion of subjects at Cycle 3 Day 24 ⁇ 1 day on active treatment (200 mg progesterone/day, 225 mg progesterone/day, or 300 mg progesterone/day) compared to placebo with complete secretory activity on endometrial biopsy (referenced in the examples as the "primary efficacy endpoint").
  • secretory activity is also measured as a proportion of subjects at Cycle 3 Day 24 ⁇ 1 day on active treatment (200 mg progesterone/day, 225 mg progesterone/day, or 300 mg progesterone/day) compared to placebo with total secretory activity (defined as the aggregate of partial and complete secretory activity) on endometrial biopsy. Included in this measurement is an observation of the proportion of subjects reporting withdrawal bleeding at cycle 2 on or after cycle day 21 or within 7 days (including 7th day) after completion of blinded treatment at cycle 2 (this and the secretor ⁇ ' measurement of the preceding sentence are referenced in the examples as the "secondary efficacy endpoints").
  • Pharmacokinetics of the pharmaceutical composition disclosed herein can be calculated using statistical analyses.
  • Analysis of Variance (“ANOVA") or Analysis of CoVariance (“ANCOVA”) are used to evaluate differences between a subject receiving treatment with a pharmaceutical composition comprising an active pharmaceutical composition (for example, a pharmaceutical composition comprising progesterone) and a subject receiving treatment with a placebo (for example, the same pharmaceutical composition but without progesterone) or a reference drag.
  • a person of ordinary skill in the art will understand how to perform statistical analysis of the data collected.
  • PK parameters for pharmacokinetic evaluation and analysis including, but not limited to, AUC, Cmax, and T ma x.
  • the pharmacokinetic evaluation was carried out by a research lab using statistical and analytical software, which could include, but is not limited to, WinNonlin ⁇ software (version 5.3), and using SAS version 9.2.
  • embodiments of the invention have been invented that have one or more favorable characteristics for development as a human drug product.
  • favorable characteristics include those described above, e.g., improved PK properties and reduced inter- and intra-patient 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 ultra-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.
  • the progesterone can be ultramicronized.
  • the progesterone is suspended or solubilized in one or more solubilizmg agents such as one or more C6 to CI 4 fatty acid mono-, di-, or triesters of glycerol, including, but not limited to, one or more C6 to C14 triglycerides, one or more C6 to CI 2 triglycerides, or one or more C8-C10 triglycerides, as well as combinations thereof.
  • MIGLYOL and in particular MIGLYOL 812.
  • the non-ionic surfactant is a polyethylene glycol saturated or unsaturated fatty acid ester or diester.
  • the non-ionic surfactant comprises C8 to C 18 fatty acid esters of glycerol and polyethylene glycol.
  • GELUCIRE e.g., GELUCIRE 44/14.
  • the non-ionic surfactant has a HLB value of about 15.
  • An illustrative example of such surfactant is G ELUCIRE. 44/14.
  • a capsule is provided containing a fill material comprising a formulation set forth in one of Tables 2, 2A, or 2B
  • the formulation in Table 2 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.
  • the formulations in Tables 2 A. and 2B are prepared as follows: melt Gelucire 44/14 by heating it to about 45 ⁇ 50°C; once Gelucire 44/14 is completely melted, add MIG YOL 812 and mix/stir until dissolved; continue mixing/stirring; during the mixing/stirring, slowly add progesterone to the solution; and, after all progesterone has been added, continue mixing for a period of time to ensure proper suspension and near dissolution equilibrium. The suspended progesterone is then passed through a colloid mill. De-gassing and applying a vacuum for complete de-aeration of the fill mass is conducted. The resultant fill mass can be used for encapsulation.
  • a capsule containing a fill material comprising:
  • 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
  • both estradiol and progesterone may be independently dissolved in a solubilizing agent.
  • 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 Img and 1200mg, preferably suitable for encapsulation in a size 3 to 22 oval or oblong capsule.
  • 50mg to lOOmg of progesterone may be dissolved in a volume of solubilizing agent; 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).
  • MIGLYOL including without limitation MIGLYOL 812, may be used in embodiments comprising fully solubilized, partially solubilized, and suspended progesterone.
  • the solubility of progesterone in CAPMUL VI ( VI 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.
  • the capsule size required to make a capsule of 50 mg solubilized progesterone would be 685 mg.
  • a 50 mg progesterone capsule would require a 526 capsule size.
  • the other capsule sizes required based on each respective solubility below includes: 1,799 mg, 579 mg, 709 mg, and 871 mg. Capsule size amounts based on respective solubilities will generally be at least 10% greater than the calculated value in order to ensure the progesterone remains in solution. Thus, a 50 mg progesterone capsule based on 73 mg/g solubility would require a 685 mg capsule, and with the at least 10% addition, it would require approximately a 754 mg sized capsule. Based on each respective solubility listed below, the capsule sizes include (approximately): 579 mg, 1979 mg, 637 mg, 780 mg, and 958 mg respectively. These values, and their corresponding 10% additions are shown in Table 4. TABLE 4
  • progesterone or estradiol may be dissolved in a CAPMUL MCM and GELUCIRE 44/14 system, wherein the ratio of CAPM UL MCM to GELUCI RE 44/14 is 9: 1.
  • a capsule containing a fill material having suspended progesterone comprising: TABLE 6
  • 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.
  • a capsule containing a fill material having partially solubilized progesterone comprising:
  • 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.
  • a capsule is provided containing a pharmaceutical composition having fully solubilized, partially solubilized, or suspended progesterone comprising the components according to the formulations specified in Tables 8 and 9: TABLE 8
  • composition above can be prepared in accordance with the procedures noted in prior examples.
  • a gel mass can be prepared in order to encapsulate the pharmaceutical compositions of the various Examples herein.
  • Gel mass compositions were formulated and produced according to the following steps. Purified water (22.2 kg) and glycerin (10.8 kg) were charged into a stainless steel tank with mixing and heated to a temperature of 80 ⁇ 5 °C. Hydrolyzed gelatin (1.8 kg) and gelatin 200 bloom limed bone, NF (24.0 kg) were then added to the water/glycerin mixture and were mixed until all solids were completely dissolved. This resulted in the formation of a gel mass. The resulting gel mass was de-gassed under vacuum. Coloring agents OPATINT® white (0,6 kg) and OPATINT® red (0.6 kg) were then added to the gel mass and the resultant was mixed for about 5 minutes. The resultant was then de-gassed under vacuum for a sufficient period of time and ultimately passed to an encapsulation device for preparation of gel capsules of the types disclosed herein.
  • a randomized single-dose oral bioequivalence study comparing 200 mg ultra- micronized progesterone capsule test product (T) and 200 mg PRO ETRIUM® (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 Cmax, AUG and optionally Tmax. Comparative bioavailability of the test product (T) and reference product are assessed.
  • test product T
  • R reference product
  • 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.
  • Operation 102 comprises mixing a carrier, a lubricant, and an antioxidant as described herein.
  • 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.
  • Operation 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.
  • Operation 104 may comprise mixing ultra-micronized progesterone into the mixture of the carrier, the lubricant, and the antioxidant. A pasty substance is thus formed . Mixing may occur in a steel tank or vat. Mixing may be facilitated by an impellor, agitator, or other suitable means. Operation 104 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N2. Operation 106 comprises degasing. The resulting mixture from operation 106 may comprise a fill material suitable for production into a softgel capsule.
  • Operation 202 comprises mixing glyercin with water.
  • the water used in operation 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.
  • Operation 202 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N 2 . Heating may be performed until the temperature reaches 80 D ⁇ 5 D C.
  • Operation 204 comprises the addition of gelatin to the glycerin water mixture. Mixing may be facilitated by an impellor, agitator, or other suitable means. Operation 204 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N 2 . A vacuum may be drawn in operation 204 to de-aerate.
  • N 2 nitrogen gas
  • Operation 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.
  • Operation 206 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N 2 .
  • Operation 208 comprises degasing. The resulting mixture from operation
  • 208 may comprise a gel capsule material suitable for use as a gel capsule in production of a softgel capsule.
  • softgel capsule assembly process 300 is shown. Operation 302 comprises heating the fill material.
  • the fill material may be heated to any suitable temperature. In various embodiments, the fill material is 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 or to dispense the fill material in controlled volumes.
  • Operation 304 comprises filling a gel mass.
  • A. gel mass may be taken from the gel capsule material produced in operation 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 MIGLYOL 812. Operation 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).
  • Operation 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.
  • 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.
  • 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.
  • 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.
  • a particle size analysis is conducted by using a Beckman Coulter LS 13 320 Laser
  • 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 um, an X75 of 14.78 jim, and an X25 of 2, 193 ⁇
  • 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 (250 mL) of a solution of. IN 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.
  • formulation 402 reaches a higher level of dissolution in a shorter time than existing product 404.
  • a particle size analysis is conducted by using the Beckman Device.
  • a sample API comprising ultra-micronized progesterone in accordance with various embodiments is provided for analysis.
  • Dissolution studies were performed using a formulation of this invention comparing the dissolution of progesterone to the dissolution of PROM ETRRJ and comparing the dissolution of estradiol to the dissolution of Estrace.
  • a formulation of the invention in capsules comprising 200 mg of progesterone and 2 mg estradiol was used.
  • a formulation of the invention in capsules comprising 50 mg of progesterone and 2 mg estradiol was used.
  • 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 0.1N HQ with 3% sodium lauryl sulfate was used at 37 C.
  • the study was an open-label, balanced, randomized, single-dose, two- treatment, three-period, three-sequence, crossover, partial replicate, reference-scaled oral bioequivalence study.
  • a total of 72 healthy, adult, human, postmenopausal female subjects were enrolled in the study.
  • Each subject was randomly assigned to a sequence (TRR, RTR, or RRT) such that each subject received T once and R twice during the course of the 32 day study (14 day washout between doses).
  • R was administered twice so that the within subject variance could be calculated for later assessment of bioequivalence of the T and R formulations.
  • T demonstrated improved bioavai lability compared to PROMETRIUM and was considered superior to PROMETRIUM, Supporting data is shown in Tables 12 and 13 below.
  • TABLE 12 Point of estimate, Within-subject SD (Sw r ) and 95% Upper Confidence Bound of Test product (T) versus Reference product (R) for, Progesterone (Baselme corrected)
  • progesterone administered include 225 mg/day and 300 mg/day of progesterone.
  • Progesterone capsule sizes are 75 mg and 150 mg capsules.
  • Subjects taking the progesterone capsules are compared to subjects taking placebos. In both cases subjects are estrogen-primed.
  • the study includes: approximately a 6-week (42 days) screening period before enrolling into the study; approximately 6 weeks of Estrace®-priming before randomization; 6 weeks of blinded treatment (along with Estrace ⁇ treatment); and up to approximately 5 weeks of follow-up.
  • the study is a phase 3, randomized, three-cycle, double-blind, placebo- controlled study to evaluate induction of secretory conversion of endometrium and withdrawal bleeding after admin stration of progesterone in estrogen- primed women with secondary amenorrhea.
  • baseline— Cycle 1, day 1 subjects are estrogen-primed using an oral estradiol (i.e. 1 .0 mg Estrace®). This priming takes place for 25 days. Compliance with estrogen-priming is determined (throughout, and at day 28 -3 day to + 1 day ).
  • Subjects will begin cycle 2 of estrogen-priming (Cycle 2, day 1),
  • Estrace® 1 .0 mg is re-started at Cycle 3, Day 1 and continued until Day 25. Subjects will return to the clinic at Cycle 2, Day 12 ( ⁇ 2d) for study assessments. At Cycle 3, Day 14, subjects will again begin taking blinded study medication through Day 25.
  • Subjects complete their final dose of Estrace® and blinded stud)' medication on Day 25 and return to the clinic for a follow-up visit approximately 10 days later (upon receipt of biopsy results). Final visit assessments are conducted. Subjects whose endometrial biopsy results show proliferative endometrium are prescribed a 14 day course of medroxyprogesterone acetate 10 mg [MP A] as standard-of-care treatment to counterbalance the effect of estrogen-induced endometrial proliferation. These subjects receive a follow 7 up telephone call at 2-4 weeks after completion of the MP A course and queried for the incidence of bleeding and adverse events. Unscheduled visits are allowed as needed.
  • progesterone soft gel capsules having the formulation disclosed in Table 9 as fill material and PROMETRiUM® soft gel capsule 200 mg in normal healthy, adult human male subjects under fasting conditions.
  • test product (T) or reference product (R) (as per a randomization schedule) was administered orally to each subject with 240 niL of water. There was a washout period of 14 days between treatments.
  • T and R had the following P parameters: TABLE 15: Summary of Primary Pharmacokinetic Profile of Test product (T), Progesterone soft gel Capsule 200 mg (Baseline Corrected)
  • T/R Ratio and 90% Confidence Intervals of Test product (T) versus Reference product (R) for, Progesterone (Baseline Corrected)
  • progesterone soft gel capsules having the formulation disclosed in Table 9 as fill material and PROMETRIUM® soft gei capsule 200 mg in normal healthy, adult human male subjects under fed conditions.
  • T and R had the following P parameters:
  • Table 18 Summary of Primary Pharmacokinetic Profile of Test product (T), Progesterone soft gel Capsule 200 mg (Baseline Corrected)

Abstract

L'invention concerne des formulations de progestérone, des méthodes pour utiliser ces formulations et leur paramètres pharmacocinétiques associés, dans des modes de réalisation particuliers. Les formulations selon l'invention permettent de réduire la quantité de progestérone administrée à un patient en ayant besoin tout en procurant les avantages d'une plus grande dose.
EP15768772.4A 2014-03-28 2015-03-27 Formulations de progestérone Withdrawn EP3122364A4 (fr)

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US7374779B2 (en) * 1999-02-26 2008-05-20 Lipocine, Inc. Pharmaceutical formulations and systems for improved absorption and multistage release of active agents
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