CA2977938A1

CA2977938A1 - Pharmaceutical formulations for treating endometriosis and uterine fibroids

Info

Publication number: CA2977938A1
Application number: CA2977938A
Authority: CA
Inventors: Jayanthy Jayanth; Kevin C. SPENCE; Gregory A. Mcclelland
Original assignee: Neurocrine Biosciences Inc; AbbVie Inc
Current assignee: Neurocrine Biosciences Inc; AbbVie Inc
Priority date: 2017-08-18
Filing date: 2017-09-01
Publication date: 2019-02-18

Abstract

The present disclosure relates to pharmaceutical compositions comprising a gonadotropin-releasing hormone (GnRH) antagonist and methods of preparing and using such compositions. The disclosure also relates to methods of facilitating release of a GnRH antagonist from a pharmaceutical composition.

Description

PHARMACEUTICAL FORMULATIONS FOR TREATING ENDOMETRIOSIS AND
UTERINE FIBROIDS
JOINT RESEARCH AGREEMENT
[0001] Subject matter disclosed in this application was made by or on behalf of AbbVie Inc. and/or Neurocrine Biosciences, Inc., whom are parties to a joint research agreement that was in effect on or before the effective filing date of this application, and such subject matter was made as a result of activities undertaken within the scope of the joint research agreement.
TECHNICAL FIELD

[0002] The present invention relates to pharmaceutical compositions and methods of use of such compositions.
BACKGROUND

[0003] Endometriosis is a disease in which tissue normally found in the uterine cavity (i.e., endometrium) is found outside the uterus, usually implanted on the peritoneal lining of the pelvis. Endometriosis affects an estimated 1 in 10 women of reproductive age and can cause pain, infertility, and sexual dysfunction. Growth of endometrial tissue outside of the uterine cavity is believed to be estrogen-dependent. Thus, current therapies for endometriosis are aimed at altering estrogen levels.

[0004] Uterine fibroids (leiomyomas) are benign tumors and are highly prevalent in women of reproductive age. Symptoms associated with uterine fibroids most commonly include heavy or prolonged menstrual bleeding, pelvic pressure and pelvic organ compression, back pain, and adverse reproductive outcomes. Heavy menstrual bleeding (HMB;
menorrhagia, defined as greater than 80 mL per menstrual cycle) (The Menorrhagia Research Group.
Quantification of menstrual blood loss. The Obstetrician & Gynaecologist.
2004; 6:88-92) is inconvenient and may lead to iron-deficiency anemia, which is the leading cause of surgical interventions that may include hysterectomy. Other symptoms, in particular pressure symptoms, are largely dependent on the size, number, and location of the tumors.

[0005] Although the pathogenesis has yet to be fully elucidated, the growth of uterine fibroids is known to be highly dependent on both estrogen and progestogen.
Fibroids tend to shrink after menopause due to a decrease in hormone production. On this basis, most medical treatments for women with symptomatic uterine fibroids are aimed at either hormone-blocking or hormone-modulating strategies.

[0006] Gonadotropin-releasing hormone (GnRH) is a peptide that stimulates the secretion of the pituitary hormones that are responsible for sex steroid production and normal reproductive function. GnRH agonists are used to treat endometriosis and uterine fibroids by suppressing the activity of the pituitary-gonadal axis. However, GnRH agonists cause an initial stimulation of gonadotropic and gonadal hormones, such as estrogen.

[0007] Peptide GnRH antagonists competitively bind to GnRH receptors in the pituitary gland, blocking the release of gonadotropins, such as luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary. Such peptide GnRH antagonists have been approved for oncology and assisted reproduction. However, administration is inconvenient, with peptide GnRH antagonists being delivered as daily subcutaneous injections or as long-acting depot formulations.

[0008] Thus, there is a need in the art for new orally administered treatments for endometriosis and uterine fibroids and, in particular, management of pain associated with endometriosis and heavy menstrual bleeding associated with uterine fibroids.
Moreover, there remains a need in the art to develop orally bioavailable dosage forms comprising such treatments and, in particular, a nonpeptide GnRH antagonist.
SUMMARY OF THE INVENTION

[0009] The disclosure is directed to pharmaceutical compositions comprising 44(R)-2-[5-(2-fluoro-3-methox y-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-meth y1-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)-butyric acid (Compound A) or a pharmaceutically acceptable salt thereof; methods of using such compositions;
and methods of facilitating the release of Compound A from such compositions.

[0010] The present application identifies at least two challenges to developing pharmaceutical formulations comprising Compound A or a pharmaceutically acceptable salt thereof. One challenge was that Compound A and, in particular, the monosodium salt of Compound A has a tendency to form a gel, particularly when present at an amount greater than about 10% by weight in the absence of an appropriate anti-gelling agent. Such gel formation limits the dissolution of API and, ultimately, can lead to highly variable inter-and intra patient bioavailability. Another challenge was that Compound A can degrade to form a compound having a lactam moiety (referred to herein as Compound B). Reducing conversion of the drug substance into its lactam-containing degradation product is desirable, for example, to maintain safety and efficacy over the life of the product. Thus, it has been determined in the present application that a preferred pharmaceutical composition reduces gelling of the API and/or reduces generation of the lactam degradation product (i.e., Compound B).

[0011] In one aspect, the disclosed pharmaceutical compositions comprise Compound A
or a pharmaceutically acceptable salt thereof, and at least one anti-gelling agent.

[0012] In certain embodiments, the salt of Compound A is the monosodium salt (sodium 44(R)-2-[5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y11-1-phenyl-ethylamino)butanoate).

[0013] In certain embodiments, the anti-gelling agent facilitates release of Compound A
or a pharmaceutically acceptable salt thereof from a solid dosage form, such as a tablet.

[0014] In certain embodiments, the anti-gelling agent also acts as a stabilizer to, for example, reduce formation of (R)-5-(2-fluoro-3-methoxypheny1)-1-(2-fluoro-6-(trifluoromethyl)benzy1)-6-methy1-3-(2-(2-oxopyrrolidin-1-y1)-2-phenylethyl)pyrimidine-2,4(1H,3H)-dione (Compound B) in the composition relative to an otherwise identical composition without the anti-gelling agent.

[0015] In certain embodiments, the anti-gelling agent acts as a buffer.

[0016] In certain embodiments, the anti-gelling agent is an alkali metal salt, such as sodium carbonate. Sodium carbonate may be either sodium carbonate monohydrate or sodium carbonate anhydrous.

[0017] In certain embodiments, the weight ratio of Compound A or a pharmaceutically acceptable salt thereof to the anti-gelling agent is from about 1:1 to about 4:1.

[0018] In certain embodiments, the weight ratio of Compound A or a pharmaceutically acceptable salt thereof to the anti-gelling agent is about 2:1.

[0019] In certain embodiments, the anti-gelling agent is present in the pharmaceutical composition in an amount from about 5% to about 35% by weight of the pharmaceutical composition.

[0020] In certain embodiments, the anti-gelling agent is present in the pharmaceutical composition in an amount from about 15% to about 25% by weight of the pharmaceutical composition.

[0021] In certain embodiments, the pharmaceutical composition further comprises at least one additional excipient selected from the group consisting of a binder, a filler, a lubricant, a glidant, and a combination thereof.

[0022] In certain embodiments, the binder is polyvinylpyrrolidone.

[0023] In certain embodiments, the filler is a starch and/or mannitol. In certain embodiments, the filler is a water soluble filler, such as mannitol or pregelitanized starch or a combination thereof. In certain embodiments, the filler is a water insoluble filler, such as microcrystalline cellulose. In some such embodiments, the pharmaceutical composition further comprises a surfactant, such as sodium lauryl sulfate.

[0024] In certain embodiments, the lubricant is magnesium stearate.

[0025] In certain embodiments, the glidant is colloidal silicon dioxide.

[0026] In certain embodiments, the pharmaceutical composition is an oral dosage form.
In some such embodiments, the oral dosage form is a tablet.

[0027] In certain embodiments, the pharmaceutical composition comprises Compound A
or a pharmaceutically acceptable salt thereof in an amount of about 100 mg to about 600 mg; and at least about 10% by weight of the anti-gelling agent. In certain embodiments, the pharmaceutical composition comprises Compound A or a pharmaceutically acceptable salt thereof in an amount of about 100 mg to about 350 mg; and at least about 10%
by weight of the anti-gelling agent.

[0028] In one aspect, the disclosed pharmaceutical compositions comprise about 150 mg of Compound A or a pharmaceutically acceptable salt thereof, at least one anti-gelling agent, and, optionally, at least one binder. In certain embodiments, the anti-gelling agent is sodium carbonate, such as sodium carbonate monohydrate. In some such embodiments, the weight ratio of Compound A or a pharmaceutically acceptable salt thereof to sodium carbonate is about 2:1.
In certain embodiments, the binder is polyvinylpyrrolidone. In certain embodiments, the salt of Compound A is the monosodium salt (sodium 44(R)-2-[5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-l-y1]-1-phenyl-ethylamino)butanoate). In some such embodiments, the weight ratio of sodium 4-((R)-2-[5-(2-fluoro-3-methox y-pheny1)-3-(2-fluoro-6-trifluorometh yl-benzy1)-4-meth y1-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)butanoate to sodium carbonate monohydrate is about 2:1.

[0029] In another aspect, the disclosed pharmaceutical compositions comprise about 200 mg of Compound A or a pharmaceutically acceptable salt thereof, at least one anti-gelling agent, and, optionally, at least one binder. In certain embodiments, the anti-gelling agent is sodium carbonate, such as sodium carbonate monohydrate. In some such embodiments, the weight ratio of Compound A or a pharmaceutically acceptable salt thereof to sodium carbonate is about 2:1.
In certain embodiments, the binder is polyvinylpyrrolidone. In certain embodiments, the salt of Compound A is the monosodium salt (sodium 44(R)-2-[5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)butanoate). In some such embodiments, the weight ratio of sodium 44(R)-2-[5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)butanoate to sodium carbonate monohydrate is about 2:1.

[0030] In still another aspect, the disclosed pharmaceutical compositions comprise about 300 mg of Compound A or a pharmaceutically acceptable salt thereof, at least one anti-gelling agent, and, optionally, at least one binder. In certain embodiments, the anti-gelling agent is sodium carbonate, such as sodium carbonate monohydrate. In some such embodiments, the weight ratio of Compound A or a pharmaceutically acceptable salt thereof to sodium carbonate is about 2:1. In certain embodiments, the binder is polyvinylpyrrolidone. In certain embodiments, the salt of Compound A is the monosodium salt (sodium 44(R)-245-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)butanoate). In some such embodiments, the weight ratio of sodium 4-((R)-2-[5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)butanoate to sodium carbonate monohydrate is about 2:1.

[0031] In certain embodiments, the pharmaceutical composition is a tablet comprising sodium 44(R)-2-{5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y11-1-phenyl-ethylamino)butanoate in an amount equivalent to about 125 mg to about 175 mg, preferably about 150 mg of Compound A; and at least about 10%, preferably between about 15% and about 20%, by weight of the anti-gelling agent; wherein the tablet when administered as a single dose to a population of human subjects provides an average Tmax value that is less than about 3 hours, and preferably less than about 2 hours, for the population of human subjects. In certain embodiments, the pharmaceutical composition is a tablet sodium 44(R)-245-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-l-y1]-1-phenyl-ethylamino)butanoate in an amount equivalent to about 175 mg to about 225 mg, preferably about 200 mg of Compound A; and at least about 10%, preferably between about 15% and about 20%, by weight of the anti-gelling agent; wherein the tablet when administered as a single dose to a population of human subjects provides an average Tmax value that is less than about 3 hours, and preferably less than about 2 hours, for the population of human subjects.
In certain embodiments, the pharmaceutical composition is a tablet comprising sodium 44(R)-245-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yI]-1-phenyl-ethylamino)butanoate in an amount equivalent to about 275 mg to about 325 mg, preferably about 300 mg of Compound A; and at least about 10%, preferably between about 15% and about 20%, by weight of the anti-gelling agent; wherein the tablet when administered as a single dose to a population of human subjects provides an average Tmax value that is less than about 3 hours, and preferably less than about 2 hours, for the population of human subjects.

[0032] In certain embodiments, the pharmaceutical composition is a tablet comprising sodium 44(R)-2-[5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)butanoate in an amount equivalent to about 125 mg to about 175 mg, preferably about 150 mg of Compound A; and at least about 10%, preferably between about 15% and about 20%, by weight of the anti-gelling agent; wherein the tablet when administered as a single dose to a population of human subjects provides an average Cmax value that is at least about 380 ng/mL for the population of human subjects. In certain embodiments, the pharmaceutical composition is a tablet comprising sodium 44(R)-2-[5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)butanoate in an amount equivalent to about 175 mg to about 225 mg, preferably about 200 mg of Compound A; and at least about 10%, preferably between about 15% and about 20%, by weight of the anti-gelling agent; wherein the tablet when administered as a single dose to a population of human subjects provides an average Cimix value that is at least about 550 ng/mL for the population of human subjects. In certain embodiments, the pharmaceutical composition is a tablet comprising sodium 4-((R)-2-[5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)butanoate in an amount equivalent to about 275 mg to about 325 mg, preferably about 300 mg of Compound A; and at least about 10%, preferably between about 15% and about 20%, by weight of the anti-gelling agent; wherein the tablet when administered as a single dose to a population of human subjects provides an average CIMIX value that is at least about 1030 ng/mL for the population of human subjects.

[0033] In certain embodiments, the pharmaceutical composition is a tablet comprising sodium 44(R)-215-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y11-1-phenyl-ethylamino)butanoate in an amount equivalent to about 125 mg to about 175 mg, preferably about 150 mg of Compound A; and at least about 10%, preferably between about 15% and about 20%, by weight of the anti-gelling agent; wherein the tablet when administered as a single dose to a population of human subjects provides an average AUCt value that is at least about 940 ng=h/mL for the population of human subjects. In certain embodiments, the pharmaceutical composition is a tablet comprising sodium 44(R)-2-[5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)butanoate in an amount equivalent to about 175 mg to about 225 mg, preferably about 200 mg of Compound A; and at least about 10%, preferably between about 15% and about 20%, by weight of the anti-gelling agent; wherein the tablet when administered as a single dose to a population of human subjects provides an average AUCt value that is at least about 1410 ng=h/mL for the population of human subjects. In certain embodiments, the pharmaceutical composition is a tablet comprising sodium 44(R)-2-15-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)butanoate in an amount equivalent to about 275 mg to about 325 mg, preferably about 300 mg of Compound A; and at least about 10%, preferably between about 15% and about 20%, by weight of the anti-gelling agent; wherein the tablet when administered as a single dose to a population of human subjects provides an average AUCt value that is at least about 2800 ng=h/mL for the population of human subjects.

[0034] In certain embodiments, the pharmaceutical composition is a tablet comprising sodium 44(R)-2-[5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)butanoate in an amount equivalent to about 125 mg to about 175 mg, preferably about 150 mg of Compound A; and at least about 10%, preferably between about 15% and about 20%, by weight of the anti-gelling agent; wherein the tablet when administered as a single dose to a population of human subjects provides an average AUG, value that is at least about 950 ng=h/mL for the population of human subjects. In certain embodiments, the pharmaceutical composition is a tablet comprising sodium 44(R)-2-[5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y11-1-phenyl-ethylamino)butanoate in an amount equivalent to about 175 mg to about 225 mg, preferably about 200 mg of Compound A; and at least about 10%, preferably between about 15% and about 20%, by weight of the anti-gelling agent; wherein the tablet when administered as a single dose to a population of human subjects provides an average AUG, value that is at least about 1430 ng-h/mL for the population of human subjects. In certain embodiments, the pharmaceutical composition is a tablet comprising sodium 4-((R)-2-[5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluorometh yl-benzy1)-4-methy1-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)butanoate in an amount equivalent to about 275 mg to about 325 mg, preferably about 300 mg of Compound A; and at least about 10%, preferably between about 15% and about 20%, by weight of the anti-gelling agent; wherein the tablet when administered as a single dose to a population of human subjects provides an average AUGDo value that is at least about 2820 ng=h/mL for the population of human subjects.

[0035] The disclosure is also directed to pharmaceutical compositions comprising Compound A or a pharmaceutically acceptable salt thereof and an amount of an alkali metal salt sufficient to facilitate release of Compound A or the pharmaceutically acceptable salt thereof from the composition.

[0036] In certain embodiments, the release is measured using USP apparatus II in 900 mL of sodium phosphate, pH 6.8, at 37 C and paddle speed of 50 rpm.

[0037] In certain embodiments, the release is measured using USP Apparatus II in 900 mL of hydrochloric acid, pH 1.2, at 37 C and paddle speed of 50 rpm.

[0038] In certain embodiments, the alkali metal salt also acts as a stabilizer.

[0039] In certain embodiments, the alkali metal salt acts as a buffer.

[0040] In certain embodiments, the weight ratio of Compound A or a pharmaceutically acceptable salt thereof to the alkali metal salt is from about 1:1 to about 4:1.

[0041] In certain embodiments, the weight ratio of Compound A or a pharmaceutically acceptable salt thereof to the alkali metal salt is about 2:1.

[0042] In certain embodiments, the alkali metal salt is present in the pharmaceutical composition in an amount from about 10% to about 30% by weight of the pharmaceutical composition.

[0043] In certain embodiments, the alkali metal salt is present in the pharmaceutical composition in an amount from about 15% to about 25% by weight of the pharmaceutical composition.

[0044] In certain embodiments, the pharmaceutical composition is an oral dosage form.

[0045] In certain embodiments, the oral dosage form is a tablet.

[0046] The disclosure is also directed to a solid oral dosage form, such as a tablet, comprising Compound A or a pharmaceutically acceptable salt thereof and sodium carbonate.

[0047] In certain embodiments, the salt of Compound A is a sodium salt.

[0048] In certain embodiments, the weight ratio of Compound A or a pharmaceutically acceptable salt thereof to sodium carbonate is from about 1:1 to about 4:1.

[0049] In certain embodiments, the weight ratio of Compound A or a pharmaceutically acceptable salt thereof to sodium carbonate is about 2:1.

[0050] In certain embodiments, sodium carbonate is present in the pharmaceutical composition in an amount from about 10% to about 30% by weight of the pharmaceutical composition.

[0051] In certain embodiments, sodium carbonate is present in the pharmaceutical composition in an amount from about 15% to about 25% by weight of the pharmaceutical composition.

[0052] The disclosure is also directed to methods of facilitating release of Compound A
or a pharmaceutically acceptable salt thereof from an oral dosage form.

[0053] In certain embodiments, the methods comprise preparing a pharmaceutical composition comprising at least one anti-gelling agent and Compound A or a pharmaceutically acceptable salt thereof.

[0054] Compound A has a tendency to form a gel in the presence of water, further complicating the development process. Thus, in one aspect this disclosure provides methods of manufacturing a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof in the substantial absence of water. In certain embodiments, the pharmaceutical composition is manufactured using a roller compaction process.

[0055] The disclosure is also directed to methods for treating endometriosis in a subject in need of such treatment, wherein the method comprises administering to the subject a pharmaceutical composition of the present disclosure. In some such embodiments, the pharmaceutical composition is administered to the subject once daily (QD). In some such embodiments, the pharmaceutical composition is administered to the subject twice daily (BID).

[0056] The disclosure is also directed to pharmaceutical compositions for use in treating endometriosis.

[0057] The disclosure is also directed to methods for treating uterine fibroids in a subject in need of such treatment, wherein the method comprises administering to the subject a pharmaceutical composition of the present disclosure. In some such embodiments, the pharmaceutical composition is administered to the subject once daily (QD). In some such embodiments, the pharmaceutical composition is administered to the subject twice daily (BID).

[0058] The disclosure is also directed to pharmaceutical compositions for use in treating uterine fibroids.

[0059] The disclosure is also directed to methods for providing rapid suppression of luteinizing hormone (LH) and/or follicle-stimulating hormone (FSH) in a female patient with endometriosis or uterine fibroids, wherein the method comprises administering to the female patient a pharmaceutical composition of the present disclosure. In some such embodiments, the pharmaceutical composition is administered to the subject once daily (QD). In some such embodiments, the pharmaceutical composition is administered to the female patient twice daily (BID).

[0060] The disclosure is also directed to pharmaceutical compositions for use in providing rapid suppression of LH and/or FSH in a female patient with endometriosis or uterine fibroids.

[0061] The disclosure is also directed to methods for providing partial to substantially full suppression of estradiol in a female patient with endometriosis or uterine fibroids, wherein to the method comprises administering to the subject a pharmaceutical composition of the present disclosure. In some such embodiments, the pharmaceutical composition is administered to the female patient once daily (QD). In some such embodiments, the pharmaceutical composition is administered to the female patient twice daily (BID).

[0062] The disclosure is also directed to pharmaceutical compositions for use in providing partial to substantially full suppression of estradiol in a female patient with endometriosis or uterine fibroids.

[0063] These and other objects of the invention are described in the following paragraphs. These objects should not be deemed to narrow the scope of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS

[0064] Figure 1 is a roller compaction process flow diagram.

[0065] Figure 2 is a plot showing apparent solubility of Compound A in water.

[0066] Figure 3 is a two-step wet granulation process flow diagram.

[0067] Figure 4 is a graph showing an in vitro dissolution profile for Formulation F5 after storage for 18 or 24 months.

[0068] Figure 5 is a graph showing an in vitro dissolution profile for Formulation F6 after storage for 1, 3, 6, or 9 months.

[0069] Figure 6 is a graph showing an in vitro dissolution profile for Formulation F10 (uncoated and film-coated tablets).

[0070] Figure 7 is a graph showing an in vitro dissolution profile for compositions containing varying amounts of sodium carbonate monohydrate.

[0071] Figure 8 is a bar graph showing percentage of a degradation product (Compound B) after storage for one week.

[0072] Figure 9 is a bar graph showing formation rate of a degradation product (Compound B) under various storage conditions.
DETAILED DESCRIPTION OF THE INVENTION

[0073] This detailed description is intended only to acquaint others skilled in the art with the present invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This description and its specific examples are intended for purposes of illustration only. This invention, therefore, is not limited to the embodiments described in this patent application, and may be variously modified.

[0074] A. DEFINITIONS

[0075] As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated:

[0076] The term "API" as used herein stands for "active pharmaceutical ingredient." The preferred API as disclosed herein is 44(R)-245-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-l-y11-1-phenyl-ethylamino)-butyric acid (Compound A) or a pharmaceutically acceptable salt thereof and, preferably is sodium 44(R)-245-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)butanoate.

[0077] As used herein, the term "pharmaceutical composition" means a composition comprising Compound A or a pharmaceutically acceptable salt thereof and, optionally, one or more pharmaceutically acceptable excipients.

[0078] The term "pharmaceutically acceptable" is used adjectivally to mean that the modified noun is appropriate for use as a pharmaceutical product for human use or as a part of a pharmaceutical product for human use.

[0079] The term "subject" includes humans and other primates as well as other mammals. The term subject includes, for example, a healthy premenopausal female as well as a female patient having, for example, endometriosis or uterine fibroids. In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult human female. In certain embodiments, the subject is a woman, typically a premenopausal woman, having endometriosis.
In certain embodiments, the subject is a woman, typically a premenopausal woman, having uterine fibroids.

[0080] The term "therapeutically effective amount" means a sufficient amount of the API
or pharmaceutical composition to treat a condition, disorder, or disease, at a reasonable benefit/risk ratio applicable to any medical treatment.

[0081] The terms "treat", "treating" and "treatment" refer to a method of alleviating or abrogating a condition, disorder, or disease and/or the attendant symptoms thereof.

[0082] B. DRUG SUBSTANCE

[0083] Pharmaceutical compositions disclosed herein comprise at least one active pharmaceutical ingredient: 44(R)-245-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)-butyric acid (Compound A) or a pharmaceutically acceptable salt thereof.

[0084] Compound A has the following formula:
,CH3 (R) LF

[0085] Compound A is an orally active, non-peptide GnRH antagonist and is unlike other GnRH agonists and injectable (peptide) GnRH antagonists. Compound A produces a dose dependent suppression of pituitary and ovarian hormones in women. Methods of making Compound A and a pharmaceutically acceptable salt thereof, as well as similar compounds, are described in W02001/055119 and WO 2005/007165, the contents of which are herein incorporated by reference.

[0086] In certain embodiments, 44(R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y11-1-phenyl-ethylamino)-butyric acid exists in zwitterionic form. For example, both the carboxylic acid and the tertiary amine are ionized and, thus, the molecule has no overall charge but does have charge separation. Such zwitterionic forms are included within the scope of the term "Compound A or a pharmaceutically acceptable salt thereof."

[0087] Compound A may be present in a pharmaceutical composition in the form of acid or base addition salts. Acid addition salts of the free amino compounds of the present invention may be prepared by methods well known in the art, and may be formed from organic and inorganic acids. Suitable organic acids include maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, trifluoroacetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids. Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids. Suitable base addition salts include those salts that form with the carboxylate anion and include salts formed with organic and inorganic cations such as those chosen from the alkali and alkaline earth metals (for example, lithium, sodium, potassium, magnesium, barium and calcium), as well as the ammonium ion and substituted derivatives thereof (for example, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, and the like). Thus, the term "pharmaceutically acceptable salt" of Compound A is intended to encompass any and all acceptable salt forms.

[0088] In certain embodiments, Compound A is present in a pharmaceutical composition in the form of a pharmaceutically acceptable salt. In certain embodiments, a pharmaceutically acceptable salt of Compound A is the sodium salt of Compound A. The monosodium salt of Compound A has a molecular formula of C32H29F5N305Na, which corresponds to a molecular weight of about 653.6 (salt) and about 631.6 (free form). The monosodium salt of Compound A
has the following formula:
,01-13 (R) =NH I

Na -0

[0089] In certain embodiments, the monosodium salt is in the form of an amorphous solid. In certain embodiments, the monosodium salt is in crystalline form, such as a partially crystalline form.

[0090] As used herein, and in the absence of a specific reference to a particular pharmaceutically acceptable salt of Compound A, any dosages, whether expressed in milligrams or as a percentage by weight or as a ratio with another ingredient, should be taken as referring to the amount of Compound A free form.

[0091] In certain embodiments, Compound A or a pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 45 mg to about 650 mg of Compound A. In certain embodiments, the amount of Compound A, or pharmaceutically acceptable salt thereof, is from about 50 mg to about 400 mg. In certain embodiments, the amount of Compound A, or pharmaceutically acceptable salt thereof, is from about 100 mg to about 350 mg. In some such embodiments, the amount of Compound A, or pharmaceutically acceptable salt thereof, is from about 140 mg to about 160 mg, preferably about 150 mg. In other such embodiments, the amount of Compound A, or pharmaceutically acceptable salt thereof, is from about 190 mg to about 210 mg, preferably about 200 mg. In still other embodiments, the amount of Compound A, or pharmaceutically acceptable salt thereof, is from about 290 mg to about 310 mg, preferably about 300 mg.

[0092] C. PHARMACEUTICAL COMPOSITIONS

[0093] Pharmaceutical compositions comprising Compound A or a pharmaceutically acceptable salt thereof may be used to treat endometriosis or uterine fibroids. Pharmaceutical compositions or dosage forms as described herein may preferably be oral dosage forms, and, in particular, solid oral dosage forms, which can be administered to humans. An oral dosage form may be in the form of, for example, capsules, granules, granulates, pellets, pills, powders, caplets and/or tablets.

[0094] The present disclosure provides pharmaceutical formulations and functional excipients to, inter alia, facilitate drug dissolution and/or enhance stability of the drug product and/or drug substance (e.g., by controlling the formation of degradation products).

[0095] In certain embodiments, the pharmaceutical composition is an immediate release pharmaceutical composition. The development of an immediate release tablet for Compound A
was not straightforward. Initial tablets prepared by granulating Compound A
with typical pharmaceutical excipients showed incomplete dissolution of Compound A into 900 mL of pH
1.2 buffer. If the percent of drug in the tablet exceeded 10%, only 30-40% of the drug load was dissolved. The remaining amount of Compound A was present as an insoluble precipitate at the top of the dissolution vessels.

[0096] In at least one aspect, the pharmaceutical compositions comprising Compound A
or a pharmaceutically acceptable salt thereof include an anti-gelling agent.

[0097] As referred to herein, an "anti-gelling agent" is an agent that reduces or prevents gel formation. In certain embodiments, the anti-gelling agent reduces or prevents gel formation relative to an otherwise identical composition without the anti-gelling agent.
In certain embodiments, the anti-gelling agent reduces or prevents gel formation such that release of Compound A or a pharmaceutically acceptable salt thereof from a composition is facilitated. In certain embodiments, the anti-gelling agent improves release of Compound A or a pharmaceutically acceptable salt thereof from a pharmaceutical composition relative to that same pharmaceutical composition without the anti-gelling agent.

[0098] In certain embodiments, the anti-gelling agent is present in the pharmaceutical composition in an amount from about 3% to about 50% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the anti-gelling agent is present in the pharmaceutical composition in an amount from about 5% to about 35% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the anti-gelling agent is present in the pharmaceutical composition in an amount from about 10% to about 25% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the anti-gelling agent is present in the pharmaceutical composition in an amount from about 15% to about 20% by weight (w/w) of the pharmaceutical composition.

[0099] In certain embodiments, the pharmaceutical composition is a film-coated tablet. In some such embodiments, the anti-gelling agent is present in an amount from about 3% to about 50%, alternatively from about 5% to about 35%, alternatively from about 10% to about 25%, alternatively from about 15% to about 20%, by weight of the uncoated tablet.
In some such embodiments, the anti-gelling agent is present in an amount from about 3% to about 50%, alternatively from about 5% to about 35%, alternatively from about 10% to about 25%, alternatively from about 15% to about 20%, by weight of the coated tablet.

[00100] In certain embodiments, the weight ratio of Compound A or a pharmaceutically acceptable salt thereof to the anti-gelling agent is from about 0.5:1 to about 4:1. In certain embodiments, the weight ratio of Compound A or a pharmaceutically acceptable salt thereof to the anti-gelling agent is from about 1:1 to about 3:1. In certain embodiments, the weight ratio of Compound A or a pharmaceutically acceptable salt thereof to the anti-gelling agent is about 2:1.

[00101] In certain embodiments, the anti-gelling agent comprises a water soluble salt of a weak acid, such as a carbonate (e.g., sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate), an acetate (e.g., sodium acetate, potassium acetate, ammonium acetate), or a phosphate (e.g., mono-, di-, or tri-sodium phosphate), or a combination thereof.

[00102] In certain embodiments, the anti-gelling agent comprises a basic amino acid, such as arginine, lysine, histidine, or combinations thereof. In certain embodiments, the buffering agent comprises poly(meth)acrylate polymers, such as Eudragit E 100, Eudragit E 12, Eudragit E
5, Eudragit E PO, or combinations thereof.

[00103] In certain embodiments, the anti-gelling agent comprises an alkali metal salt or a combination thereof. Exemplary alkali metal salts include sodium carbonate, sodium hydrogen carbonate, or sodium phosphate.

[00104] In certain embodiments, the alkali metal salt is present in an amount sufficient to provide a microenvironment to reduce or prevent gel formation. In certain embodiments, the alkali metal salt is present in an amount sufficient to provide a microenvironment to facilitate release of Compound A or the pharmaceutically acceptable salt thereof from the tablet in an aqueous medium. In certain embodiments, the microenvironment to facilitate release of Compound A or the pharmaceutically acceptable salt thereof from the tablet comprises a pH of about 3.5 to about 8Ø

[00105] In certain embodiments, the anti-gelling agent is sodium carbonate, such as sodium carbonate monohydrate or sodium carbonate anhydrous.

[00106] In certain embodiments, sodium carbonate is present in the pharmaceutical composition in an amount from about 3% to about 50% by weight (w/w) of the pharmaceutical composition. In certain embodiments, sodium carbonate is present in the pharmaceutical composition in an amount from about 5% to about 35% by weight (w/w) of the pharmaceutical composition. In certain embodiments, sodium carbonate is present in the pharmaceutical composition in an amount from about 10% to about 25% by weight (w/w) of the pharmaceutical composition. In certain embodiments, sodium carbonate is present in the pharmaceutical composition in an amount from about 15% to about 20% by weight (w/w) of the pharmaceutical composition.

[00107] In certain embodiments, the pharmaceutical composition is a film-coated tablet. In some such embodiments, sodium carbonate is present in an amount from about 3%
to about 50%, alternatively from about 5% to about 35%, alternatively from about 10% to about 25%, alternatively from about 15% to about 20%, by weight of the uncoated tablet.
In some such embodiments, sodium carbonate is present in an amount from about 3% to about 50%, alternatively from about 5% to about 35%, alternatively from about 10% to about 25%, alternatively from about 15% to about 20%, by weight of the coated tablet.

[00108] In certain embodiments, the weight ratio of Compound A or a pharmaceutically acceptable salt thereof to sodium carbonate is from about 0.5:1 to about 4:1.
In certain embodiments, the weight ratio of Compound A or a pharmaceutically acceptable salt thereof to sodium carbonate is from about 1:1 to about 3:1. In certain embodiments, the weight ratio of Compound A or a pharmaceutically acceptable salt thereof to sodium carbonate is about 2:1.

[00109] In certain embodiments, the weight ratio of sodium 44(R)-2-[5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)butanoate to sodium carbonate monohydrate is from about 0.5:1 to about 4:1. In certain embodiments, the weight ratio of sodium 44(R)-245-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)butanoate to sodium carbonate monohydrate is from about 1:1 to about 3:1. In certain embodiments, the weight ratio of sodium 44(R)-2-[5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-l-y11-1-phenyl-ethylamino)butanoate to sodium carbonate monohydrate is about 2:1.

[00110] As used herein, and in the absence of a specific reference to a particular hydrate (or anhydrous) form of sodium carbonate, any amounts, whether expressed in milligrams or as a percentage by weight or as a ratio with another ingredient, should be taken as referring to the amount of sodium carbonate monohydrate.

[00111] Drugs administered via oral solid dosage forms should dissolve in viva before systemic absorption can take place. There are number of factors which affect drug dissolution, including physicochemical properties of the drug substance. Poorly water soluble drugs, such as BCS class II (low solubility and high permeability), often exhibit poor dissolution and bioavailability. Even highly soluble drugs, such as BCS class III (high solubility and low permeability), may exhibit poor dissolution and bioavailability. Incomplete dissolution may result in highly variable inter-and intra patient bioavailability. It has been determined in the present application that Compound A is a BCS class III drug. It also has been determined in the present application that the monosodium salt of Compound A has a tendency to form a gel, particularly when present at an amount greater than about 10% by weight in the absence of an appropriate anti-gelling agent. Thus, it is desirable to provide oral solid dosage forms that facilitate drug dissolution.

[00112] In certain embodiments, dissolution is assessed utilizing USP
apparatus II in 900 mL of sodium phosphate, pH 6.8, at 37 C and paddle speed of 50 rpm. In certain embodiments, dissolution is assessed utilizing USP apparatus II in 900 mL of hydrochloric acid, pH 1.2, at 37 C and paddle speed of 50 rpm. The analytical finish may be by a high performance liquid chromatography (HPLC) system with ultraviolet (UV) detection

[00113] The solid oral dosage forms described herein will typically be in the form of a tablet and, in particular, an immediate release tablet. In certain embodiments, the immediate release tablet releases at least 80% of Compound A or a pharmaceutically acceptable salt thereof in 30 minutes, measured using USP apparatus II, in 900 mL of sodium phosphate, pH 6.8, at 37 C and paddle speed of 50 rpm. In certain embodiments, the immediate release tablet releases at least 80% of Compound A or a pharmaceutically acceptable salt thereof in 45 minutes, measured using USP apparatus II, in 900 mL of sodium phosphate, pH 6.8, at 37 C and paddle speed of 50 rpm.

[00114] In at least one aspect, the pharmaceutical compositions disclosed herein are stable during, for example, storage, distribution, and the duration of the product's shelf-life (e.g., up to two years at room temperature/ambient conditions). A stable pharmaceutical composition may, for example, exhibit less degradation of the API and/or lower amounts of degradation products. Degradation products that arise during storage of the drug substance and/or drug product are undesirable and, in extreme cases, might even be harmful to a patient being treated with such drug product. Thus, it is desirable to control the formation of degradation products, particularly potentially harmful impurities in the drug product.

[00115] Assay and degradation product determination of pharmaceutical compositions, particularly solid oral dosage forms, and more particularly tablets, may be performed using HPLC with UV detection.

[00116] Pharmaceutical compositions may be assessed for degradation products following storage for at least two weeks, at least one month, at least two months, at least three months, at least six months, at least twelve months, at least eighteen months, or at least twenty four months.
In particular, degradation products may be assessed at time intervals of one, three, six, nine, twelve, eighteen, twenty four, thirty six, and/or forty eight months. Storage conditions may be long term, intermediate, or accelerated conditions. In particular, storage conditions may be, for example, 25 C 2 C/40% relative humidity (RH) 5% RH, 25 C 2 C/60% RH 5%
RH, 30 C 2 C/35% RH 5% RH, 30 C 2 C/65% RH 5% RH, 40 C 2 C/25% RH 5% RH, 40 C 2 C/75% RH 5% RH, 50 C + 2 C/75% RH + 5 A) RH, 60 C 2 C/5% RH 5%
RH, 60 C 2 C/40% RH 5% RH, 70 C 2 C/5% RH 5% RH, 70 C + 2 C/75% RH 5% RH, and/or 80 C + 2 C/40% RH 5% RH.

[00117] One exemplary degradation product of Compound A is (R)-5-(2-fluoro-methoxypheny1)-1-(2-fluoro-6-(trifluoromethyl)benzy1)-6-meth y1-3-(2-(2-oxopyrrolidin-1-y1)-2-phenylethyl)pyrimidine-2,4(1H,3H)-dione (Compound B), which has the following structure:
õCH3 (R) 01\1 CH3

[00118] It has been identified in the present application that formation of Compound B
was not adequately controlled in certain formulations. For example, in formulations without sodium carbonate monohydrate stored for one week at 65 C/75% RH, Compound B
was present at greater than 1%. Thus, in certain embodiments, sodium carbonate is included in the pharmaceutical composition as a stabilizing agent to decrease degradation and/or to reduce or prevent gel formation.

[00119] In certain embodiments, sodium carbonate is present in amount from about 10%
to about 25%, and preferably from about 15% to about 20%, by weight of the pharmaceutical composition. In certain embodiments, the weight ratio of Compound A or a pharmaceutically acceptable salt thereof to sodium carbonate is from about 1:1 to about 4:1, and preferably about 2:1 (drug substance:sodium carbonate).

[00120] In certain embodiments, Compound B is present in a pharmaceutical composition in an amount less than about 1.0% by weight after storage for at least one month, at least two months, at least six months, at least twelve months, at least eighteen months, or at least twenty-four months at 25 C and 60% relative humidity. In certain embodiments, Compound B is present in a pharmaceutical composition in an amount less than about 0.7% by weight after storage for at least one month, at least two months, at least six months, at least twelve months, at least eighteen months, or at least twenty-four months at 25 C and 60% relative humidity. In certain embodiments, Compound B is present in a pharmaceutical composition in an amount less than about 0.5% by weight after storage for at least one month, at least two months, at least six months, at least twelve months, at least eighteen months, or at least twenty-four months at 25 C
and 60% relative humidity. In certain embodiments, Compound B is present in a pharmaceutical composition in an amount less than about 0.03% by weight after storage for at least one month, at least two months, at least six months, at least twelve months, at least eighteen months, or at least twenty-four months at 25 C and 60% relative humidity.

[00121] In one aspect, this disclosure provides a stable pharmaceutical composition comprising Compound A or pharmaceutically acceptable salt thereof. A stable pharmaceutical composition may, for example, contain less than 1% Compound B following storage for at least one, at least three, at least six, at least nine, at least twelve, at least eighteen, or at least twenty-four months.

[00122] In certain embodiments, Compound B is present in a pharmaceutical composition in an amount less than about 1.0% by weight after storage for at least one month, at least two months, at least six months, at least twelve months, at least eighteen months, or at least twenty-four months at 40 C and 75% relative humidity. In certain embodiments, Compound B is present in a pharmaceutical composition in an amount less than about 0.7% by weight after storage for at least one month, at least two months, at least six months, at least twelve months, at least eighteen months, or at least twenty-four months at 40 C and 75% relative humidity. In certain embodiments, Compound B is present in a pharmaceutical composition in an amount less than about 0.5% by weight after storage for at least one month, at least two months, at least six months, at least twelve months, at least eighteen months, or at least twenty-four months at 40 C
and 75% relative humidity. In certain embodiments, Compound B is present in a pharmaceutical composition in an amount less than about 0.03% by weight after storage for at least one month, at least two months, at least six months, at least twelve months, at least eighteen months, or at least twenty-four months at 40 C and 75% relative humidity.

[00123] The solid oral dosage forms described herein will typically be in the form of a tablet. The provision of a tablet with particular pharmacokinetic parameters is a particular advantage afforded by the present invention. Pharmacokinetic parameters refer to any suitable pharmacokinetic parameters, such as Trnax, Cmax, and AUC. Parameters should be measured in accordance with standards and practices which would be acceptable to a pharmaceutical regulatory agency such as FDA, EMA, MHLW, or WHO. The values may be based on measurements taken at appropriate intervals following the time of tablet ingestion, such as every hour, or at increasingly sparse sampling intervals, such as 2, 4, 6, 8, 10, 12, 16, and 24 hours after ingestion. The pharmacokinetic parameters can be assessed either following a single-dose of drug or at steady state, preferably following a single-dose. In certain embodiments, pharmacokinetic parameters are determined following a single dose of the pharmaceutical composition. In certain embodiments, pharmacokinetic parameters are determined in a multiple dosing regimen. For example, pharmacokinetic parameters may be determined after several dosing intervals, e.g., at steady state. The pharmacokinetic parameters can be assessed under fasting or fed conditions, preferably under fasting conditions.

[00124] Cmax refers to the peak concentration and, in particular, the maximum observed plasma/serum concentration of drug. T. refers to the time to reach the peak concentration.
AUCt refers to the area under the plasma concentration-time curve, where t is the time of the last measurable plasma concentration in the study. AUC,, refers to the area under the plasma concentration-time curve from time zero to infinity following a single dose.

[00125] In certain embodiments, a solid oral dosage form (in particular a tablet) is ' provided as described herein, wherein the dosage form when administered as a single dose to a population of human subjects provides an average T. less than about 3 hours for the population of human subjects. In certain embodiments, a solid oral dosage form (in particular a tablet) is provided as described herein, wherein the dosage form when administered as a single dose to a population of human subjects provides an average Trnax from about 0.5 hours to about 2.0 hours for the population of human subjects. In some such embodiments, the solid oral dosage form is administered under fasting conditions.

[00126] In certain embodiments, a solid oral dosage form (in particular, a tablet) is provided as described herein, wherein the dosage comprises sodium 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)butanoate in an amount equivalent to about 150 mg of Compound A and wherein the dosage form when administered as a single dose to a population of human subjects provides an average Cmcix from about 400 ng/mL to about 660 ng/mL, an average AUCt from about 1000 ng=hr/mL to about 1600 ng=hr/mL, and/or an average AUC.
from about 1010 ng=hr/mL to about 1610 ng=hr/mL for the population of human subjects. In some such embodiments, the solid oral dosage form is administered under fasting conditions.

[00127] In certain embodiments, a solid oral dosage form (in particular a tablet) is provided as described herein, wherein the dosage comprises sodium 44(R)-2-[5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)butanoate in an amount equivalent to about 200 mg of Compound A and wherein the dosage form when administered as a single dose to a population of human subjects provides an average C. from about 590 ng/mL to about 1100 ng/mL, preferably from about 590 ng/mL to about 930 ng/mL, an average AUCt from about ng=hr/mL to about 2980 ng-hr/mL, preferably from about 1520 ng=hr/mL to about ng=hr/mL, and/or an average AUC. from about 1520 ng=hr/mL to about 2990 ng-hr/mL, preferably from about 1530 ng=hr/mL to about 2400 ng=hr/mL, for the population of human subjects. In some such embodiments, the solid oral dosage form is administered under fasting conditions.

[00128] In certain embodiments, a solid oral dosage form (in particular a tablet) is provided as described herein, wherein the dosage comprises sodium 44(R)-2-[5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)butanoate in an amount equivalent to about 300 mg of Compound A and wherein the dosage form when administered as a single dose to a population of human subjects provides an average Cmax from about 1100 ng/mL to about 1730 ng/mL, an average AUCt from about 2990 ng=hr/mL to about 4670 ng=hr/mL, and/or an average AUG-, from about 3020 ng=hr/mL to about 4720 ng-hr/mL for the population of human subjects. In some such embodiments, the solid oral dosage form is administered under fasting conditions.

[00129] In some embodiments, a solid oral dosage form (in particular a tablet) as described herein is provided, for which the 90% confidence interval of log -transformed C.x, log-transformed AUCt, and/or log-transformed AUC. for Compound A or a pharmaceutically acceptable salt thereof in a population of human subjects falls completely within the range 80-125% of the log -transformed C., log-transformed AUCt, and/or log-transformed AUC., respectively, of a reference tablet, wherein the reference tablet comprises sodium 44(R)-2-[5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-l-y1]-1-phenyl-ethylamino)butanoate in an amount equivalent to about 150 mg of Compound A; about 150 mg mannitol; about 44 mg pregelatinized starch; about 14 mg povidone; about 78 mg sodium carbonate monohydrate; about 8 mg magnesium stearate; and a film coating consisting of polyvinyl alcohol; titanium dioxide; polyethylene glycol; talc; and high tint carmine (such as Opadry 0 II Pink).

[00130] In some embodiments, a solid oral dosage form (in particular a tablet) as described herein is provided, for which the 90% confidence interval of log -transformed Cmax, log-transformed AUCt, and/or log-transformed AUC. for Compound A or a pharmaceutically acceptable salt thereof in a population of human subjects falls completely within the range 80-125% of the log -transformed Cmax, log-transformed AUCt, and/or log-transformed AUC., respectively, of a reference tablet, wherein the reference tablet comprises sodium 44(R)-245-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y11-1-phenyl-ethylamino)butanoate in an amount equivalent to about 200 mg of Compound A; about 200 mg mannitol; about 59 mg pregelatinized starch; about 18 mg povidone; about 104 mg sodium carbonate monohydrate; about 11 mg magnesium stearate;
and a film coating consisting of polyvinyl alcohol; titanium dioxide;
polyethylene glycol; talc;
and iron oxide red (such as Opadry 8 II Salmon).

[00131] In some embodiments, a solid oral dosage form (in particular a tablet) as described herein is provided, for which the 90% confidence interval of log -transformed C., log-transformed AUCt, and/or log-transformed AUC. for Compound A or a pharmaceutically acceptable salt thereof in a population of human subjects falls completely within the range 80-125% of the log -transformed Cmax, log-transformed AUCt, and/or log-transformed AUC., respectively, of a reference tablet, wherein the reference tablet comprises sodium 44(R)-2-[5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)butanoate in an amount equivalent to about 300 mg of Compound A; mannitol; pregelatinized starch; povidone; sodium carbonate monohydrate; magnesium stearate; and a film coating.

[00132] In certain embodiments, administration of a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof results in rapid suppression of luteinizing hormone (LH) and/or follicle-stimulating hormone (FSH) levels in a female patient with endometriosis or uterine fibroids. In certain embodiments, administration of a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof results in partial to substantially full suppression of estradiol levels in a female patient with endometriosis or uterine fibroids. In some such embodiments, estradiol levels are less than about 50 pg/mL. In some such embodiments, estradiol levels are between about 20 pg/mL and about 50 pg/mL. In some such embodiments, estradiol levels are less than about 20 pg/mL. In some such embodiments, estradiol levels are less than about 12 pg/mL (e.g., below the lowest limit of quantitation).

[00133] The pharmaceutical compositions may comprise other excipients such as excipents that function as fillers, binders, disintegrants, glidants and lubricants. Thus, a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof, further optionally comprises one or more conventional pharmaceutically acceptable excipients.

[00134] In certain embodiments, the disclosed pharmaceutical compositions comprise at least one excipient that functions as a filler. Fillers may include polyols, such as dextrose, isomalt, mannitol, sorbitol, lactose, and sucrose; natural or pre-gelatinized potato or corn starch;
microcrystalline cellulose (e.g., Avice10); or a combination thereof. Examples of suitable fillers include mannitol, such as spray dried mannitol (e.g., Pearlito10 100SD, Pearlitolg 200SD);
pregelatinized starch, such as Starch 1500e; microcrystalline cellulose, such as Avice10 ;
lactose monohydrate, such as Foremost 316 Fast Floe; mixtures of isomaltulose derivatives such as gaIenIQTM 720; and other suitable fillers and combinations thereof.

[00135] In certain embodiments, the disclosed pharmaceutical compositions comprise at least one water soluble filler. In some such embodiments, the water soluble filler is a polyol, such as mannitol, sorbitol, lactose, or sucrose; a pregelatinized starch; or a combination thereof.
In some such embodiments, the water soluble filler is mannitol. In some such embodiments, the water soluble filler is mannitol and pregelitanized starch. In certain embodiments, the disclosed pharmaceutical compositions comprise at least one water insoluble filler. In some such embodiments, the water insoluble filler is a starch, microcrystalline cellulose (e.g., Avice10), or calcium phosphate. In some such embodiments, the disclosed pharmaceutical compositions comprise a water insoluble filler and a surfactant, such as sodium lauryl sulfate (SLS).
[001361 In certain embodiments, a filler is present in the pharmaceutical composition in an amount from about 5% to about 70% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the filler is present in the pharmaceutical composition in an amount from about 10% to about 60% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the filler is present in the pharmaceutical composition in an amount from about 20% to about 50% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the filler is present in the pharmaceutical composition in an amount from about 30% to about 45% by weight (w/w) of the pharmaceutical composition.
[00137] In certain embodiments, the pharmaceutical composition includes a first filler in an amount from about 20% to about 50% by weight and a second filler in an amount from about 1% to about 20% by weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition includes a first filler in an amount from about 25%
to about 40% by weight and a second filler in an amount from about 5% to about 15% by weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition includes a first filler in an amount from about 30% to about 35% by weight and a second filler in an amount from about 8% to about 12% by weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition includes a first filler in an amount of about 33%
by weight and a second filler in an amount of about 10% by weight of the pharmaceutical composition. In certain embodiments, the first filler is mannitol and the second filler is pregelitanized starch.
[00138] In certain embodiments, the disclosed pharmaceutical compositions comprise at least one excipient that functions as a binder. Binders may include polyvinylpyrrolidone (e.g., povidone), a copolymer of vinylpyrrolidone and vinyl acetate (e.g., copovidone); cellulose, such as hydroxymethylpropylcellulose (HPMC), hydroxypropylethylcellulose, or microcrystalline cellulose; sucrose, starches, and combinations thereof. In certain embodiments, the binder is a hydrophilic polymer. The hydrophilic polymer may be selected from copolymer of N-vinyl lactam, cellulose ester, cellulose ether, polyalkylene glycol, polyacrylate, polymethacrylate, polyacrylamide, polyvinyl alcohol, vinyl acetate polymer, oligosaccharide, polysaccharide, or combinations thereof. In some such embodiments, the binder is polyvinylpyrrolidone.

[00139] In certain embodiments, a binder is present in the pharmaceutical composition in an amount from about 0.1% to about 20% by weight (w/w) of the pharmaceutical composition.
In certain embodiments, a binder is present in the pharmaceutical composition in an amount from about 1% to about 10% by weight (w/w) of the pharmaceutical composition. In certain embodiments, a binder is present in the pharmaceutical composition in an amount from about 2%
to about 5% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition includes about 3% by weight of a binder. In certain embodiments, the binder is polyvinylpyrrolidone.
[00140] In certain embodiments, the disclosed pharmaceutical compositions comprise at least one excipient that functions as a glidant. Glidants may include, for example, colloidal silicon dioxide, including highly dispersed silica (Aerosile) or any other suitable glidant such as animal or vegetable fats or waxes.
[00141] In certain embodiments, a glidant is present in the pharmaceutical composition in an amount from about 0.1% to about 5% by weight (w/w) of the pharmaceutical composition. In certain embodiments, a glidant is present in the pharmaceutical composition in an amount from about 0.3% to about 2% by weight (w/w) of the pharmaceutical composition. In certain embodiments, a glidant is present in the pharmaceutical composition in an amount from about 0.3% to about 1.2% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition includes about 0.5% by weight of a glidant. In certain embodiments, the glidant is colloidal silicon dioxide.
[00142] In certain embodiments, a glidant is included in an intragranular portion of the pharmaceutical composition. In certain embodiments, the intragranular portion of the pharmaceutical composition comprises a glidant in an amount from about 0.1% to about 5% by weight (w/w), on the basis of the weight of the total pharmaceutical composition. In certain embodiments, the intragranular portion of the pharmaceutical composition comprises a glidant in an amount from about 0.5% to about 3% by weight (w/w), on the basis of the weight of the total pharmaceutical composition.
[00143] In certain embodiments, a glidant is included in an extragranular portion of the pharmaceutical composition. In certain embodiments, the extragranular portion of the pharmaceutical composition comprises a glidant in an amount from about 0.1% to about 5% by weight (w/w), on the basis of the weight of the total pharmaceutical composition. In certain embodiments, the extragranular portion of the pharmaceutical composition comprises a glidant in an amount from about 0.5% to about 3% by weight (w/w), on the basis of the weight of the total pharmaceutical composition.
[001441 In certain embodiments, a glidant is included in both an intragranular portion and an extragranular portion of the pharmaceutical composition. In certain embodiments, the intragranular portion of the pharmaceutical composition comprises a glidant in an amount from about 0.1% to about 5% by weight (w/w), on the basis of the weight of the total pharmaceutical composition and the extragranular portion of the pharmaceutical composition comprises a glidant in an amount from about 0.1% to about 5% by weight (w/w), on the basis of the weight of the total pharmaceutical composition. In certain embodiments, the intragranular portion of the pharmaceutical composition comprises a glidant in an amount from about 0.5% to about 3% by weight (w/w), on the basis of the weight of the total pharmaceutical composition and the extragranular portion of the pharmaceutical composition comprises a glidant in an amount from about 0.5% to about 3% by weight (w/w), on the basis of the weight of the total pharmaceutical composition.
[00145] In certain embodiments, the disclosed pharmaceutical compositions comprise at least one excipient that functions as a lubricant. Lubricants may include, for example, magnesium and calcium stearates, sodium stearyl fumarate, talc, or any other suitable lubricant.
[00146] In certain embodiments, a lubricant is present in the pharmaceutical composition in an amount from about 0.1% to about 10% by weight (w/w) of the pharmaceutical composition. In certain embodiments, a lubricant is present in the pharmaceutical composition in an amount from about 0.5% to about 5% by weight (w/w) of the pharmaceutical composition. In certain embodiments, a lubricant is present in the pharmaceutical composition in an amount from about 1% to about 3% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition includes about 1.9% by weight of a lubricant. In certain embodiments, the lubricant is magnesium stearate.
[00147] In certain embodiments, a lubricant is included in an intragranular portion of the pharmaceutical composition. In certain embodiments, the intragranular portion of the pharmaceutical composition comprises a lubricant in an amount from about 0.5%
to about 5% by weight (w/w), on the basis of the weight of the total pharmaceutical composition. In certain embodiments, the intragranular portion of the pharmaceutical composition comprises a lubricant in an amount from about 1% to about 3% by weight (w/w), on the basis of the weight of the total pharmaceutical composition.
[00148] In certain embodiments, a lubricant is included in an extragranular portion of the pharmaceutical composition. In certain embodiments, the extragranular portion of the pharmaceutical composition comprises a lubricant in an amount from about 0.5%
to about 5% by weight (w/w), on the basis of the weight of the total pharmaceutical composition. In certain embodiments, the extragranular portion of the pharmaceutical composition comprises a lubricant in an amount from about 1% to about 3% by weight (w/w), on the basis of the weight of the total pharmaceutical composition. In certain embodiments, magnesium stearate is used as a lubricant and the magnesium stearate is in the extragranular portion.
[00149] In certain embodiments, a lubricant is included in both an intragranular portion and an extragranular portion of the pharmaceutical composition. In certain embodiments, the intragranular portion of the pharmaceutical composition comprises a lubricant in an amount from about 0.5% to about 5% by weight (w/w), on the basis of the weight of the total pharmaceutical composition and the extragranular portion of the pharmaceutical composition comprises a lubricant in an amount from about 0.5% to about 5% by weight (w/w), on the basis of the weight of the total pharmaceutical composition. In certain embodiments, the intragranular portion of the pharmaceutical composition comprises a lubricant in an amount from about 1% to about 3% by weight (w/w), on the basis of the weight of the total pharmaceutical composition and the extragranular portion of the pharmaceutical composition comprises a lubricant in an amount from about 1% to about 3% by weight (w/w), on the basis of the weight of the total pharmaceutical composition. In certain embodiments, the intragranular portion of the pharmaceutical composition comprises a lubricant in an amount of about 0.9% by weight (w/w), on the basis of the weight of the total pharmaceutical composition and the extragranular portion of the pharmaceutical composition comprises a lubricant in an amount of about 1% by weight (w/w), on the basis of the weight of the total pharmaceutical composition. In certain embodiments, magnesium stearate is used as a lubricant at a level of about 1.9% weight/weight of the formulation with about 0.9% added intragranular and about I% added extragranular.
[00150] In certain embodiments, the disclosed pharmaceutical compositions comprise at least one excipient that functions as a disintegrant. Disintegrants may include, for example, sodium starch glycolate (e.g., Explotab), cross-linked polymers such as cross-linked modified starches, cross-linked polyvinylpyrrolidone, also known as crospovidone, and cross-linked carboxymethyl cellulose, also known as croscarmellose. In certain embodiments, a disintegrant is present in the pharmaceutical composition in an amount from about 0.1% to about 20% by weight (w/w) of the pharmaceutical composition.
[00151] In certain embodiments, the pharmaceutical composition is a tablet, which may be coated with any suitable coating such as a film coat. A film coat may be used to, for example, contribute to the ease with which the tablet can be swallowed. A film coat may also be employed to improve taste and provide an elegant appearance. The film coat may comprise a polyvinyl alcohol-polyethylene glycol graft copolymer, such as Opadry II and Kollicoat IR. The film coat may also comprise talc as an anti-adhesive. The film coat may account for less than about 5% by weight of the weight of the tablet.
[00152] In at least one aspect, this disclosure is directed to providing Compound A or a pharmaceutically acceptable salt thereof in a single, stable solid oral dosage form that is pharmacologically efficacious and physically acceptable. The solid oral dosage forms disclosed herein are intended for pharmaceutical use in human subjects. Accordingly, they should be of an appropriate size and weight for oral human administration (e.g., they should have a total weight of less than about 1.5 g), in addition to being therapeutically efficacious.
In order to facilitate the intake of such a dosage form by a mammal, the dosage form may be shaped into an appropriate shape such as a round or elongated shape.
[00153] For example, as set forth in Table 1, the disclosed pharmaceutical compositions may include one or more fillers, disintegrants, glidants and/or lubricants in combination with the active agent and anti-gelling agent.
[00154] Compound A referenced in Table 1 below is Compound A sodium salt and the corresponding weight percent is provided based on that salt form.
[001551 Table 1.
Quantity %a Quantity %a Ingredient Function (mg/Tablet) (w/w) (mg/Tablet) (w/w) Tablet Core Intragranular Compound A, sodium salt Drug Substance 155.2 33 207.0 33 Mannitol, USP Filler 150.3 32 200.3 32 Pregelatinized Starch, NF Filler/Binder 44.3 9 59.1 9 Povidone K 29/32, USP Binder 13.8 3 18.4 3 Sodium carbonate Anti-gelling 78.0 17 104.0 17 monohydrate, NF Agent Magnesium stearate, NF Lubricant 3.9 1 5.2 1 Weight subtotal of intragranular 445.5 594.0 components Extragranular Magnesium stearate, NF Lubricant 4.5 1 6.0 1 Uncoated tablet weight 450.0 600.0 Film Coating Film-Coating Powder Film Coat 18.0 4 24.0 4 (Op adry0 II) Coated tablet weight 468.0 100 624.0 100 [00156]
"Percents given based on the coated tablet weight. Total percentage may not be 100% due to rounding.
[00157] The amount (mg) of Compound A or pharmaceutically acceptable salt thereof referenced in the following tables refers to the amount (mg) of Compound A
free form (i.e., in the case of a pharmaceutically acceptable salt, the free form equivalent weight).
[00158] In certain embodiments, the pharmaceutical composition comprises:
Ingredient Amount (mg) Compound A or pharmaceutically acceptable salt thereof 125-175 Mannitol 125-175 Pregelitanized starch 35-55 Povidone 13-15 Sodium Carbonate 66-90 Magnesium Stearate 7-10 Optional film-coating 16-20 [00159] In certain embodiments, the pharmaceutical composition comprises:
Ingredient Amount (mg) Compound A or pharmaceutically acceptable salt thereof 170-230 Mannitol 170-230 Pregelitanized starch 47-71 Povidone 17-20 Sodium Carbonate 88-120 Magnesium Stearate 9-13 Optional film-coating 21-27 [00160] In certain embodiments, the pharmaceutical composition comprises:
Ingredient Amount (mg) Compound A or pharmaceutically acceptable salt thereof 255-345 Mannitol 255-345 Pregelitanized starch 70-107 Povidone 25-30 Sodium Carbonate 132-180 Magnesium Stearate 14-20 Optional film-coating 24-30 [00161] In certain embodiments, the pharmaceutical composition comprises:
Ingredient Amount (mg) Compound A or pharmaceutically acceptable salt thereof 150 Mannitol 150 Pregelitanized starch 44.3 Povidone 13.8 Sodium Carbonate 78 Magnesium Stearate 8.4 Optional film-coating 18 [00162] In certain embodiments, the pharmaceutical composition comprises:
Ingredient Amount (mg) Compound A or pharmaceutically acceptable salt thereof 200 Mannitol 200 Pregelitanized starch 59.1 Povidone 18.4 Sodium Carbonate 104 Magnesium Stearate 11.2 Optional film-coating 24 [00163] In certain embodiments, the pharmaceutical composition comprises:
Ingredient Amount (mg) Compound A or pharmaceutically acceptable salt thereof 300 Mannitol 300 Pregelitanized starch 88.7 Povidone 27.7 Sodium Carbonate 156 Magnesium Stearate 16.8 Optional film-coating 27 [00164] D. METHODS OF MANUFACTURE
[00165] The disclosed pharmaceutical compositions may be prepared by any suitable method. Methods such as direct compression, fluid bed granulation, roller compaction or dry granulation, and wet granulation may be used to blend Compound A or a pharmaceutically acceptable salt thereof with an anti-gelling agent and any other excipients of the pharmaceutical composition, including a water soluble filler or a water insoluble filler and a surfactant.
[00166] In certain embodiments, the disclosed pharmaceutical compositions are prepared using a wet granulation process and by compressing the final blend into tablets.
[00167] In certain embodiments, the disclosed pharmaceutical compositions are prepared using a roller compaction process. The roller compaction process may include any suitable steps.
For example, as illustrated in Figure 1, roller compaction may include steps such as blending the active agent with one or more intragranular excipients sized for blending;
feeding the blend into a roller compactor to densify loose powder into ribbons; milling the resultant ribbons into granules; optionally blending the granules with extragranular excipients such as lubricants;
compressing the granules into tablets; and optionally coating the tablets with a film-coating.
[00168] E. METHODS OF USE
[00169] In at least one aspect, the present invention includes a method of treating endometriosis comprising administering to a patient a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof. In certain embodiments, the method of treating endometriosis comprises administration of a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof at a dose of about 150 mg. In some such embodiments, the composition is administered once per day ("QD"). In certain embodiments, the method of treating endometriosis comprises administration of a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof at a dose of about 200 mg. In some such embodiments, the composition is administered twice per day ("BID"). In certain embodiments, the method of treating endometriosis comprises administration of a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof at a dose of about 300 mg. In some such embodiments, the composition is administered twice per day ("BID"). In certain embodiments, the method of treating endometriosis comprises administration of a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof at a dose of about 600 mg. In some such embodiments, the composition is administered once per day ("QD").
[00170] In at least one aspect, the present invention includes a method of treating uterine fibroids comprising administering to a patient a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof. In certain embodiments, the method of treating uterine fibroids comprises administration of a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof at a dose of about 150 mg. In some such embodiments, the composition is administered QD. In certain embodiments, the method of treating uterine fibroids comprises administration of a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof at a dose of about 200 mg. In some such embodiments, the composition is administered BID. In certain embodiments, the method of treating uterine fibroids comprises administration of a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof at a dose of about 300 mg. In some such embodiments, the composition is administered BID. In certain embodiments, the method of treating uterine fibroids comprises administration of a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof at a dose of about 600 mg. In some such embodiments, the composition is administered QD.
[001711 In certain embodiments, any of the above methods further comprise administering to the subject a hormone to reduce or alleviate potential side effects of Compound A or a pharmaceutically acceptable salt thereof. For example, the method may comprise administration of an estrogen, a progestin, or a combination thereof. Such treatments are commonly referred to as "add-back" therapy.
(00172) In some such embodiments, the add-back therapy comprises a progestogen, such as a progestin. In some such embodiments, the add-back therapy comprises an estrogen. In some such embodiments, the add-back therapy comprises a progestin and an estrogen.
[00173] The estrogen and/or progestogen can be administered orally, transdermally or intravaginally. Suitable progestogens for use in the add-back therapy include, for example, progesterone, norethindrone, norethindrone acetate, norgestimate, drospirenone, and medroxyprogestogen. Suitable estrogens for use in the add-back therapy include, for example, estradiol, ethinyl estradiol, and conjugated estrogens. Combined oral formulations containing an estrogen and a progestogen are known in the art and include, for example, Activellae, Angeliqe, FemHRTO, JenteliTM, MimveyTM, PrefestTM, Premphaset, and Premproe.
[00174] In certain embodiments, the estrogen is estradiol, ethinyl estradiol, or a conjugated estrogen. In some such embodiments, the estrogen is estradiol. In some such embodiments, the estradiol is administered once a day. In some such embodiments, the dose of estradiol is 0.5 mg. In other such embodiments, the dose of estradiol is 1.0 mg. In some such embodiments, the estrogen is ethinyl estradiol. In some such embodiments, the ethinyl estradiol is administered once a day. In some such embodiments, the dose of ethinyl estradiol is 2.5 meg.
In other such embodiments, the dose of ethinyl estradiol is 5.0 meg. In some such embodiments, the estrogen is a conjugated estrogen. In some such embodiments, the conjugated estrogen is administered once a day. In some such embodiments, the dose of conjugated estrogen is 0.3 mg.
In other such embodiments, the dose of conjugated estrogen is 0.45 mg or 0.625 mg.
[00175] In certain embodiments, the progestogen is progesterone, norethindrone, norethindrone acetate, norgestimate, medroxyprogesterone, or drospirenone. In some such embodiments, the progestogen is oral progesterone. In some such embodiments, the oral progesterone is used cyclically (for the last 12 days of the 28-30 day cycle).
In some such embodiments, the dose of the oral progesterone is 100 or 200 mg. In some such embodiments, the progestogen is norethindrone or norethindrone acetate. In some such embodiments, the norethindrone or norethindrone acetate is administered once a day. In some such embodiments, the dose of norethindrone or norethindrone acetate is 0.1 mg. In some such embodiments, the dose of norethindrone or norethindrone acetate is 0.5 mg. In some such embodiments, the dose of norethindrone or norethindrone acetate is 1.0 mg. In some such embodiments, the progestogen is norgestimate. In some such embodiments, the norgestimate is administered once a day. In some such embodiments, the dose of norgestimate is 0.09 mg. In some such embodiments, the progestogen is medroxyprogesterone. In some such embodiments, the medroxyprogesterone is administered once a day. In some such embodiments, the dose of medroxyprogesterone is 1.5 mg. In some such embodiments, the dose of medroxyprogesterone is 2.5 mg or 5 mg. In some such embodiments, the progestogen is drospirenone. In some such embodiments, the drospirenone is administered once a day. In some such embodiments, the dose of drospirenone is 0.25 mg. In some such embodiments, the dose of drospirenone is 0.5 mg.

[00176] In certain embodiments, the add-back therapy comprises a norethisterone prodrug, such as norethindrone acetate. In some such embodiments, the add-back therapy further comprises estradiol. Thus, in some such embodiments, the add-back therapy comprises estradiol and norethindrone acetate. In some such embodiments, estradiol and norethindrone acetate are administered orally once per day. In some such embodiments, estradiol is administered in an amount of about 0.5 mg and norethindrone acetate is administered in an amount of about 0.1 mg per day. In other such embodiments, estradiol is administered in an amount of about 1.0 mg and norethindrone acetate is administered in an amount of about 0.5 mg per day.
Alternatively, in certain embodiments, estradiol is administered continuously and norethindrone acetate is administered once per day during the last 12-14 days of a menstrual cycle.
[00177] In certain embodiments, the dose of Compound A or a pharmaceutically acceptable salt thereof is administered twice a day. In some such embodiments, add-back therapy is administered once a day. The administration of Compound A or a pharmaceutically acceptable salt thereof may be prior to, immediately prior to, during, immediately subsequent to or subsequent to the administration of the add-back therapy.
[00178] In certain embodiments, a dose of Compound A or pharmaceutically acceptable salt thereof (e.g., 300 mg) is administered in the morning with add-back therapy, such as a combination of an estrogen and a progestogen (e.g., estradiol and norethindrone acetate) and a dose of Compound A or pharmaceutically acceptable salt thereof (e.g., 300 mg) is administered in the evening without add-back therapy.
[00179] In certain embodiments, Compound A or a pharmaceutically acceptable salt thereof is co-packaged with the add-back therapy. For example, a blister pack may contain a dose of Compound A or a pharmaceutically acceptable salt thereof and a dose of the add-back therapy.
[00180] In certain embodiments, Compound A or a pharmaceutically acceptable salt thereof is present in a fixed dose combination with the add-back therapy. For example, a capsule may contain a caplet or tablet comprising Compound A or a pharmaceutically acceptable salt thereof and a caplet or tablet comprising the add-back therapy, such as a combination of an estrogen and a progestogen (e.g., estradiol and norethindrone acetate). In some such embodiments, the capsule comprises 300 mg Compound A or a pharmaceutically acceptable salt thereof, 1 mg estradiol, and 0.5 mg norethindrone acetate.

[00181] The pharmaceutical compositions, methods, and uses described herein will be better understood by reference to the following exemplary embodiments and examples, which are included as an illustration of and not a limitation upon the scope of the invention.
[00182] F. EXEMPLARY EMBODIMENTS
[00183] This disclosure provides at least the following enumerated exemplary embodiments:
Al. A pharmaceutical composition comprising about 150 mg, about 200 mg, or about 300 mg 4-((R)-2-[5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-meth y1-2,6-dioxo-3,6-dihydro-2H-pyrimidin-l-y11-1-phenyl-ethylamino)-butyric acid (Compound A) or a pharmaceutically acceptable salt thereof; and an anti-gelling agent; wherein the pharmaceutical composition comprises at least 10% by weight of Compound A
or the pharmaceutically acceptable salt thereof.
A2. The pharmaceutical composition of embodiment Al, wherein the anti-gelling agent is a water soluble salt of a weak acid, a basic amino acid, or a poly(meth)acrylate polymer.
A3. The pharmaceutical composition of embodiment Al or embodiment A2, wherein the anti-gelling agent further acts as a stabilizer to reduce formation of (R)-5-(2-fluoro-3-methox ypheny1)-1-(2-fluoro-6-(trifluoromethyl)benzy1)-6-meth y1-3-(2-(2-oxopyrrolidin-l-y1)-2-phenylethyl)pyrimidine-2,4(1H,3H)-dione (Compound B) in the composition relative to an otherwise identical composition without the anti-gelling agent.
A4. The pharmaceutical composition of embodiment A3, wherein the anti-gelling agent comprises an alkali metal salt.
A5. The pharmaceutical composition of embodiment A4, wherein the alkali metal salt is selected from the group consisting of sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium phosphate, and combinations thereof.
A6. The pharmaceutical composition of embodiment A4, wherein the alkali metal salt is sodium carbonate, preferably sodium carbonate monohydrate.

A7. The pharmaceutical composition of any one of embodiments A3-A6, wherein the weight ratio of Compound Aor the pharmaceutically acceptable salt thereof to the anti-gelling agent, is from about 1:1 to about 4:1, preferably about 2:1.
A8. The pharmaceutical composition of any one of embodiments A3-A6, wherein the anti-gelling agent is present in an amount from about 5% by weight to about 35% by weight of the pharmaceutical composition, preferably in an amount from about 10% by weight to about 25% by weight of the pharmaceutical composition.
A9. The pharmaceutical composition of any one of the preceding embodiments, further comprising (a) at least one water soluble filler or (b) at least one water insoluble filler and a surfactant.
A10. The pharmaceutical composition of any one of the preceding embodiments, wherein the composition releases at least about 80% of Compound A or the pharmaceutically acceptable salt thereof in about 45 minutes, preferably at least about 80% of Compound Aor the pharmaceutically acceptable salt thereof in about 30 minutes, measured using USP apparatus II
in 900 mL of sodium phosphate, pH 6.8, at 37 C and paddle speed of 50 rpm.
All. The pharmaceutical composition of any one of the preceding embodiments, further comprising at least one lubricant.
Al2. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is a solid oral dosage form.
A13. The pharmaceutical composition of embodiment Al2, wherein the solid oral dosage form is a tablet.
A14. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition comprises a salt of Compound A.
A15. The pharmaceutical composition of embodiment A14, wherein the salt of Compound A is sodium 44(R)-245-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-l-y11-1-phenyl-ethylamino)butanoate.

A16. The pharmaceutical composition of embodiment A14, wherein the salt of Compound A is amorphous sodium 44(R)-2-[5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylarnino)butanoate.
A17. The pharmaceutical composition of embodiment A15, wherein the composition when administered as a single dose to a population of human subjects provides an average Tmax value that is less than about 3 hours, preferably about 0.5 to about 2.0 hours.
A18. The pharmaceutical composition of embodiment A15, wherein 44(R)-2-[5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y11-1-phenyl-ethylamino)butanoate is present in an amount equivalent to about 150 mg of Compound A and the composition when administered as a single dose to a population of human subjects provides an average Cmax value that is about 400 ng/mL to about 660 ng/mL for the population of human subjects.
A19. The pharmaceutical composition of embodiment A15, wherein 4-((R)-2-[5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y11-1-phenyl-ethylamino)butanoate is present in an amount equivalent to about 150 mg of Compound A and the composition when administered as a single dose to a population of human subjects provides an average AUCt from about 1000 ng=hr/mL
to about 1600 ng=hr/mL for the population of human subjects.
A20. The pharmaceutical composition of embodiment A15, wherein 4-((R)-2-[5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-l-y11-1-phenyl-ethylamino)butanoate is present in an amount equivalent to about 150 mg of Compound A and the composition when administered as a single dose to a population of human subjects provides an average AUC. from about 1010 ng=hr/mL
to about 1610 ng=hr/mt for the population of human subjects.
A21. The pharmaceutical composition of embodiment A15, wherein 4-((R)-215-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)butanoate is present in an amount equivalent to about 200 mg of Compound A and the solid oral dosage form when administered as a single dose to a population of human subjects provides an average Cmax from about 590 ng/mL to about 1100 ng/mL for the population of human subjects.
A22. The pharmaceutical composition of embodiment A15, wherein 44(R)-245-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)butanoate is present in an amount equivalent to about 200 mg of Compound A and the solid oral dosage form when administered as a single dose to a population of human subjects provides an average AUCt from about 1510 ng=hr/mL to about 2980 ng=hr/mL for the population of human subjects.
A23. The pharmaceutical composition of embodiment A15, wherein 44(R)-245-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-l-y1]-1-phenyl-ethylamino)butanoate is present in an amount equivalent to about 200 mg of Compound A and the solid oral dosage form when administered as a single dose to a population of human subjects provides an average AUG from about 1520 ng=hr/mL to about 2990 ng-hr/mL for the population of human subjects.
A24. The pharmaceutical composition of embodiment A15, wherein 44(R)-2-[5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)butanoate is present in an amount equivalent to about 300 mg of Compound A and the solid oral dosage form when administered as a single dose to a population of human subjects provides an average Cmax from about 1100 ng/mL to about 1730 ng/mL for the population of human subjects.
A25. The pharmaceutical composition of embodiment A15, wherein Compound A or the pharmaceutically acceptable salt thereof is present in an amount equivalent to about 300 mg of Compound A and the solid oral dosage form when administered as a single dose to a population of human subjects provides an average AUCt from about 2990 ng=hr/mL
to about 4670 ng=hr/mL for the population of human subjects.
A26. The pharmaceutical composition of embodiment A15, wherein Compound A or the pharmaceutically acceptable salt thereof is present in an amount equivalent to about 300 mg of Compound A and the solid oral dosage form when administered as a single dose to a population of human subjects provides an average AUC. from about 3020 ng=hr/mL
to about 4720 ng=hr/mL for the population of human subjects.
A27. The pharmaceutical composition of any one of the preceding embodiments, wherein the composition when administered to a female subject provides rapid suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels.
A28. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition comprises less than about 0.7% (R)-5-(2-fluoro-3-methoxypheny1)-1-(2-fluoro-6-(trifluoromethyl)benzy1)-6-methyl-3-(2-(2-oxopyrrolidin-1-y1)-2-phenylethyl)pyrimidine-2,4(1H,3H)-dione after storage for at least one month at 25 C and 60%
relative humidity.
A29. The pharmaceutical composition of any one of embodiments A1-A27, wherein the pharmaceutical composition comprises less than about 0.7% (R)-5-(2-fluoro-methoxypheny1)-1-(2-fluoro-6-(trifluoromethyl)benzy1)-6-methyl-3-(2-(2-oxopyrrolidin-1-y1)-2-phenylethyl)pyrimidine-2,4(1H,31/)-dione after storage from about one month to about three months at 25 C and 60% relative humidity.
B1. A pharmaceutical composition comprising about 150 mg of 44(R)-245-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)-butyric acid (Compound A) or a pharmaceutically acceptable salt thereof; and an anti-gelling agent; wherein the weight ratio of Compound A or the pharmaceutically acceptable salt thereof is from about 1:1 to about 4:1, preferably about 2:1.
B2. A pharmaceutical composition comprising about 200 mg of 44(R)-245-(2-fluoro-3-metboxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)-butyric acid (Compound A) or a pharmaceutically acceptable salt thereof; and an anti-gelling agent; wherein the weight ratio of Compound A or the pharmaceutically acceptable salt thereof is from about 1:1 to about 4:1, preferably about 2:1.
B3. A pharmaceutical composition comprising about 300 mg of 44(R)-2-[5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)-butyric acid (Compound A) or a pharmaceutically acceptable salt thereof; and an anti-gelling agent; wherein the weight ratio of Compound A or the pharmaceutically acceptable salt thereof is from about 1:1 to about 4:1, preferably about 2:1.
B4. The pharmaceutical composition of any one of embodiments B1-B3, wherein the anti-gelling agent is sodium carbonate.
B5. The pharmaceutical composition of embodiment B4, wherein the weight ratio of Compound A or a pharmaceutically acceptable salt thereof to sodium carbonate is about 2:1.
B6. The pharmaceutical composition of any one of embodiments B1-B5, further comprising a water soluble filler.
B7. The pharmaceutical composition of any one of embodiments B1-B5, further comprising a water insoluble filler and a surfactant.
B8. The pharmaceutical composition of any one of embodiments B1-B7, further comprising a binder.
B9. The pharmaceutical composition of embodiment B8, wherein the binder is polyvinylpyrrolidone.
B10. The pharmaceutical composition of any one of embodiments B1-B9, wherein the pharmaceutical composition comprises a salt of Compound A.
B11. The pharmaceutical composition of embodiment B10, wherein the salt of Compound A is sodium 4-((R)-2-[5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)butanoate.
Cl. A pharmaceutical composition comprising:
(a) about 20 to about 50% by weight of 4-((R)-2-[5-(2-fluoro-3-methoxy-pheny1)-(2-fluoro-6-trifluoromethyl-benzy1)-4-methy1-2,6-dioxo-3,6-dihydro-2H-pyrimidin-l-y1]-1-phenyl-ethylamino)-butyric acid (Compound A)or a pharmaceutically acceptable salt thereof;
(b) a binder;

(c) an anti-gelling agent; and (d) a water soluble filler.
C2. The pharmaceutical composition of embodiment Cl, wherein the binder is selected from the group consisting of polyvinylpyrrolidone, hydroxymethylpropylcellulose (HPMC), hydroxypropylethylcellulose, microcrystalline cellulose, starch, and a combination thereof.
C3. The pharmaceutical composition of embodiment Cl, wherein the binder comprises polyvinylpyrrolidone.
C4. The pharmaceutical composition of any one of embodiments C1-C3, wherein the binder is present in an amount from about 1% to about 10% by weight.
C5. The pharmaceutical composition of any one of embodiments C1-C4, wherein the anti-gelling agent comprises an alkali metal salt.
C6. The pharmaceutical composition of embodiment C5, wherein the alkali metal salt is selected from the group consisting of sodium carbonate, sodium hydrogen carbonate, sodium phosphate, and combinations thereof.
C7. The pharmaceutical composition of embodiment Cl, wherein the anti-gelling agent comprises sodium carbonate, preferably sodium carbonate monohydrate.
C8. The pharmaceutical composition of any one of embodiments C1-C7, wherein the anti-gelling agent is present in an amount from about 10% to about 25% by weight.
C9. The pharmaceutical composition of any one of embodiments C1-C8, wherein the water soluble filler comprises mannitol and pregelatinized starch.
C10. The pharmaceutical composition of any one of embodiments C1-C9, wherein the water soluble filler is present in an amount from about 30% to about 50% by weight.
C11. The pharmaceutical composition of any one of embodiments Cl-C10, further comprising about 1 to about 5% lubricant.

C12. The pharmaceutical composition of embodiment C11, wherein the lubricant is magnesium stearate.
C13. The pharmaceutical composition of any one of embodiments C1-C12, wherein the pharmaceutical composition is a solid oral dosage form.
C14. The pharmaceutical composition of embodiment C13, wherein the solid oral dosage form is a tablet.
C15. The pharmaceutical composition of embodiment C14, wherein the tablet comprises a film coating.
C16. The pharmaceutical composition of any one of embodiments C1-C15, wherein the pharmaceutical composition comprises a salt of Compound A.
C17. The pharmaceutical composition of embodiment C16, wherein the salt of Compound A is sodium 44(R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y11-1-phenyl-ethylamino)butanoate.
C18. The pharmaceutical composition of embodiment C16, wherein the salt of Compound A is amorphous sodium 44(R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)butanoate.
Dl. A solid oral dosage form comprising:
(a) about 33.2% by weight of sodium 4-((R)-2-[5-(2-fluoro-3-methoxy-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methy1-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y1]-1-phenyl-ethylamino)butanoate;
(b) about 16.7% by weight of an alkali metal salt; and (c) about 51.1% by weight of one or more excipients.
D2. The solid oral dosage form of embodiment D1, wherein the one or more excipients comprises a binder, a water soluble filler, a lubricant, and a film-coating.
El. A solid oral dosage form comprising:

(d) about 33.2% by weight of sodium 44(R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-y11-1-phenyhethylamino)butanoate;
(e) about 2.9% by weight of a binder;
(f) about 16.7% by weight of an alkali metal salt;
(g) about 41.6% by weight of a water soluble filler;
(h) about 1.8% by weight of a lubricant; and (i) about 3.8% by weight of a film-coating.
E2. The solid oral dosage form of embodiment El, wherein the binder is polyvinylpyrrolidone.
E3. The solid oral dosage form of embodiment El or embodiment E2, wherein the alkali metal salt is sodium carbonate, preferably sodium carbonate monohydrate.
E4. The solid oral dosage form of any one of embodiments E1-E3, wherein the water soluble filler comprises mannitol and pregelatinized starch.
ES. The solid oral dosage form of embodiment E4, wherein the solid oral dosage form comprises about 32% by weight of mannitol and about 9% by weight of pregelatinized starch.
E6. The solid oral dosage form of any one of embodiments El-ES, wherein the lubricant is magnesium stearate.
E7. The solid oral dosage form of any one of embodiments E1-E6, wherein the dosage form comprises an intragranular portion and an extragranular portion.
Fl. A pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof and Compound B or a salt thereof; wherein Compound A
is 4-((R)-2-[5-(2-fluoro-3-methox y-pheny1)-3-(2-fluoro-6-trifluoromethyl-benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-l-y1]-1-phenyl-ethylamino)-butyric acid; Compound B is (R)-5-(2-fluoro-3-methox ypheny1)-1-(2-fluoro-6-(trifluoromethyl)benzy1)-6-methyl-3-(2-(2-oxopyrrolidin-1-y1)-2-phenylethyl)pyrimidine-2,4(1H,3H)-dione; and Compound B is present in the composition in an amount less than about 0.7% by weight.

F2. The pharmaceutical composition of embodiment Fl, wherein Compound B
is present in the composition in an amount less than about 0.7% by weight after storage for at least one month, at least two months, or preferably at least six months at 25 C and 60% relative humidity.
G1. A method of treating endometriosis, the method comprising administering the pharmaceutical composition of embodiments Al-A29, B1-B11, C1-C18, D1-D2, or Fl-F2 or the solid oral dosage form of embodiments El-E7 to a patient in need thereof.
H1. A method of treating uterine fibroids, the method comprising administering the pharmaceutical composition of embodiments A1-A29, B1-B11, Cl-C18, Dl-D2, or F1-F2 or the solid oral dosage form of embodiments E1-E7 to a patient in need thereof.
J1. A method for providing partial to substantially full suppression of estradiol in a female patient with endometriosis or uterine fibroids, the method comprising administering the pharmaceutical composition of embodiments Al-A29, Bl-B11, C1-C18, D1-D2, or F1-F2 or the solid oral dosage form of embodiments E1-E7to the patient.
J2. The method of embodiment J1, wherein estradiol levels in the female patient are less than about 50 pg/mL.
J3. The method of embodiment J1, wherein estradiol levels in the female patient are less than about 20 pg/mL.
[00184] G. EXAMPLES
[00185] The following Examples demonstrate certain challenges encountered during formulation development and describe formulations that overcome those challenges.
[00186] Example 1: Gel Formation by Compound A Monosodium Salt [00187] To estimate the solubility of Compound A in water, various amounts of Compound A sodium salt were added to a fixed volume of 1.5 mL and equilibrated at 37 C;
solutions were assayed for Compound A concentration.
[00188] Table 2 lists the raw data and observations of the experiment, and Figure 2 shows the concentration as a function of the amount of Compound A solid added. The dotted line in Figure 2 is the theoretical concentration based on the weights of the solids added and the volume of water. As shown in Figure 2, the concentration of Compound A agrees with the simple calculation up to 100 mg solid / 1.5 mL. Deviation of the concentrations from the theoretical line is due to the volume expansion upon dissolution of large amount of solutes.
Beyond that, the concentrations deviate from the theoretical line, but the solution is still clear and no visible gelling was observed. When more than 500 mg of Compound A solid was added, visible gelling was observed, therefore, concentrations were not determined.
[00189] Table 2: Raw Data of Compound A Solubility Experiment in Water at Amount Measured Concentration (mg) added (mg/mL) Observation Final pH
to 1.5 mL
0 0 N/A ¨6 12.2 7.45 Clear solution 9.66 28.7 17.3 Clear solution 9.96 49.8 28.0 Clear solution 10.10 100.4 60.8 Clear solution 10.16 202.5 111 Clear solution 10.18 295.6 149 Clear solution 10.20 503.2 170 Clear solution 10.17 700.9 N/A Gel formation N/A
990.0 N/A Gel formation N/A
[00190] Further experiments revealed that if the percent of Compound A or a salt thereof in a tablet formulation is greater than 10 percent (and in the absence of an appropriate anti-gelling agent), incomplete dissolution occurs ¨ Compound A was present as an insoluble precipitate. Therefore, a formulation of Compound A sodium salt was evaluated, at about 10%
drug loading, where minimal gelling was observed.
[00191] Example 2: In Vitro Release in the Absence of an Anti-Gelling Agent [00192] An immediate release formulation was prepared without an anti-gelling agent. All components, except magnesium stearate, were blended in a high-shear granulator and granulated with neat, de-ionized water. The granules were tray-dried at 40 C and passed through a #20 US
Standard sieve and tubed with magnesium stearate. Compound A referenced in the table below is the Compound A sodium salt.

[00193] Composition of Formulation without Anti-Gelling Agent Quantity Ingredient (mg/Tablet) Compound A, sodium salt 207.3 Mannitol 304.0 Pregelatinized Starch 59.1 Povidone K 29/32 18.4 Magnesium stearate 11.2 [00194] The dissolution profile for the uncoated tablets in pH 1.2 medium is shown in Table 3.
[00195] Table 3:
Time (min) Mean % (Std Dev) 15 15 (0.5) 30 31(0.5) 45 45 (0.6) 60 57 (0.7) [00196] Example 3: Formulations Having an Anti-Gelling Agent [00197] Table 4 presents additional non-limiting examples of components of the disclosed formulations and their percentage by weight (w/w) of the final coated tablet.
Compound A
referenced in the table below is the Compound A sodium salt and the corresponding amount (mg/tablet) and weight percent is provided based on that salt form.

n 1001981 Table 4. Composition of Exemplary Formulations.
i..) to ,.1 ,.1 Fl (150 mg) F2 (50 mg) F3 (150 mg) to w Ingredient Function co Quantity %a Quantity c/oa Quantity Voa i..) (mg/Tablet) (w/w) (mg/Tablet) (w/w) (mg/Tablet) (w/w) I-.
,.1 Compound A, sodium salt Drug Substance 155.5 25.2 51.8 33.5 155.5 33.5 , to 1 Mannitol, USP Filler 271.0 43.9 50.2 32.5 150.5 32.5 1-.
Corn Starch, NF Filler 68.2 11.0 16.0 10.4 48.0 10.4 Pregelatinized Starch Filler/Binder -- -- ---- -- --Povidone K 29/32, USP Binder 21.3 3.4 5.0 3.9 15.0 3.2 Sodium carbonate Anti-gelling 75.0 12.1 25.0 16.2 75.0 16.2 monohydrate, NF Agent/Buffer Silicon Dioxide, NF Glidant 3.0 0.5 ---- -- --Magnesium stearate, NF Lubricant 6.0 1.0 2.0 1.3 6.0 1.3 Uncoated tablet weight 600.0 -- 150.0 -- 450.0 Opadry Film Coat 18.0 2.9 4.5 2.9 13.5 2.9 Opadry II Film Coat -- ---- -- -- --Eudragit L 30 D-55 +
Enteric Coat -- -- ---- -- --plasticizer + glidant Coated tablet weight 618.0 100 154.5 100 463.5 100 "Percents given based on the coated tablet weight. Total percentage may not be 100% due to rounding.

n 100199j Table 4, cont. Composition of Exemplary Formulations.
I) to =-.1 F4 (100 mg) F5 (150 mg) =-.1 to Ingredient Function w Quantity %a Quantity %a co (mg/Tablet) (w/vv) (mg/Tablet) (w/w) n.) 1-.
=-.1 Compound A, sodium salt Drug Substance 103.7 33.6 155.5 33.5 to Mannitol, USP Filler 100.0 32.4 150.0 32.4 1-. Corn Starch, NF Filler -- -- ----Pregelatinized Starch Filler/Binder 29.5 9.5 44.3 9.6 Povidone K 29/32, USP Binder 9.2 3.0 13.8 3.0 Sodium carbonate Anti-gelling 52.0 16.8 78.0 16.8 monohydrate, NF Agent/Buffer Silicon Dioxide, NF Glidant -- -- ----Magnesium stearate, NF Lubricant 5.6 1.8 8.4 1.8 Uncoated tablet weight 300.0 -- 450.0 --Opadry Film Coat 9.0 2.9 13.5 2.9 Opadry II Film Coat -- -- ----Eudragit L 30 D-55 +
Enteric Coat -- -- ----plasticizer + glidant Coated tablet weight 309.0 100 463.5 100 "Percents given based on the coated tablet weight. Total percentage may not be 100% due to rounding.

n [00200] Table 4, cont. Composition of Exemplary Formulations.
I) to F6 (150 mg) F7 (200 mg) F7DR (200 mg) F8 (300 mg) =-.1 =-.1 to di Ingreent Function w Quantity (Yoa Quantity (3/0" Quantity (Yoa Quantity %a co (mg/Tablet) (w/w) (mg/Tablet) (w/w) (mg/Tablet) (w/w) (mg/Tablet) (w/w) n.) 1-.
=-.1 Compound A, sodium salt Drug Substance 155.5 33.5 207.4 33.6 207.4 32.0 310.9 33.5 to Mannitol, USP Filler 150.01 32.4 199.9h 32.3 199.91? 30.8 299.91? 32.4 1-. Corn Starch, NF Filler -- -- ---- -- -- --Pregelatinized Starch Filler/Binder 44.3 9.6 59.1 9.6 59.1 9.1 88.7 9.6 Povidone K 29/32, USP Binder 13.8 3.0 18.5 3.0 18.5 2.9 27.7 3.0 Sodium carbonate Anti-gelling 78.0 16.8 104.0 16.8 104.0 16.0 156.0 16.8 monohydrate, NF Agent/Buffer Silicon Dioxide, NF Glidant -- -- ---- -- -- -- --Magnesium stearate, NF Lubricant 8.4 1.8 11.2 1.8 11.2 1.7 16.8 1.8 Uncoated tablet weight 450.0 -- 600.1 600.1 --900.0 --Opadry Film Coat -- -- ---- -- -- -- --Opadry II Film Coat 13.5 2.9 18.0 2.9 -- -- 27.0 2.9 Eudragit L 30 D-55 +
Enteric Coat -- -- ---- 48.0 7.4 -- --plasticizer + glidant Coated tablet weight 463.5 100 618.1 100 648.1 100 927.0 100 'Percents given based on the coated tablet weight. Total percentage may not be 100% due to rounding.
hMannitol (12.3%) added extragranular.

n 100201] Table 4, cont. Composition of Exemplary Formulations.
I'.) to =-.1 F9 (150 mg) F10 (200 mg) Fll (200 mg) =-.1 to Ingredient Function w Quantity %a Quantity %a Quantity %a co (mg/Tablet) (w/w) (mg/Tablet) (w/w) (mg/Tablet) (w/w) i..) 1-.
=-.1 Compound A, sodium salt Drug Substance 155.2 33.2 207.4 33.2 207.4 50.3 to Mannitol, USP Filler 150.3 32.1 200.3 32.1 74.2 18.0 1-. Corn Starch, NF Filler -- -- ---- -- --Pregelatinized Starch Filler/Binder 44.3 9.5 59.1 9.5 -- --Povidone K 29/32, USP Binder 13.8 2.9 18.4 2.9 12.0 2.9 Sodium carbonate Anti-gelling 78.0 16.7 104.0 16.7 100.0 24.3 monohydrate, NF Agent/Buffer Silicon Dioxide, NF Glidant -- -- ---- -- --Magnesium stearate, NF Lubricant 8.4 1.8 11.2 1.8 6.4 1.6 Uncoated tablet weight 450.0 -- 600.0 -- 400.0 --Opadry Film Coat -- -- ---- -- --Opadry II Film Coat 18.0 3.8 24.0 3.8 12.0 29 Eudragit L 30 D-55 +
Enteric Coat -- -- ---- -- --plasticizer + glidant Coated tablet weight 468.0 100 624.0 100 412.0 100 'Percents given based on the coated tablet weight. Total percentage may not be 100% due to rounding.

Docket No. 025148.8372 (ABV12349USL1) [00202] 3.1. Preparation.
[00203] Fl was prepared using a two-step granulation process. The manufacturing process flow diagram is presented in Figure 3. In this process, the binder and a portion of the filler were added to the single pot processor bowl. Sodium carbonate, the remaining filler, Compound A, and colloidal silicon dioxide are blended in an IBC. In the first granulation step, the filler/binder blend in the SPP bowl was granulated with water. In the second granulation step, the Compound A blend was added to the SPP bowl and granulated by mixing for a short time.
The granulation was then dried in the SPP bowl using vacuum and swing mode. The dried granulation was milled using a Comil into another IBC. The lubricant magnesium stearate was added to the granules and blended. The granules were compressed into 600 mg tablet for 150 mg dose strength.
[00204] Formulations F2 and F3 were prepared using blending, fluid bed granulation, milling, tableting, and tablet coating.
[00205] Formulations F4-F11 were prepared using blending, roller compaction and milling, tableting, and tablet coating, generally as shown in Figure 1.
Formulations F4 and F5 were developed with a target drug loading of ¨35% Compound A to obtain uncoated tablet weights of 300 and 450 mg for 100 and 150 mg dose strengths, respectively.
[00206] A subset of the immediate release tablets were coated with an enteric coating to provide delayed release tablets (F7DR). The tablets were coated with an enteric coating comprising Eudragit L 30 D-55, Plasacryl T20, and triethyl citrate. Typical coating parameters were maintained during this process.
[00207] 3.2. In Vitro Dissolution Profile for Formulations Fl & F5 in pH
1.2 Buffer [00208] Multiple batches of the formulation with 25% drug loading were manufactured.
The dissolution profile for Fl tablets in pH 1.2 medium is shown in Table 5.
[00209] Table 5.
Mean % Dissolution (SD) Time (min) Batch 1 Batch 2 15 54(3.4) 46(1.7) 30 99 (1.1) 87 (0.3) 45 102 (1) 99 (1.9) 60 104 (0.7) 101 (1.5) [00210] The dissolution profile for F5 tablets in pH 1.2 medium is shown in Table 6.
[00211] Table 6:
Time (min) Mean % Dissolution [00212] 3.3. In Vitro Dissolution Profile After Storage for up to 24 months [00213] Formulations F5, F6, and F10 were tested for dissolution using USP
apparatus II
in 900 mL of sodium phosphate, pH 6.8, at 37 C and paddle speed of 50 rpm.
Formulations F5, F6, and F10 all showed similar dissolution profiles both tested initially and upon storage for up to 24 months. The dissolution profiles of Formulation F5 tablets at 18 and 24 months are shown in Figure 4. The stability dissolution profile of Formulation F7 tablets is shown in Figure 5. The dissolution profile of uncoated and film coated Formulation F10 tablets is shown in Figure 6.
[00214] 3.4. Pharmacokinetic Profile for 150 mg, 200 mg, & 300 mg Dosage.
[00215] 3.4.1. Pharmacokinetics of F3 and F5 (150 mg) [00216] A study was conducted to explore the bioayailability of single doses of 2 IR tablet formulations (F3 and F5) at a 150 mg dose under fasting conditions. The pharmacokinetic parameters are shown in Table 7. Data for pharmacokinetic parameters are presented as the mean SD.

[00217] Table 7:
Formulations 150 mg IR tablet 150 mg IR tablet Pharmacokinetic (N = 23) (N = 23) Parameters (units) Cmax (ng/mL) 523 + 247 510 + 225 Tmd. (hr) 1.07 + 0.35 1.12 + 0.42 AUCt (ng=hr/mL) 1263 560 1273 520 AUC. (ng=hr/mL) 1271 + 560 1281 + 520 (hr) 2.03 0.41 2.21 0.60 [00218] 3.4.2. Pharmacokinetics of F4 and F7 (200 mg) [00219] A study was conducted to compare the relative bioavailability of single doses of one 200 mg IR tablet of Formulation F7 with that of two 100 mg IR tablets of Formulation F4 under fasting conditions. Pharmacokinetic assessments showed that Formulation F7 (200 mg IR
tablet) was bioequivalent to Formulation F4 (2 x 100 mg IR), with respect to maximum concentration (Cmax) and area under the curve (AUC), with 90% CI that fell within the limits of 0.80 to 1.25. The pharmacokinetic parameters are shown in Table 8. Data for pharmacokinetic parameters are presented as the mean + SD.
[00220] Table 8:
Formulations 2 x 100 mg IR tablets 200 mg IR tablet Pharmacokinetic (N = 23) (N = 23) Parameters (units) Cmax (ng/mL) 879 + 401 845 +329 TillaX (hr) 1.1 + 0.4 1.1 +0.3 AUC, (ng=hr/mL) 2384 + 916 2211 853 AUC. (ng=hr/mL) 2391 + 917 2217 + 854 t1/2 (hr) 3.86 0.70 3.91 + 0.48 [00221] 3.4.3. Pharmacokinetics of F4 and F10 (200 mg) [00222] A further study was conducted to explore the bioavailability a single dose of one 200 mg IR tablet of Formulation F10 with that of two 100 mg IR tablets of Formulation F4 under fasting conditions. The pharmacokinetic parameters are shown in Table 9. Data for pharmacokinetic parameters are presented as the mean SD.

[00223] Table 9:
Formulations 2 x 100 mg IR tablets 200 mg IR tablet Pharmacokinetic (N = 54) (N = 54) Parameters (units) Cmt. (ng/mL) 744 + 353 (47) 738 + 419 (57) Tma. (h) 1.0 (0.5 - 3.0) 1.0 (0.5 - 3.0) t1/2 (h) 5.91 2.82 6.20 + 2.93 AUCt (ng=h/mL) 1890 + 852 (45) 1910 960 (50) AUC. (ng=h/mL) 1900 + 853 (45) 1920 961(50) [00224] 3.4.4. Phartnacokinetics of F5 (300 rng) [00225] A study was conducted to explore the bioavailability of a single dose of two 150 mg IR tablets of Formulation F5 under fasting conditions. The pharmacokinetic parameters are shown in Table 10. Data for pharmacokinetie parameters are presented as the mean SD.
[00226] Table 10:

2x 150 mg IR tablet Pharmacokinetic (N = 10) Parameters (units) Cmax (ng/mL) 1378 487 TIMIX (hr) 1.6 0.6 AUCt (ng=hr/mL) 3732 1356 AUC. (ng=hr/mL) 3772 1368 [00227] 3.4.5. Pharmacokinetics of F7 & F7DR (200 mg) [00228] A clinical study was conducted to compare the in vivo performance of F7 and F7DR. Additionally, the study assessed the potential effects of a high-fat meal on the pharmacokinetics of F7DR. Adult premenopausal healthy female subjects were administered a single dose of F7DR under fasting conditions, a single dose of F7DR 30 minutes after consuming a high-fat meal, or a single dose of F7 under fasting conditions.
[00229] A high-fat meal reduced the concentrations of the F7DR tablet formulation. A
delay in absorption was observed for the F7DR tablet formulation, regardless of the meal conditions. Food reduced the C.. and AUC of F7DR. The delay of absorption was longer for under fed conditions.

[00230] .. The pharmacokinetic parameters are shown in Table 11. Data for C.
and AUC
are presented as the mean (% CV); data for Tmax are presented as median (min ¨
max); and data for t1/2 are presented as harmonic mean (pseudo CV).
[00231] Table 11:
Regimens F7 - fasted F7DR - fasted F7DR - fed 200 mg IR tablet 200 mg eIR tablet 200 mg eIR tablet Pharmacokinetic (N = 24) (N = 11) (N = 11) Parameters (units) CMdX (ng/mL) 850 (34) 977 (63) 332 (51) TMdX (hr) 1.0 (0.75 ¨ 1.5) 3.0 (1.5 ¨6.0) 7.0 (4.0 ¨ 12.0) AUCt (ng=hr/mL) 2106 (43) 2253 (53) 1241 (46) AUC. (ng=hr/mL) 2115 (43) 2262 (53) 1250 (46) t1/2 (hr) 4.4 (33) 3.80 (34) 3.01 (26) [00232] Example 4: Estradiol Concentrations Following Treatment with F4 or [00233] A further study was conducted in premenopausal women with moderate to severe endometriosis-associated pain. The women enrolled in this study were representative of the general population of women with moderate to severe endometriosis-associated pain. Baseline characteristics, including the subjects' endometriosis-associated pain at study entry, were comparable across treatment groups.
[00234] Treatment groups were: (a) one F5 tablet once daily (i.e., 150 mg QD) and (b) two F4 tablets twice daily (i.e., 200 mg BID). Blood samples were collected during the monthly clinic visits to measure hormone concentrations. Over 800 female subjects across 151 sites in North America were randomized into the study in a 3:2:2 ratio to placebo, 150 mg QD, or 200 mg BID, respectively.
[00235] A dose-dependent suppression of estradiol was observed in the treatment groups, compared with placebo during the treatment period. For the placebo group, the median estradiol levels at their monthly visits were between 70.0 and 91.6 pg/mL, with 2% to 4%
of women with estradiol concentrations <20 pg/mL. For the 150 mg QD group, the median estradiol levels at their monthly visits were between 36.8 and 45.7 pg/mL, with 15% to 24% of women with estradiol concentrations < 20 pg/mL. For the 200 mg BID group, the median estradiol levels at their monthly visits were at the limit of quantification (12.4 pg/mL), with 71% to 81% of women with estradiol concentrations <20 pg/mL.

Docket No. 025148.8372 (ABV12349USL1) n [00236] Table 12: Estradiol Serum Concentrations n.) to 1 =-.1 Treatment/Parameter Day Month 1 Month 2 Month 3 Month 4 Month 5 Month 6 =-.1 (Predose) to w Placebo co n.) N 366 342 329 1-.
=-.1 Median 48.6 70.0 83.4 88.6 77.7 82.9 91.6 0 (Mean SD) (66.5+56.3) (91.8174.8) (104.4179.4) (110.6+89.7) (107.1+86.8) (107.3182.7) (111.7179.9) to 0 % subjects < 20 pg/mL 6.3 3.8 4.0 1.9 2.7 3.8 2.7 1-.
% subjects 20-50 pg/mL 45.6 33.6 23.4 26.1 25.7 23.6 21.1 % subjects > 50 pg/mL 48.1 62.6 72.6 71.9 71.7 72.6 76.2 150 mg QD

Median 45.7 36.8 39.2 41.0 41.2 41.5 45.7 (Mean+SD) (70.9+70.0) (56.7+58.5) (60.7+59.0) (65.8+66.9) (66.7+82.4) (70.1+72.5) (75.4177.6) % subjects <20 pg/mL 9.4 23.6 19.4 21.1 20.7 15.4 15.2 % subjects 20-50 pg/mL 45.5 43.7 44.7 37.1 38.9 41.5 41.2 % subjects > 50 pg/mL 45.1 32.8 35.9 41.8 40.4 43.1 43.6 200 mg BID

Median 46.5 12.4 12.4 12.4 12.4 12.4 12.4 (Mean+SD) (77.5+84.9) (25.0+38.2) (25.5+44.7) (27.4+42.9) (22.8+32.4) (25.3135.3) (31.1+50.8) % subjects <20 pg/mL 8.1 80.6 80.8 76.1 78.2 75.1 70.7 % subjects 20-50 pg/mL 45.5 8.6 11.1 13.7 14.4 14.9 15.3 % subjects > 50 pg/mL 46.3 10.8 8.2 10.2 7.4 9.9 14.0 Docket No. 025148.8372 (ABV12349USL1) [00237] Example 5: Estradiol Concentrations Following Treatment with F4 or [00238] Another study was conducted in premenopausal women with moderate to severe endometriosis-associated pain. The women enrolled in this study were representative of the general population of women with moderate to severe endometriosis-associated pain. Baseline characteristics, including the subjects' endometriosis-associated pain at study entry, were comparable across treatment groups.
[00239] Treatment groups were: (a) one FS tablet once daily (i.e., 150 mg QD) and (b) two F4 tablets twice daily (i.e., 200 mg BID). Blood samples were collected during the monthly clinic visits to measure hormone concentrations. Over 800 female subjects across 187 sites in North America, South America, Europe, Africa, and Australia were randomized into the study in a 3:2:2 ratio to placebo, 150 mg QD, or 200 mg BID, respectively.
[00240] A dose-dependent suppression of estradiol was observed in the treatment groups, compared with placebo during the treatment period. For the placebo group, the median estradiol levels at their monthly visits were between 70.7 and 105 pg/mL with 4% to 6%
of women with estradiol concentrations < 20 pg/mL. For the 150 mg QD dose, the median estradiol levels at their monthly visits were between 37.2 and 55.8 pg/mL, with 14% to 22% of women with estradiol concentrations <20 pg/mL. For the 200 mg BID dose, the median estradiol levels at their monthly visits were between 8.43 and 13.1 pg/mL, with 62% to 77% of women with estradiol concentrations < 20 pg/mL.

Docket No. 025148.8372 (ABV12349USL1) n 100241i Table 13: Estradiol Serum Concentrations n.) to 1 =-.1 Treatment/Parameter Day Month 1 Month 2 Month 3 Month 4 Month 5 Month 6 =-.1 (Predose) to w Placebo co n.) N 324 312 293 1-.
=-.1 Median 58.1 70.7 85.2 84.9 77.8 80.2 105 to (Mean+SD) (91.4+81.5) (99.6187.1) (105+79.1) (106+80.6) (100+89.4) (107+101) (114+79.6) 0 % subjects < 20 pg/mL 5.6 4.8 4.1 3.7 6.1 3.5 4.7 1-.
% subjects 20-50 pg/mL 37.4 29.2 25.6 26.8 24.9 26.6 19.0 % subjects > 50 pg/mL 57.1 66.0 70.3 69.5 69.0 69.9 76.3 150 mg QD

Median 67.0 43.6 37.2 41.7 47.5 46.9 55.8 (Mean+SD) (87.1169.6) (74.6196.5) (56.6+53.1) (64.9+63.4) (69.5+82.6) (61.1+52.0) (76.8+64.9) % subjects <20 pg/mL 5.9 18.4 22.2 20.5 19.2 18.3 13.9 % subjects 20-50 pg/mL 28.3 38.8 41.6 35.3 32.9 36.0 32.9 % subjects > 50 pg/mL 65.9 42.8 36.2 44.2 47.9 45.7 53.2 200 mg BID

Median 63.2 8.43 8.95 10.9 10.6 13.0 13.1 (Mean+SD) (83.9+74.5) (22.4152.2) (21.2+32.0) (28.6+45.6) (24.3+34.9) (35.0162.9) (31.8+46.6) A subjects <20 pg/mL 5.7 77.1 70.8 67.4 70.0 63.8 62.1 % subjects 20-50 pg/mL 35.1 13.5 17.8 16.3 15.0 17.0 18.3 % subjects > 50 pg/mL 59.2 9.4 11.4 16.3 15.0 19.2 19.6 Docket No. 025148.8372 (ABV12349USL1) [00242] Example 6: Impact of Water-Insoluble Filler & Surfactant An immediate release formulation containing sodium carbonate was prepared. All components, except magnesium stearate, were blended in a high-shear granulator and granulated with neat, de-ionized water. The granules were tray-dried at 40 C and passed through a #20 US Standard sieve and lubed with magnesium stearate. Compound A referenced in Table 14 below is the Compound A sodium salt.
[00243] Table 14: Composition of Formulation F12 Quantity (mg/Tablet) Ingredient F12 Fl2A
Compound A, sodium salt 155.5 153.1 Microcrystalline Cellulose 150.5 148.2 Corn Starch 48.0 47.3 Povidone K 29/32 15.0 14.8 Sodium Carbonate, monohydrate 75.0 73.8 Magnesium stearate 6.0 5.9 Sodium dodecyl sulfate 6.8 [00244] Formulation F12A was prepared by combining 6.3 g Formulation F12 and 97.3mg sodium dodecyl sulfate (1.5% w/w) in a bottle and rolling the bottle by hand to blend.
[00245] An in vitro dissolution study was conducted. The release of Compound A was monitored using USP apparatus II in 900 mL of pH 6.8 buffer, at 37 C and paddle speed of 50 rpm. The dissolution results are presented in Table 15:
[00246] Table 15: Percent Compound A released in pH 6.8 buffer Mean %
Minutes F12 Fl2A
15 14.3 27.4 30 39.2 62.1 45 59.6 86.4 [00247] Example 7: Impact of sodium carbonate on dissolution [00248] The impact of sodium carbonate monohydrate level on dissolution was examined.
The amount of sodium carbonate monohydrate was varied by 20% of the nominal level to study the impact on dissolution. Mannitol level was adjusted in the formulation to maintain the overall tablet weight. A slugging process was used to manufacture tablets to a target solid fraction of 0.88 hardness of 125 N. Dissolution profiles for tablets from the batches are presented in Figure 7. All results passed the proposed dissolution specification at t=
30 minutes. The results indicate the 20% change in the level of sodium carbonate monohydrate does not impact dissolution.
[00249] Example 8: Impact of sodium carbonate on degradation products, including Compound B
[00250] One degradation product of Compound A is Compound B, which has a lactam moiety.
[00251] Excipient compatibility studies were conducted using mixtures of excipients and Compound A with and without sodium carbonate. The results are shown in Figure 8. All excipients (corn starch, mannitol, pregelatinized starch (PGS), microcrystalline cellulose (MCC), dibasic calcium phosphate (DCP), isomalt, colloidal silicon dioxide (SiO2)) showed much higher formation of lactam in absence of sodium carbonate. In the presence of sodium carbonate, the excipients showed much lower content of lactam, very close to the detectable limit of about 0.03%.
[00252] Formulations using 2:1, 3:1, and 4: 1 w/w ratio of Compound A to sodium carbonate monohydrate were prepared. These formulations contained ¨35%
Compound A, sodium carbonate monohydrate, mannitol, pregelatinized starch, povidone, and magnesium stearate. The tablets were film coated and tested under accelerated stability protocol conditions of 50 C/75% RH, 60 C/5% RH, 60 C/40% RH, 70 C/5% RH, 70 C/75% RH, 80 C/40% RH
over a period ranging from 2 to 25 days. The results are shown in Figure 9.
Formulations prepared with 3:1 and 4:1 w/w ratio of Compound A to sodium carbonate showed higher presence of the lactam degradant, whereas formulations with 2:1 w/w ratio showed relatively less formation of the lactam degradant.
[00253] Additional stability testing was performed on Formulations F5 and F7. The tablets were prepared, placed in clear blister pack with aluminum foil, and stored under the following conditions: 25 C/60% RH or 40 C/75% RH. Tablets were assessed for the presence of degradation products, including Compound B, at 0 (initial), 1, 3, 6, 9, 12, 18, and 24 months for the 25 C/60% RH condition and at 0 (initial), 1, 3, and 6 months for the 40 C/75% RH
condition. The results are presented in Table 16.

Docket No. 025148.8372 (ABV12349USL1) n 1002541 Table 16: Stability of F5 and F7 up to 24 months IS.) to =-.1 =-.1 to Storage Degradation Months w Formulation co Condition Product [%] 0 1 3 n.) 0 Compound B
ND ND ND ND ND ND ND ND
1-. =-.1 25 C F5 Total 0 0 0.10 0.10 0 0.11 0.10 0.11 0 60%RH F7 Compound B
ND ND ND ND ND ND ND ND
to 1 Total 0 0 0 0 0 0 0.11 0.22 1-.
F5 Compound B ND ND <0.10 <0.10 NT NT NT NT
40 C Total 0 0 0.23 0.35 NT NT NT NT
75%RH F7 Compound B ND ND <0.10 <0.10 NT NT NT NT
Total 0 0 0.10 0.33 NT NT NT NT
1002551 ND = not detected; NT = not tested Docket No. 025148.8372 (ABV12349USL1) [00256] It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations, or methods, or any combination of such changes and modifications of use of the invention, may be made without departing from the spirit and scope thereof.
[00257] All references (patent and non-patent) cited above are incorporated by reference into this patent application. The discussion of those references is intended merely to summarize the assertions made by their authors. No admission is made that any reference (or a portion of any reference) is relevant prior art (or prior art at all). Applicant reserves the right to challenge the accuracy and pertinence of the cited references.

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical composition comprising about 150 mg, about 200 mg, or about 300 mg 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid (Compound A) or a pharmaceutically acceptable salt thereof; and an anti-gelling agent; wherein the pharmaceutical composition comprises at least 10% by weight of Compound A
or the pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition of claim 1, wherein the anti-gelling agent comprises an alkali metal salt.

3. The pharmaceutical composition of claim 2, wherein the alkali metal salt is selected from the group consisting of sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium phosphate, and combinations thereof.

4. The pharmaceutical composition of claim 2, wherein the weight ratio of Compound A or the pharmaceutically acceptable salt thereof to the anti-gelling agent, is from about 1:1 to about 4:1.

5. The pharmaceutical composition of claim 2, wherein the anti-gelling agent is present in an amount from about 5% by weight to about 35% by weight of the pharmaceutical composition.

6. The pharmaceutical composition of claim 1, wherein the anti-gelling agent further acts as a stabilizer to reduce formation of (R)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methyl-3-(2-(2-oxopyrrolidin-1-yl)-2-phenylethyl)pyrimidine-2,4(1H,3H)-dione (Compound B) in the composition relative to an otherwise identical composition without the anti-gelling agent.

7. The pharmaceutical composition of claim 1, further comprising (a) at least one water soluble filler or (b) at least one water insoluble filler and a surfactant.

8. The pharmaceutical composition of claim 1, wherein the composition releases at least about 80% of Compound A or the pharmaceutically acceptable salt thereof in about 45 minutes, measured using USP apparatus II in 900 mL of sodium phosphate, pH
6.8, at 37 °C and paddle speed of 50 rpm.

9. The pharmaceutical composition of claim 1, wherein the salt of Compound A is sodium 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)butanoate.

10. The pharmaceutical composition of claim 9, wherein the composition when administered as a single dose to a population of human subjects provides an average T max value that is less than about 3 hours, preferably about 0.5 to about 2.0 hours.

11. The pharmaceutical composition of claim 9, wherein 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)butanoate is present in an amount equivalent to about 150 mg of Compound A and the composition when administered as a single dose to a population of human subjects provides an average C max value that is about 400 ng/mL to about 660 ng/mL for the population of human subjects, an average AUC t from about 1000 ng.cndot.hr/mL to about 1600 ng.cndot.hr/mL for the population of human subjects, and an average AUC.infin.
from about 1010 ng.cndot.hr/mL to about 1610 ng.cndot.hr/mL for the population of human subjects.

12. The pharmaceutical composition of claim 9, wherein 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)butanoate is present in an amount equivalent to about 200 mg of Compound A and the solid oral dosage form when administered as a single dose to a population of human subjects provides an average C max from about 590 ng/mL to about 1100 ng/mL for the population of human subjects, an average AUC t from about 1510 ng.cndot.hr/mL to about 2980 ng.cndot.hr/mL for the population of human subjects, an average AUC.infin. from about 1520 ng.cndot.hr/mL to about 2990 ng.cndot.hr/mL for the population of human subjects.

13. The pharmaceutical composition of claim 15, wherein 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)butanoate is present in an amount equivalent to about 300 mg of Compound A and the solid oral dosage form when administered as a single dose to a population of human subjects provides an average C max from about 1100 ng/mL
to about 1730 ng/mL for the population of human subjects, an average AUC t from about 2990 ng-hr/mL to about 4670 ng.cndot.hr/naL for the population of human subjects, and an average AUG, from about 3020 ng.cndot.hr/mL to about 4720 ng.cndot.hr/mL for the population of human subjects.

14. The pharmaceutical composition of claim 1, wherein the composition when administered to a female subject provides rapid suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels.

15. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises less than about 0.7% (R)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methyl-3-(2-(2-oxopyrrolidin-1-yl)-2-phenylethyl)pyrimidine-2,4(1H,3H)-dione after storage from about one month to about three months at 25°C and 60%
relative humidity.

16. A pharmaceutical composition comprising about 150 mg of 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid (Compound A) or a pharmaceutically acceptable salt thereof; and an anti-gelling agent; wherein the weight ratio of Compound A or the pharmaceutically acceptable salt thereof is from about 1:1 to about 4:1.

17. A pharmaceutical composition comprising about 200 mg of 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid (Compound A) or a pharmaceutically acceptable salt thereof; and an anti-gelling agent; wherein the weight ratio of Compound A or the pharmaceutically acceptable salt thereof is from about 1:1 to about 4:1.

18. A pharmaceutical composition comprising about 300 mg of 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid (Compound A) or a pharmaceutically acceptable salt thereof; and an anti-gelling agent; wherein the weight ratio of Compound A or the pharmaceutically acceptable salt thereof is from about 1:1 to about 4:1.

19. The pharmaceutical composition of any one of claims 16-18, wherein the anti-gelling agent is sodium carbonate.

20. The pharmaceutical composition of claim 19, wherein the weight ratio of Compound A or a pharmaceutically acceptable salt thereof to sodium carbonate is about 2:1.

21. The pharmaceutical composition of claim 20, wherein the pharmaceutical composition comprises a salt of Compound A.

22. The pharmaceutical composition of claim 21, wherein the salt of Compound A is sodium 44(R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)butanoate.

23. A solid oral dosage form comprising:
(a) about 33.2% by weight of sodium 44(R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)butanoate;
(b) about 2.9% by weight of a binder;
(c) about 16.7% by weight of an alkali metal salt;
(d) about 41.6% by weight of a water soluble filler;
(e) about 1.8% by weight of a lubricant; and (f) about 3.8% by weight of a film-coating.

24. The solid oral dosage form of claim 23, wherein the binder is polyvinylpyrrolidone.

25. The solid oral dosage form of claim 23, wherein the alkali metal salt is sodium carbonate.

26. The solid oral dosage form of claim 23, wherein the water soluble filler comprises mannitol and pregelatinized starch.

27. A pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof and Compound B or a salt thereof; wherein Compound A
is 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-meth yl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid; Compound B is (R)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methyl-3-(2-(2-oxopyrrolidin-1-yl)-2-phenylethyl)pyrimidine-2,4(1H,3H)-dione; and Compound B is present in the composition in an amount less than about 0.7% by weight.

28. The pharmaceutical composition of claim 27, wherein Compound B is present in the composition in an amount less than about 0.7% by weight after storage for at least one month, at least two months, or preferably at least six months at 25°C
and 60% relative humidity.

29. A method of treating endometriosis, the method comprising administering the pharmaceutical composition of claim 1 to a patient in need thereof.

30. A method of treating uterine fibroids, the method administering the pharmaceutical composition of claim 1 to a patient in need thereof.