Solid oral dosage form of estrogen receptor degrading agent

Abstract

Disclosed herein are solid oral dosage forms comprising Compound A:, or a pharmaceutically acceptable salt thereof.

Description

[0001] Related applications

[0002] This application claims priority and benefit to U.S. Provisional Application No. 63 / 472,523, filed June 12, 2023, the contents of which are incorporated herein by reference in their entirety for all purposes. Background Technology

[0003] Certain bifunctional compounds target specific cellular proteins for degradation via the ubiquitin-proteasome system. Examples of such proteolytic-targeting chimeric compounds (i.e., “PROTAC® protein degraders”) that target the estrogen receptor (ER) for ubiquitination and subsequent degradation are disclosed in International Publication No. WO 2018 / 102725, which is incorporated herein by reference in its entirety. Such bifunctional molecules exhibit a range of pharmacological activities consistent with ER degradation, including but not limited to treating or improving disease symptoms such as cancer (e.g., breast cancer, uterine cancer, ovarian cancer, prostate cancer, endometrial cancer) or endometriosis.

[0004] Of particular interest is the (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione or (3S)-3-[1,3-dihydro-1-oxo-5-[4-[[1-[4-[(1R,2S)-1,2,3,4-tetrahydro-6-hydroxy-2-phenyl-1-naphthylphenyl]-4-piperidinyl]methyl]-1-piperazinyl]-2H-isoindolin-2-yl]-2,6-piperidindione (referred to herein as "compound A" or "Cpd A"), which has C 45 H 49 The molecular formula and the following structure of N5O4:

[0005] .

[0006] Compound A is being developed as a PROTAC® protein degrader targeting ER for potential treatment of breast cancer and has shown to be a useful regulator of protein ubiquitination and degradation via the ubiquitin-proteasome pathway.

[0007] There is a need to develop dosage forms for compound A, including those suitable for oral administration. Such dosage forms may have certain advantages (e.g., increased oral bioavailability) and can be used to safely, effectively, and / or conveniently administer compound A to patients for, for example, the treatment of cancer (e.g., breast cancer). Summary of the Invention

[0008] The present invention is provided to introduce, in a simplified form, a series of concepts further described in the detailed embodiments described below. The present invention is not intended to identify key or essential features of the claimed subject matter, nor is it intended to be used alone as an aid in determining the scope of the claimed subject matter.

[0009] This article partially discloses solid oral dosage forms (e.g., tablets) that contain compound A:

[0010] ,

[0011] Or a pharmaceutically acceptable salt thereof. In particular, this document discloses solid oral dosage forms comprising compound A or a pharmaceutically acceptable salt thereof, a polymer, and a surfactant. In embodiments, the amount of compound A in the solid oral dosage form is from about 5 mg to about 500 mg. In embodiments, the solid oral dosage form is a tablet, sachet, or capsule.

[0012] In the implementation scheme, the solid oral dosage form further comprises one or more excipients selected from fillers, disintegrants, flow aids, and lubricants. Exemplary fillers include, but are not limited to, microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate, mannitol, sorbitol, xylitol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, pullulan, rapidly dissolving carbohydrates, and combinations thereof. Exemplary disintegrants include, but are not limited to, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, chitosan, agar, alginate, calcium alginate, methylcellulose, microcrystalline cellulose, powdered cellulose, lower alkyl-substituted hydroxypropyl cellulose, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, potassium polycrystallin, starch, pregelatinized starch, sodium alginate, potassium polycrystallin, povidone, and combinations thereof. Exemplary flow aids include, but are not limited to, silica, colloidal silica, calcium silicate, magnesium silicate, magnesium trisilicate, talc, starch, and combinations thereof. Exemplary lubricants include, but are not limited to, magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl behenate, glyceryl palmitate, hexagonal boron nitride, hydrogenated vegetable oil, light mineral oil, mineral oil, polyethylene glycol, poloxamer, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate, and combinations thereof.

[0013] In this implementation, the solid oral dosage form is a tablet. In this implementation, the tablet is film-coated.

[0014] In the implementation scheme, the solid oral dosage form (e.g., tablet) comprises:

[0015] Compound A, approximately 15% w / w to approximately 50% w / w;

[0016] Hydroxypropyl methylcellulose, approximately 10% w / w to approximately 40% w / w;

[0017] D-α-tocopherol polyethylene glycol succinate, approximately 0.5% w / w to approximately 5% w / w;

[0018] Microcrystalline cellulose of approximately 10% w / w to approximately 40% w / w;

[0019] Lactose monohydrate at approximately 5% w / w to approximately 15% w / w;

[0020] Crosslinked carboxymethyl cellulose sodium, approximately 5% w / w to approximately 15% w / w;

[0021] Silica of approximately 0% w / w to approximately 5% w / w; and

[0022] Sodium stearyl fumarate, approximately 0% w / w to approximately 2% w / w.

[0023] In the implementation scheme, the solid oral dosage form (e.g., tablet) comprises:

[0024] Compound A, 15% to 50% w / w;

[0025] 10% to 40% w / w hydroxypropyl methylcellulose;

[0026] 0.5% to 5% w / w D-α-tocopherol polyethylene glycol succinate;

[0027] 10% to 40% w / w microcrystalline cellulose;

[0028] 5% to 15% w / w lactose monohydrate;

[0029] 5% to 15% w / w croscarmellose sodium;

[0030] 0% to 5% w / w silica; and

[0031] 0% to 2% w / w sodium stearate fumarate.

[0032] In the implementation scheme, the solid oral dosage form (e.g., tablet) comprises:

[0033] Compound A has approximately 42% w / w.

[0034] Approximately 15% w / w hydroxypropyl methylcellulose;

[0035] Approximately 3% w / w D-α-tocopherol polyethylene glycol succinate;

[0036] Approximately 17% w / w microcrystalline cellulose;

[0037] Approximately 8.8% w / w lactose monohydrate;

[0038] Approximately 12% w / w of croscarmellose sodium;

[0039] Approximately 1% w / w of silica; and

[0040] Approximately 1.5% w / w sodium stearate fumarate.

[0041] In the implementation scheme, the solid oral dosage form (e.g., tablet) comprises:

[0042] Compound A, approximately 20% w / w;

[0043] Approximately 28% w / w hydroxypropyl methylcellulose;

[0044] Approximately 2.5% w / w D-α-tocopherol polyethylene glycol succinate;

[0045] Approximately 27% w / w microcrystalline cellulose;

[0046] Approximately 9% w / w lactose monohydrate;

[0047] Approximately 12% w / w of croscarmellose sodium;

[0048] Approximately 1% w / w of silica; and

[0049] Approximately 1.5% w / w sodium stearate fumarate.

[0050] In the embodiments, the solid oral dosage form (e.g., tablet) comprises an intragranular portion and an extragranular portion, and optionally, a film coating.

[0051] The intragranular portion includes:

[0052] Compound A, approximately 15% to approximately 50% w / w;

[0053] Hydroxypropyl methylcellulose, approximately 10% to approximately 40% w / w;

[0054] D-α-tocopherol polyethylene glycol succinate, approximately 0.5% to approximately 5% w / w;

[0055] Microcrystalline cellulose, approximately 5% to approximately 10% w / w;

[0056] Lactose monohydrate, approximately 5% to approximately 10% w / w;

[0057] Approximately 1% to approximately 10% w / w of croscarmellose sodium;

[0058] Approximately 0% to approximately 5% w / w of silica; and

[0059] Sodium stearyl fumarate, approximately 0% to approximately 2% w / w.

[0060] And the extragranular portion includes:

[0061] Microcrystalline cellulose of approximately 5% to approximately 25% w / w;

[0062] About 0% to about 10% w / w of croscarmellose sodium; and

[0063] Sodium stearyl fumarate, approximately 0% to approximately 2% w / w;

[0064] The weight percentage is relative to the total weight of uncoated tablets.

[0065] In the embodiments, the solid oral dosage form (e.g., tablet) comprises an intragranular portion and an extragranular portion, and optionally, a film coating.

[0066] The intragranular portion includes:

[0067] Compound A has approximately 42% w / w.

[0068] Approximately 14% w / w hydroxypropyl methylcellulose;

[0069] Approximately 3% w / w d-α-tocopherol polyethylene glycol succinate;

[0070] Approximately 9% w / w microcrystalline cellulose;

[0071] Approximately 9% w / w lactose monohydrate;

[0072] Approximately 6% w / w of croscarmellose sodium;

[0073] Approximately 1% w / w of silica; and

[0074] Approximately 0.75% w / w sodium stearate fumarate;

[0075] And the extragranular portion includes:

[0076] Approximately 8% w / w microcrystalline cellulose;

[0077] Approximately 6% w / w of croscarmellose sodium; and

[0078] Approximately 0.75% w / w sodium stearate fumarate;

[0079] The weight percentage is relative to the total weight of uncoated tablets.

[0080] In the embodiments, the solid oral dosage form (e.g., tablet) comprises an intragranular portion and an extragranular portion, and optionally, a film coating.

[0081] The intragranular portion includes:

[0082] Compound A, approximately 20% w / w;

[0083] Approximately 28% w / w hydroxypropyl methylcellulose;

[0084] Approximately 2.5% w / w D-α-tocopherol polyethylene glycol succinate;

[0085] Approximately 8% w / w microcrystalline cellulose;

[0086] Approximately 9% w / w lactose monohydrate;

[0087] Approximately 6% w / w of croscarmellose sodium;

[0088] Approximately 1% w / w of silica; and

[0089] Approximately 0.75% w / w sodium stearate fumarate,

[0090] And the extragranular portion includes:

[0091] Approximately 18% w / w microcrystalline cellulose;

[0092] Approximately 6% w / w of croscarmellose sodium; and

[0093] Approximately 0.75% w / w sodium stearate fumarate;

[0094] The weight percentage is relative to the total weight of uncoated tablets.

[0095] In one embodiment, the solid oral dosage form (e.g., tablet) comprises about 5 mg, about 10 mg, about 15 mg, about 10 mg, about 25 mg, about 30 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg of compound A. In another embodiment, the solid oral dosage form comprises about 200 mg of compound A. In yet another embodiment, the solid oral dosage form comprises about 100 mg of compound A. In yet another embodiment, the solid oral dosage form comprises about 250 mg of compound A. In yet another embodiment, the solid oral dosage form comprises about 50 mg of compound A.

[0096] This article also discloses mixtures comprising compound A or a pharmaceutically acceptable salt thereof, a polymer, and a surfactant.

[0097] This article further discloses a spray-dried dispersion comprising compound A or a pharmaceutically acceptable salt thereof, a polymer, and a surfactant.

[0098] Methods for preparing the spray-dried dispersions disclosed herein are also provided. Such methods include:

[0099] Compound A, the polymer, and the surfactant are dissolved in a solvent to provide a solution containing compound A;

[0100] A solution containing compound A is introduced into a spray dryer;

[0101] A solution containing compound A is sprayed from a spray dryer to form a dispersion of compound A; and

[0102] Optionally, residual solvent is removed from the dispersion of compound A.

[0103] In one embodiment of the method, the solvent is a mixture of dichloromethane and methanol. In another embodiment, the solvent is a mixture of about 90:10 (w / w) to about 70:30 (w / w) dichloromethane:methanol. In yet another embodiment, the solvent is a mixture of about 80:20 (w / w) dichloromethane:methanol. And in yet another embodiment, the solvent is a mixture of about 85:15 (w / w) dichloromethane:methanol.

[0104] In an embodiment of the method, removal of residual solvent includes drying (e.g., stirred cone drying). Attached Figure Description

[0105] Figure 1 Results of a pharmacokinetic (PK) study in fasted female dogs after oral administration of an aqueous suspension of compound A, as described in Example 2, are presented. For formulation BF, the indicated bioavailability was improved relative to formulation A.

[0106] Figures 2A to 2D The results of a PK study in fasted female dogs, as described in Example 3, were shown.

[0107] Figures 3A to 3D The results of a PK study in female dogs that had been orally administered tablets of compound A, as described in Example 3, are shown. Detailed Implementation

[0108] The invention can be more readily understood by referring to the following detailed description of embodiments of the invention and examples included herein. It should be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0109] (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione or (3S)-3-[1,3-dihydro-1-oxo-5-[4-[[1-[4-[(1R,2S)-1,2,3,4-tetrahydro-6-hydroxy-2-phenyl-1-naphthylphenyl]-4-piperidinyl]methyl]-1-piperazinyl]-2H-isoindolin-2-yl]-2,6-piperidindione (referred to herein as "Compound A" or "Cpd A"):

[0110]

[0111] PROTAC is being developed as a potential treatment for breast cancer targeting ER. ® It is a protein degrader and has been shown to be a useful regulator of protein ubiquitination and degradation via the ubiquitin-proteasome pathway.

[0112] Compound A and its pharmaceutically acceptable salts are disclosed in International Publication No. 2018 / 102725 and U.S. Patent Nos. 10,647,698, 10,899,742 and 11,104,666; International Publication No. 2021 / 041348; U.S. Serial No. 17 / 472,847; U.S. Serial No. 17 / 548,842; and U.S. Serial No. 17 / 873,748. The contents of each of the foregoing references are incorporated herein by reference in their entirety.

[0113] definition

[0114] Unless otherwise defined herein, scientific and technical terms used in connection with this invention have the meanings commonly understood by one of ordinary skill in the art.

[0115] The invention described herein may be practiced in the absence of any one or more elements not specifically disclosed herein.

[0116] As used herein, unless otherwise specified, the singular forms “a,” “an,” and “the” include plural indicators. For example, “a” excipient includes one or more excipients.

[0117] As used herein, when used to modify a parameter defined numerically (e.g., the dosage of a compound), the term “about” means that the parameter may vary by up to 10% below or above the stated value of the parameter. For example, a dosage of about 5 mg means 5 mg ± 10%, that is, it may vary from 4.5 mg to 5.5 mg.

[0118] As used herein, the terms “pharmaceutical,” “composition,” “compound,” “drug,” and “therapeutic agent,” including but not limited to, are used interchangeably to refer to compounds included in the methods and uses of this disclosure.

[0119] The term "amorphous" refers to a solid in which molecules are arranged randomly and do not have a distinguishable crystal lattice.

[0120] Compound A has the following structure:

[0121] .

[0122] Compound A is a Class IV compound (low solubility / low permeability) in the biopharmaceutical classification system. Compound A can interconvert with its epimeric counterpart, compound B.

[0123] .

[0124] Unwilling to be bound by theory, preclinical data suggest that exposure to compound B was limited compared to compound A (<26%). Evidence indicates that compound B does not degrade ER; however, compound B exhibits similar antagonistic effects on ER-dependent transcription compared to compound A.

[0125] Other embodiments involve pharmaceutically acceptable salts of the compounds described herein. Pharmaceutically acceptable salts of the compounds described herein include their acid addition salts and base addition salts.

[0126] Other embodiments also involve pharmaceutically acceptable acid addition salts of the compounds described herein. Suitable acid addition salts are formed from acids that form non-toxic salts. Non-limiting examples of suitable acid addition salts are salts containing pharmacologically acceptable anions, including but not limited to acetates, acid citrates, adipates, aspartates, benzoates, benzenesulfonates, bicarbonates / carbonates, bisulfates / sulfates, tartrates, borates, camphor sulfonates, citrates, cyclohexylaminosulfonates, ethanedisulfonates, ethanesulfonates, ethylsulfonates, formates, fumarates, gluconate, gluconate, glucuronate, hexafluorophosphate, hydantoinate, etc. Hydrochloride / chloride, hydrobromide / bromate, hydroiodide / iodide, hydroxyethyl sulfonate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfonate, methyl sulfate, naphthate, 2-naphthalenesulfonate, nicotinate, nitrate, lactate, oxalate, palmitate, dihydroxynaphthalate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, glycosides, stearate, succinate, tannin, tartrate, p-toluenesulfonate, toluenesulfonate, trifluoroacetate, and sine.

[0127] Other embodiments involve base addition salts of the compounds described herein. Suitable base addition salts are formed from bases that form non-toxic salts. Non-limiting examples of suitable base salts include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts.

[0128] The basic compounds described herein can form a variety of salts with various inorganic and organic acids. Pharmaceutically acceptable acid addition salts that can be used to prepare such basic compounds are acids that form non-toxic acid addition salts, such as salts containing pharmacologically acceptable anions, like hydrochlorides, hydrobroms, hydroiodates, nitrates, sulfates, hydrogen sulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, acid citrates, tartrates, pantothenates, hydrogen tartrates, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glucurons, glycosides, formates, benzoates, glutamates, methanesulfonates, ethylsulfonates, benzenesulfonates, p-toluenesulfonates, and bis(hydroxynaphthyl)ate [i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthyl)ate]. In addition to the acids mentioned above, the compounds described herein that include basic moieties (such as amino groups) can form pharmaceutically acceptable salts with a variety of amino acids.

[0129] The chemical base that can be used as a reagent for preparing pharmaceutically acceptable base salts of the compounds described herein that are acidic in nature is a chemical base that forms a non-toxic base salt with such compounds. Such non-toxic base salts include, but are not limited to, base salts derived from such pharmacologically acceptable cations, such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts, such as N-methylglucosamine-(glucosamine), and other base salts of lower alkyl ammonium and pharmaceutically acceptable organic amines.

[0130] It can also form hemisales of acids and bases, such as hemisulfates and hemicalcium salts.

[0131] For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.

[0132] As used herein, the terms "subject" and "patient" are used interchangeably to refer to any animal, including mammals. Mammals according to this disclosure include canines, felines, bovines, goats, equines, sheep, suidae, rodents, rabbits, primates, humans, etc., and encompass mammals in the womb. In embodiments, humans are suitable subjects. Human subjects can be of any sex and at any developmental stage.

[0133] When compounding compounds into tablets or other solid oral dosage forms, it is desirable to develop formulations that are stable at temperatures and relative humidity levels higher than typically encountered. Other desired properties in the formulation, such as rapid dissolution, are also sought, allowing the tablets to dissolve quickly and the drug to be readily absorbed. Therefore, good storage stability and rapid dissolution are particularly sought as desirable characteristics of this invention.

[0134] An active pharmaceutical ingredient (API) is an active ingredient contained in any drug. Any active ingredient that directly affects or targets a disease and is intended for use in manufacturing is called an API. These substances are considered essential because they provide pharmacological activity or direct action in the diagnosis, cure, treatment, prevention, or influence of bodily structures.

[0135] As used herein, "oral dosage form" means a pharmaceutical product containing a specified amount (dose) of the disclosed compound as an API or a pharmaceutically acceptable salt and / or solvate thereof, and an inactive component (excipient), formulated into a specific configuration suitable for oral administration, such as an oral tablet, liquid, or capsule. In some embodiments, the oral dosage form comprises tablets. In some embodiments, the oral dosage form comprises scoreable tablets. In some embodiments, the oral dosage form comprises sublingual tablets.

[0136] As used in this article, "oral administration" refers to drugs administered orally, in the form of tablets, capsules, syrups, powders, granules, lozenges, solutions, tinctures, elixirs, emulsions, hydrogels, teas, films, disintegrating tablets, mouthwashes, etc.

[0137] Drug dissolution represents a key factor influencing systemic absorption rate. Various in vitro methods have been developed to assess the solubility properties of drug formulations, and dissolution tests are sometimes used as an alternative to directly assessing drug bioavailability. See, for example, Emmanuel et al., Pharmaceutics (2010), 2:351-63 and the references cited therein. A dissolution test measures the percentage of API released from a drug product (e.g., tablets) and dissolved in a dissolution medium over a defined time period under controlled test conditions. To maintain sedimentation conditions, the saturated solubility of the drug in the dissolution medium should be at least three times the drug concentration. For compounds with low solubility, dissolution can sometimes be determined under non-sedimentation conditions. Dissolution is affected by the properties of the API (e.g., particle size, crystal form, bulk density), the composition of the drug product (e.g., drug loading, excipients), the manufacturing process (e.g., compression pressure), and stability under storage conditions (e.g., temperature, humidity).

[0138] Methods for assessing the chemical storage stability of solid dosage forms under accelerated aging conditions have been described in the literature. See, for example, ST Colgan, TJ Watson, RD Whipple, R. Nosal, JVBeaman, D. De Antonis, “The Application of Science and Risk Based Concepts to Drug Substance Stability Strategies” J. Pharm. Innov. 7:205–2013 (2012); Waterman KC, Carella AJ, Gumkowski MJ et al. Improved protocol and data analysis for accelerated shelf-life estimation of solid dosage forms. PharmRes 2007; 24(4):780–90; and ST Colgan, RJ Timpano, D. Diaz, M. Roberts, R. Weaver, K. Ryan, K. Fields, G. Scrivens, “Opportunities for Lean Stability Strategies” J. Pharm. Innov. 9:259–71 (2014).

[0139] The "solid oral dosage form" of the present invention is a pharmaceutically acceptable solid oral dosage form that is safe for oral administration to a subject, wherein all excipients in the dosage form are pharmaceutically acceptable for use in the oral formulation, in other words, safe for ingestion. In an embodiment, the solid oral dosage form is a tablet.

[0140] Solid oral dosage forms include, but are not limited to, immediate-release tablets and capsules, controlled-release (CR) tablets and capsules, rapidly dissolving dosage forms, chewable dosage forms, sachets, etc. Preferably, the dosage forms of the present invention are in the form of tablets, including single-layer or double-layer tablets.

[0141] As used herein, the term "unit dose" refers to a physically discrete unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect. Unit doses may be in the form of tablets, capsules, sachets, etc., referred to herein as "unit dosage forms".

[0142] As used herein, the term "fasting" is defined as follows: a drug administration state following an overnight fast of at least 10 hours (in which zero calorie intake has occurred). Flush the administration tube with 10 mL of water. Provide food 2 hours after administration. Drinking water may be permitted if necessary.

[0143] As used herein, the term "feeding" is defined as follows: a drug administration status defined after an overnight fast of at least 10 hours (with zero calorie intake having occurred). Food should be provided 0.5–1 hour prior to administration. Flush the feeding tube with 10 mL of water. Drinking water may be permitted if necessary.

[0144] The term "dry granulation" refers to a process in which a bulk active product is blended with at least one excipient. The blend is then pressed or compacted to form a pressed material or "compacted material." This material can be crushed to form granules by crushing, grinding, or cutting into dry granular particles. Optionally, the particles can be further processed. Crushing, grinding, or cutting processes involve operations that reduce the size of the pressed material, such as by grinding or by other operations known to those skilled in the art.

[0145] As used herein, the expression "% w / w" means a weight percentage of a component relative to the total weight of the composition. It should be understood that when describing compositions in which a range of multiple components is provided, the total amount of all stated components does not exceed 100%. Those skilled in the art are capable of adjusting the amounts within the provided ranges to achieve this.

[0146] Unless otherwise stated, as used herein, the term "solid dispersion" refers to a solid state comprising at least two components, one of which is substantially homogeneously dispersed in one or more other components. It includes solids or glassy solutions, i.e., the components are dispersed in such a manner that the composition is essentially chemically and physically homogeneous. In embodiments, the first component is an API, and the second component is a matrix comprising a polymer, wherein the API is substantially homogeneously dispersed within the matrix (polymer). The API can be present in an amorphous state or a fine crystalline dispersion. Furthermore, the API can be obtained as a mixture of amorphous and crystalline forms. A solid dispersion may comprise more than two components. For example, two or more APIs may be dispersed in a matrix, and / or the matrix may comprise two or more polymers. Without limitation, solid dispersions can be physically classified as eutectic mixtures, solid solutions, glassy solutions or suspensions, amorphous precipitates in a glassy state or on a crystalline support, complexes, composite formations, or combinations of different systems. Solid dispersions can be prepared using a variety of techniques known to those skilled in the art, such as by co-dissolving the API and polymer in a solvent and then spray drying, spray condensation, evaporation, curing or microwave, blending and direct pressing, mechanical mixing at elevated but non-melting temperatures, wet granulation, extrusion-spheronization, melt fusion, hot melt extrusion, etc.

[0147] Mixture of compound A

[0148] Compound A can be prepared according to the method disclosed in U.S. Patent No. 10,647,698, the entire contents of which are incorporated herein by reference.

[0149] This document discloses a mixture comprising compound A, a polymer, and a surfactant. In embodiments, the mixture is a dispersion. In embodiments, the mixture is a spray-dried dispersion.

[0150] In the embodiments, the polymer is hydroxypropyl methylcellulose (HPMC, also known as hydroxypropyl methylcellulose), hydroxypropyl methylcellulose derivatives, polyvinylpyrrolidone copolymers, methacrylic acid copolymers, polyethylene glycol, or polyethylene glycol derivatives. HPMC can also be described by letters (e.g., E, K) and numbers (e.g., 3, 5, 15), which indicate the polymer's viscosity and substitution chemistry.

[0151] Hydroxypropyl methylcellulose derivatives include organic esters such as HPMC. Hydroxypropyl methylcellulose derivatives may be selected from the group consisting of, for example, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose succinate (HPMCS), hydroxypropyl methylcellulose trimellitate (HPMCT), hydroxypropyl methylcellulose acetate phthalate (HPMCAP), and hydroxypropyl methylcellulose acetate maleate (HPMCAM).

[0152] "Polyvinylpyrrolidone copolymer," "polymer of vinylpyrrolidone," or "PVP copolymer" refers to a copolymer comprising vinylpyrrolidone and one or more other monomers, such as acrylic monomers, styrene, vinyl acetate, etc. Polyvinylpyrrolidone vinyl acetate copolymers and copovidone (polymers of vinylpyrrolidone with other vinyl derivatives) are exemplary polyvinylpyrrolidone copolymers and are commercially available from many sources. In embodiments, the polyvinylpyrrolidone copolymer has an average molecular weight of about 1,000 Daltons to about 1,000,000 Daltons; or about 1,000 Daltons to about 500,000 Daltons; or about 1,000 Daltons to about 200,000 Daltons. In embodiments, the polyvinylpyrrolidone copolymer has an average molecular weight of about 1,000 Daltons to about 150,000 Daltons. In embodiments, the polyvinylpyrrolidone copolymer has an average molecular weight of about 10,000 Daltons to about 150,000 Daltons. In one embodiment, the polyvinylpyrrolidone copolymer has an average molecular weight of about 50,000 Daltons to about 150,000 Daltons. In another embodiment, the PVP copolymer is a polyvinylpyrrolidone vinyl acetate copolymer.

[0153] "Vinyl pyrrolidone vinyl acetate copolymer," "polymer of vinyl pyrrolidone," "vinyl acetate," and "PVPVA" refer to a class of copolymers of vinyl pyrrolidone and vinyl acetate with different weight % ratios of vinyl pyrrolidone to vinyl acetate, such as about 30:70 to about 70:30, including about 30:70, about 35:65, about 50:50, about 60:40, and about 70:30. The weight % ratio of vinyl pyrrolidone to vinyl acetate can result in different properties of the copolymer, including its glass transition temperature. Vinyl pyrrolidone vinyl acetate copolymers are exemplary pharmaceutically acceptable polymers and thermoplastic polymers. Vinyl pyrrolidone vinyl acetate copolymers are commercially available from many sources.

[0154] The term "methacrylic acid copolymer" refers to a class of polymeric compounds described by the following formula:

[0155]

[0156] Wherein R1 is an alkyl group, R2 is a carboxylic acid, and R3 is H. In the embodiments, the methacrylic acid copolymer is Eudragit® methacrylic acid copolymer.

[0157] The term "Eudragit® methacrylic acid copolymer" is used in its conventional sense to refer to a copolymer of esters derived from acrylic acid and methacrylic acid. In embodiments, the Eudragit® polymer can be a methacrylic acid copolymer (e.g., the functional group is a carboxylic acid). In embodiments, the Eudragit® polymer is a methacrylic acid Eudragit® polymer, such as Eudragit® L100 or Eudragit® L100-55. Eudragit® polymers are commercially available.

[0158] In this embodiment, the surfactant is selected from polyethylene glycol, polyethylene glycol esters, glycerides, and mixtures thereof. In this embodiment, the surfactant is a vitamin E ester of polyethylene glycol. In this embodiment, the surfactant is D-α-tocopherol polyethylene glycol succinate (i.e., vitamin E TPGS). In this embodiment, the surfactant is D-α-tocopherol polyethylene glycol 1000 succinate.

[0159] In an embodiment, the mixture (e.g., a dispersion (e.g., a spray-dried dispersion)) comprises compound A, hydroxypropyl methylcellulose, and D-α-tocopherol polyethylene glycol succinate.

[0160] In one embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains about 20% (w / w) to about 60% (w / w) of compound A. In another embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains about 30% (w / w) to about 50% (w / w) of compound A. In another embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains about 35% (w / w) to about 45% (w / w) of compound A. In yet another embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains 20% (w / w) to 60% (w / w) of compound A. In yet another embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains 30% (w / w) to 50% (w / w) of compound A. In yet another embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains 35% (w / w) to 45% (w / w) of compound A.

[0161] In the embodiments, the mixture (e.g., the dispersion (e.g., the spray-dried dispersion)) comprises about 20% (w / w), about 25% (w / w), about 30% (w / w), about 35% (w / w), about 36% (w / w), about 37% (w / w), about 38% (w / w), about 39% (w / w), about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w), about 45% (w / w), about 50% (w / w), about 55% (w / w), or about 60% (w / w) of compound A.

[0162] In one embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains about 50% (w / w) to about 90% (w / w) of compound A. In another embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains about 60% (w / w) to about 80% (w / w) of compound A. In another embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains about 65% (w / w) to about 75% (w / w) of compound A. In another embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains both 50% (w / w) and 90% (w / w) of compound A. In another embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains both 60% (w / w) and 80% (w / w) of compound A. In another embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains both 65% (w / w) and 75% (w / w) of compound A.

[0163] In the embodiments, the mixture (e.g., the dispersion (e.g., the spray-dried dispersion)) comprises about 50% (w / w), about 55% (w / w), about 60% (w / w), about 65% (w / w), about 66% (w / w), about 67% (w / w), about 68% (w / w), about 69% (w / w), about 70% (w / w), about 71% (w / w), about 72% (w / w), about 73% (w / w), about 74% (w / w), about 75% (w / w), about 80% (w / w), about 85% (w / w), or about 90% (w / w) of compound A.

[0164] In one embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains about 35% (w / w) to about 75% (w / w) of polymer. In another embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains about 45% (w / w) to about 65% (w / w) of polymer. In another embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains about 40% (w / w) to about 50% (w / w) of polymer. In yet another embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains 35% (w / w) to 75% (w / w) of polymer. In yet another embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains 45% (w / w) to 65% (w / w) of polymer. In yet another embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains 40% (w / w) to 50% (w / w) of polymer.

[0165] In the embodiments, the mixture (e.g., the dispersion (e.g., the spray-dried dispersion)) comprises about 35% (w / w), about 40% (w / w), about 45% (w / w), about 50% (w / w), about 51% (w / w), about 52% (w / w), about 53% (w / w), about 54% (w / w), about 55% (w / w), about 56% (w / w), about 57% (w / w), about 58% (w / w), about 59% (w / w), about 60% (w / w), about 65% (w / w), about 70% (w / w), or about 75% (w / w) of polymer.

[0166] In one embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains about 10% (w / w) to about 40% (w / w) of polymer. In another embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains about 15% (w / w) to about 35% (w / w) of polymer. In another embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains about 20% (w / w) to about 30% (w / w) of polymer. In yet another embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains 10% (w / w) to 40% (w / w) of polymer. In yet another embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains 15% (w / w) to 35% (w / w) of polymer. In yet another embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains 20% (w / w) to 30% (w / w) of polymer.

[0167] In the embodiments, the mixture (e.g., the dispersion (e.g., the spray-dried dispersion)) comprises about 10% (w / w), about 15% (w / w), about 20% (w / w), about 21% (w / w), about 22% (w / w), about 23% (w / w), about 24% (w / w), about 25% (w / w), about 26% (w / w), about 27% (w / w), about 28% (w / w), about 29% (w / w), about 30% (w / w), about 35% (w / w), or about 40% (w / w) of polymer.

[0168] In one embodiment, the mixture (e.g., the dispersion (e.g., a spray-dried dispersion)) contains about 35% (w / w) to about 75% (w / w) of hydroxypropyl methylcellulose. In another embodiment, the mixture (e.g., the dispersion (e.g., a spray-dried dispersion)) contains about 45% (w / w) to about 65% (w / w) of hydroxypropyl methylcellulose. In another embodiment, the mixture (e.g., the dispersion (e.g., a spray-dried dispersion)) contains about 40% (w / w) to about 50% (w / w) of hydroxypropyl methylcellulose. In yet another embodiment, the mixture (e.g., the dispersion (e.g., a spray-dried dispersion)) contains 35% (w / w) to 75% (w / w) of hydroxypropyl methylcellulose. In yet another embodiment, the mixture (e.g., the dispersion (e.g., a spray-dried dispersion)) contains 45% (w / w) to 65% (w / w) of hydroxypropyl methylcellulose. In an embodiment, the mixture (e.g., a dispersion (e.g., a spray-dried dispersion)) contains 40% (w / w) to 50% (w / w) of hydroxypropyl methylcellulose.

[0169] In the embodiments, the mixture (e.g., the dispersion (e.g., the spray-dried dispersion)) comprises about 35% (w / w), about 40% (w / w), about 45% (w / w), about 50% (w / w), about 51% (w / w), about 52% (w / w), about 53% (w / w), about 54% (w / w), about 55% (w / w), about 56% (w / w), about 57% (w / w), about 58% (w / w), about 59% (w / w), about 60% (w / w), about 65% (w / w), about 70% (w / w), or about 75% (w / w) of hydroxypropyl methylcellulose.

[0170] In one embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains about 10% (w / w) to about 40% (w / w) of hydroxypropyl methylcellulose. In another embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains about 15% (w / w) to about 35% (w / w) of hydroxypropyl methylcellulose. In yet another embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains about 20% (w / w) to about 30% (w / w) of hydroxypropyl methylcellulose. In yet another embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains 10% (w / w) to 40% (w / w) of hydroxypropyl methylcellulose. In yet another embodiment, the mixture (e.g., the dispersion (e.g., spray-dried dispersion)) contains 15% (w / w) to 35% (w / w) of hydroxypropyl methylcellulose. In an embodiment, the mixture (e.g., a dispersion (e.g., a spray-dried dispersion)) contains 20% (w / w) to 30% (w / w) of hydroxypropyl methylcellulose.

[0171] In the embodiments, the mixture (e.g., the dispersion (e.g., the spray-dried dispersion)) comprises about 10% (w / w), about 15% (w / w), about 20% (w / w), about 21% (w / w), about 22% (w / w), about 23% (w / w), about 24% (w / w), about 25% (w / w), about 26% (w / w), about 27% (w / w), about 28% (w / w), about 29% (w / w), about 30% (w / w), about 35% (w / w), or about 40% (w / w) of hydroxypropyl methylcellulose.

[0172] In one embodiment, the mixture (e.g., a dispersion (e.g., a spray-dried dispersion)) contains about 1% (w / w) to about 10% (w / w) of surfactant. In another embodiment, the mixture contains about 3% (w / w) to about 8% (w / w) of surfactant. In yet another embodiment, the mixture contains about 4% (w / w) to about 6% (w / w) of surfactant. In yet another embodiment, the mixture contains 1% (w / w) to 10% (w / w) of surfactant. In yet another embodiment, the mixture contains 3% (w / w) to 8% (w / w) of surfactant. In yet another embodiment, the mixture contains 4% (w / w) to 6% (w / w) of surfactant.

[0173] In an embodiment, the mixture (e.g., the dispersion (e.g., the spray-dried dispersion)) contains about 1% (w / w), about 2% (w / w), about 3% (w / w), about 4% (w / w), about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), or about 10% (w / w) of a surfactant.

[0174] In one embodiment, the mixture contains about 1% (w / w) to about 10% (w / w) of D-α-tocopherol polyethylene glycol succinate. In another embodiment, the mixture contains about 3% (w / w) to about 8% (w / w) of D-α-tocopherol polyethylene glycol succinate. In yet another embodiment, the mixture contains about 4% (w / w) to about 6% (w / w) of D-α-tocopherol polyethylene glycol succinate. In yet another embodiment, the mixture contains 1% (w / w) to 10% (w / w) of D-α-tocopherol polyethylene glycol succinate. In yet another embodiment, the mixture contains 3% (w / w) to 8% (w / w) of D-α-tocopherol polyethylene glycol succinate. In yet another embodiment, the mixture contains 4% (w / w) to 6% (w / w) of D-α-tocopherol polyethylene glycol succinate.

[0175] In an embodiment, the mixture (e.g., the dispersion (e.g., the spray-dried dispersion)) contains about 1% (w / w), about 2% (w / w), about 3% (w / w), about 4% (w / w), about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), or about 10% (w / w) of D-α-tocopherol polyethylene glycol succinate.

[0176] In the embodiments, the mixture (e.g., the dispersion (e.g., the spray-dried dispersion)) comprises:

[0177] Compound A comprises approximately 20% (w / w) to approximately 60% (w / w).

[0178] The polymer content is approximately 35% (w / w) to approximately 75% (w / w), and

[0179] Surfactants of approximately 1% (w / w) to approximately 10% (w / w).

[0180] In the embodiments, the mixture (e.g., the dispersion (e.g., the spray-dried dispersion)) comprises:

[0181] Approximately 40% (w / w) of compound A,

[0182] Approximately 55% (w / w) of the polymer, and

[0183] Approximately 5% (w / w) of surfactant.

[0184] In some embodiments, the mixture (e.g., the dispersion (e.g., the spray-dried dispersion)) comprises:

[0185] Compound A comprises approximately 50% to approximately 90% (w / w).

[0186] Approximately 10% to approximately 40% (w / w) of the polymer, and

[0187] Surfactants of approximately 1% to approximately 10% (w / w).

[0188] In the embodiments, the mixture (e.g., the dispersion (e.g., the spray-dried dispersion)) comprises:

[0189] Approximately 70% (w / w) of compound A,

[0190] Approximately 25% (w / w) of the polymer, and

[0191] Approximately 5% (w / w) of surfactant.

[0192] In the embodiments, the mixture (e.g., the dispersion (e.g., the spray-dried dispersion)) comprises:

[0193] Compound A comprises approximately 20% (w / w) to approximately 60% (w / w).

[0194] Approximately 35% (w / w) to approximately 75% (w / w) of hydroxypropyl methylcellulose, and

[0195] D-α-tocopherol polyethylene glycol succinate, approximately 1% (w / w) to approximately 10% (w / w).

[0196] In the embodiments, the mixture (e.g., the dispersion (e.g., the spray-dried dispersion)) comprises:

[0197] Approximately 40% (w / w) of compound A,

[0198] Approximately 55% (w / w) hydroxypropyl methylcellulose, and

[0199] Approximately 5% (w / w) of D-α-tocopherol polyethylene glycol succinate.

[0200] In some embodiments, the mixture (e.g., the dispersion (e.g., the spray-dried dispersion)) comprises:

[0201] Compound A comprises approximately 50% to approximately 90% (w / w).

[0202] Approximately 10% to approximately 40% (w / w) of hydroxypropyl methylcellulose, and

[0203] D-α-tocopherol polyethylene glycol succinate, approximately 1% to approximately 10% (w / w).

[0204] In the embodiments, the mixture (e.g., the dispersion (e.g., the spray-dried dispersion)) comprises:

[0205] Approximately 70% (w / w) of compound A,

[0206] Approximately 25% (w / w) hydroxypropyl methylcellulose, and

[0207] Approximately 5% (w / w) of D-α-tocopherol polyethylene glycol succinate.

[0208] In one embodiment, the mixture (e.g., a dispersion (e.g., a spray-dried dispersion)) comprises compound A in an amorphous form. In another embodiment, the mixture (e.g., a spray-dried dispersion) comprises a dispersion of amorphous compound A, hydroxypropyl methylcellulose, and d-α-tocopherol polyethylene glycol succinate.

[0209] Method for preparing dispersion of compound A

[0210] In this embodiment, the mixture of compound A is in the form of a dispersion. In this embodiment, the dispersion is a solid dispersion.

[0211] In the embodiments, the dispersion is produced by spray drying, freeze drying, hot melt extrusion, grinding, solvent evaporation, supercritical fluid processing, or high-shear mixing. Preferably, the dispersion is produced by spray drying.

[0212] In one embodiment, the dispersion (e.g., a spray-dried dispersion) comprises compound A, a polymer, and a surfactant. In another embodiment, the dispersion (e.g., a spray-dried dispersion) comprises compound A, D-α-tocopherol polyethylene glycol succinate, and hydroxypropyl methylcellulose.

[0213] In the embodiments, this document discloses a method for preparing a dispersion (e.g., a spray-dried dispersion) comprising compound A disclosed herein. In the embodiments, the method includes:

[0214] Compound A, the polymer, and the surfactant are dissolved in a solvent to provide a solution containing compound A;

[0215] A solution containing compound A is introduced into a spray dryer;

[0216] A solution containing a compound is sprayed from a spray dryer to form a dispersion of compound A (e.g., a spray-dried dispersion); and

[0217] Optionally, residual solvent is removed from the dispersion of compound A (e.g., a spray-dried dispersion).

[0218] The solvent can be a single organic solvent or a mixture of organic solvents. For example, in an embodiment, the solvent is dichloromethane, methanol, or a combination thereof. In an embodiment, the solvent is dichloromethane. Alternatively, the solvent is methanol. In an embodiment, the solvent is a mixture of dichloromethane and methanol. For example, the ratio of dichloromethane to methanol is about 90:10 (w / w) to about 10:90 (w / w). In an embodiment, the ratio of dichloromethane to methanol is about 90:10 (w / w) to about 50:50 (w / w). In an embodiment, the ratio of dichloromethane to methanol is about 90:10 (w / w) to about 70:30 (w / w). In an embodiment, the ratio of dichloromethane to methanol is about 85:15 (w / w) to about 75:25 (w / w). In an embodiment, the ratio of dichloromethane to methanol is 90:10 (w / w) to 70:30 (w / w). In the implementation scheme, the ratio of dichloromethane to methanol is from 85:15 (w / w) to 75:25 (w / w). In the implementation scheme, the ratio of dichloromethane to methanol is 70:30 (w / w), about 75:25 (w / w), about 80:20 (w / w), about 85:15 (w / w), or about 90:10 (w / w).

[0219] In the implementation scheme, the step of removing residual solvent is achieved by drying. In the implementation scheme, drying is achieved by convection drying, tray drying, filtration drying, drum drying, stirred cone drying, or fluidized bed drying. In the implementation scheme, drying is achieved by stirred cone drying.

[0220] dosage form of compound A

[0221] In the implementation scheme, compound A is in the form of a solid oral dosage form. In the implementation scheme, the solid oral dosage form is a tablet, sachet, or capsule. In the implementation scheme, the solid oral dosage form is a tablet.

[0222] Suitable forms for oral administration may include one or more pharmaceutically acceptable excipients, including, for example, carriers, fillers, surfactants, diluents, sweeteners, disintegrants, binders, lubricants, glidants, colorants, flavorings, stabilizers, coatings, or any mixtures thereof.

[0223] Carriers include, but are not limited to, pharmaceutically acceptable excipients and diluents, and are meant to be materials, compositions, or media that participate in carrying or transporting a drug from one organ or body part of a subject to another, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials. Examples include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers (such as polyethylene glycol).

[0224] Fillers include, but are not limited to, mannitol, sucrose, sorbitol, xylitol, microcrystalline cellulose, lactose, silicic acid, silicified microcrystalline cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, starch, pullulan, and rapidly dissolving carbohydrates (such as Pharmaburst™ rapidly disintegrating tablets), mixtures thereof, etc. For examples of rapidly dissolving carbohydrates, see, for example, U.S. Patent No. 8,617,588, the entire contents of which are incorporated herein by reference.

[0225] Surfactants include, but are not limited to, nonionic, anionic, cationic, amphoteric, or zwitterionic surfactants. Examples of suitable nonionic surfactants include ethoxylated triglycerides; fatty alcohol ethoxylates; alkylphenol ethoxylates; fatty acid ethoxylates; fatty amide ethoxylates; fatty amine ethoxylates; sorbitan alkyl esters; ethylated sorbitan alkyl esters; alkyl ethoxylates; and Pluronics. TM Alkyl polyglucosides; stearyl alcohol ethoxylates; alkyl glycosides. Examples of suitable anionic surfactants include alkyl ether sulfates; alkyl ether carboxylates; alkylbenzene sulfonates; alkyl ether phosphates; dialkyl sulfosuccinates; sarcosine salts; alkyl sulfonates; soaps; alkyl sulfates; alkyl carboxylates; alkyl phosphates; paraffin sulfonates; secondary n-alkane sulfonates; α-olefin sulfonates; hydroxyethyl sulfonates. Examples of suitable cationic surfactants include aliphatic amine salts; aliphatic diamine salts; quaternary ammonium compounds; phosphonium surfactants; sulfonium surfactants; sulfoxide surfactants. Examples of suitable zwitterionic surfactants include N-alkyl derivatives of amino acids (such as glycine, betaine, aminopropionic acid); imidazoline surfactants; amine oxides; amide betaine. Non-limiting examples of surfactants that can be used in ospemifene solid dispersions include, for example, Tween 20, Tween 80, Span 20, Span 80, sodium docusate (e.g., AOT), sodium dodecyl sulfate, and poloxamer (e.g., poloxamer 407, Kolliphor® EL, Pluronic F68). Poloxamer is also marketed under the trade names Synperonics®, Pluronics®, and Kolliphor® / Cremophor®.

[0226] Diluents include, but are not limited to: carbohydrates, such as monosaccharides (glucose), oligosaccharides (sucrose and lactose (including anhydrous lactose and lactose monohydrate)); starches, such as corn starch, potato starch, rice starch and wheat starch; pregelatinized starch; dicalcium phosphate; and sugar alcohols (sorbitol, mannitol, erythritol and xylitol).

[0227] Sweeteners include, but are not limited to, sucrose, high-fructose corn syrup, fructose, glucose, aspartame, acesulfame K, sucralose, cyclamate, sodium saccharin, neotame, rebaudioside A, and other stevia sweeteners.

[0228] Disintegrants include, but are not limited to, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium carboxymethyl cellulose, crospovidone, chitosan, agar, alginate, calcium alginate, methylcellulose, microcrystalline cellulose, powdered cellulose, lower alkyl-substituted hydroxypropyl cellulose, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, potassium polycrylamide, starch, pregelatinized starch, sodium alginate, magnesium aluminum silicate, potassium polycrylamide, povidone, sodium starch glycolate, and mixtures thereof.

[0229] Binders include, but are not limited to, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), povidone, copovidone, methylcellulose, powdered gum arabic, gelatin, gum arabic, guar gum, carbomer (such as carbopol), and polymethyl methacrylate.

[0230] Lubricants include, but are not limited to, calcium stearate, glyceryl monostearate, glyceryl behenate, glyceryl palmitate, hexagonal boron nitride, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, poloxamer, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate, and mixtures thereof.

[0231] Gliders include, but are not limited to, silica, colloidal silica, calcium silicate, magnesium silicate, magnesium trisilicate, talc, starch, and mixtures thereof.

[0232] Flavorings include, but are not limited to, menthol, peppermint oil, peppermint liqueur, vanillin, and almond oil.

[0233] In some embodiments, the amount of compound A in a solid oral dosage form (e.g., tablet) is from about 5 mg to about 1000 mg. In some embodiments, the amount of compound A in a solid oral dosage form (e.g., tablet) is from about 5 mg to about 500 mg. In some embodiments, the amount of compound A in a solid oral dosage form (e.g., tablet) is from about 5 mg to about 250 mg. In some embodiments, the amount of compound A in a solid oral dosage form (e.g., tablet) is from about 25 mg to about 250 mg. In some embodiments, the amount of compound A in a solid oral dosage form (e.g., tablet) is from about 25 mg to about 200 mg. In some embodiments, the amount of compound A in a solid oral dosage form (e.g., tablet) is from about 25 mg to about 150 mg. In some embodiments, the amount of compound A in a solid oral dosage form (e.g., tablet) is from about 50 mg to about 150 mg. In some embodiments, the amount of compound A in a solid oral dosage form (e.g., tablet) is from about 75 mg to about 125 mg. In one embodiment, the amount of compound A in a solid oral dosage form (e.g., tablet) is from about 5 mg to about 50 mg. In another embodiment, the amount of compound A in a solid oral dosage form (e.g., tablet) is from about 30 mg to about 40 mg. In another embodiment, the amount of compound A in a solid oral dosage form (e.g., tablet) is from about 65 mg to about 70 mg. In another embodiment, the amount of compound A in a solid oral dosage form (e.g., tablet) is from about 100 mg to about 110 mg. In another embodiment, the amount of compound A in a solid oral dosage form (e.g., tablet) is from about 135 mg to about 145 mg. In another embodiment, the amount of compound A in a solid oral dosage form (e.g., tablet) is from about 75 mg to about 300 mg. In another embodiment, the amount of compound A in a solid oral dosage form (e.g., tablet) is from about 100 mg to about 300 mg. In another embodiment, the amount of compound A in a solid oral dosage form (e.g., tablet) is from about 100 mg to about 250 mg.

[0234] In the implementation scheme, the amount of compound A in the solid oral dosage form (e.g., tablet) is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 ... mg, approximately 210 mg, approximately 215 mg, approximately 220 mg, approximately 225 mg, approximately 230 mg, approximately 235 mg, approximately 240 mg, approximately 245 mg, approximately 250 mg, approximately 255 mg, approximately 260 mg, approximately 265 mg, approximately 270 mg, approximately 275 mg, approximately 280 mg, approximately 285 mg, approximately 290 mg, approximately 295 mg, approximately 300 mg, approximately 305 mg, approximately 310 mg, approximately 315 mg, approximately 320 mg, approximately 325 mg, approximately 330 mg, approximately 335 mg, approximately 340 mg, approximately 345 mg, approximately 350 mg, approximately 355 mg, approximately 360 mg, approximately 365 mg, approximately 370 mg, approximately 375 mg, approximately 380 mg, approximately 385 mg, approximately 390 mg, approximately 395 mg, approximately 400 mg, approximately 405 mg, approximately 410 mg mg, approximately 415 mg, approximately 420 mg, approximately 425 mg, approximately 430 mg, approximately 435 mg, approximately 440 mg, approximately 445 mg, approximately 450 mg, approximately 455 mg, approximately 460 mg, approximately 465 mg, approximately 470 mg, approximately 475 mg, approximately 480 mg, approximately 485 mg, approximately 490 mg, approximately 495 mg, approximately 500 mg, approximately 750 mg, or approximately 1000 mg.

[0235] In the implementation scheme, the solid oral dosage form (e.g., tablets) contains approximately 0.1% w / w, approximately 0.2% w / w, approximately 0.3% w / w, approximately 0.4% w / w, approximately 0.5% w / w, approximately 0.6% w / w, approximately 0.7% w / w, approximately 0.8% w / w, approximately 0.9% w / w, approximately 1.0% w / w, approximately 1.1% w / w, approximately 1.2% w / w, approximately 1.3% w / w, approximately 1.4% w / w, approximately 1.5% w / w, approximately 1.6% w / w, approximately 1.7% w / w, approximately 1.8% w / w, approximately 1.9% w / w, approximately 2.0% w / w, approximately 2.1% w / w, approximately 2.2% w / w, approximately 2.3% w / w, approximately 2.4% w / w, approximately 2.5% w / w, and approximately 2.6% w / w. w / w, approximately 2.7% w / w, approximately 2.8% w / w, approximately 2.9% w / w, approximately 3.0% w / w, approximately 3.1% w / w, approximately 3.2% w / w, approximately 3.3% w / w, approximately 3.4% w / w, approximately 3.5% w / w, approximately 3.6% w / w, approximately 3.7% w / w, approximately 3.8% w / w, approximately 3.9% w / w, approximately 4.0% w / w, approximately 4.1% w / w, approximately 4.2% w / w, approximately 4.3% w / w, approximately 4.4% w / w, approximately 4.5% w / w, approximately 4.6% w / w, approximately 4.7% w / w, approximately 4.8% w / w, approximately 4.9% w / w, approximately 5.0% w / w, approximately 5.5% w / w, approximately 6.0% w / w, approximately 6.5% w / w, approximately 7.0% w / w, approximately 7.5% w / w, approximately 8.0% w / w, approximately 8.5% w / w, approximately 9.0% w / w, approximately 9.5% w / w, approximately 10.0% w / w, approximately 10.5% w / w, approximately 11.0% w / w, approximately 11.5% w / w, approximately 12.0% w / w, approximately 12.5% ​​w / w, approximately 13.0% w / w, approximately 13.5% w / w, approximately 14.0% w / w, approximately 14.5% w / w, approximately 15.0% w / w, approximately 15.5% w / w, approximately 16.0% w / w, approximately 16.5% w / w, approximately 17.0% w / w, approximately 17.5% w / w, approximately 18.0% w / w, approximately 18.5% w / w, approximately 19.0% w / w, approximately 19.5% w / w, approximately 20.0% w / w, approximately 20.5% w / w, approximately 21.0% w / w, approximately 21.5% w / w, approximately 22.0% w / w, approximately 22.5% w / w, approximately 23.0% w / w, approximately 23.5% w / w, approximately 24.0% w / w, approximately 24.5% w / w, approximately 25.0% w / w, approximately 25.5% w / w, approximately 26.0% w / w, approximately 26.5% w / w, approximately 27.0% w / w, approximately 27.5% w / w, approximately 28.0% w / w, approximately 28.5% w / w, approximately 29.0% w / w, approximately 29.5% w / w, approximately 30.0% w / w, approximately 30.5% w / w, approximately 31.0% w / w, approximately 31.5% w / w, approximately 32.0% w / w, approximately 32.5% w / w, approximately 33.0% w / w, approximately 33.5% w / w, approximately 34.0% w / w, approximately 34.5% w / w, approximately 35.0% w / w, approximately 35.5% w / w, approximately 36.0% w / w, approximately 36.5% w / w, approximately 37.0% w / w, approximately 37.5% w / w, approximately 38.0% w / w, approximately 38.5% w / w, approximately 39.0% w / w, approximately 39.5% Compound A, at approximately 40.0% w / w, approximately 40.5% w / w, approximately 41.0% w / w, approximately 41.5% w / w, approximately 42.0% w / w, approximately 42.5% w / w, approximately 43.0% w / w, approximately 43.5% w / w, approximately 44.0% w / w, approximately 44.5% w / w, approximately 45.0% w / w, approximately 45.5% w / w, approximately 46.0% w / w, approximately 46.5% w / w, approximately 47.0% w / w, approximately 47.5% w / w, approximately 48.0% w / w, approximately 48.5% w / w, approximately 49.0% w / w, approximately 49.5% w / w, or approximately 50.0% w / w.

[0236] In the implementation scheme, the solid oral dosage form (e.g., tablets) comprises about 1% w / w to about 5% w / w of compound A, about 2.5% w / w to about 7.5% w / w of compound A, about 10% w / w to about 15% w / w of compound A, about 12.5% ​​w / w to about 17.5% w / w of compound A, about 15% w / w to about 20% w / w of compound A, about 17.5% w / w to about 22.5% w / w of compound A, about 20% w / w to about 25% w / w of compound A, about 22.5% w / w to about 27.5% w / w of compound A, about 25% w / w to about 30% w / w of compound A, about 27.5% w / w to about 32.5% w / w of compound A, about 30% w / w to about 35% w / w of compound A, and about 32.5% w / w to about 37.5% w / w of compound A. Compound A, w / w of about 35% w / w to about 40% w / w of compound A, w / w of about 37.5% w / w to about 42.5% w / w of compound A, w / w of about 40% w / w to about 45% w / w of compound A, w / w of about 42.5% w / w to about 47.5% w / w of compound A, w / w of about 45% to about 50% w / w of compound A, w / w of about 47.5% w / w to about 52.5% w / w of compound A, or w / w of about 50% w / w to about 55% w / w of compound A.

[0237] In the implementation scheme, the solid oral dosage form (e.g., tablets) comprises 1% w / w to 5% w / w of compound A, 2.5% w / w to 7.5% w / w of compound A, 10% to 15% w / w of compound A, 12.5% ​​w / w to 17.5% w / w of compound A, 15% w / w to 20% w / w of compound A, 17.5% w / w to 22.5% w / w of compound A, 20% w / w to 25% w / w of compound A, 22.5% w / w to 27.5% w / w of compound A, 25% w / w to 30% w / w of compound A, 27.5% w / w to 32.5% w / w of compound A, 30% w / w to 35% w / w of compound A, 32.5% w / w to 37.5% w / w of compound A, and 35% w / w to 40% w / w of compound A. Compound A, 37.5% w / w to 42.5% w / w, 40% w / w to 45% w / w, 42.5% w / w to 47.5% w / w, 45% w / w to 50% w / w, 47.5% w / w to 52.5% w / w, and 50% w / w to 55% w / w.

[0238] In one embodiment, the solid oral dosage form (e.g., tablet) comprises about 40% w / w to about 70% w / w of the mixtures (e.g., solid dispersions) disclosed herein. In another embodiment, the solid oral dosage form (e.g., tablet) comprises about 40% w / w to about 60% w / w of the mixtures (e.g., solid dispersions) disclosed herein. In yet another embodiment, the solid oral dosage form (e.g., tablet) comprises about 45% w / w to about 55% w / w of the mixtures (e.g., solid dispersions) disclosed herein. In yet another embodiment, the solid oral dosage form (e.g., tablet) comprises about 55% w / w to about 65% w / w of the mixtures (e.g., solid dispersions) disclosed herein.

[0239] In one embodiment, the solid oral dosage form (e.g., tablet) comprises 40% w / w to 70% w / w of the mixtures (e.g., solid dispersions) disclosed herein. In another embodiment, the solid oral dosage form (e.g., tablet) comprises 40% w / w to 60% w / w of the mixtures (e.g., solid dispersions) disclosed herein. In yet another embodiment, the solid oral dosage form (e.g., tablet) comprises 45% w / w to 55% w / w of the mixtures (e.g., solid dispersions) disclosed herein. In yet another embodiment, the solid oral dosage form (e.g., tablet) comprises 55% w / w to 65% w / w of the mixtures (e.g., solid dispersions) disclosed herein.

[0240] In some implementations, the solid oral dosage form (e.g., tablet) comprises:

[0241] About 40% to about 60% w / w of the mixtures (e.g., solid dispersions) disclosed herein;

[0242] Microcrystalline cellulose, approximately 10% to approximately 40% w / w;

[0243] Lactose monohydrate, approximately 5% to approximately 15% w / w;

[0244] Approximately 5% to approximately 15% w / w of croscarmellose sodium;

[0245] Approximately 0% to approximately 5% w / w of silica; and

[0246] Sodium stearyl fumarate, approximately 0% to approximately 2% w / w.

[0247] In the implementation scheme, the solid oral dosage form (e.g., tablet) comprises:

[0248] 40% to 60% w / w of the mixtures (e.g., solid dispersions) disclosed herein;

[0249] 10% to 40% w / w microcrystalline cellulose;

[0250] 5% to 15% w / w lactose monohydrate;

[0251] 5% to 15% w / w croscarmellose sodium;

[0252] 0% to 5% w / w silica; and

[0253] 0% to 2% w / w sodium stearate fumarate.

[0254] In the implementation scheme, the solid oral dosage form (e.g., tablet) comprises:

[0255] Approximately 40% to approximately 70% w / w of the mixtures (e.g., solid dispersions) disclosed herein.

[0256] Microcrystalline cellulose, approximately 10% to approximately 40% w / w;

[0257] Lactose monohydrate, approximately 5% to approximately 15% w / w;

[0258] Approximately 5% to approximately 15% w / w of croscarmellose sodium;

[0259] Approximately 0% to approximately 5% w / w of silica; and

[0260] Sodium stearyl fumarate, approximately 0% to approximately 2% w / w.

[0261] In the implementation scheme, the solid oral dosage form (e.g., tablet) comprises:

[0262] 40% to 70% w / w of the mixtures (e.g., solid dispersions) disclosed herein;

[0263] 10% to 40% w / w microcrystalline cellulose;

[0264] 5% to 15% w / w lactose monohydrate;

[0265] 5% to 15% w / w croscarmellose sodium;

[0266] 0% to 5% w / w silica; and

[0267] 0% to 2% w / w sodium stearate fumarate.

[0268] In the implementation scheme, the solid oral dosage form (e.g., tablet) comprises:

[0269] About 45% to about 55% w / w of the mixtures disclosed herein (e.g., solid dispersions) (e.g., a mixture comprising compound A / HPMC / TPGS in a ratio of about 40:55:5 (w / w) (e.g., a solid dispersion).

[0270] Microcrystalline cellulose, approximately 10% to approximately 40% w / w;

[0271] Lactose monohydrate, approximately 5% to approximately 15% w / w;

[0272] Approximately 5% to approximately 15% w / w of croscarmellose sodium;

[0273] Approximately 0% to approximately 5% w / w of silica; and

[0274] Sodium stearyl fumarate, approximately 0% to approximately 2% w / w.

[0275] In the implementation scheme, the solid oral dosage form (e.g., tablet) comprises:

[0276] 45% to 55% w / w of the mixtures disclosed herein (e.g., solid dispersions) (e.g., a mixture comprising compound A / HPMC / TPGS in a ratio of about 40:55:5 (w / w) (e.g., a solid dispersion).

[0277] 10% to 40% w / w microcrystalline cellulose;

[0278] 5% to 15% w / w lactose monohydrate;

[0279] 5% to 15% w / w croscarmellose sodium;

[0280] 0% to 5% w / w silica; and

[0281] 0% to 2% w / w sodium stearate fumarate.

[0282] In some implementations, the solid oral dosage form (e.g., tablet) comprises:

[0283] About 55% to about 65% w / w of the mixtures disclosed herein (e.g., solid dispersions) (e.g., a mixture comprising compound A / HPMC / TPGS in a ratio of about 70:25:5 (w / w) (e.g., a solid dispersion).

[0284] Microcrystalline cellulose, approximately 10% to approximately 40% w / w;

[0285] Lactose monohydrate, approximately 5% to approximately 15% w / w;

[0286] Approximately 5% to approximately 15% w / w of croscarmellose sodium;

[0287] Approximately 0% to approximately 5% w / w of silica; and

[0288] Sodium stearyl fumarate, approximately 0% to approximately 2% w / w.

[0289] In the implementation scheme, the solid oral dosage form (e.g., tablet) comprises:

[0290] 55% to 65% w / w of the mixtures disclosed herein (e.g., solid dispersions) (e.g., mixtures or dispersions containing about 70% by weight of compound A, preferably mixtures of compound A / HPMC / TPGS in a ratio of about 70:25:5 (w / w) (e.g., solid dispersions)).

[0291] 10% to 40% w / w microcrystalline cellulose;

[0292] 5% to 15% w / w lactose monohydrate;

[0293] 5% to 15% w / w croscarmellose sodium;

[0294] 0% to 5% w / w silica; and

[0295] 0% to 2% w / w sodium stearate fumarate.

[0296] In the implementation scheme, the solid oral dosage form (e.g., tablet) comprises:

[0297] About 50% w / w of the mixtures disclosed herein (e.g., solid dispersions) (e.g., a mixture containing about 70% by weight of compound A (e.g., a solid dispersion), preferably a mixture containing compound A / HPMC / TPGS in a ratio of about 40:55:5 (w / w) (e.g., a solid dispersion)).

[0298] Approximately 27% w / w microcrystalline cellulose;

[0299] Approximately 9% w / w lactose monohydrate;

[0300] Approximately 12% w / w of croscarmellose sodium;

[0301] Approximately 1% w / w of silica; and

[0302] Approximately 1.5% w / w sodium stearate fumarate.

[0303] In the implementation scheme, the solid oral dosage form (e.g., tablet) comprises:

[0304] About 60% w / w of the mixtures disclosed herein (e.g., solid dispersions) (e.g., a mixture containing about 70% by weight of compound A (e.g., a solid dispersion), preferably a mixture containing compound A / HPMC / TPGS in a ratio of about 70:25:5 (w / w) (e.g., a solid dispersion)).

[0305] Approximately 17% w / w microcrystalline cellulose;

[0306] Approximately 8.8% w / w lactose monohydrate;

[0307] Approximately 12% w / w of croscarmellose sodium;

[0308] Approximately 1% w / w of silica; and

[0309] Approximately 1.5% w / w sodium stearate fumarate.

[0310] In embodiments, the solid oral dosage form (e.g., tablet) comprises an intragranular portion and an extragranular portion, and optionally, a film coating, wherein the intragranular portion comprises:

[0311] Compound A has approximately 42% w / w.

[0312] Approximately 14% w / w hydroxypropyl methylcellulose;

[0313] Approximately 3% w / w D-α-tocopherol polyethylene glycol succinate;

[0314] Approximately 9% w / w microcrystalline cellulose;

[0315] Approximately 9% w / w lactose monohydrate;

[0316] Approximately 6% w / w of croscarmellose sodium;

[0317] Approximately 1% w / w of silica; and

[0318] Approximately 0.75% w / w sodium stearate fumarate,

[0319] And the extragranular portion includes:

[0320] Approximately 8% w / w microcrystalline cellulose;

[0321] Approximately 6% w / w of croscarmellose sodium; and

[0322] Approximately 0.75% w / w sodium stearate fumarate.

[0323] In embodiments, the solid oral dosage form (e.g., tablet) comprises an intragranular portion and an extragranular portion, and optionally, a film coating, wherein the intragranular portion comprises:

[0324] Approximately 40% to approximately 70% w / w of the mixtures (e.g., solid dispersions) disclosed herein.

[0325] Microcrystalline cellulose, approximately 5% to approximately 10% w / w;

[0326] Lactose monohydrate, approximately 5% to approximately 10% w / w;

[0327] Approximately 1% to approximately 10% w / w of croscarmellose sodium;

[0328] Approximately 0% to approximately 5% w / w of silica; and

[0329] Sodium stearyl fumarate, approximately 0% to approximately 2% w / w.

[0330] And the extragranular portion includes:

[0331] Microcrystalline cellulose of approximately 5% to approximately 25% w / w;

[0332] About 0% to about 10% w / w of croscarmellose sodium; and

[0333] Sodium stearyl fumarate, approximately 0% to approximately 2% w / w.

[0334] In embodiments, the solid oral dosage form (e.g., tablet) comprises an intragranular portion and an extragranular portion, and optionally, a film coating, wherein the intragranular portion comprises:

[0335] 40% to 70% w / w of mixtures (e.g., solid dispersions) as disclosed herein.

[0336] 5% to 10% w / w microcrystalline cellulose;

[0337] 5% to 10% w / w lactose monohydrate;

[0338] 1% to 10% w / w of croscarmellose sodium;

[0339] 0% to 5% w / w silica; and

[0340] 0% to 2% w / w sodium stearate fumarate,

[0341] And the extragranular portion includes:

[0342] 5% to 25% w / w microcrystalline cellulose;

[0343] 0% to 10% w / w croscarmellose sodium; and

[0344] 0% to 2% w / w sodium stearate fumarate.

[0345] In embodiments, the solid oral dosage form (e.g., tablet) comprises an intragranular portion and an extragranular portion, and optionally, a film coating, wherein the intragranular portion comprises:

[0346] About 40% to about 60% w / w of mixtures (e.g., solid dispersions) as disclosed herein;

[0347] Microcrystalline cellulose, approximately 5% to approximately 10% w / w;

[0348] Lactose monohydrate, approximately 5% to approximately 10% w / w;

[0349] Approximately 1% to approximately 10% w / w of croscarmellose sodium;

[0350] Approximately 0% to approximately 5% w / w of silica; and

[0351] Sodium stearyl fumarate, approximately 0% to approximately 2% w / w.

[0352] And the extragranular portion contains

[0353] Microcrystalline cellulose of approximately 5% to approximately 25% w / w;

[0354] About 0% to about 10% w / w of croscarmellose sodium; and

[0355] Sodium stearyl fumarate, approximately 0% to approximately 2% w / w.

[0356] In embodiments, the solid oral dosage form (e.g., tablet) comprises an intragranular portion and an extragranular portion, and optionally, a film coating, wherein the intragranular portion comprises:

[0357] 40% to 60% w / w of mixtures and / or solid dispersions as disclosed herein.

[0358] 5% to 10% w / w microcrystalline cellulose;

[0359] 5% to 10% w / w lactose monohydrate;

[0360] 1% to 10% w / w of croscarmellose sodium;

[0361] 0% to 5% w / w silica; and

[0362] 0% to 2% w / w sodium stearate fumarate,

[0363] And the extragranular portion contains

[0364] 5% to 25% w / w microcrystalline cellulose;

[0365] 0% to 10% w / w croscarmellose sodium; and

[0366] 0% to 2% w / w sodium stearate fumarate.

[0367] In some embodiments, the solid oral dosage form (e.g., tablet) comprises an intragranular portion and an extragranular portion, and optionally, a film coating, wherein the intragranular portion comprises:

[0368] About 50% w / w of the mixtures (e.g., solid dispersions) disclosed herein (e.g., a mixture containing about 70% by weight of compound A (e.g., a solid dispersion), preferably a mixture of compound A / HPMC / TPGS in a ratio of about 40:55:5 (w / w) (e.g., a solid dispersion)).

[0369] Approximately 8% w / w microcrystalline cellulose;

[0370] Approximately 9% w / w lactose monohydrate;

[0371] Approximately 6% w / w of croscarmellose sodium;

[0372] Approximately 1% w / w of silica; and

[0373] Approximately 0.75% w / w sodium stearate fumarate,

[0374] And the extragranular portion contains

[0375] Approximately 18% w / w microcrystalline cellulose;

[0376] Approximately 6% w / w of croscarmellose sodium; and

[0377] Approximately 0.75% w / w sodium stearate fumarate.

[0378] In embodiments, the solid oral dosage form (e.g., tablet) comprises an intragranular portion and an extragranular portion, and optionally, a film coating, wherein the intragranular portion comprises:

[0379] About 60% w / w of the mixtures (e.g., solid dispersions) as disclosed herein (e.g., a mixture containing about 70% by weight of compound A (e.g., a solid dispersion), preferably a mixture of compound A / HPMC / TPGS in a ratio of about 70:25:5 (w / w) (e.g., a solid dispersion)).

[0380] Approximately 9% w / w microcrystalline cellulose;

[0381] Approximately 9% w / w lactose monohydrate;

[0382] Approximately 6% w / w of croscarmellose sodium;

[0383] Approximately 1% w / w of silica; and

[0384] Approximately 0.75% w / w sodium stearate fumarate,

[0385] And the extragranular portion includes:

[0386] Approximately 8% w / w microcrystalline cellulose;

[0387] Approximately 6% w / w of croscarmellose sodium; and

[0388] Approximately 0.75% w / w sodium stearate fumarate.

[0389] In the implementation scheme, the solid oral dosage form (e.g., tablet) comprises:

[0390] Compound A, approximately 15% w / w to approximately 50% w / w;

[0391] Hydroxypropyl methylcellulose, approximately 10% w / w to approximately 40% w / w;

[0392] D-α-tocopherol polyethylene glycol succinate, approximately 0.5% w / w to approximately 5% w / w;

[0393] Microcrystalline cellulose of approximately 10% w / w to approximately 40% w / w;

[0394] Lactose monohydrate at approximately 5% w / w to approximately 15% w / w;

[0395] Crosslinked carboxymethyl cellulose sodium, approximately 5% w / w to approximately 15% w / w;

[0396] Silica of approximately 0% w / w to approximately 5% w / w; and

[0397] Sodium stearyl fumarate, approximately 0% w / w to approximately 2% w / w.

[0398] In the implementation scheme, the solid oral dosage form (e.g., tablet) comprises:

[0399] Compound A, 15% to 50% w / w;

[0400] 10% to 40% w / w hydroxypropyl methylcellulose;

[0401] 0.5% to 5% w / w D-α-tocopherol polyethylene glycol succinate;

[0402] 10% to 40% w / w microcrystalline cellulose;

[0403] 5% to 15% w / w lactose monohydrate;

[0404] 5% to 15% w / w croscarmellose sodium;

[0405] 0% to 5% w / w silica; and

[0406] 0% to 2% w / w sodium stearate fumarate.

[0407] In the implementation scheme, the solid oral dosage form (e.g., tablet) comprises:

[0408] Compound A, approximately 20% w / w;

[0409] Approximately 28% w / w hydroxypropyl methylcellulose;

[0410] Approximately 2.5% w / w D-α-tocopherol polyethylene glycol succinate;

[0411] Approximately 27% w / w microcrystalline cellulose;

[0412] Approximately 9% w / w lactose monohydrate;

[0413] Approximately 12% w / w of croscarmellose sodium;

[0414] Approximately 1% w / w of silica; and

[0415] Approximately 1.5% w / w sodium stearate fumarate.

[0416] In the implementation scheme, the solid oral dosage form (e.g., tablet) comprises:

[0417] Compound A has approximately 42% w / w.

[0418] Approximately 15% w / w hydroxypropyl methylcellulose;

[0419] Approximately 3% w / w D-α-tocopherol polyethylene glycol succinate;

[0420] Approximately 17% w / w microcrystalline cellulose;

[0421] Approximately 8.8% w / w lactose monohydrate;

[0422] Approximately 12% w / w of croscarmellose sodium;

[0423] Approximately 1% w / w of silica; and

[0424] Approximately 1.5% w / w sodium stearate fumarate.

[0425] In the embodiments, the solid oral dosage form (e.g., tablet) comprises an intragranular portion and an extragranular portion, and optionally, a film coating.

[0426] The intragranular portion includes:

[0427] Compound A, approximately 15% to approximately 50% w / w;

[0428] Hydroxypropyl methylcellulose, approximately 10% to approximately 40% w / w;

[0429] D-α-tocopherol polyethylene glycol succinate, approximately 0.5% to approximately 5% w / w;

[0430] Microcrystalline cellulose, approximately 5% to approximately 10% w / w;

[0431] Lactose monohydrate, approximately 5% to approximately 10% w / w;

[0432] Approximately 1% to approximately 10% w / w of croscarmellose sodium;

[0433] Approximately 0% to approximately 5% w / w of silica; and

[0434] Sodium stearyl fumarate, approximately 0% to approximately 2% w / w.

[0435] And the extragranular portion includes:

[0436] Microcrystalline cellulose of approximately 5% to approximately 25% w / w;

[0437] About 0% to about 10% w / w of croscarmellose sodium; and

[0438] Sodium stearyl fumarate, approximately 0% to approximately 2% w / w;

[0439] The weight percentage is relative to the total weight of uncoated tablets.

[0440] In the embodiments, the solid oral dosage form (e.g., tablet) comprises an intragranular portion and an extragranular portion, and optionally, a film coating.

[0441] The intragranular portion includes:

[0442] Compound A, approximately 20% w / w;

[0443] Approximately 28% w / w hydroxypropyl methylcellulose;

[0444] Approximately 2.5% w / w D-α-tocopherol polyethylene glycol succinate;

[0445] Approximately 8% w / w microcrystalline cellulose;

[0446] Approximately 9% w / w lactose monohydrate;

[0447] Approximately 6% w / w of croscarmellose sodium;

[0448] Approximately 1% w / w of silica; and

[0449] Approximately 0.75% w / w sodium stearate fumarate,

[0450] And the extragranular portion includes:

[0451] Approximately 18% w / w microcrystalline cellulose;

[0452] Approximately 6% w / w of croscarmellose sodium; and

[0453] Approximately 0.75% w / w sodium stearate fumarate;

[0454] The weight percentage is relative to the total weight of uncoated tablets.

[0455] In the embodiments, the solid oral dosage form (e.g., tablet) comprises an intragranular portion and an extragranular portion, and optionally, a film coating.

[0456] The intragranular portion includes:

[0457] Compound A has approximately 42% w / w.

[0458] Approximately 14% w / w hydroxypropyl methylcellulose;

[0459] Approximately 3% w / w D-α-tocopherol polyethylene glycol succinate;

[0460] Approximately 9% w / w microcrystalline cellulose;

[0461] Approximately 9% w / w lactose monohydrate;

[0462] Approximately 6% w / w of croscarmellose sodium;

[0463] Approximately 1% w / w of silica; and

[0464] Approximately 0.75% w / w sodium stearate fumarate;

[0465] And the extragranular portion includes:

[0466] Approximately 8% w / w microcrystalline cellulose;

[0467] Approximately 6% w / w of croscarmellose sodium; and

[0468] Approximately 0.75% w / w sodium stearate fumarate;

[0469] The weight percentage is relative to the total weight of uncoated tablets.

[0470] Method for preparing dosage forms of compound A

[0471] Solid formulations intended for oral administration can be formulated as immediate-release and / or modulated-release formulations. Modulated-release formulations include delayed-release, sustained-release, pulsatile-release, controlled-release, targeted-release, and programmed-release formulations. For a general description of modulated-release formulations, see U.S. Patent No. 6,106,864.

[0472] Drugs in the form of solid tablets are typically manufactured by compressing the materials constituting the final product into the desired tablet form. Such materials may include active pharmaceutical ingredients that impart necessary or useful properties to the product during and after the manufacturing process, as well as pharmaceutically inactive excipients. Tablet stiffness or tensile strength can be used as a measure of the cohesiveness of the tablet's components. If a tablet does not possess sufficient cohesive properties, it may crumble during handling. The final formulation may contain one or more layers and may be coated or uncoated.

[0473] As is known in the art, granulation is a process used to improve the handling and manufacturing properties of formulations, for example, by increasing particle size to improve flowability. Granulation does not substantially alter the physical form of the drug, such as its crystalline or amorphous characteristics. Various processes are used by those skilled in the art to prepare tablet dosage forms. Examples of such processes include dry granulation, wet granulation, fluidized bed granulation, and direct compression. The type of method used can depend on factors such as the physical properties of the active pharmaceutical ingredient in the formulation, the type of excipients used, and the desired physical properties of the final product. Each of these processes includes steps involving the mixing of dosage form components.

[0474] Typically, a certain amount of dosage form components needs to be mixed to obtain a homogeneous and consistent final product. However, in the preparation of drug tablets by wet granulation and dry granulation, it has been found that the degree and intensity of component mixing before compression is related to the loss of compressibility and cohesiveness of the formulation, resulting in a decrease in tablet hardness.

[0475] Similar results can be observed when roller pressing is used, for example, in dry granulation methods. Roller pressing can be used as a method to form granules that are subsequently compressed into tablets. Roller pressing can reduce the subsequent compressibility and cohesiveness of the dosage form.

[0476] Dry granulation is a process in which granules are formed through a compaction step, followed by grading the compacted material into particles that are easier to process. It is commonly used to improve flow properties and / or densify formulations, which can facilitate further manufacturing processes such as tableting, encapsulation, and powder filling. The compacted material is made directly from powder blends that typically contain active ingredients and other excipients, including lubricants.

[0477] Dry granulation technology may be superior to wet granulation methods due to its shorter processing time and cost advantages. However, dry granulation is generally limited to those cases where the drug or active ingredient has physical properties suitable for forming pharmaceutically acceptable particles and dosage forms (such as tablets).

[0478] Typically, at least one excipient needs to be added to the formulation, which helps increase the tablet size of the final product. Since tablet size must be within certain parameters to be used as a suitable dosage form, there is a limit beyond which increasing the tablet size to accommodate an increased amount of excipient to improve compatibility becomes impractical. Therefore, manufacturers often limit the use of dry granulation methods for formulations containing low doses of active ingredient per compressed tablet, allowing the formulation to accommodate sufficient levels of excipient to make dry granulation practical.

[0479] In the development of drug dosage forms, it is important to balance several different objectives. It is crucial to prepare the drug dosage form as economically as possible. A simple manufacturing method involving only a few processing steps is desirable. The dosage form should also optimally make the active compound it contains available to the patient. Furthermore, the dosage form should be easy to swallow. Smaller dosage forms are more readily accepted by patients and can improve patient compliance.

[0480] The final pharmaceutical composition is processed into unit dosage forms (e.g., tablets or capsules) and then packaged for dispensing. The processing steps will vary depending on the specific unit dosage form. For example, tablets are typically compressed into the desired shape under pressure, while capsules are produced using a simple filling operation. Those skilled in the art are familiar with the procedures used to manufacture various unit dosage forms.

[0481] Tablets are typically formed by applying pressure to the material to be tableted on a tableting machine. The formulation must have good flow properties to allow the material to be fed precisely by volume into the mold cavity, and suitable compressibility, compatibility, and ejection properties to form tablets.

[0482] There are several types of tablet presses, each with different productivity, but their basic functions and operations are similar. All of them compress tablet formulations within a die cavity by applying pressure between two steel punches, a lower punch, and an upper punch. Tablet presses are typically designed with a hopper for receiving and feeding the formulation, a feeding mechanism for feeding the formulation into the die cavity, a device for placing the punches and dies, and, in rotary tablet presses, a cam track for guiding the punch movement. Two types of tablet presses are single-station or single-punch tablet presses and multi-station rotary tablet presses. Some tablet presses offer longer residence times than others, thus increasing adhesion. Other presses can provide pre-compression.

[0483] Wet granulation methods can also be used to prepare particles of pharmaceutical compositions. Wet granulation methods are described in Remington: The Science and Practice of Pharmacy, Mack Publishing Company, Easton, Pa., 19th edition, 1995. These and other methods are generally known to those skilled in the art. If wet granulation is used, volatile agents can be incorporated into the mixture before, during, or after mixing the components, but before granulation. For example, solid volatile agents can be blended with the powder of the mixture before, during, or after the addition of a binder solution. Other solid dosage forms can be prepared using techniques including rotating bed granulation or spray-dried dispersions (SDD).

[0484] In this embodiment, standard coating procedures, such as those described in Remingtons's Pharmaceutical Sciences, 20th edition (2000), are used to provide a film coating around a solid oral dosage form (e.g., a tablet) of compound A. In this embodiment, some or all of the particles of the solid oral dosage form (e.g., a tablet) of compound A are coated. In embodiments where a film coating is provided around a solid oral dosage form (e.g., a tablet) of compound A, all weight percentages are relative to the total weight of the uncoated tablet.

[0485] Alternatively, some or all of the particles of a solid oral dosage form (e.g., tablet) of compound A are microencapsulated. In an embodiment, the particles of a solid oral dosage form (e.g., tablet) of compound A are not microencapsulated and are not coated.

[0486] Treatment

[0487] In the implementation scheme, this document provides a method for treating a subject's cancer, comprising administering to the subject a solid oral dosage form containing an effective amount of compound A as described herein.

[0488] Solid oral dosage forms containing compound A can be administered alone or in combination with other drugs, particularly CDK4 / 6 inhibitors (e.g., dalpiciclib, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, or palbociclib, or pharmaceutically acceptable salts thereof).

[0489] As used herein, unless otherwise stated, the term "combination" refers to the use of compound A with one or more therapeutic agents, wherein compound A and one or more therapeutic agents are administered intermittently, simultaneously or sequentially according to the same or different routes of administration and according to the same or different dose schedules.

[0490] As used herein, the term “locally advanced” is used because it is associated with cancer and may or may not be treated with a curative intent. For example, locally advanced breast cancer (LABC) is defined by the US National Comprehensive Cancer Network as a subset of breast cancer characterized by: the most advanced breast tumor in the absence of distant metastasis, wherein the tumor is larger than 5 cm in size and has regional lymphadenopathy; any size tumor (including ulcers or satellite nodules) extending directly to the chest wall or skin or both, regardless of the presence of regional lymphadenopathy; and the presence of regional lymphadenopathy (clinically fixed or entangled axillary lymph nodes, or any of the subclavian, supraclavicular, or internal mammary lymphadenopathy), regardless of the tumor stage. (Garg et al., Curr Oncol. Oct 2015; 22(5):e409–e410; National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Fort Washington, PA: NCCN; 2015. Ver.2.2015.)

[0491] As used in this article, the term "metastatic" is not intended for curative treatment because it is associated with cancer. For example, metastatic breast cancer refers to breast cancer that has spread beyond the breast and nearby lymph nodes to other parts of the body, such as bones, liver, lungs, and brain. (www.cancer.org / cancer / breast-cancer.)

[0492] Those skilled in the art will be able to identify and diagnose locally advanced and metastatic cancer in patients or subjects.

[0493] For convenience, this article may use certain well-known abbreviations, including: castration-resistant prostate cancer (CRPC), estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-), hormone receptor (HR), human epidermal growth factor receptor 2 positive (HER2+), non-small cell lung cancer (NSCLC), and progesterone receptor (PR).

[0494] In the implementation plan, the cancer is selected from lung cancer, mesothelioma, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, liver cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, hematologic malignancies, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphoma, spinal axis tumors, glioblastoma, brainstem glioma, pituitary adenoma, head and neck cancer, and combinations of two or more of the aforementioned cancers.

[0495] This document also discloses methods for treating cancer in a subject. In embodiments, these methods include treating a subject's cancer by administering to the subject a solid oral dosage form containing an amount effective in treating cancer, as described herein.

[0496] In the implementation plan, cancer is breast cancer, lung cancer, colon cancer, brain cancer, head and neck cancer, prostate cancer, stomach cancer, pancreatic cancer, ovarian cancer, melanoma, endocrine cancer, uterine cancer, testicular cancer, or bladder cancer.

[0497] In the implementation plan, the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

[0498] In the implementation plan, the cancer is breast cancer, lung cancer, or prostate cancer.

[0499] In the implementation plan, the cancer is breast cancer.

[0500] In the implementation plan, breast cancer refers to metastatic breast cancer.

[0501] In the implementation plan, the breast cancer is locally advanced breast cancer.

[0502] In the implementation plan, breast cancer is defined as HR+ breast cancer.

[0503] In the implementation plan, HR+ breast cancer is PR+ and / or ER+ breast cancer.

[0504] In some implementation schemes, breast cancer is classified as PR+ breast cancer.

[0505] In the implementation plan, breast cancer is ER+ breast cancer.

[0506] In the implementation plan, breast cancer is ER+ HER2- breast cancer.

[0507] In the implementation plan, breast cancer is defined as ER+ HER2+ breast cancer.

[0508] In the implementation plan, breast cancer is locally advanced or metastatic ER+ breast cancer.

[0509] In the implementation plan, breast cancer is locally advanced or metastatic ER+ HER2- breast cancer.

[0510] In the implementation plan, breast cancer is locally advanced or metastatic ER+ HER2+ breast cancer.

[0511] In the implementation plan, breast cancer is defined as metastatic ER+, HER2- breast cancer.

[0512] In the implementation plan, the breast cancer is metastatic ER+, HER2- breast cancer, and the breast cancer is also locally advanced.

[0513] In the implementation plan, lung cancer refers to non-small cell lung cancer.

[0514] In the implementation plan, lung cancer refers to locally advanced or metastatic non-small cell lung cancer.

[0515] In the implementation plan, prostate cancer is CRPC.

[0516] In the implementation plan, prostate cancer is locally advanced or metastatic CRPC.

[0517] This document also discloses a method for treating a subject with a solid tumor. In an embodiment, this document discloses a method for treating a subject with a solid tumor, comprising administering to the subject a solid oral dosage form containing an amount effective for treating the solid tumor, as described herein.

[0518] In the implementation plan, solid tumors are breast tumors, lung tumors, colon tumors, brain tumors, head and neck tumors, prostate tumors, stomach tumors, pancreatic tumors, ovarian tumors, melanomas, endocrine tumors, uterine tumors, testicular tumors, or bladder tumors.

[0519] In the implementation plan, solid tumors are breast tumors, lung tumors, prostate tumors, pancreatic tumors, or ovarian tumors.

[0520] In the implementation plan, solid tumors are breast tumors, lung tumors, or prostate tumors.

[0521] In the implementation scheme, the solid tumor is breast cancer. For example, in some implementations, the breast cancer is HR+ breast cancer. In other implementations, HR+ breast cancer is PR+ and / or ER+ breast cancer.

[0522] In the implementation plan, the solid tumor is breast cancer. For example, in some implementation plans, the breast cancer is ER+ HER2- breast cancer.

[0523] In the implementation plan, the solid tumor is breast cancer. For example, in some implementation plans, the breast cancer is ER+ HER2+ breast cancer.

[0524] In the implementation plan, the solid tumor is breast cancer. For example, in some implementation plans, the breast cancer is locally advanced or metastatic ER+ HER2- breast cancer.

[0525] In the implementation plan, the solid tumor is breast cancer. For example, in some implementation plans, the breast cancer is locally advanced or metastatic ER+ HER2+ breast cancer.

[0526] In the implementation plan, the solid tumor is lung cancer. For example, in some implementation plans, the lung cancer is non-small cell lung cancer.

[0527] In the implementation plan, the solid tumor is lung cancer. For example, in some implementation plans, the lung cancer is locally advanced or metastatic non-small cell lung cancer.

[0528] In the implementation plan, the solid tumor is prostate cancer. For example, in some implementation plans, the prostate cancer is CRPC.

[0529] In the implementation plan, the solid tumor is prostate cancer. For example, in some implementation plans, the prostate cancer is locally advanced or metastatic castration-resistant prostate cancer.

[0530] This document also discloses a method for treating a subject's hematologic malignancy. In some embodiments, the method includes treating the subject's hematologic malignancy by administering to the subject a solid oral dosage form containing an amount effective for treating the hematologic malignancy, as described herein.

[0531] In the implementation plan, hematologic malignancies are leukemia, lymphoma, or multiple myeloma.

[0532] In the implementation plan, hematologic malignancies are leukemia or lymphoma.

[0533] This article also discloses methods for treating cancer in subjects with locally advanced or metastatic ER+HER2- breast cancer, CRPC, or NSCLC whose disease has progressed on or is intolerant to standard therapy.

[0534] This article also discloses methods for treating cancer in subjects with locally advanced or metastatic ER+HER2- breast cancer, CRPC, or NSCLC whose disease has progressed on or is intolerant to standard therapy.

[0535] This article also discloses a method for treating cancer in subjects with locally advanced or metastatic 2L+ER+HER2 breast cancer who had previously received hormone / endocrine therapy and chemotherapy in a locally advanced / metastatic setting.

[0536] This article also discloses a method for treating cancer in subjects with locally advanced or metastatic 2L+ER+HER2 breast cancer who had previously received CDK4 / 6 inhibitor therapy.

[0537] Example

[0538] To better understand the present invention, the following embodiments are described. These embodiments are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

[0539] Example 1. Preparation of 50 mg, 100 mg, 200 mg and 250 mg tablets of compound A

[0540] 50 mg, 100 mg, 200 mg, and 250 mg tablets of compound A were prepared using two different formulations, yielding drug loadings of 20% and 42% for compound A. Compound A was prepared as a spray-dried solid dispersion (SDD) consisting of compound A / HPMC E3 / vitamin E TPGS in a ratio of 70:25:5% w / w or 40:55:5% w / w.

[0541] The compositions of 50 mg, 100 mg, 200 mg, and 250 mg tablets of compound A as an SDD, consisting of compound A / HPMC E3 / vitamin E TPGS, and the composition of 100 mg tablets of compound A as an SDD, consisting of a 40:55:5% w / w ratio, are shown in Table 2 below. The materials used to prepare the spray-dried dispersion (SDD) are shown in Table 4 below.

[0542] Those skilled in the art of pharmaceutical manufacturing will understand that the values ​​provided in Tables 1 through 4 are theoretical formulations (QQue formula) for a single unit. When a drug product is scaled up to multiple units, the quantity of each component is multiplied by the required number of units. Due to variations in balance accuracy and tolerances, the QQ values ​​may differ slightly when calculated based on the weight used in the manufacturing batch. Furthermore, certain limitations are permitted on the weight provided during manufacturing; however, these values ​​will be the same as the QQ formula as a percentage of the measured weight. This is generally accepted by the industry and regulatory bodies.

[0543] Table 1: Tablet Compositions for 50 mg Tablets

[0544]

[0545] *4% w / w weight increase (based on core weight)

[0546] Table 2: Tablet compositions for 100 mg tablets.

[0547]

[0548] *4% w / w weight increase (based on core weight)

[0549] Table 3: Tablet compositions for 200 mg and 250 mg tablets.

[0550]

[0551]

[0552] *4% w / w weight increase (based on core weight)

[0553] Preparation of two spray-dried dispersions

[0554] The materials used to prepare spray-dried dispersions (SDDs) are shown in Table 4 below.

[0555] Table 4: Materials used for spray-dried dispersions

[0556]

[0557] Dichloromethane and methanol are charged into a stainless steel reactor under a nitrogen atmosphere. The mixture is stirred with low vortex (25-100 rpm) and the temperature is maintained at 2-8°C (for the 70 / 25 / 5 dispersion) or 15-25°C (for the 40 / 55 / 5 dispersion). Vitamin E TPGS is added and the solution is stirred until no solids are present in the suspension. Methocel (i.e., HPMC) is added and the solution is stirred until no solids are present in the suspension. The temperature is adjusted to 15-25°C (for the 70 / 25 / 5 dispersion) and the solution is stirred for at least 30 minutes until a clear solution is obtained. Compound A is added, followed by a second charge of dichloromethane. For the 70 / 25 / 5 dispersion, the reactor temperature is adjusted to 2-8°C. The solution is stirred for at least 1 hour until a substantially clear solution is obtained, and then spray-dried according to the parameters shown in Table 5 below.

[0558] Table 5: Spray Drying Parameters - Compound A Solution

[0559]

[0560] The collected solids were transferred to a stainless steel double-cone dryer and dried under vacuum until the dichloromethane content was ≤480 ppm and the methanol content was ≤2400 ppm. The drying parameters are shown in Table 6 below:

[0561] Table 6: Parameters after drying

[0562]

[0563] Once the desired solvent level is achieved, reduce the jacket temperature to 20°C and allow the product to cool to 40°C.

[0564] Tablet manufacturing

[0565] The intragranular material is blended and compacted, then mixed with the extragranular excipients, and further blended. The resulting granules are compressed into 120 mg, 240 mg, 480 mg, 500 mg, or 600 mg tablets. The resulting tablets may be film-coated.

[0566] Example 2: Study of amorphous and crystalline suspensions in dogs

[0567] Fasted female dogs were orally administered compound A (7.5 mg / kg), which was a spray-dried dispersion (SDD), a pure amorphous API, or a crystalline API, at a concentration of 2 mL / kg in an aqueous suspension containing 0.5% Methocel A4M. Animals were pretreated with 0.5 mg / kg famotidine IV one hour prior to administration of compound A to raise gastric pH. One group of study animals were pretreated intramuscularly with pentagastrin (6 µg / kg) one hour prior to administration of crystalline compound A as a low gastric pH comparator.

[0568] Table 7: Suspension formulations tested in canine pharmacokinetic studies.

[0569]

[0570] API = Active pharmaceutical ingredient; HPMC E3LV = Low viscosity E3 grade hydroxypropyl methylcellulose; HPMCAS-L = L grade hydroxypropyl methylcellulose acetate succinate; SDD = Spray dried dispersion; VitE TPGS = D-α-tocopherol polyethylene glycol 1000 succinate; wt = Weight.

[0571] The data from the PK study are described in Table 7 and presented in... Figure 1 And in Table 8 below.

[0572] Table 7:

[0573]

[0574] Compared to that achieved under more favorable acidic gastric pH conditions, a significant reduction in exposure to crystalline materials was observed in animals with a neutral gastric pH. However, amorphous polymer dispersions were able to compensate for this loss of crystalline solubility, as evidenced by the high exposure observed when delivering compound A via such formulations. Indeed, even in dogs pretreated with pentapeptide-gastrin, the exposure obtained with all polymer dispersions exceeded that provided by the crystalline free base. Without being bound by theory, this suggests exposure due to the limited solubility or dissolution rate of the crystalline form. Pure amorphous compound A performed inferiorly to the polymer dispersion. Among the polymer dispersions, hydroxypropyl methylcellulose acetate succinate (HPMC) / vitamin E TPGS provided the highest exposure.

[0575] Example 3. Dog study using amorphous and crystalline tablets

[0576] To confirm the canine pharmacokinetic results of the suspension formulations described in Table 7 above, prototype 50 mg strength Compound A tablets were prepared on a laboratory scale using Compound A with the compositions shown in Table 8: low viscosity E3 grade hydroxypropyl methylcellulose (HPMC E3LV): vitamin E TPGS (40:55:5) dispersion and crystalline drug substance (with and without acidifier - fumaric acid). An acidifier (fumaric acid) was added to the tablet compositions to test whether lowering the pH of the microenvironment surrounding the crystalline drug particles would improve bioavailability compared to the crystalline drug without the acidifier.

[0577] Table 8: Compositions of the 50 mg Compound A tablet prototype

[0578]

[0579] D 50 = Dimensions where less than 50% of the material volume exists; HPMC E3LV = Low viscosity E3 grade hydroxypropyl methylcellulose; SDD = Spray-dried dispersion; VitE TPGS = D-α-tocopherol polyethylene glycol 1000 succinate.

[0580] Female dogs were pretreated with 0.5 mg / kg famotidine IV one hour prior to administration of a single 50 mg compound A tablet. Study animals were either fasted (followed by feeding 4 hours after compound A administration) or fed (0.5 hours before administration).

[0581] Figures 2A to 2D The results from the fasting studies shown in the illustration indicate that exposure to the reduced-size API was slightly improved by microenvironment acidification (using fumaric acid) - see [link to study]. Figure 2B and Figure 2D The comparison also noted that increased particle size did not affect exposure in the presence of acid - see [link to comparison]. Figure 2C and Figure 2D A comparison was made. Overall, spray-dried dispersions in HPMC and TPGS provided the best exposure.

[0582] Figures 3A to 3D The results for the feeding studies shown in the illustrations indicate that exposure to all formulations was approximately three times greater compared to fasted subjects. As with the fasted subjects, the spray-dried dispersions in HPMC and TPGS provided optimal exposure.

Claims

1. A solid oral dosage form comprising compound A: , Or a pharmaceutically acceptable salt, polymer, and surfactant thereof, wherein the amount of compound A in the solid oral dosage form is from about 5 mg to about 500 mg, and the solid oral dosage form is a tablet, sachet, or capsule.

2. The solid oral dosage form as described in claim 1, wherein the solid oral dosage form is a tablet.

3. A tablet comprising compound A: , Or a pharmaceutically acceptable salt, polymer, or surfactant thereof, wherein the amount of compound A in the solid oral dosage form is from about 5 mg to about 500 mg.

4. The solid oral dosage form or tablet according to any one of claims 1 to 3, wherein the polymer is hydroxypropyl methylcellulose (HPMC), a hydroxypropyl methylcellulose derivative, a polyvinylpyrrolidone copolymer, a methacrylic acid copolymer, polyethylene glycol, or a polyethylene glycol derivative.

5. The solid oral dosage form or tablet as described in any one of claims 1 to 4, wherein the polymer is hydroxypropyl methylcellulose.

6. The solid oral dosage form or tablet according to any one of claims 1 to 5, wherein the surfactant is selected from polyethylene glycol, polyethylene glycol esters, glycerides, and mixtures thereof.

7. The solid oral dosage form or tablet according to any one of claims 1 to 6, wherein the surfactant is a vitamin E ester of polyethylene glycol.

8. The solid oral dosage form or tablet according to any one of claims 1 to 7, wherein the surfactant is D-α-tocopherol polyethylene glycol succinate.

9. The solid oral dosage form or tablet according to any one of claims 1 to 8, wherein the surfactant is D-α-tocopherol polyethylene glycol 1000 succinate.

10. The solid oral dosage form or tablet of claim 1, wherein the polymer is hydroxypropyl methylcellulose and the surfactant is D-α-tocopherol polyethylene glycol succinate.

11. The solid oral dosage form or tablet as described in any one of claims 1 to 10, further comprising one or more excipients selected from fillers, disintegrants, gliding agents and lubricants.

12. The solid oral dosage form or tablet of claim 11, wherein the filler is microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate, mannitol, sorbitol, xylitol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, pullulan, fast-dissolving carbohydrates, or combinations thereof.

13. The solid oral dosage form or tablet of claim 11, wherein the disintegrant is sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium carboxymethyl cellulose, crospovidone, chitosan, agar, alginate, calcium alginate, methylcellulose, microcrystalline cellulose, powdered cellulose, lower alkyl-substituted hydroxypropyl cellulose, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, potassium polycrystallin, starch, pregelatinized starch, sodium alginate, potassium polycrystallin, povidone, or combinations thereof.

14. The solid oral dosage form or tablet of claim 11, wherein the gliding agent is silica, colloidal silica, calcium silicate, magnesium silicate, magnesium trisilicate, talc, starch, or a combination thereof.

15. The solid oral dosage form or tablet according to claim 11, wherein the lubricant is magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl behenate, glyceryl palmitate, hexagonal boron nitride, hydrogenated vegetable oil, light mineral oil, mineral oil, polyethylene glycol, poloxamer, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate, or any combination thereof.

16. The solid oral dosage form or tablet as described in any one of claims 1 to 3 and 10 to 15, comprising: Compound A, approximately 15% w / w to approximately 50% w / w; Hydroxypropyl methylcellulose, approximately 10% w / w to approximately 40% w / w; D-α-tocopherol polyethylene glycol succinate, approximately 0.5% w / w to approximately 5% w / w; Microcrystalline cellulose of approximately 10% w / w to approximately 40% w / w; Lactose monohydrate at approximately 5% w / w to approximately 15% w / w; Crosslinked carboxymethyl cellulose sodium, approximately 5% w / w to approximately 15% w / w; Silica of approximately 0% w / w to approximately 5% w / w; and Sodium stearyl fumarate, approximately 0% w / w to approximately 2% w / w.

17. The solid oral dosage form or tablet as described in any one of claims 1 to 3 and 10 to 15, comprising: Compound A, 15% to 50% w / w; 10% to 40% w / w hydroxypropyl methylcellulose; 0.5% to 5% w / w D-α-tocopherol polyethylene glycol succinate; 10% to 40% w / w microcrystalline cellulose; 5% to 15% w / w lactose monohydrate; 5% to 15% w / w croscarmellose sodium; 0% to 5% w / w silica; and 0% to 2% w / w sodium stearate fumarate.

18. The solid oral dosage form or tablet as described in any one of claims 1 to 3 and 10 to 15, comprising: Compound A has approximately 42% w / w. Approximately 15% w / w hydroxypropyl methylcellulose; Approximately 3% w / w D-α-tocopherol polyethylene glycol succinate; Approximately 17% w / w microcrystalline cellulose; Approximately 8.8% w / w lactose monohydrate; Approximately 12% w / w of croscarmellose sodium; Approximately 1% w / w of silica; and Approximately 1.5% w / w sodium stearate fumarate.

19. The solid oral dosage form or tablet as described in any one of claims 1 to 3 and 10 to 15, comprising: Compound A, approximately 20% w / w; Approximately 28% w / w hydroxypropyl methylcellulose; Approximately 2.5% w / w D-α-tocopherol polyethylene glycol succinate; Approximately 27% w / w microcrystalline cellulose; Approximately 9% w / w lactose monohydrate; Approximately 12% w / w of croscarmellose sodium; Approximately 1% w / w of silica; and Approximately 1.5% w / w sodium stearate fumarate.

20. The solid oral dosage form or tablet as claimed in any one of claims 1 to 3 and 10 to 15, comprising an intragranular portion and an extragranular portion.

21. The solid oral dosage form or tablet of claim 20, wherein the intragranular portion comprises: Compound A, approximately 15% to approximately 50% w / w; Hydroxypropyl methylcellulose, approximately 10% to approximately 40% w / w; D-α-tocopherol polyethylene glycol succinate, approximately 0.5% to approximately 5% w / w; Microcrystalline cellulose, approximately 5% to approximately 10% w / w; Lactose monohydrate, approximately 5% to approximately 10% w / w; Approximately 1% to approximately 10% w / w of croscarmellose sodium; Approximately 0% to approximately 5% w / w of silica; and Sodium stearyl fumarate, approximately 0% to approximately 2% w / w. And the extragranular portion comprises: Microcrystalline cellulose of approximately 5% to approximately 25% w / w; About 0% to about 10% w / w of croscarmellose sodium; and Sodium stearyl fumarate, approximately 0% to approximately 2% w / w; The weight percentage is relative to the total weight of uncoated tablets.

22. The solid oral dosage form or tablet of claim 20, wherein the intragranular portion comprises: Compound A has approximately 42% w / w. Approximately 14% w / w hydroxypropyl methylcellulose; Approximately 3% w / w d-α-tocopherol polyethylene glycol succinate; Approximately 9% w / w microcrystalline cellulose; Approximately 9% w / w lactose monohydrate; Approximately 6% w / w of croscarmellose sodium; Approximately 1% w / w of silica; and Approximately 0.75% w / w sodium stearate fumarate; And the extragranular portion comprises: Approximately 8% w / w microcrystalline cellulose; Approximately 6% w / w of croscarmellose sodium; and Approximately 0.75% w / w sodium stearate fumarate; The weight percentage is relative to the total weight of uncoated tablets.

23. The solid oral dosage form or tablet of claim 20, wherein the intragranular portion comprises: Compound A, approximately 20% w / w; Approximately 28% w / w hydroxypropyl methylcellulose; Approximately 2.5% w / w D-α-tocopherol polyethylene glycol succinate; Approximately 8% w / w microcrystalline cellulose; Approximately 9% w / w lactose monohydrate; Approximately 6% w / w of croscarmellose sodium; Approximately 1% w / w of silica; and Approximately 0.75% w / w sodium stearate fumarate, And the extragranular portion comprises: Approximately 18% w / w microcrystalline cellulose; Approximately 6% w / w of croscarmellose sodium; and Approximately 0.75% w / w sodium stearate fumarate; The weight percentage is relative to the total weight of uncoated tablets.

24. The solid oral dosage form or tablet as claimed in any one of claims 1 to 23, wherein the tablet is film-coated.

25. The solid oral dosage form or tablet according to any one of claims 1 to 24, wherein the amount of compound A in the solid oral dosage form is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg.

26. The solid oral dosage form or tablet as described in any one of claims 1 to 25, wherein the amount of compound A in the solid oral dosage form is about 200 mg.

27. The solid oral dosage form or tablet according to any one of claims 1 to 25, wherein the amount of compound A in the solid oral dosage form is about 100 mg.

28. The solid oral dosage form or tablet as claimed in any one of claims 1 to 25, wherein the amount of compound A in the solid oral dosage form is about 250 mg.

29. The solid oral dosage form or tablet according to any one of claims 1 to 25, wherein the amount of compound A in the solid oral dosage form is about 50 mg.

30. A mixture comprising compound A: , Or its pharmaceutically acceptable salts, polymers, and surfactants.

31. The mixture of claim 30, wherein the polymer is hydroxypropyl methylcellulose (HPMC), a hydroxypropyl methylcellulose derivative, a polyvinylpyrrolidone copolymer, a methacrylic acid copolymer, polyethylene glycol, or a polyethylene glycol derivative.

32. The mixture form as described in claim 30 or 31, wherein the polymer is hydroxypropyl methylcellulose.

33. The mixture form according to any one of claims 30 to 32, wherein the surfactant is selected from polyethylene glycol, polyethylene glycol esters, glycerol esters, and mixtures thereof.

34. The mixture of any one of claims 30 to 33, wherein the surfactant is a vitamin E ester of polyethylene glycol.

35. The mixture of any one of claims 30 to 34, wherein the surfactant is D-α-tocopherol polyethylene glycol succinate.

36. The mixture of any one of claims 30 to 35, wherein the surfactant is D-α-tocopherol polyethylene glycol 1000 succinate.

37. The mixture of claim 30, wherein the polymer is hydroxypropyl methylcellulose and the surfactant is D-α-tocopherol polyethylene glycol succinate.

38. The mixture according to any one of claims 30 to 37, comprising: Compound A comprises approximately 20% (w / w) to approximately 60% (w / w). The polymer, comprising approximately 35% (w / w) to approximately 75% (w / w), and Surfactants of approximately 1% (w / w) to approximately 10% (w / w).

39. The mixture according to any one of claims 30 to 37, comprising: Approximately 40% (w / w) of compound A, Approximately 55% (w / w) of the polymer, and Approximately 5% (w / w) of the surfactant.

40. The mixture of any one of claims 30 to 37, comprising: Compound A comprises approximately 50% to approximately 90% (w / w). The polymer, comprising approximately 10% to approximately 40% (w / w), and The surfactant is present in approximately 1% to approximately 10% (w / w).

41. The mixture according to any one of claims 30 to 37, comprising: Approximately 70% (w / w) of compound A, Approximately 25% (w / w) of the polymer, and Approximately 5% (w / w) of the surfactant.

42. The mixture of claim 38, comprising: Compound A comprises approximately 20% (w / w) to approximately 60% (w / w). Approximately 35% (w / w) to approximately 75% (w / w) of hydroxypropyl methylcellulose, and D-α-tocopherol polyethylene glycol succinate, approximately 1% (w / w) to approximately 10% (w / w).

43. The mixture of claim 39, comprising: Approximately 40% (w / w) of compound A, Approximately 55% (w / w) hydroxypropyl methylcellulose, and Approximately 5% (w / w) of D-α-tocopherol polyethylene glycol succinate.

44. The mixture of claim 40, comprising: Compound A comprises approximately 50% to approximately 90% (w / w). Approximately 10% to approximately 40% (w / w) of hydroxypropyl methylcellulose, and D-α-tocopherol polyethylene glycol succinate, approximately 1% to approximately 10% (w / w).

45. The mixture of claim 41, comprising: Approximately 70% (w / w) of compound A, Approximately 25% (w / w) hydroxypropyl methylcellulose, and Approximately 5% (w / w) of D-α-tocopherol polyethylene glycol succinate.

46. ​​The mixture of any one of claims 30 to 45, wherein the mixture is a dispersion.

47. The mixture of claim 46, wherein the dispersion is a solid dispersion.

48. The mixture of claim 46 or 47, wherein the dispersion is produced by spray drying, freeze drying, hot melt extrusion, grinding, solvent evaporation, supercritical fluid processing, or high-shear mixing.

49. The mixture of any one of claims 46 to 48, wherein the dispersion is produced by spray drying.

50. A spray-dried dispersion comprising compound A: , Or its pharmaceutically acceptable salts, polymers, and surfactants.

51. The spray-dried dispersion of claim 50, wherein the polymer is hydroxypropyl methylcellulose (HPMC), a hydroxypropyl methylcellulose derivative, a polyvinylpyrrolidone copolymer, a methacrylic acid copolymer, polyethylene glycol, or a polyethylene glycol derivative.

52. The spray-dried dispersion of claim 50 or 51, wherein the polymer is hydroxypropyl methylcellulose.

53. The spray-dried dispersion according to any one of claims 50 to 52, wherein the surfactant is selected from polyethylene glycol, polyethylene glycol esters, glycerol esters, and mixtures thereof.

54. The spray-dried dispersion according to any one of claims 50 to 53, wherein the surfactant is a vitamin E ester of polyethylene glycol.

55. The spray-dried dispersion according to any one of claims 50 to 54, wherein the surfactant is D-α-tocopherol polyethylene glycol succinate.

56. The spray-dried dispersion according to any one of claims 50 to 55, wherein the surfactant is D-α-tocopherol polyethylene glycol 1000 succinate.

57. The spray-dried dispersion of claim 50, wherein the polymer is hydroxypropyl methylcellulose and the surfactant is D-α-tocopherol polyethylene glycol succinate.

58. The spray-dried dispersion of claim 50, comprising: Compound A comprises approximately 20% (w / w) to approximately 60% (w / w). The polymer, comprising approximately 35% (w / w) to approximately 75% (w / w), and The surfactant is present in approximately 1% (w / w) to approximately 10% (w / w).

59. The spray-dried dispersion of claim 50, comprising: Approximately 40% (w / w) of compound A, Approximately 55% (w / w) of the polymer, and Approximately 5% (w / w) of the surfactant.

60. The spray-dried dispersion of claim 50, comprising: Compound A comprises approximately 50% to approximately 90% (w / w). The polymer, comprising approximately 10% to approximately 40% (w / w), and The surfactant is present in approximately 1% to approximately 10% (w / w).

61. The spray-dried dispersion of claim 50, comprising: Approximately 70% (w / w) of compound A, Approximately 25% (w / w) of the polymer, and Approximately 5% (w / w) of surfactant.

62. The spray-dried dispersion of claim 51, comprising: Compound A comprises approximately 20% (w / w) to approximately 60% (w / w). Approximately 35% (w / w) to approximately 75% (w / w) of hydroxypropyl methylcellulose, and D-α-tocopherol polyethylene glycol succinate, approximately 1% (w / w) to approximately 10% (w / w).

63. The spray-dried dispersion of claim 59, comprising: Approximately 40% (w / w) of compound A, Approximately 55% (w / w) hydroxypropyl methylcellulose, and Approximately 5% (w / w) of D-α-tocopherol polyethylene glycol succinate.

64. The spray-dried dispersion of claim 60, comprising: Compound A comprises approximately 50% to approximately 90% (w / w). Approximately 10% to approximately 40% (w / w) of hydroxypropyl methylcellulose, and D-α-tocopherol polyethylene glycol succinate, approximately 1% to approximately 10% (w / w).

65. The spray-dried dispersion of claim 61, comprising: Approximately 70% (w / w) of compound A, Approximately 25% (w / w) hydroxypropyl methylcellulose, and Approximately 5% (w / w) of D-α-tocopherol polyethylene glycol succinate.

66. A method for preparing a spray-dried dispersion as described in any one of claims 50 to 65, comprising: Compound A, the polymer, and the surfactant are dissolved in a solvent to provide a solution containing compound A; The solution containing compound A is introduced into a spray dryer; The solution containing compound A is sprayed from the spray dryer to form a spray-dried dispersion of compound A; and Optionally, residual solvent is removed from the spray-dried dispersion of compound A.

67. The method of claim 66, wherein the solvent is a mixture of dichloromethane and methanol.

68. The method of claim 66, wherein the solvent is a mixture of about 90:10 (w / w) to about 70:30 (w / w) dichloromethane:methanol.

69. The method of claim 66, wherein the solvent is a mixture of about 80:20 (w / w) dichloromethane:methanol.

70. The method of claim 66, wherein the solvent is a mixture of about 85:15 (w / w) dichloromethane:methanol.

71. The method of any one of claims 66 to 70, wherein removing the residual solvent comprises drying.

72. The method of claim 71, wherein drying comprises stirring cone drying.

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