Solid oral dosage form of estrogen receptor degrading agent

Abstract

In this specification, compound A: [Formula 1] JPEG2026522318000021.jpg53170 A solid oral dosage form containing a pharmaceutically acceptable salt thereof is disclosed.

Description

Technical Field

[0001] (Cross - reference to related applications) This application claims the priority and benefit of U.S. Provisional Patent Application No. 63 / 472,523, filed on June 12, 2023, the content of which is hereby incorporated by reference in its entirety.

Background Art

[0002] Certain bifunctional compounds target specific cellular proteins for degradation via the ubiquitin - proteasome system. Examples of such proteolysis - targeting chimeric compounds (i.e., "PROTAC® proteolysis agents") that target estrogen receptor (ER) for ubiquitination and subsequent degradation are disclosed in International Publication No. WO2018 / 102725, which is hereby incorporated by reference in its entirety. Such bifunctional molecules exhibit various pharmacological activities consistent with the degradation of ER, including, but not limited to, the treatment or amelioration of disease states such as cancer (e.g., breast cancer, uterine cancer, ovarian cancer, prostate cancer, endometrial cancer), or endometriosis. Particularly interesting bifunctional molecules are those having the molecular formula C 45 H 49 N5O4 and the following structure: (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-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-naphthalenylphenyl]-4-piperidinyl]methyl]-1-piperazinyl]-2H-isoindol-2-yl]-2,6-piperidinedione (referred to herein as "Compound A" or "Cpd A").

Chemical Formula

[0003] Compound A is being developed as an ER-targeted PROTAC® proteolytic agent for the potential treatment of breast cancer and has been shown to be a useful regulator of ubiquitination and degradation of target proteins via the ubiquitin-proteasome pathway.

[0004] There is a need to develop dosage forms of compound A, including those suitable for oral administration. Such dosage forms may offer specific advantages (e.g., improved oral bioavailability) and may be useful for the safe, effective, and / or convenient administration of compound A to patients, for example, to treat cancer (e.g., breast cancer). [Overview of the Initiative]

[0005] This summary is provided to introduce the selected concepts in a simplified form, which are further explained below in a more detailed description. This summary is not intended to identify the main 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.

[0006] In part, in this specification, Compound A [ka] Solid oral dosage forms (e.g., tablets) comprising compound A or a pharmaceutically acceptable salt thereof are disclosed herein. In particular, solid oral dosage forms comprising compound A, a pharmaceutically acceptable salt thereof, a polymer, and a surfactant are disclosed herein. In some embodiments, the amount of compound A in the solid oral dosage form is about 5 mg to about 500 mg. In some embodiments, the solid oral dosage form is a tablet, a sachet, or a capsule.

[0007] In several embodiments, the solid oral dosage form further comprises one or more excipients selected from fillers, disintegrants, flow enhancers, and lubricants. Typical fillers include, but are not limited to, microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate, mannitol, sorbitol, xylitol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, pullulan, rapidly soluble carbohydrates, or any combination thereof. Typical disintegrants include, but are not limited to, sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium croscarmellose, crospovidone, chitosan, agar, alginic acid, calcium alginate, methylcellulose, microcrystalline cellulose, powdered cellulose, lower alkyl-substituted hydroxypropyl cellulose, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, potassium polaritrin, starch, pregelatinized starch, sodium alginate, potassium polaritrin, povidone, and any mixture thereof. Typical fluidity enhancers include, but are not limited to, silicon dioxide, colloidal silicon dioxide, calcium silicate, magnesium silicate, magnesium trisilicate, talc, starch, and mixtures thereof. Typical lubricants include, but are not limited to, magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, hexagonal boron nitride, hydrogenated vegetable oil, diesel fuel, mineral oil, polyethylene glycol, poloxamer, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate, and any combination thereof.

[0008] In several embodiments, the solid oral dosage form is a tablet. In several embodiments, the tablet is film-coated.

[0009] In some embodiments, the solid oral dosage form (e.g., a tablet) is: Compound A, approximately 15% w / w to approximately 50% w / w Approximately 10% w / w to approximately 40% w / w hydroxypropyl methylcellulose, Approximately 0.5% w / w to approximately 5% w / w of d-α-tocopheryl polyethylene glycol succinate, Microcrystalline cellulose of approximately 10% w / w to approximately 40% w / w, Lactose monohydrate at approximately 5% w / w to approximately 15% w / w, Croscarmellose sodium at approximately 5% w / w to approximately 15% w / w Approximately 0% w / w to approximately 5% w / w of silicon dioxide, and Contains approximately 0% w / w to approximately 2% w / w of sodium stearyl fumarate.

[0010] In some embodiments, the solid oral dosage form (e.g., a tablet) is: Compound A, 15%~50% w / w 10%~40% w / w hydroxypropyl methylcellulose, 0.5%~5% w / w d-α-tocopheryl polyethylene glycol succinate, Microcrystalline cellulose with a content of 10% to 40% w / w, 5%~15% w / w lactose monohydrate, 5%~15% w / w croscarmellose sodium, 0% to approximately 5% w / w silicon dioxide, and Contains 0% to 2% w / w sodium stearyl fumarate.

[0011] In some embodiments, the solid oral dosage form (e.g., a tablet) is: Compound A at approximately 42% w / w Approximately 15% w / w hydroxypropyl methylcellulose, Approximately 3% w / w d-α-tocopheryl polyethylene glycol succinate, Approximately 17% w / w microcrystalline cellulose, Approximately 8.8% w / w lactose monohydrate, Approximately 12% w / w croscarmellose sodium, Approximately 1% w / w silicon dioxide, and It contains about 1.5% w / w of sodium stearyl fumarate.

[0012] In multiple embodiments, the solid oral dosage form (e.g., tablet) contains about 20% w / w of Compound A, about 28% w / w of hydroxypropyl methylcellulose, about 2.5% w / w of d-α-tocopheryl polyethylene glycol succinate, about 27% w / w of microcrystalline cellulose, about 9% w / w of lactose monohydrate, about 12% w / w of croscarmellose sodium, about 1% w / w of silicon dioxide, and about 1.5% w / w of sodium stearyl fumarate.

[0013] In multiple embodiments, the solid oral dosage form (e.g., tablet) includes an intragranular portion and an extragranular portion, and optionally includes a film coating. The intragranular portion contains about 15% to about 50% w / w of Compound A, [[ID=二十九]] about 10% to about 40% w / w of hydroxypropyl methylcellulose, about 0.5% to about 5% w / w of d-α-tocopheryl polyethylene glycol succinate, about 5% to about 10% w / w of microcrystalline cellulose, about 5% to about 10% w / w of lactose monohydrate, about 1% to about 10% w / w of croscarmellose sodium, about 0% to about 5% w / w of silicon dioxide, and about 0% to about 2% w / w of sodium stearyl fumarate. The extragranular portion contains about 5 to about 25% w / w of microcrystalline cellulose, about 0% to about 10% w / w of croscarmellose sodium, and about 0% to about 2% w / w of sodium stearyl fumarate. The weight percentages are based on the total weight of the uncoated tablet.

[0014] In several embodiments, the solid oral dosage form (e.g., a tablet) comprises an internal granule portion and an external granule portion, and optionally includes a film coating. The granular portion is Compound A at approximately 42% w / w Approximately 14% w / w hydroxypropyl methylcellulose, Approximately 3% w / w d-α-tocopheryl polyethylene glycol succinate, Approximately 9% w / w microcrystalline cellulose, Approximately 9% w / w lactose monohydrate, Approximately 6% w / w croscarmellose sodium, Approximately 1% w / w silicon dioxide, and Contains approximately 0.75% w / w sodium stearyl fumarate. The outer part of the granules is Approximately 8% w / w microcrystalline cellulose, Approximately 6% w / w croscarmellose sodium, and Contains approximately 0.75% w / w sodium stearyl fumarate. The weight percentage is relative to the total weight of the uncoated tablets.

[0015] In several embodiments, the solid oral dosage form (e.g., a tablet) comprises an internal granule portion and an external granule portion, and optionally includes a film coating. The granular portion is Compound A at approximately 20% w / w Approximately 28% w / w hydroxypropyl methylcellulose, Approximately 2.5% w / w of d-α-tocopheryl polyethylene glycol succinate, Approximately 8% w / w microcrystalline cellulose, Approximately 9% w / w lactose monohydrate, Approximately 6% w / w croscarmellose sodium, Approximately 1% w / w silicon dioxide, and Contains approximately 0.75% w / w sodium stearyl fumarate. The outer part of the granules is Approximately 18% w / w microcrystalline cellulose, Approximately 6% w / w croscarmellose sodium, and Contains approximately 0.75% w / w sodium stearyl fumarate. The weight percentage is relative to the total weight of the uncoated tablets.

[0016] In several embodiments, the solid oral dosage form (e.g., a tablet) contains 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 several embodiments, the solid oral dosage form contains about 200 mg of compound A. In several embodiments, the solid oral dosage form formulation contains about 100 mg of compound A. In several embodiments, the solid oral dosage form contains about 250 mg of compound A. In several embodiments, the solid oral dosage form contains about 50 mg of compound A.

[0017] Compound A, or mixtures comprising its pharmaceutically acceptable salts, polymers, and surfactants, are also disclosed herein.

[0018] Furthermore, spray-dried dispersions comprising compound A, or its pharmaceutically acceptable salts, polymers, and surfactants are disclosed herein.

[0019] Methods for preparing the spray-dried dispersions disclosed herein are also provided. Such methods include To obtain a solution containing compound A by dissolving compound A, a polymer, and a surfactant in a solvent. Introducing a solution containing compound A into a spray dryer. Forming a dispersion of compound A by spraying a solution containing compound A from a spray dryer, and Depending on the circumstances, this may include removing the residual solvent from the dispersion of compound A. In several embodiments of the method, the solvent is a mixture of dichloromethane and methanol. In several embodiments, the solvent is a mixture of dichloromethane:methanol in a ratio of about 90:10 (w / w) to about 70:30 (w / w). In several embodiments, the solvent is a mixture of dichloromethane:methanol in a ratio of about 80:20 (w / w). In several embodiments, the solvent is a mixture of dichloromethane:methanol in a ratio of about 85:15 (w / w). In embodiments of this method, the removal of residual solvent includes drying (e.g., stirred conical drying). [Brief explanation of the drawing]

[0020] [Figure 1] Figure 1 shows the results of a pharmacokinetic (PK) test in which an aqueous suspension of compound A was orally administered to fasted female dogs, as described in Example 2. Formulations B to F show improved bioavailability compared to formulation A. [Figure 2A] Figures 2A to 2D show the results of the PK test conducted when tablets of compound A were orally administered to fasting female dogs, as described in Example 3. [Figure 2B] Figures 2A to 2D show the results of the PK test conducted when tablets of compound A were orally administered to fasting female dogs, as described in Example 3. [Figure 2C] Figures 2A to 2D show the results of the PK test conducted when tablets of compound A were orally administered to fasting female dogs, as described in Example 3. [Figure 2D] Figures 2A to 2D show the results of the PK test conducted when tablets of compound A were orally administered to fasting female dogs, as described in Example 3. [Figure 3A] Figures 3A to 3D show the results of a pharmacokinetic study in female dogs that ingested orally administered tablets of compound A, as described in Example 3. [Figure 3B] Figures 3A to 3D show the results of a pharmacokinetic study in female dogs that ingested orally administered tablets of compound A, as described in Example 3. [Figure 3C]Figures 3A to 3D show the results of a pharmacokinetic study in female dogs that ingested orally administered tablets of compound A, as described in Example 3. [Figure 3D] Figures 3A to 3D show the results of a pharmacokinetic study in female dogs that ingested orally administered tablets of compound A, as described in Example 3. [Modes for carrying out the invention]

[0021] The present invention may be more readily understood by referring to the following detailed description of embodiments of the present invention and examples included herein. It should also be understood that the technical terms used herein are for illustrative purposes only and are not intended to limit the use of specific embodiments.

[0022] (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalene-1-yl)phenyl)piperidine-4-yl)methyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidine-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-naphthalenylphenyl]-4-piperidinyl]methyl]-1-piperazinyl]-2H-isoindole-2-yl]-2,6-piperidinedione (also referred to herein as "Compound A" or "Cpd A")) is, [ka] Developed as an ER-targeted PROTAC® proteolytic agent for potential breast cancer treatment, it has been shown to be a useful modulator of ubiquitination and degradation of target proteins via the ubiquitin-proteasome pathway.

[0023] Compound A and its pharmaceutically acceptable salts are disclosed in International Publication No. 2018 / 102725 and U.S. Patents No. 10,647,698, 10,899,742, and 11,104,666, International Publication No. 2021 / 041348, U.S. Patents No. 17 / 472,847, 17 / 548,842, and 17 / 873,748. The contents of each of the aforementioned references are incorporated herein by reference in their entirety.

[0024] definition Unless otherwise specified, all technical and scientific terms used in connection with the present invention have the same meanings as those commonly understood by those skilled in the art in which the present invention pertains.

[0025] The inventions described herein may be adequately implemented in the absence of any elements not specifically disclosed herein.

[0026] As used herein, the singular forms "a," "an," and "the" include multiple references unless otherwise indicated. For example, "an" excipient includes one or more excipients.

[0027] Where used herein, the term “about” used to modify a numerically defined parameter (e.g., the dose of a compound) means that the parameter may vary by up to 10% below or above the value stated for that parameter. For example, a dose of about 5 mg means 5 mg ± 10%, i.e., it may vary between 4.5 mg and 5.5 mg.

[0028] As used herein, the terms “reagent,” “composition,” “compound,” “drug,” and “therapeutic agent” may be used interchangeably to refer to the compounds included in the methods and uses of this disclosure, but are not limited to these terms.

[0029] The term "amorphous" refers to a solid with a disordered arrangement of molecules that does not possess a discernible crystalline lattice.

[0030] Compound A has the following structure: [ka] .

[0031] Compound A is a biopharmaceutical classification system class IV compound (low solubility / low permeability). Compound A can be interconverted with its epimer, compound B, described below. [ka] .

[0032] While we do not wish to be bound by theory, preclinical data suggest that exposure to compound B is limited (<26%) compared to compound A. Evidence indicates that compound B does not degrade ER, yet compound B exhibits similar antagonism to ER-dependent transcription compared to compound A.

[0033] Other embodiments relate to pharmaceutically acceptable salts of the compounds described herein. Examples of pharmaceutically acceptable salts of the compounds described herein include acid addition salts and base addition salts thereof.

[0034] Other embodiments also relate to 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, i.e., salts containing pharmaceutically acceptable anions, include, but are not limited to, acetates, citrates, adipic acid, aspartic acid, benzoates, besilates, bicarbonates / carbonates, bisulfates / sulfates, tartarates, borates, cansilates, citrates, cyclamates, edisylates, esylates, ethanesulfons, formates, fumarates, gluceptates, glucons, glucurons, hexafluorophosphates, hibenzates, hydrochlorides / chlorides, and bromides. Examples include hydrochlorides / bromids, hydroiodides / iodides, isethionates, lactates, malates, maleates, malons, mesilates, methanesulfons, methylsulfates, napsilates, 2-napsylates, nicotinates, nitrates, orotates, oxalates, palmitates, pamoates, phosphates / hydrogen phosphates / dihydrogen phosphates, pyroglutamates, sugarates, stearates, succinates, tannates, tartrates, p-toluenesulfons, tosilates, trifluoroacetates, and xinafoates.

[0035] Additional embodiments relate to 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 salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, diolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, allamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts.

[0036] The compounds described herein, which are essentially basic, can form a wide variety of salts having various inorganic and organic acids. The acids used to prepare pharmaceutically acceptable acid addition salts of the useful aforementioned compounds according to this embodiment are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidic phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acidic citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, sugarate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonic acid, and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)] salts. Compounds described herein that include a basic moiety such as an amino group may form pharmaceutically acceptable salts having various amino acids in addition to the acids mentioned above.

[0037] Chemical bases that can be used as reagents for preparing pharmaceutically acceptable base salts of compounds that are acidic among the compounds described herein are bases that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, base salts derived from 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-methylglucamine-(meglumine), as well as lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.

[0038] Hemi salts of acids and bases, such as hemisulfates and hemicalcium salts, can also be formed.

[0039] For suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by 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.

[0040] As used herein, the terms “subject” and “patient” are used interchangeably to refer to any animal, including mammals. Mammals as used herein include dogs, cats, cattle, goats, horses, sheep, pigs, rodents, rabbits, primates, and humans, and include mammals in utero. In embodiments, humans are preferred subjects. Human subjects may be of any sex and at any developmental stage.

[0041] When formulating compounds into tablets or other solid oral dosage forms, it is desirable to develop formulations that are storage stable at temperatures and relative humidity levels exceeding those typically encountered. Other desirable properties in the formulation may also be required, such as rapid dissolution, so that the tablets dissolve quickly and the drug becomes available for absorption. Therefore, good storage stability and rapid dissolution were particularly sought-after features as desirable characteristics of the present invention.

[0042] An active pharmaceutical ingredient (API) refers to the active ingredient contained in any drug. Any active ingredient is a substance that directly affects or targets a disease and is intended for use in manufacturing, and is known as an API. These substances are considered extremely important because they provide pharmacological activity and have direct effects in diagnosis, treatment, management, prevention, or because they affect the structure of the body.

[0043] In this specification, “oral dosage form” means a pharmaceutical product formulated in a specific form suitable for oral administration (such as an oral tablet, liquid, or capsule) and containing a predetermined amount (dose) of the disclosed compound as an active ingredient (API), or a pharmaceutically acceptable salt and / or solvate thereof, and further containing an inactive ingredient (excipient). In some embodiments, the oral dosage form includes a tablet. In some embodiments, the oral dosage form includes a tablet which may be scored. In some embodiments, the oral dosage form includes a sublingual tablet.

[0044] In this specification, “oral administration” means drugs administered enterally, buccally, sublabially, or sublingually, in the form of tablets, capsules, syrups, powders, granules, pastels, solutions, tinctures, elixirs, emulsions, hydrogels, teas, films, disintegrating tablets, mouthwashes, or other forms.

[0045] Drug solubility represents a crucial factor influencing the rate of systemic absorption. Various in vitro methods have been developed to evaluate the solubility properties of pharmaceutical formulations, and solubility tests may be used as an alternative to direct assessment of drug bioavailability. See, for example, Emmanuel et al., Pharmaceutics (2010), 2:351-63, and the references cited therein. A solubility test measures the percentage of the active ingredient (API) released from a formulation (e.g., a tablet) and dissolved in a dissolving medium under controlled test conditions over a defined period. To maintain sedimentation conditions, the saturation solubility of the drug in the dissolving medium should be at least three times the drug concentration. For poorly soluble compounds, solubility may be measured under non-sedimentation conditions. Solubility is influenced by the properties of the API (e.g., particle size, crystalline form, bulk density), the composition of the pharmaceutical product (e.g., drug load, excipients), the manufacturing process (e.g., compressive force), and stability under storage conditions (e.g., temperature, humidity).

[0046] Methods for evaluating the chemical storage stability of solid dosage forms under accelerated aging conditions are described in the literature. For example, see ST. Colgan, T. J. Watson, RD. Whipple, R. Nosal, J. V. Beaman, 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. Pharm Res 2007;24(4):780-90; and ST. Colgan, R. J. 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).

[0047] 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, in which case all excipients in the dosage form are pharmaceutically acceptable for use in an oral dosage form, or in other words, safe for ingestion. In some embodiments, the solid oral dosage form is a tablet.

[0048] Examples of 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, and pouches. The dosage form of the present invention is preferably in the form of a tablet containing a single-layer or double-layer tablet.

[0049] As used herein, the terms “unit dose” or “unit dosage” refer to a physically distinct unit containing a predetermined amount of the active ingredient calculated to produce a desired therapeutic effect. A unit dose or unit dosage may be in the form of a tablet, capsule, sachet, or the like, which is referred herein to as a unit dosage form.

[0050] As used herein, the term “fasting” is defined as follows: an administration state defined after fasting for at least 10 hours overnight (where zero calorie intake has occurred). The nasogastric tube for administration was washed with 10 mL of water. Food was given 2 hours after administration. Water may be drunk as desired.

[0051] As used herein, the term “feeding” is defined as: an administration state defined after at least 10 hours of overnight fasting (where zero calorie intake has occurred). Food was given 0.5 to 1 hour prior to administration. The gastric tube was washed with 10 mL of water. Water may be drunk as desired.

[0052] The term “dry granulation” refers to the process of mixing a bulk active product with at least one excipient. The mixture is then compressed or compacted to form a compressed material, or “compacted” material. This material may be broken down to form granules by grinding, pulverizing, or cutting into dry granulated particles. Optionally, the particles may be further processed. The grinding, pulverizing, or cutting process involves operations that reduce the size of the compressed material, such as by grinding or by other operations known to those skilled in the art.

[0053] As used herein, the expression "%w / w" means the weight percentage of an ingredient to the total weight of the composition. Where a composition is described for which a range is provided for multiple components, it is understood that the total amount of all listed components does not exceed 100%. Those skilled in the art can adjust the amounts within the specified range to achieve this objective.

[0054] Unless otherwise specified, as used herein, the term “solid dispersion” refers to a solid state comprising at least two components, one of which is substantially uniformly dispersed over the other. This includes solid or glassy solutions, i.e., the dispersion of components such that the composition is essentially chemically and physically homogeneous. In several embodiments, the first component is an API, and the second component is a matrix containing a polymer, with the API significantly uniformly dispersed within the matrix (polymer). The API may exist in an amorphous or microcrystalline dispersion form. Alternatively, the API may be available as a mixture of amorphous and crystalline forms. A solid dispersion may comprise two or more components. For example, two or more APIs may be dispersed within a matrix, and / or the matrix may contain two or more polymers. Solid dispersions may, but are not limited to, be physically classified as eutectic mixtures, solid solutions, glassy solutions, or suspensions, amorphous precipitates in glassy or crystalline carriers, complexes, complex formations, or combinations of different systems. Solid dispersions can be prepared using various techniques known to those skilled in the art, such as co-dissolving the active pharmaceutical ingredient and polymer in a solvent, followed by spray drying, spray solidification, evaporation, curing or microwave treatment, mixing and direct compression, mechanical mixing at high temperatures without melting, wet granulation, extrusion spheronization, melt fusion, or hot melt extrusion.

[0055] A mixture of compound A Compound A can be prepared according to the method disclosed in U.S. Patent No. 10,647,698, the whole thereof is incorporated herein.

[0056] A mixture comprising compound A, a polymer, and a surfactant is disclosed herein. In some embodiments, the mixture is a dispersion. In some embodiments, the mixture is a spray-dried dispersion.

[0057] In several embodiments, the polymer is hydroxypropyl methylcellulose (HPMC, also known as hypromellose), a hydroxypropyl methylcellulose derivative, polyvinylpyrrolidone copolymer, methacrylate copolymer, polyethylene glycol, or a polyethylene glycol derivative. HPMC may be further described by letters (e.g., E, K) and numbers (e.g., 3, 5, 15) indicating the viscosity and substitution chemistry of the polymer.

[0058] Examples of hydroxypropyl methylcellulose derivatives include organic acid esters of HPMC. Hydroxypropyl methylcellulose derivatives may be selected from the group consisting of, for example, methylcellulose hydroxypropyl succinate acetate (HPMCAS), methylcellulose hydroxypropyl phthalate (HPMCP), methylcellulose hydroxypropyl succinate (HPMCS), methylcellulose hydroxypropyl trimellitate (HPMCT), methylcellulose hydroxypropyl phthalate acetate (HPMCAP), and methylcellulose hydroxypropyl maleate acetate (HPMCAM).

[0059] "Polyvinylpyrrolidone copolymer," "vinylpyrrolidone copolymer," or "PVP copolymer" refers to a copolymer comprising vinylpyrrolidone with one or more other monomers such as acrylic monomer, styrene, or vinyl acetate. Polyvinylpyrrolidone vinyl acetate copolymer and copovidone (a copolymer of vinylpyrrolidone and other vinyl derivatives) are exemplary polyvinylpyrrolidone copolymers and are commercially available from numerous sources. In several embodiments, polyvinylpyrrolidone copolymers have 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 several embodiments, polyvinylpyrrolidone copolymers have an average molecular weight of about 1,000 daltons to about 150,000 daltons. In several embodiments, the polyvinylpyrrolidone copolymer has an average molecular weight of about 10,000 daltons to about 150,000 daltons. In several embodiments, the polyvinylpyrrolidone copolymer has an average molecular weight of about 50,000 daltons to about 150,000 daltons. In several embodiments, the PVP copolymer is a polyvinylpyrrolidone vinyl acetate copolymer.

[0060] "Polyvinylpyrrolidone vinyl acetate copolymer," "polyvinylpyrrolidone copolymer," "vinyl acetate," and "PVPVA" refer to a class of vinylpyrrolidone and vinyl acetate copolymers having various weight percentage ratios of vinylpyrrolidone and vinyl acetate, such as approximately 30:70 to approximately 70:30, including approximately 30:70, approximately 35:65, approximately 50:50, approximately 60:40, and approximately 70:30. The weight percentage ratio of vinylpyrrolidone to vinyl acetate can result in different properties of the copolymer, including the glass transition temperature. Polyvinylpyrrolidone vinyl acetate copolymer is an exemplary pharmaceutically acceptable polymer and thermoplastic polymer. Polyvinylpyrrolidone vinyl acetate copolymer is commercially available from numerous sources.

[0061] The term "methacrylic acid copolymer" refers to a class of polymer compounds described by the following formula: [ka] In the formula, R1 is an alkyl group, R2 is a carboxylic acid, and R3 is H. In several embodiments, the methacrylic acid copolymer is Eudragit® methacrylic acid copolymer.

[0062] The term "Eudragit® methacrylic acid copolymer" is used in its conventional sense to refer to copolymers derived from esters of acrylic acid and methacrylic acid. In some embodiments, the Eudragit® polymer may be a methacrylic acid copolymer (e.g., having a carboxylic acid functional group). In some embodiments, the Eudragit® polymer is a methacrylic acid Eudragit® polymer such as Eudragit® L100 or Eudragit® L100-55. Eudragit® polymers are commercially available.

[0063] In several embodiments, the surfactant is selected from polyethylene glycol, polyethylene glycol esters, glycerol esters, and mixtures thereof. In several embodiments, the surfactant is a vitamin E ester of polyethylene glycol. In several embodiments, the surfactant is d-α-tocopheryl polyethylene glycol succinate (i.e., vitamin E TPGS). In several embodiments, the surfactant is d-α-tocopheryl polyethylene glycol 1000 succinate.

[0064] In several embodiments, the mixture (e.g., a dispersion (e.g., a spray-dried dispersion)) comprises compound A, hydroxypropyl methylcellulose, and d-α-tocopheryl polyethylene glycol succinate.

[0065] In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains about 20% (w / w) to about 60% (w / w) of compound A. In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains about 30% (w / w) to about 50% (w / w) of compound A. In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains about 35% (w / w) to about 45% (w / w) of compound A. In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains 20% (w / w) to 60% (w / w) of compound A. In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains 30% (w / w) to 50% (w / w) of compound A. In several embodiments, the mixture (e.g., a dispersion (e.g., a spray-dried dispersion)) contains 35% (w / w) to 45% (w / w) of compound A.

[0066] In several embodiments, the mixture (e.g., a dispersion (e.g., a spray-dried dispersion)) contains compound A in amounts of 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).

[0067] In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains about 50% (w / w) to about 90% (w / w) of compound A. In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains about 60% (w / w) to about 80% (w / w) of compound A. In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains about 65% (w / w) to about 75% (w / w) of compound A. In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains 50% (w / w) to 90% (w / w) of compound A. In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains 60% (w / w) to 80% (w / w) of compound A. In several embodiments, the mixture (e.g., a dispersion (e.g., a spray-dried dispersion)) contains 65% (w / w) to 75% (w / w) of compound A.

[0068] In several embodiments, the mixture (e.g., a dispersion (e.g., a spray-dried dispersion)) contains compound A in amounts of 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).

[0069] In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains about 35% (w / w) to about 75% (w / w) of polymer. In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains about 45% (w / w) to about 65% (w / w) of polymer. In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains about 40% (w / w) to about 50% (w / w) of polymer. In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains 35% (w / w) to 75% (w / w) of polymer. In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains 45% (w / w) to 65% (w / w) of polymer. In several embodiments, the mixture (e.g., a dispersion (e.g., a spray-dried dispersion)) contains 40% (w / w) to 50% (w / w) of the polymer.

[0070] In several embodiments, the mixture (e.g., a dispersion (e.g., a spray-dried dispersion)) contains 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 the polymer.

[0071] In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains about 10% (w / w) to about 40% (w / w) of polymer. In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains about 15% (w / w) to about 35% (w / w) of polymer. In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains about 20% (w / w) to about 30% (w / w) of polymer. In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains 10% (w / w) to 40% (w / w) of polymer. In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains 15% (w / w) to 35% (w / w) of polymer. In several embodiments, the mixture (e.g., a dispersion (e.g., a spray-dried dispersion)) contains 20% (w / w) to 30% (w / w) of the polymer.

[0072] In several embodiments, the mixture (e.g., a dispersion (e.g., a spray-dried dispersion)) contains 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 the polymer.

[0073] In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains about 35% (w / w) to about 75% (w / w) of hydroxypropyl methylcellulose. In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains about 45% (w / w) to about 65% (w / w) of hydroxypropyl methylcellulose. In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains about 40% (w / w) to about 50% (w / w) of hydroxypropyl methylcellulose. In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains 35% (w / w) to 75% (w / w) of hydroxypropyl methylcellulose. In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains 45% (w / w) to 65% (w / w) of hydroxypropyl methylcellulose. In several embodiments, the mixture (e.g., a dispersion (e.g., a spray-dried dispersion)) contains 40% (w / w) to 50% (w / w) hydroxypropyl methylcellulose.

[0074] In several embodiments, the mixture (e.g., a dispersion (e.g., a 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.

[0075] In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains about 10% (w / w) to about 40% (w / w) of hydroxypropyl methylcellulose. In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains about 15% (w / w) to about 35% (w / w) of hydroxypropyl methylcellulose. In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains about 20% (w / w) to about 30% (w / w) of hydroxypropyl methylcellulose. In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains 10% (w / w) to 40% (w / w) of hydroxypropyl methylcellulose. In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains 15% (w / w) to 35% (w / w) of hydroxypropyl methylcellulose. In several embodiments, the mixture (e.g., a dispersion (e.g., a spray-dried dispersion)) contains 20% (w / w) to 30% (w / w) hydroxypropyl methylcellulose.

[0076] In several embodiments, the mixture (e.g., a dispersion (e.g., a spray-dried dispersion)) contains 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.

[0077] In several embodiments, the mixture (e.g., dispersion (e.g., spray-dried dispersion)) contains about 1% (w / w) to about 10% (w / w) of surfactant. In several embodiments, the mixture contains about 3% (w / w) to about 8% (w / w) of surfactant. In several embodiments, the mixture contains about 4% (w / w) to about 6% (w / w) of surfactant. In several embodiments, the mixture contains 1% (w / w) to 10% (w / w) of surfactant. In several embodiments, the mixture contains 3% (w / w) to 8% (w / w) of surfactant. In several embodiments, the mixture contains 4% (w / w) to 6% (w / w) of surfactant.

[0078] In several embodiments, the mixture (e.g., a dispersion (e.g., a 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 surfactant.

[0079] In several embodiments, the mixture contains about 1% (w / w) to about 10% (w / w) of d-α-tocopheryl polyethylene glycol succinate. In several embodiments, the mixture contains about 3% (w / w) to about 8% (w / w) of d-α-tocopheryl polyethylene glycol succinate. In several embodiments, the mixture contains about 4% (w / w) to about 6% (w / w) of d-α-tocopheryl polyethylene glycol succinate. In several embodiments, the mixture contains 1% (w / w) to 10% (w / w) of d-α-tocopheryl polyethylene glycol succinate. In several embodiments, the mixture contains 3% (w / w) to 8% (w / w) of d-α-tocopheryl polyethylene glycol succinate. In several embodiments, the mixture contains 4% (w / w) to 6% (w / w) of d-α-tocopheryl polyethylene glycol succinate.

[0080] In several embodiments, the mixture (e.g., a dispersion (e.g., a 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-tocopheryl polyethylene glycol succinate.

[0081] In several embodiments, the mixture (e.g., a dispersion (e.g., a spray-dried dispersion)) is Compound A is present in a concentration of approximately 20% (w / w) to approximately 60% (w / w). Polymers of approximately 35% (w / w) to approximately 75% (w / w), Contains approximately 1% (w / w) to 10% (w / w) of surfactants.

[0082] In several embodiments, the mixture (e.g., a dispersion (e.g., a spray-dried dispersion)) is Compound A is approximately 40% (w / w). Approximately 55% (w / w) polymer, Contains approximately 5% (w / w) surfactant.

[0083] In some embodiments, the mixture (e.g., a dispersion (e.g., a spray-dried dispersion)) is Compound A is approximately 50% to 90% (w / w). Approximately 10% to 40% (w / w) of polymer, Contains approximately 1% to 10% (w / w) of surfactants.

[0084] In several embodiments, the mixture (e.g., a dispersion (e.g., a spray-dried dispersion)) is Compound A is approximately 70% (w / w). Approximately 25% (w / w) polymer, and Contains approximately 5% (w / w) surfactant.

[0085] In several embodiments, the mixture (e.g., a dispersion (e.g., a spray-dried dispersion)) is Compound A is present in a concentration of approximately 20% (w / w) to approximately 60% (w / w). Approximately 35% (w / w) to approximately 75% (w / w) hydroxypropyl methylcellulose, Contains approximately 1% (w / w) to approximately 10% (w / w) of d-α-tocopheryl polyethylene glycol succinate.

[0086] In several embodiments, the mixture (e.g., a dispersion (e.g., a spray-dried dispersion)) is Compound A is approximately 40% (w / w). Approximately 55% (w / w) hydroxypropyl methylcellulose, and Contains approximately 5% (w / w) of d-α-tocopheryl polyethylene glycol succinate.

[0087] In some embodiments, the mixture (e.g., a dispersion (e.g., a spray-dried dispersion)) is Compound A is approximately 50% to 90% (w / w). Approximately 10% to 40% (w / w) hydroxypropyl methylcellulose, Contains approximately 1% to 10% (w / w) of d-α-tocopheryl polyethylene glycol succinate.

[0088] In several embodiments, the mixture (e.g., a dispersion (e.g., a spray-dried dispersion)) is Compound A is approximately 70% (w / w). Approximately 25% (w / w) hydroxypropyl methylcellulose, Contains approximately 5% (w / w) of d-α-tocopheryl polyethylene glycol succinate.

[0089] In several embodiments, the mixture (e.g., a dispersion (e.g., a spray-dried dispersion)) comprises compound A in an amorphous form. In several embodiments, the mixture (e.g., a spray-dried dispersion) comprises a dispersion of amorphous compound A, hydroxypropyl methylcellulose, and d-α-tocopheryl polyethylene glycol succinate.

[0090] Method for preparing a dispersion of compound A In some embodiments, the mixture of compound A is in the form of a dispersion. In some embodiments, the dispersion is a solid dispersion.

[0091] In several embodiments, the dispersion is prepared by spray drying, freeze-drying, hot-melt extrusion, grinding, solvent evaporation, supercritical fluid treatment, or high-shear mixing. Spray drying is preferred for the preparation of the dispersion.

[0092] In several embodiments, the dispersion (e.g., a spray-dried dispersion) comprises compound A, a polymer, and a surfactant. In several embodiments, the dispersion (e.g., a spray-dried dispersion) comprises compound A, d-α-tocopheryl polyethylene glycol succinate, and hydroxypropyl methylcellulose.

[0093] In several embodiments, methods for preparing a dispersion (e.g., a spray-dried dispersion) containing compound A disclosed herein are disclosed herein. In several embodiments, the method is as follows: To obtain a solution containing compound A by dissolving compound A, a polymer, and a surfactant in a solvent. Introducing a solution containing compound A into a spray dryer. The process involves spraying a solution containing the compound from a spray dryer to form a dispersion of compound A (e.g., a spray-dried dispersion), and Depending on the circumstances, this may include removing the residual solvent from a dispersion of compound A (e.g., a spray-dried dispersion).

[0094] The solvent may be a single organic solvent or a mixture of organic solvents. For example, in several embodiments, the solvent is dichloromethane, methanol, or a combination thereof. In some embodiments, the solvent is dichloromethane. Alternatively, the solvent is methanol. In several embodiments, 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 several embodiments, the ratio of dichloromethane to methanol is about 90:10 (w / w) to about 50:50 (w / w). In several embodiments, the ratio of dichloromethane to methanol is about 90:10 (w / w) to about 70:30 (w / w). In several embodiments, the ratio of dichloromethane to methanol is about 85:15 (w / w) to about 75:25 (w / w). In several embodiments, the ratio of dichloromethane to methanol is 90:10 (w / w) to 70:30 (w / w). In several embodiments, the ratio of dichloromethane to methanol is 85:15 (w / w) to 75:25 (w / w). In several embodiments, 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).

[0095] In several embodiments, the step of removing residual solvent is achieved by drying. In several embodiments, drying is achieved by convection drying, tray drying, filter drying, tumble drying, agitated cone drying, or fluidized bed drying. In several embodiments, drying is achieved by agitated cone drying.

[0096] Dosage form of compound A In several embodiments, the dosage form of compound A is a solid oral dosage form. In several embodiments, the solid oral dosage form is a tablet, sachet, or capsule. In several embodiments, the solid oral dosage form is a tablet.

[0097] Forms suitable for oral administration may include one or more pharmaceutically acceptable excipients, such as carriers, fillers, surfactants, diluents, sweeteners, disintegrants, binders, lubricants, flow enhancers, colorants, flavorings, stabilizers, coatings, or any mixture thereof.

[0098] Carriers include, but are not limited to, pharmaceutically acceptable excipients and diluents, and refer to materials, compositions, or vehicles such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials that are involved in the transport or delivery of pharmaceuticals from one organ or part of the body to another. Examples include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

[0099] Examples of 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 disintegrating carbohydrates such as Pharmaburst® tablets, and mixtures thereof. For an example of rapidly disintegrating carbohydrates, see, for example, U.S. Patent No. 8,617,588, incorporated herein by reference.

[0100] Examples of surfactants include, but are not limited to, nonionic, anionic, cationic, amphoteric, or zwitterionic surfactants. Suitable nonionic surfactants include ethoxylated triglycerides, fatty alcohol ethoxylates, alkylphenol ethoxylates, fatty acid ethoxylates, fatty amide ethoxylates, fatty amine ethoxylates, sorbitan alkanoates, ethylated sorbitan alkanoates, alkyl ethoxylates, Pluronics®, alkyl polyglucosides, stearol ethoxylates, and alkyl polyglycosides. Suitable anionic surfactants include alkyl ether sulfates, alkyl ether carboxylates, alkylbenzene sulfons, alkyl ether phosphates, dialkyl sulfosuccinates, sarcosinates, alkyl sulfons, soaps, alkyl sulfates, alkyl carboxylates, alkyl phosphates, paraffin sulfons, secondary n-alkane sulfons, alpha-olefin sulfons, and isethionate sulfons. Suitable cationic surfactants include fatty amine salts, fatty diamine salts, quaternary ammonium compounds, phosphonium surfactants, sulfonium surfactants, and sulfoxynium surfactants. Suitable zwitterionic surfactants include N-alkyl derivatives of amino acids (such as glycine, betaine, and aminopropionic acid), imidazoline surfactants, amine oxides, and 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 doxate (e.g., AOT), sodium lauryl sulfate, and poloxamers (e.g., poloxamer 407, Kolliphor® EL, Pluronic F68). Poloxamers are also known by the trademark names Synperonics®, Pluronics®, and Kolliphor® / Cremophor®.

[0101] Examples of diluents include, but are not limited to, carbohydrates such as monosaccharides like glucose, oligosaccharides such as sucrose and lactose (including anhydrous lactose and lactose monohydrate), starches such as corn starch, potato starch, rice starch, and wheat starch, and pregelatinized starch, calcium hydrogen phosphate, and sugar alcohols such as sorbitol, mannitol, erythritol, and xylitol.

[0102] Examples of 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-based sweeteners.

[0103] Examples of disintegrants include, but are not limited to, sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium croscarmellose, crospovidone, chitosan, agar, alginic acid, calcium alginate, methylcellulose, microcrystalline cellulose, powdered cellulose, lower alkyl-substituted hydroxypropylcellulose, hydroxypropyl starch, low-substituted hydroxypropylcellulose, potassium polariphosphate, starch, pregelatinized starch, sodium alginate, magnesium aluminum silicate, potassium polariphosphate, povidone, sodium starch glycolate, and any mixtures thereof.

[0104] Examples of binders include, but are not limited to, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), povidone, copovidone, methylcellulose, powdered acacia, gelatin, gum arabic, guar gum, carbomers such as Carbopol, and polymethacrylates.

[0105] Examples of lubricants include, but are not limited to, calcium stearate, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, hexagonal boron nitride, hydrogenated vegetable oil, diesel fuel, magnesium stearate, mineral oil, polyethylene glycol, poloxamer, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate, and any mixture thereof.

[0106] Examples of fluidity enhancers include, but are not limited to, silicon dioxide, colloidal silicon dioxide, calcium silicate, magnesium silicate, magnesium trisilicate, talc, starch, and mixtures thereof.

[0107] Flavoring agents include, but are not limited to, menthol, peppermint oil, peppermint spirit, vanillin, and almond oil.

[0108] In several embodiments, the amount of compound A in a solid oral dosage form (e.g., a tablet) is about 5 mg to about 1000 mg. In several embodiments, the amount of compound A in a solid oral dosage form (e.g., a tablet) is about 5 mg to about 500 mg. In several embodiments, the amount of compound A in a solid oral dosage form (e.g., a tablet) is about 5 mg to about 250 mg. In several embodiments, the amount of compound A in a solid oral dosage form (e.g., a tablet) is about 25 mg to about 250 mg. In several embodiments, the amount of compound A in a solid oral dosage form (e.g., a tablet) is about 25 mg to about 200 mg. In several embodiments, the amount of compound A in a solid oral dosage form (e.g., a tablet) is about 25 mg to about 150 mg. In several embodiments, the amount of compound A in a solid oral dosage form (e.g., a tablet) is about 50 mg to about 150 mg. In several embodiments, the amount of compound A in a solid oral dosage form (e.g., a tablet) is about 75 mg to about 125 mg. In several embodiments, the amount of compound A in a solid oral dosage form (e.g., a tablet) is about 5 mg to about 50 mg. In several embodiments, the amount of compound A in a solid oral dosage form (e.g., a tablet) is about 30 mg to about 40 mg. In several embodiments, the amount of compound A in a solid oral dosage form (e.g., a tablet) is about 65 mg to about 70 mg. In several embodiments, the amount of compound A in a solid oral dosage form (e.g., a tablet) is about 100 mg to about 110 mg. In several embodiments, the amount of compound A in a solid oral dosage form (e.g., a tablet) is about 135 mg to about 145 mg. In several embodiments, the amount of compound A in a solid oral dosage form (e.g., a tablet) is about 75 mg to about 300 mg. In several embodiments, the amount of compound A in a solid oral dosage form (e.g., a tablet) is about 100 mg to about 300 mg. In several embodiments, the amount of compound A in a solid oral dosage form (e.g., a tablet) is approximately 100 mg to approximately 250 mg.

[0109] In several embodiments, the amount of compound A in a solid oral dosage form (e.g., a tablet) is approximately 5 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, approximately 50 mg, approximately 55 mg, approximately 60 mg, approximately 65 mg, approximately 70 mg, approximately 75 mg, approximately 80 mg, approximately 85 mg, approximately 90 mg, approximately 95 mg, approximately 100 mg, approximately 105 mg, approximately 110 mg, approximately 115 mg, approximately 120 mg, approximately 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170, about 175mg, about 180mg, about 185mg, about 19 0mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255 mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320 mg, about 325mg, about 330mg, about 335mg, about 340mg, about 345mg, about 350mg, about 355mg, about 360mg, about 365mg, about 370mg, about 375mg, about 380mg, about 385m g, approximately 390 mg, approximately 395 mg, approximately 400 mg, approximately 405 mg, approximately 410 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.

[0110] In several embodiments, the solid oral dosage form (e.g., tablet) is 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, 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, Approximately 2.6% 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%w / w, approximately 40.0%w / w, approximately 40.5%w / w, approximately 41.0%w / w, approximately 4 Contains compound A in amounts of 1.5% 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.

[0111] In several embodiments, the solid oral dosage form (e.g., tablet) contains approximately 1% w / w to approximately 5% w / w of compound A, approximately 2.5% w / w to approximately 7.5% w / w of compound A, approximately 10% w / w to approximately 15% w / w of compound A, approximately 12.5% ​​w / w to approximately 17.5% w / w of compound A, approximately 15% w / w to approximately 20% w / w of compound A, approximately 17.5% w / w to approximately 22.5% w / w of compound A, approximately 20% w / w to approximately 25% w / w of compound A, approximately 22.5% w / w to approximately 27.5% w / w of compound A, approximately 25% w / w to approximately 30% w / w of compound A, and approximately 27 Contains compound A in the following concentrations: 0.5% w / w to approximately 32.5% w / w, compound A in the following concentrations: approximately 30% w / w to approximately 35% w / w, compound A in the following concentrations: approximately 32.5% w / w to approximately 37.5% w / w, compound A in the following concentrations: approximately 35% w / w to approximately 40% w / w, compound A in the following concentrations: approximately 37.5% w / w to approximately 42.5% w / w, compound A in the following concentrations: approximately 40% w / w to approximately 45% w / w, compound A in the following concentrations: approximately 42.5% w / w to approximately 47.5% w / w, compound A in the following concentrations: approximately 45% to approximately 50% w / w, compound A in the following concentrations: approximately 47.5% w / w to approximately 52.5% w / w, or compound A in the following concentrations: approximately 50% w / w to approximately 55% w / w.

[0112] In several embodiments, the solid oral dosage form (e.g., tablet) is compound A at 1% w / w to 5% w / w, compound A at 2.5% w / w to 7.5% w / w, compound A at 10% to 15% w / w, compound A at 12.5% ​​w / w to 17.5% w / w, compound A at 15% w / w to 20% w / w, compound A at 17.5% w / w to 22.5% w / w, compound A at 20% w / w to 25% w / w, compound A at 22.5% w / w to 27.5% w / w, compound A at 25% w / w to 30% w / w, and 27. This includes compound A at 5% w / w to 32.5% w / w, compound A at 30% w / w to 35% w / w, compound A at 32.5% w / w to 37.5% w / w, compound A at 35% w / w to 40% w / w, compound A at 37.5% w / w to 42.5% w / w, compound A at 40% w / w to 45% w / w, compound A at 42.5% w / w to 47.5% w / w, compound A at 45% w / w to 50% w / w, compound A at 47.5% w / w to 52.5% w / w, and compound A at 50% w / w to 55% w / w.

[0113] In several embodiments, the solid oral dosage form (e.g., a tablet) comprises about 40% w / w to about 70% w / w of the mixture disclosed herein (e.g., a solid dispersion). In several embodiments, the solid oral dosage form (e.g., a tablet) comprises about 40% w / w to about 60% w / w of the mixture disclosed herein (e.g., a solid dispersion). In several embodiments, the solid oral dosage form (e.g., a tablet) comprises about 45% w / w to about 55% w / w of the mixture disclosed herein (e.g., a solid dispersion). In several embodiments, the solid oral dosage form (e.g., a tablet) comprises about 55% w / w to about 65% w / w of the mixture disclosed herein (e.g., a solid dispersion).

[0114] In several embodiments, the solid oral dosage form (e.g., a tablet) comprises 40% w / w to 70% w / w of the mixture disclosed herein (e.g., a solid dispersion). In several embodiments, the solid oral dosage form (e.g., a tablet) comprises 40% w / w to 60% w / w of the mixture disclosed herein (e.g., a solid dispersion). In several embodiments, the solid oral dosage form (e.g., a tablet) comprises 45% w / w to 55% w / w of the mixture disclosed herein (e.g., a solid dispersion). In several embodiments, the solid oral dosage form (e.g., a tablet) comprises 55% w / w to 65% w / w of the mixture disclosed herein (e.g., a solid dispersion).

[0115] In some embodiments, the solid oral dosage form (e.g., a tablet) is: A mixture disclosed herein (e.g., a solid dispersion) containing approximately 40% to approximately 60% w / w Microcrystalline cellulose of approximately 10% to 40% w / w, Approximately 5% to 15% w / w lactose monohydrate, Approximately 5% to 15% w / w croscarmellose sodium, Approximately 0% to approximately 5% w / w silicon dioxide, and Contains approximately 0% to 2% w / w sodium stearyl fumarate.

[0116] In some embodiments, the solid oral dosage form (e.g., a tablet) is: A mixture disclosed herein (e.g., a solid dispersion) containing 40% to 60% w / w Microcrystalline cellulose with a content of 10% to 40% w / w, 5%~15% w / w lactose monohydrate, 5%~15% w / w croscarmellose sodium, 0%~5% w / w silicon dioxide, and Contains 0% to 2% w / w sodium stearyl fumarate.

[0117] In some embodiments, the solid oral dosage form (e.g., a tablet) is: A mixture disclosed herein (e.g., a solid dispersion) containing approximately 40% to approximately 70% w / w Microcrystalline cellulose of approximately 10% to 40% w / w, Approximately 5% to 15% w / w lactose monohydrate, Approximately 5% to 15% w / w croscarmellose sodium, Approximately 0% to approximately 5% w / w silicon dioxide, and Contains approximately 0% to 2% w / w sodium stearyl fumarate.

[0118] In some embodiments, the solid oral dosage form (e.g., a tablet) is: A mixture disclosed herein (e.g., a solid dispersion) containing 40% to 70% w / w Microcrystalline cellulose with a content of 10% to 40% w / w, 5%~15% w / w lactose monohydrate, 5%~15% w / w croscarmellose sodium, 0-5% w / w silicon dioxide, and Contains 0% to 2% w / w sodium stearyl fumarate.

[0119] In some embodiments, the solid oral dosage form (e.g., a tablet) is: A mixture of the compounds disclosed herein (e.g., a solid dispersion) containing approximately 45% to approximately 55% w / w of compound A / HPMC / TPGS (e.g., a solid dispersion) in a ratio of approximately 40:55:5 (w / w) Microcrystalline cellulose of approximately 10% to 40% w / w, Approximately 5% to 15% w / w lactose monohydrate, Approximately 5% to 15% w / w croscarmellose sodium, Approximately 0% to approximately 5% w / w silicon dioxide, and Contains approximately 0% to 2% w / w sodium stearyl fumarate.

[0120] In some embodiments, the solid oral dosage form (e.g., a tablet) is: A mixture disclosed herein containing 45% to 55% w / w of compound A / HPMC / TPGS (e.g., a solid dispersion) (e.g., a mixture containing compound A / HPMC / TPGS in a ratio of approximately 40:55:5 (w / w)), Microcrystalline cellulose with a content of 10% to 40% w / w, 5%~15% w / w lactose monohydrate, 5%~15% w / w croscarmellose sodium, 0-5% w / w silicon dioxide, and Contains 0% to 2% w / w sodium stearyl fumarate.

[0121] In some embodiments, the solid oral dosage form (e.g., a tablet) is: A mixture of the compounds disclosed herein (e.g., a solid dispersion) containing approximately 55% to approximately 65% ​​w / w of the compounds (e.g., a mixture containing compound A / HPMC / TPGS in a ratio of approximately 70:25:5 (w / w) (e.g., a solid dispersion)), Microcrystalline cellulose of approximately 10% to 40% w / w, Approximately 5% to 15% w / w lactose monohydrate, Approximately 5% to 15% w / w croscarmellose sodium, Approximately 0% to approximately 5% w / w silicon dioxide, and Contains approximately 0% to 2% w / w sodium stearyl fumarate.

[0122] In some embodiments, the solid oral dosage form (e.g., a tablet) is: A mixture of the compounds disclosed herein in a ratio of 55% to 65% w / w (e.g., a solid dispersion) (e.g., a mixture or dispersion containing about 70% by weight of compound A, preferably a mixture containing compound A / HPMC / TPGS in a ratio of about 70:25:5 (w / w) (e.g., a solid dispersion)), Microcrystalline cellulose with a content of 10% to 40% w / w, 5%~15% w / w lactose monohydrate, 5%~15% w / w croscarmellose sodium, 0%~5% w / w silicon dioxide, and Contains 0% to 2% w / w sodium stearyl fumarate.

[0123] In some embodiments, the solid oral dosage form (e.g., a tablet) is: A mixture of the compounds disclosed herein (e.g., a solid dispersion) containing about 50% w / w 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), Approximately 27% w / w microcrystalline cellulose, Approximately 9% w / w lactose monohydrate, Approximately 12% w / w croscarmellose sodium, Approximately 1% w / w silicon dioxide, and Contains approximately 1.5% w / w sodium stearyl fumarate.

[0124] In some embodiments, the solid oral dosage form (e.g., a tablet) is: Approximately 60% by weight of the mixture disclosed herein (e.g., a solid dispersion) (e.g., a mixture containing approximately 70% by weight of compound A (e.g., a solid dispersion), preferably a mixture containing compound A / HPMC / TPGS in a ratio of approximately 70:25:5 (w / w) (e.g., a solid dispersion)), Approximately 17% w / w microcrystalline cellulose, Approximately 8.8% w / w lactose monohydrate, Approximately 12% w / w croscarmellose sodium, Approximately 1% w / w silicon dioxide, and Contains approximately 1.5% w / w sodium stearyl fumarate.

[0125] In several embodiments, the solid oral dosage form (e.g., a tablet) comprises an internal granule portion and an external granule portion, and optionally includes a film coating. The granular portion is Compound A at approximately 42% w / w Approximately 14% w / w hydroxypropyl methylcellulose, Approximately 3% w / w d-α-tocopheryl polyethylene glycol succinate, Approximately 9% w / w microcrystalline cellulose, Approximately 9% w / w lactose monohydrate, Approximately 6% w / w croscarmellose sodium, Approximately 1% w / w silicon dioxide, and Contains approximately 0.75% w / w sodium stearyl fumarate. The outer part of the granules is Approximately 8% w / w microcrystalline cellulose, Approximately 6% w / w croscarmellose sodium, and Contains approximately 0.75% w / w sodium stearyl fumarate.

[0126] In several embodiments, the solid oral dosage form (e.g., a tablet) comprises an internal granule portion and an external granule portion, and optionally includes a film coating. The granular portion is A mixture disclosed herein (e.g., a solid dispersion) containing approximately 40% to approximately 70% w / w Microcrystalline cellulose of approximately 5% to 10% w / w, Approximately 5% to 10% w / w lactose monohydrate, Approximately 1% to approximately 10% w / w croscarmellose sodium, Approximately 0% to approximately 5% w / w silicon dioxide, and Contains approximately 0% to 2% w / w sodium stearyl fumarate. The outer part of the granules is Microcrystalline cellulose of approximately 5% to 25% w / w, Croscarmellose sodium in an amount of approximately 0% to approximately 10% w / w, and Contains approximately 0% to 2% w / w sodium stearyl fumarate.

[0127] In several embodiments, the solid oral dosage form (e.g., a tablet) comprises an internal granule portion and an external granule portion, and optionally includes a film coating. The granular portion is A mixture disclosed herein (e.g., a solid dispersion) containing 40% to 70% w / w 5%~10% w / w microcrystalline cellulose, 5%~10% w / w lactose monohydrate, 1%~10% w / w croscarmellose sodium, 0%~5% w / w silicon dioxide, and Contains 0% to 2% w / w sodium stearyl fumarate. The outer part of the granules is 5%~25% w / w microcrystalline cellulose, Croscarmellose sodium in a 0% to 10% w / w concentration, and Contains 0% to 2% w / w sodium stearyl fumarate.

[0128] In several embodiments, the solid oral dosage form (e.g., a tablet) comprises an internal granule portion and an external granule portion, and optionally includes a film coating. The granular portion is A mixture disclosed herein (e.g., a solid dispersion) containing approximately 40% to approximately 60% w / w Microcrystalline cellulose of approximately 5% to 10% w / w, Approximately 5% to 10% w / w lactose monohydrate, Approximately 1% to approximately 10% w / w croscarmellose sodium, Approximately 0% to approximately 5% w / w silicon dioxide, and Contains approximately 0% to 2% w / w sodium stearyl fumarate. The outer part of the granules is Microcrystalline cellulose of approximately 5% to 25% w / w, Croscarmellose sodium in an amount of approximately 0% to approximately 10% w / w, and Contains approximately 0% to 2% w / w sodium stearyl fumarate.

[0129] In several embodiments, the solid oral dosage form (e.g., a tablet) comprises an internal granule portion and an external granule portion, and optionally includes a film coating. The granular portion is Mixtures and / or solid dispersions disclosed herein in a concentration of 40% to 60% w / w, 5%~10% w / w microcrystalline cellulose, 5%~10% w / w lactose monohydrate, 1%~10% w / w croscarmellose sodium, 0%~5% w / w silicon dioxide, and Contains 0% to 2% w / w sodium stearyl fumarate. The outer part of the granules is 5%~25% w / w microcrystalline cellulose, Croscarmellose sodium in a 0% to 10% w / w concentration, and Contains 0% to 2% w / w sodium stearyl fumarate.

[0130] In some embodiments, the solid oral dosage form (e.g., a tablet) comprises an internal granule portion and an external granule portion, and optionally includes a film coating. The granular portion is A mixture of the compounds disclosed herein (e.g., a solid dispersion) containing about 50% w / w 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), Approximately 8% w / w microcrystalline cellulose, Approximately 9% w / w lactose monohydrate, Approximately 6% w / w croscarmellose sodium, Approximately 1% w / w silicon dioxide, and Contains approximately 0.75% w / w sodium stearyl fumarate. The outer part of the granules is Approximately 18% w / w microcrystalline cellulose, Approximately 6% w / w croscarmellose sodium, and Contains approximately 0.75% w / w sodium stearyl fumarate.

[0131] In several embodiments, the solid oral dosage form (e.g., a tablet) comprises an internal granule portion and an external granule portion, and optionally includes a film coating. The granular portion is Approximately 60% by weight of the mixture disclosed herein (e.g., a solid dispersion) (e.g., a mixture containing approximately 70% by weight of compound A (e.g., a solid dispersion), preferably a mixture containing compound A / HPMC / TPGS in a ratio of approximately 70:25:5 (w / w) (e.g., a solid dispersion)), Approximately 9% w / w microcrystalline cellulose, Approximately 9% w / w lactose monohydrate, Approximately 6% w / w croscarmellose sodium, Approximately 1% w / w silicon dioxide, and Contains approximately 0.75% w / w sodium stearyl fumarate. The outer part of the granules is Approximately 8% w / w microcrystalline cellulose, Approximately 6% w / w croscarmellose sodium, and Contains approximately 0.75% w / w sodium stearyl fumarate.

[0132] In some embodiments, the solid oral dosage form (e.g., a tablet) is: Compound A, approximately 15% w / w to approximately 50% w / w Approximately 10% w / w to approximately 40% w / w hydroxypropyl methylcellulose, Approximately 0.5% w / w to approximately 5% w / w of d-α-tocopheryl polyethylene glycol succinate, Microcrystalline cellulose of approximately 10% w / w to approximately 40% w / w, Lactose monohydrate at approximately 5% w / w to approximately 15% w / w, Croscarmellose sodium at approximately 5% w / w to approximately 15% w / w Approximately 0% w / w to approximately 5% w / w of silicon dioxide, and Contains approximately 0% w / w to approximately 2% w / w of sodium stearyl fumarate.

[0133] In some embodiments, the solid oral dosage form (e.g., a tablet) is: Compound A, 15%~50% w / w 10%~40% w / w hydroxypropyl methylcellulose, 0.5%~5% w / w d-α-tocopheryl polyethylene glycol succinate, Microcrystalline cellulose with a content of 10% to 40% w / w, 5%~15% w / w lactose monohydrate, 5%~15% w / w croscarmellose sodium, 0%~5% w / w silicon dioxide, and Contains 0% to 2% w / w sodium stearyl fumarate.

[0134] In some embodiments, the solid oral dosage form (e.g., a tablet) is: Compound A at approximately 20% w / w Approximately 28% w / w hydroxypropyl methylcellulose, Approximately 2.5% w / w of d-α-tocopheryl polyethylene glycol succinate, Approximately 27% w / w microcrystalline cellulose, Approximately 9% w / w lactose monohydrate, Approximately 12% w / w croscarmellose sodium, Approximately 1% w / w silicon dioxide, and Contains approximately 1.5% w / w sodium stearyl fumarate.

[0135] In some embodiments, the solid oral dosage form (e.g., a tablet) is: Compound A at approximately 42% w / w Approximately 15% w / w hydroxypropyl methylcellulose, Approximately 3% w / w d-α-tocopheryl polyethylene glycol succinate, Approximately 17% w / w microcrystalline cellulose, Approximately 8.8% w / w lactose monohydrate, Approximately 12% w / w croscarmellose sodium, Approximately 1% w / w silicon dioxide, and Contains approximately 1.5% w / w sodium stearyl fumarate.

[0136] In several embodiments, the solid oral dosage form (e.g., a tablet) comprises an internal granule portion and an external granule portion, and optionally includes a film coating. The granular portion is Compound A at approximately 15% to 50% w / w Approximately 10% to 40% w / w hydroxypropyl methylcellulose, Approximately 0.5% to approximately 5% w / w of d-α-tocopheryl polyethylene glycol succinate, Microcrystalline cellulose of approximately 5% to 10% w / w, Approximately 5% to 10% w / w lactose monohydrate, Approximately 1% to approximately 10% w / w croscarmellose sodium, Approximately 0% to approximately 5% w / w silicon dioxide, and Contains approximately 0% to 2% w / w sodium stearyl fumarate. The outer part of the granules is Microcrystalline cellulose of approximately 5% to 25% w / w, Croscarmellose sodium in an amount of approximately 0% to approximately 10% w / w, and Contains approximately 0% to 2% w / w sodium stearyl fumarate.

[0137] The weight percentage is relative to the total weight of the uncoated tablets. In several embodiments, the solid oral dosage form (e.g., a tablet) comprises an internal granule portion and an external granule portion, and optionally includes a film coating. The granular portion is Compound A at approximately 20% w / w Approximately 28% w / w hydroxypropyl methylcellulose, Approximately 2.5% w / w of d-α-tocopheryl polyethylene glycol succinate, Approximately 8% w / w microcrystalline cellulose, Approximately 9% w / w lactose monohydrate, Approximately 6% w / w croscarmellose sodium, Approximately 1% w / w silicon dioxide, and Contains approximately 0.75% w / w sodium stearyl fumarate. The outer part of the granules is Approximately 18% w / w microcrystalline cellulose, Approximately 6% w / w croscarmellose sodium, and Contains approximately 0.75% w / w sodium stearyl fumarate. The weight percentage is relative to the total weight of the uncoated tablets.

[0138] In several embodiments, the solid oral dosage form (e.g., a tablet) comprises an internal granule portion and an external granule portion, and optionally includes a film coating. The granular portion is Compound A at approximately 42% w / w Approximately 14% w / w hydroxypropyl methylcellulose, Approximately 3% w / w d-α-tocopheryl polyethylene glycol succinate, Approximately 9% w / w microcrystalline cellulose, Approximately 9% w / w lactose monohydrate, Approximately 6% w / w croscarmellose sodium, Approximately 1% w / w silicon dioxide, and Contains approximately 0.75% w / w sodium stearyl fumarate. The outer part of the granules is Approximately 8% w / w microcrystalline cellulose, Approximately 6% w / w croscarmellose sodium, and Contains approximately 0.75% w / w sodium stearyl fumarate. The weight percentage is relative to the total weight of the uncoated tablets.

[0139] Method for preparing the dosage form of compound A Solid dosage forms for oral administration may be formulated to be immediate-release and / or controlled-release. Controlled-release formulations include delayed-release, sustained-release, pulsed-release, controlled-release, targeted-release, and programmed-release formulations. For a general description of controlled-release formulations, see U.S. Patent No. 6,106,864.

[0140] Pharmaceuticals in the form of solid tablets are typically manufactured by compressing the materials that constitute the final product into the desired tablet form. These materials may include the active pharmaceutical ingredient as well as pharmaceutically inactive additives that impart the desired or useful properties to the product during and after the manufacturing process. Tablet hardness, or tensile strength, may be used as a measure of the tackiness of the tablet's components. If a tablet does not have sufficient tackiness, it may disintegrate during handling. The final formulation may contain one or more layers, may be coated, or may not be coated.

[0141] As is well known in the art, granulation is a process used to improve the handling and manufacturing properties of a pharmaceutical formulation, for example, by increasing the particle size to improve flow rate. Granulation does not substantially alter the physical form of the drug, such as its crystalline or amorphous nature. 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 may 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 involves a step of mixing the components of the dosage form.

[0142] Mixing the components of a dosage form to some extent is usually necessary to obtain a homogeneous and consistent final product. However, in the preparation of pharmaceutical tablets by wet and dry granulation, the degree and intensity of mixing of the components before compression have been found to be related to the loss of compressibility and tackiness of the formulation, resulting in a reduction in tablet hardness.

[0143] For example, similar results can be observed when roller compression is used in dry granulation. Roller compression can be used as a method for forming granules that are subsequently compressed into tablets. Roller compression can reduce the subsequent compressibility and stickiness of the dosage form.

[0144] Dry granulation is a process in which granules are formed by a compression process, and then the compressed material is sized into particles that can be easily processed. It is often used to improve fluidity and densify formulations, which can facilitate manufacturing processes such as tableting, encapsulation, and powder filling. Compressions are typically prepared directly from powder blends containing active ingredients and other excipients, including lubricants.

[0145] The use of dry granulation techniques may be preferable to wet granulation methods due to reduced processing time and cost advantages. However, dry granulation is generally limited to cases where the drug or active ingredient has physical properties suitable for forming pharmaceutically acceptable granules and dosage forms such as tablets.

[0146] It is generally necessary to add at least one excipient to a formulation, which increases the size of the final tablet. Since tablet size must be within certain parameters to function as a suitable dosage form, increasing the tablet size to increase the amount of excipient to improve suitability is impractical beyond a certain limit. As a result, manufacturers are often limited to using dry granulation for formulations with low amounts of active ingredient per formulation, as this allows for formulation designs that incorporate sufficient levels of excipients to make dry granulation practical.

[0147] In developing pharmaceutical dosage forms, it is crucial to balance several different objectives. It is important to prepare the drug dosage form as economically as possible. A simple manufacturing method involving several processing steps is desirable. The dosage form should also make the active compound contained within it optimally available to the patient. Furthermore, the dosage form should be easy to swallow. Smaller dosage forms may be better accepted by patients and potentially improve patient compliance.

[0148] The final pharmaceutical composition is processed into a unit dosage form (e.g., tablet or capsule) and then packaged for distribution. The processing steps vary depending on the specific unit dosage form. For example, tablets are generally compressed into the desired shape under pressure, while capsules use a simple filling operation. Those skilled in the art are familiar with the procedures used to mass-produce various single-dose dosage forms.

[0149] Tablets are typically formed by the pressure applied to the material being formed on a tablet press. The formulation must have good flow properties for accurate volume delivery of the material into the die cavity, as well as appropriate compressibility, conformability, and discharge properties for forming tablets.

[0150] There are several types of tablet presses, each with varying productivity, but their basic functions and operations are similar. All compress and form the tablet within a die cavity by the pressure applied between two steel punches, a lower die and an upper die. Tablet presses are typically designed with a hopper for holding and feeding the formulation, a feeding mechanism for supplying the formulation to the die cavity, and equipment for positioning the punches and dies. Rotary tablet presses also feature a cam track to guide the movement of the punches. Two types of tablet presses are single-station or single-punch presses and multi-station rotary presses. Some tablet presses offer longer residence times than others, allowing for enhanced bonding. Other presses may offer pre-pressure.

[0151] Wet granulation can also be employed to prepare granules 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. When using wet granulation, volatile agents may be incorporated into the mixture before, during, or after mixing of the components, but before the formation of granules. For example, a solid volatile agent can be mixed with the powder of the mixture before, during, or after the addition of the binder solution. Other solid dosage forms may be prepared using techniques including rotary bed granulation or spray-dried dispersion (SDD).

[0152] In several embodiments, a film coating is provided around a solid oral dosage form (e.g., a tablet) of compound A using a standard coating procedure, such as that described in Remingtons's Pharmaceutical Sciences, 20th Edition (2000). In several embodiments, some or all of the particles of the solid oral dosage form (e.g., a tablet) of compound A are coated. In embodiments where the 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.

[0153] Alternatively, some or all of the particles of the solid oral dosage form of compound A (e.g., a tablet) are microencapsulated. In some embodiments, the particles of the solid oral dosage form of compound A (e.g., a tablet) are not microencapsulated and are not coated.

[0154] Treatment method In several embodiments, methods for treating cancer in a subject are provided herein, comprising administering to the subject a solid oral dosage form containing an effective amount of compound A described herein.

[0155] The solid oral dosage form containing compound A may be administered alone or in combination with other agents, particularly CDK4 / 6 inhibitors (e.g., darpiciclib, trilaciclib, rerocyclib, AT7519M, dinaciclib, ribociclib, abemaciclib, or palbociclib, or pharmaceutically acceptable salts thereof).

[0156] As used herein, the term “combination” means, unless otherwise indicated, the use of compound A and one or more therapeutic agents, which are administered intermittently, concurrently, or over time, according to the same or different routes of administration and according to the same or different administration schedules.

[0157] As used herein, in relation to cancer, the term “locally advanced” may or may not be treated with curative intent. For example, locally advanced breast cancer (LABC) is defined by the National Comprehensive Cancer Information Network as a subset of breast cancers characterized by the absence of distant metastases and the most advanced breast tumors, the tumor being greater than 5 cm in size with regional lymphadenopathy, any size having direct expansion to the chest wall and / or skin (including ulceration or satellite nodules), regardless of regional lymphadenopathy, and regardless of tumor stage, the presence of regional lymphadenopathy (either clinically fixed or matted axillary lymph nodes or subclavian, supraclavicular, or internal mammary lymphadenopathy). (Garg et al. Curr Oncol. 2015 Oct; 22(5): e409-e410; National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology: Breast Cancer.Fort Washington, PA: NCCN; 2015. Ver. 2.2015.)

[0158] As used herein, the term “metastatic” is used in relation to cancer and therefore cannot be treated with the intention of curing. Metastatic breast cancer, or metastasis, refers to breast cancer that has spread beyond the breast and nearby lymph nodes to other parts of the body, such as the bones, liver, lungs, or brain (https: / / www.cancer.org / cancer / breast-cancer).

[0159] Those skilled in the art will be able to recognize and diagnose locally advanced and metastatic cancer in a patient or subject.

[0160] For convenience, certain well-known abbreviations may be used herein, 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).

[0161] In this embodiment, cancers include lung cancer, mesothelioma, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous melanoma or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, liver cancer, colon cancer, breast cancer, uterine cancer, malignant tumors of the fallopian tubes, malignant tumors of the endometrium, malignant tumors of the cervix, malignant tumors of the vagina, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, and parathyroid cancer. Cancers of the urethra, adrenal gland cancer, soft tissue sarcomas, urethral cancer, penile cancer, prostate cancer, hematological malignancies, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal cell carcinoma, malignancies of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, axial vertebral tumors, glioblastoma, brainstem glioma, pituitary adenoma, head and neck cancer, and any combination of two or more of the aforementioned cancers.

[0162] Furthermore, methods for treating cancer in a subject are disclosed herein. In some embodiments, the method comprises treating cancer in a subject, which comprises administering to the subject an amount of compound A described herein that is effective in treating cancer.

[0163] In multiple embodiments, the cancer is breast cancer, lung cancer, colon cancer, brain cancer, head and neck cancer, prostate cancer, gastric cancer, pancreatic cancer, ovarian cancer, melanoma, endocrine cancer, uterine cancer, testicular cancer, or bladder cancer.

[0164] In multiple embodiments, the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

[0165] In multiple embodiments, the cancer is breast cancer, lung cancer, or prostate cancer.

[0166] In multiple embodiments, the cancer is breast cancer.

[0167] In multiple embodiments, the breast cancer is metastatic breast cancer.

[0168] In an embodiment, the breast cancer is locally advanced breast cancer.

[0169] In multiple embodiments, the breast cancer is HR+ breast cancer.

[0170] In multiple embodiments, the HR+ breast cancer is PR+ and / or ER+ breast cancer.

[0171] In some embodiments, the breast cancer is PR+ breast cancer.

[0172] In multiple embodiments, the breast cancer is ER+ breast cancer.

[0173] In multiple embodiments, the breast cancer is ER+ HER2- breast cancer.

[0174] In multiple embodiments, the breast cancer is ER+ HER2+ breast cancer.

[0175] >In multiple embodiments, the breast cancer is locally advanced or metastatic ER+ breast cancer.

[0176] In several embodiments, the breast cancer is locally advanced or metastatic ER+ HER2- breast cancer.

[0177] In several embodiments, the breast cancer is locally advanced or metastatic, ER+ HER2+ breast cancer.

[0178] In several embodiments, the breast cancer is metastatic ER+ HER2- breast cancer.

[0179] In several embodiments, the breast cancer is locally advanced but metastatic ER+ HER2- breast cancer.

[0180] In several embodiments, the lung cancer is non-small cell lung cancer.

[0181] In several embodiments, the lung cancer is locally advanced or metastatic non-small cell lung cancer.

[0182] In several embodiments, prostate cancer is CRPC.

[0183] In several embodiments, the prostate cancer is metastatic or locally advanced CRPC.

[0184] Furthermore, this specification also discloses methods for treating solid tumors in a subject. In several embodiments, methods for treating solid tumors in a subject are disclosed, which include administering a subject an amount of compound A described herein that is effective for treating the solid tumor.

[0185] In several embodiments, the solid tumor 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.

[0186] In several embodiments, the solid tumor is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

[0187] In multiple embodiments, the solid tumor is breast cancer, lung cancer, or prostate cancer.

[0188] In multiple embodiments, the solid tumor is breast cancer. For example, in certain embodiments, the breast cancer is HR+ breast cancer. In other embodiments, the HR+ breast cancer is PR+ and / or ER+ breast cancer ER+ breast cancer.

[0189] In multiple embodiments, the solid tumor is breast cancer. For example, in certain embodiments, the breast cancer is ER+ HER2- breast cancer.

[0190] In multiple embodiments, the solid tumor is breast cancer. For example, in certain embodiments, the breast cancer is ER+ HER2+ breast cancer.

[0191] In multiple embodiments, the solid tumor is breast cancer. For example, in certain embodiments, the breast cancer is locally advanced or metastatic ER+ HER2- breast cancer.

[0192] In multiple embodiments, the solid tumor is breast cancer. For example, in certain embodiments, the breast cancer is locally advanced or metastatic ER+ HER2+ breast cancer.

[0193] In multiple embodiments, the solid tumor is lung cancer. For example, in certain embodiments, the lung cancer is non-small cell lung cancer.

[0194] In multiple embodiments, the solid tumor is lung cancer. For example, in certain embodiments, the lung cancer is locally advanced or metastatic non-small cell lung cancer.

[0195] In multiple embodiments, the solid tumor is prostate cancer. For example, in certain embodiments, the prostate cancer is CRPC.

[0196] In multiple embodiments, the solid tumor is prostate cancer. For example, in certain embodiments, the prostate cancer is locally advanced or metastatic castration-resistant prostate cancer.

[0197] Furthermore, methods for treating hematological malignancies in a subject are disclosed herein. In certain embodiments, the method comprises treating a hematological malignancy in a subject, and includes administering a subject an amount of compound A described herein that is effective for treating a hematological malignancy.

[0198] In several embodiments, the hematological malignancy is leukemia, lymphoma, or multiple myeloma.

[0199] In some embodiments, the hematological malignancy is leukemia or lymphoma.

[0200] Furthermore, this specification discloses methods for treating cancer in subjects with locally advanced or metastatic ER+HER2- breast cancer, CRPC, or NSCLC, where the disease is progressing with standard treatment or the disease is intolerant to standard treatment.

[0201] Furthermore, this specification discloses methods for treating cancer in subjects with locally advanced or metastatic ER+HER2- breast cancer, CRPC, or NSCLC, where the disease is progressing with standard treatment or the disease is intolerant to standard treatment.

[0202] Furthermore, methods for treating cancer in subjects with locally advanced or metastatic 2L+ ER+HER2 breast cancer who have previously received hormone / endocrine therapy and chemotherapy in a locally advanced / metastatic state are disclosed herein.

[0203] Furthermore, a method for treating cancer in subjects with locally advanced or metastatic 2L+ ER+ HER2 breast cancer who have previously received treatment with CDK4 / 6 inhibitors is disclosed herein. [Examples]

[0204] To better understand the present invention, the following examples are provided. These examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

[0205] Example 1. Preparation of 50 mg, 100 mg, 200 mg, and 250 mg tablets of compound A. Tablets of compound A in 50 mg, 100 mg, 200 mg, and 250 mg doses were produced using two different formulations, resulting in compound A drug loads of 20% and 42%, respectively. Compound A was also prepared in the form of 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.

[0206] The compositions of 50 mg, 100 mg, 200 mg, and 250 mg tablets of compound A as an SDD composed of compound A / HPMC E3 / vitamin E TPGS, and the composition of a 100 mg tablet of compound A as an SDD composed of a 40:55:5% w / w ratio are shown in Table 2 below. The materials used in the preparation of the spray-dried dispersion (SDD) are shown in Table 4 below.

[0207] Those skilled in the art of pharmaceutical manufacturing will understand that the values ​​provided in Tables 1-4 represent theoretical formulations of a single unit (QQ formula (Qua Que)). When a drug is scaled up to multiple units, the amount of each component is multiplied by the required number of units. Due to differences in balance accuracy and tolerances, slight discrepancies may occur in the QQ values ​​when calculated backward from the weights used in batch production. Furthermore, while certain limits are permissible for the weights supplied during manufacturing, these values ​​are the same as those in the QQ formula as a percentage of the measured weight. This is recognized within the industry and by regulatory authorities. [Table 1] [Table 2] [Table 3] [Table 4]

[0208] A stainless steel reactor was packed with dichloromethane and methanol under a nitrogen atmosphere. The mixture was stirred at a low speed vortex (25–100 rpm) and the temperature was maintained at 2–8°C (for the 70 / 25 / 5 dispersion) or 15–25°C (for the 40 / 55 / 5 dispersion). Vitamin E TPGS was added and the solution was stirred until no solids remained in the suspension. Methocel (i.e., HPMC) was added and the solution was stirred until no solids remained in the suspension. The temperature was adjusted to 15–25°C (for the 70 / 25 / 5 dispersion) and the solution was stirred for at least 30 minutes until a clear solution was achieved. Compound A was added, followed by the second packing of dichloromethane. For the 70 / 25 / 5 dispersion, the reactor temperature was adjusted to 2–8°C. The solution was stirred for at least 1 hour until it was substantially clear, and then spray-dried according to the parameters shown in Table 5 below. [Table 5]

[0209] The obtained solid was collected and transferred to a stainless steel double-cone dryer, where it was 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. [Table 6]

[0210] Once the desired solvent level was achieved, the jacket temperature was reduced to 20°C, and the product was cooled to 40°C.

[0211] Tablet manufacturing The granular materials were blended and compressed, mixed with the external excipients, and blended again. The resulting granules were compressed into 120 mg, 240 mg, 480 mg, 500 mg, or 600 mg tablets. The resulting tablets may be film-coated.

[0212] Example 2: Tests using amorphous and crystalline suspensions in dogs Fasted female dogs were orally administered compound A (7.5 mg / kg) in an aqueous suspension containing 0.5% Methocel A4M at a concentration of 2 mL / kg, as a spray-dried dispersion (SDD), pure amorphous API, or crystalline API. The animals were pre-treated with famotidine at 0.5 mg / kg IV one hour prior to compound A administration to raise gastric pH. One group of test animals was intramuscularly administered pentagastrin (6 μg / kg) one hour prior to administration of crystalline compound A as a low-gastric pH control. [Table 7]

[0213] The data from the PK test are shown in Table 7, Figure 1, and Table 8 below. [Table 8]

[0214] Exposure to crystalline substances was significantly reduced in animals with neutral gastric pH compared to values ​​achieved under more favorable acidic gastric pH conditions. However, amorphous polymer dispersions can compensate for the reduced crystalline solubility, as demonstrated by the high exposure levels observed when compound A is administered in such formulations. In fact, the exposure levels obtained with all polymer dispersions exceeded those obtained with crystalline free bases, even in pentagastrin-pretreated dogs. While we do not wish to be bound by theory, this suggests exposure levels limited by solubility or dissolution rate relative to the crystalline form. Pure amorphous compound A did not perform similarly to the polymer dispersions. Of the polymer dispersions, methylcellulose hydroxypropyl succinate acetate (HPMC) / vitamin E TPGS resulted in the highest exposure levels.

[0215] Example 3. Tests in dogs using amorphous and crystalline tablets. Table 7 shows the canine PK results for the suspension formulations described above. To confirm these results, 50 mg strength Compound A tablet prototypes were prepared on a laboratory scale. The formulation used consisted of Compound A: low viscosity E3 grade hydroxypropyl methylcellulose (HPMC E3LV): vitamin E TPGS (40:55:5) dispersion and crystalline active pharmaceutical ingredient (with or without an acidulant containing fumaric acid), prepared with the compositions shown in Table 8. The hypothesis was tested as to whether adding an acidulant (fumaric acid) to the tablet composition to reduce the pH of the microenvironment surrounding the crystalline drug particles improves bioavailability compared to crystalline drugs without an acidulant. [Table 9]

[0216] Female dogs were pre-treated with famotidine at a dose of 0.5 mg / kg IV one hour before administration of a single 50 mg tablet of compound A. The test animals were either fasted (then fed 4 hours after compound A administration) or fed (0.5 hours before administration).

[0217] The results for fasting test animals shown in Figures 2A to 2D indicate that exposure to size-reduced API was slightly improved by acidification of the microenvironment (using fumaric acid). See the comparison of Figure 2D to Figure 2B. It was also noted that increasing particle size did not affect exposure in the presence of acid. See the comparison of Figure 2D to Figure 2C. Overall, spray-dried dispersions in HPMC and TPGS provided the best exposure.

[0218] As shown in Figures 3A to 3D, the results for the feeding test animals showed approximately a three-fold increase in exposure for all formulations compared to the fasted control group. Similar to the fasted control group, the spray-dried dispersions in HPMC and TPGS resulted in the best exposure.

Claims

1. Compound A: 【Chemistry 1】 A solid oral dosage form comprising a pharmaceutically acceptable salt, polymer, and surfactant thereof, wherein the amount of compound A in the solid oral dosage form is 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 according to claim 1, wherein the solid oral dosage form is a tablet.

3. Compound A: 【Chemistry 2】 A tablet comprising a pharmaceutically acceptable salt, polymer, and surfactant thereof, wherein the amount of compound A in the solid oral dosage form is 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, polyvinylpyrrolidone copolymer, methacrylic acid copolymer, polyethylene glycol, or a polyethylene glycol derivative.

5. The solid oral dosage form or tablet according to 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 ester, glycerol ester, 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-tocopheryl 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-tocopheryl polyethylene glycol 1000 succinate.

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

11. A solid oral dosage form or tablet according to any one of claims 1 to 10, further comprising one or more excipients selected from fillers, disintegrants, flow promoters, and lubricants.

12. The solid oral dosage form or tablet according to claim 11, wherein the filler is microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate, mannitol, sorbitol, xylitol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, pullulan, fast-soluble carbohydrates, or any combination thereof.

13. The solid oral dosage form or tablet according to claim 11, wherein the disintegrant comprises sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium croscarmellose, crospovidone, chitosan, agar, alginic acid, calcium alginate, methylcellulose, microcrystalline cellulose, powdered cellulose, lower alkyl-substituted hydroxypropylcellulose, hydroxypropyl starch, low-substituted hydroxypropylcellulose, potassium polaritrin, starch, pregelatinized starch, sodium alginate, potassium polaritrin, povidone, or any combination thereof.

14. The solid oral dosage form or tablet according to claim 11, wherein the flow promoter is silicon dioxide, colloidal silicon dioxide, calcium silicate, magnesium silicate, magnesium trisilicate, talc, starch, or any 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 palmitostearate, hexagonal boron nitride, hydrogenated vegetable oil, light oil, mineral oil, polyethylene glycol, poloxamer, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate, or any combination thereof.

16. Compound A, approximately 15% w / w to approximately 50% w / w Approximately 10% w / w to approximately 40% w / w hydroxypropyl methylcellulose, Approximately 0.5% w / w to approximately 5% w / w of d-α-tocopheryl polyethylene glycol succinate, Microcrystalline cellulose of approximately 10% w / w to approximately 40% w / w, Lactose monohydrate at approximately 5% w / w to approximately 15% w / w Croscarmellose sodium at approximately 5% w / w to approximately 15% w / w Approximately 0% w / w to approximately 5% w / w silicon dioxide, and A solid oral dosage form or tablet according to any one of claims 1 to 3 and 10 to 15, comprising approximately 0% w / w to approximately 2% w / w of sodium stearyl fumarate.

17. Compound A, 15% to 50% w / w 10% to 40% w / w hydroxypropyl methylcellulose, 0.5% to 5% w / w d-α-tocopheryl polyethylene glycol succinate, Microcrystalline cellulose of 10% to 40% w / w, 5% to 15% w / w lactose monohydrate, 5% to 15% w / w croscarmellose sodium, 0% to approximately 5% w / w silicon dioxide, and A solid oral dosage form or tablet according to any one of claims 1 to 3 and 10 to 15, comprising 0% to 2% w / w sodium stearyl fumarate.

18. Compound A at approximately 42% w / w Approximately 15% w / w hydroxypropyl methylcellulose, Approximately 3% w / w d-α-tocopheryl polyethylene glycol succinate, Approximately 17% w / w microcrystalline cellulose, Approximately 8.8% w / w lactose monohydrate, Approximately 12% w / w croscarmellose sodium, Approximately 1% w / w silicon dioxide, and A solid oral dosage form or tablet according to any one of claims 1 to 3 and 10 to 15, comprising approximately 1.5% w / w sodium stearyl fumarate.

19. Compound A at approximately 20% w / w Approximately 28% w / w hydroxypropyl methylcellulose, Approximately 2.5% w / w d-α-tocopheryl polyethylene glycol succinate, Approximately 27% w / w microcrystalline cellulose, Approximately 9% w / w lactose monohydrate, Approximately 12% w / w croscarmellose sodium, Approximately 1% w / w silicon dioxide, and A solid oral dosage form or tablet according to any one of claims 1 to 3 and 10 to 15, comprising approximately 1.5% w / w sodium stearyl fumarate.

20. A solid oral dosage form or tablet according to any one of claims 1 to 3 and 10 to 15, comprising an internal granule portion and an external granule portion.

21. The portion inside the granules, Compound A, approximately 15% to approximately 50% w / w Approximately 10% to approximately 40% w / w hydroxypropyl methylcellulose, Approximately 0.5% to approximately 5% w / w of d-α-tocopheryl polyethylene glycol succinate, Microcrystalline cellulose of approximately 5% to 10% w / w, Approximately 5% to approximately 10% w / w lactose monohydrate, Approximately 1% to approximately 10% w / w croscarmellose sodium, Approximately 0% to approximately 5% w / w silicon dioxide, and Contains approximately 0% to approximately 2% w / w sodium stearyl fumarate. The extragranular part is Microcrystalline cellulose of approximately 5% to approximately 25% w / w, Approximately 0% to approximately 10% w / w croscarmellose sodium, and Contains approximately 0% to approximately 2% w / w sodium stearyl fumarate. The solid oral dosage form or tablet according to claim 20, wherein the weight percentage is relative to the total weight of the uncoated tablet.

22. The portion inside the granules, Compound A at approximately 42% w / w Approximately 14% w / w hydroxypropyl methylcellulose, Approximately 3% w / w d-α-tocopheryl polyethylene glycol succinate, Approximately 9% w / w microcrystalline cellulose, Approximately 9% w / w lactose monohydrate, Approximately 6% w / w croscarmellose sodium, Approximately 1% w / w silicon dioxide, and It contains approximately 0.75% w / w sodium stearyl fumarate. The extragranular part is Approximately 8% w / w microcrystalline cellulose, Approximately 6% w / w croscarmellose sodium, It contains approximately 0.75% w / w sodium stearyl fumarate. The solid oral dosage form or tablet according to claim 20, wherein the weight percentage is relative to the total weight of the uncoated tablet.

23. The portion inside the granules, Compound A at approximately 20% w / w Approximately 28% w / w hydroxypropyl methylcellulose, Approximately 2.5% w / w d-α-tocopheryl polyethylene glycol succinate, Approximately 8% w / w microcrystalline cellulose, Approximately 9% w / w lactose monohydrate, Approximately 6% w / w croscarmellose sodium, Approximately 1% w / w silicon dioxide, and It contains approximately 0.75% w / w sodium stearyl fumarate. The extragranular part is Approximately 18% w / w microcrystalline cellulose, Approximately 6% w / w croscarmellose sodium, and It contains approximately 0.75% w / w sodium stearyl fumarate. The solid oral dosage form or tablet according to claim 20, wherein the weight percentage is relative to the total weight of the uncoated tablet.

24. The solid oral dosage form or tablet according to 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 according to 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 according to 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. Compound A: 【Transformation 3】 A mixture comprising a pharmaceutically acceptable salt thereof, a polymer, and a surfactant.

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

32. The mixture form according to 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 ester, glycerol ester, and mixtures thereof.

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

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

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

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

38. Compound A is present in a concentration of approximately 20% (w / w) to approximately 60% (w / w). The polymer in an amount of approximately 35% (w / w) to approximately 75% (w / w), and A mixture according to any one of claims 30 to 37, comprising approximately 1% (w / w) to approximately 10% (w / w) of surfactant.

39. Compound A at approximately 40% (w / w), Approximately 55% (w / w) of the aforementioned polymer, and A mixture according to any one of claims 30 to 37, comprising approximately 5% (w / w) of the surfactant.

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

41. Compound A is approximately 70% (w / w). Approximately 25% (w / w) of the aforementioned polymer, and A mixture according to any one of claims 30 to 37, comprising approximately 5% (w / w) of the surfactant.

42. Compound A is present in a concentration of approximately 20% (w / w) to approximately 60% (w / w). Approximately 35% (w / w) to approximately 75% (w / w) hydroxypropyl methylcellulose, and The mixture according to claim 38, comprising approximately 1% (w / w) to approximately 10% (w / w) of D-α-tocopheryl polyethylene glycol succinate.

43. Compound A at approximately 40% (w / w), Approximately 55% (w / w) hydroxypropyl methylcellulose, and The mixture according to claim 39, comprising approximately 5% (w / w) of D-α-tocopheryl polyethylene glycol succinate.

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

45. Compound A is approximately 70% (w / w). Approximately 25% (w / w) hydroxypropyl methylcellulose, The mixture according to claim 41, comprising approximately 5% (w / w) of D-α-tocopheryl polyethylene glycol succinate.

46. A mixture according to any one of claims 30 to 45, which is a dispersion.

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

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

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

50. Compound A: 【Chemistry 4】 A spray-dried dispersion comprising a pharmaceutically acceptable salt thereof, a polymer, and a surfactant.

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

52. The spray-dried dispersion according to 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 ester, glycerol ester, 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-tocopheryl polyethylene glycol succinate.

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

57. The spray-dried dispersion according to claim 50, wherein the polymer is hydroxypropyl methylcellulose and the surfactant is d-α-tocopheryl polyethylene glycol succinate.

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

59. Compound A at approximately 40% (w / w), Approximately 55% (w / w) of the aforementioned polymer, and The spray-dried dispersion according to claim 50, comprising approximately 5% (w / w) of the surfactant.

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

61. Compound A is approximately 70% (w / w). Approximately 25% (w / w) of the aforementioned polymer, and The spray-dried dispersion according to claim 50, comprising approximately 5% (w / w) of surfactant.

62. Compound A is present in a concentration of approximately 20% (w / w) to approximately 60% (w / w). Approximately 35% (w / w) to approximately 75% (w / w) hydroxypropyl methylcellulose, and The spray-dried dispersion according to claim 51, comprising approximately 1% (w / w) to approximately 10% (w / w) of d-α-tocopheryl polyethylene glycol succinate.

63. Compound A at approximately 40% (w / w), Approximately 55% (w / w) hydroxypropyl methylcellulose, and The spray-dried dispersion according to claim 59, comprising approximately 5% (w / w) of d-α-tocopheryl polyethylene glycol succinate.

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

65. Compound A is approximately 70% (w / w). Approximately 25% (w / w) hydroxypropyl methylcellulose, The spray-dried dispersion according to claim 61, comprising approximately 5% (w / w) of d-α-tocopheryl polyethylene glycol succinate.

66. A method for producing a spray-dried dispersion according to any one of claims 50 to 65, A solution containing compound A is obtained by dissolving compound A, the polymer, and the surfactant in a solvent. The solution containing compound A is introduced into a spray dryer. The solution containing compound A is sprayed from a spray dryer to form a spray-dried dispersion of compound A, and A method that, depending on the circumstances, includes removing a residual solvent from a spray-dried dispersion of compound A.

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

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

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

70. The process according to claim 66, wherein the solvent is a mixture of dichloromethane and methanol in a ratio of about 85:15 (w / w).

71. The method according to any one of claims 66 to 70, wherein the removal of the residual solvent includes drying.

72. The method according to claim 71, wherein drying includes agitated conical drying.

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