Compositions Comprising ERK Inhibitors

Abstract

The present disclosure generally relates to compositions comprising Compound (I).

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 USC §119(e) of U.S. Provisional Application No. 63 / 271,977, filed October 26, 2021, which is incorporated by reference in its entirety.

[0002] The present application relates to compositions of ERK1 / 2 inhibitors. [Background technology]

[0003] Extracellular signal-regulated kinases (ERK1 / 2) are ubiquitously expressed protein serine / threonine kinases that constitute major components of the mitogen-activated protein kinase (MAPK) signaling pathway. The MAPK pathway is an evolutionarily conserved cell signaling pathway that regulates a variety of cellular processes, including cell cycle progression, cell migration, cell survival, differentiation, metabolism, proliferation and transcription. ERK1 / 2 activity is commonly upregulated in cancer as a result of activating mutations within upstream components of the MAPK pathway. ERK1 / 2 inhibitors are useful in therapy, particularly in the treatment of cancer. Summary of the Invention [Problem to be solved by the invention]

[0004] There is a need for compositions comprising ERK1 / 2 inhibitor compounds that are stable and / or easy to formulate and / or have improved bioavailability and / or improved pharmacokinetic profiles. The bioavailability of an active ingredient can affect therapeutic efficacy. [Means for solving the problem]

[0005] overview The present disclosure provides, in one embodiment, a composition comprising Compound I, or a pharma- ceutically acceptable salt or solvate thereof. [ka]

[0006] Compound I is referred to as (2R)-2-(6-{5-chloro-2-[(tetrahydro-2H-pyran-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide. In one aspect, the compound is represented herein by the formula: [ka] or a pharma- ceutically acceptable salt or solvate thereof, and a water soluble polymer.

[0007] In one aspect, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt or solvate thereof, Compound I, or a pharma- ceutically acceptable salt or solvate thereof, is molecularly dispersed within a polymer matrix comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS); A solid dispersion is provided.

[0008] In another aspect, the present disclosure provides a method for preparing a pharmaceutical composition comprising the steps of: formula: [ka] or a pharma- ceutically acceptable salt or solvate thereof, Compound I, or a pharma- ceutically acceptable salt or solvate thereof, is molecularly dispersed within a polymer matrix comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS); and the ratio of the weight of Compound I, or a pharma- ceutically acceptable salt or solvate thereof in the solid dispersion to the weight of HPMCAS in the solid dispersion is about 1:3. Tablets are provided.

[0009] Also provided herein is the use of any composition comprising compound I, or a pharma- ceutically acceptable salt or solvate thereof, as described herein, for treating cancer.Further provided is a method of treating cancer, comprising administering to an individual in need thereof a composition comprising compound I, or a pharma- ceutically acceptable salt or solvate thereof, as described herein.

[0010] Embodiments of the present application will now be described, by way of example only, with reference to the accompanying drawings, in which: [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 shows the dissolution profile of certain compositions of Compound I. [Diagram 2] FIG. 2 shows drug speciation data following dissolution testing of certain compositions of Compound I. [Diagram 3] FIG. 3 shows the dissolution profile of certain compositions of Compound I. [Figure 4A] 4A shows plasma concentrations following administration of Compound I free base hydrate formulation in a dog pharmacokinetic (PK) study as described in Example 4. Error bars represent standard deviation. [Figure 4B] 4B shows a comparison of area under the curve (AUC) following administration of Compound I free base hydrate formulations in a dog PK study as described in Example 4. Error bars represent standard deviation. [Figure 4C] FIG. 4C shows the AUC in a dog pharmacokinetic (PK) study as described in Example 4. [Figure 5A]FIG. 5A shows the AUClast following administration of Compound I free base hydrate formulation in a primate PK study. [Figure 5B] FIG. 5B shows the Cmax following administration of Compound I free base hydrate formulation in a primate PK study. [Figure 5C] FIG. 5C shows a comparison of area under the curve (AUC) following administration of Compound I free base hydrate formulations in a primate PK study. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Detailed Description Compound I is described as Example 685 in WO2017 / 068412, the entirety of which is incorporated herein by reference. Compound I is useful for the treatment of cancer and other conditions described in WO2017 / 068412. In formulating Compound I, it has been found that the relative amounts of Compound I and polymer by weight in the solid dispersion have an unexpected effect on the bioavailability of Compound I.

[0013] definition The following description illustrates exemplary embodiments of the present technology, however, it should be appreciated that such description is not intended to limit the scope of the disclosure, but is instead provided as a description of exemplary embodiments.

[0014] As used herein, the following words, phrases and symbols are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0015] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -C(O)NH2 is attached through a carbon atom. Dashes at the beginning or end of a chemical group are for convenience, and chemical groups may be shown with one, multiple dashes, or none, without loss of normal meaning. A drawn wavy line in a structure indicates the point of attachment of a group. No directionality is given or implied by the order in which chemical groups are written or named unless chemically or structurally necessary.

[0016] As used herein, reference to "about" a value or parameter includes (describes) embodiments directed to the value or parameter itself. In certain embodiments, the term "about" includes ±10% of the indicated amount. In other embodiments, the term "about" includes ±5% of the indicated amount. In certain other embodiments, the term "about" includes ±1% of the indicated amount. Also, the term "about X" includes a description of "X." Additionally, the singular forms "a" and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to a "compound" includes a plurality of such compounds, and reference to an "assay" includes reference to one or more assays and equivalents thereof known to those of skill in the art.

[0017] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl), or 1 to 4 carbon atoms (i.e., C1-4 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a particular number of carbons is indicated in a chemical name or specified by a molecular formula, all positional isomers having that number of carbons can be included, thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0018] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkenyl), from 2 to 8 carbon atoms (i.e., C2-8 alkenyl), from 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or from 2 to 4 carbon atoms (i.e., C2-4 alkenyl). Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0019] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings, including fused systems (e.g., bicyclic or tricyclic). As used herein, an aryl has 6 to 20 ring carbon atoms (i.e., C6-20 aryl), 6 to 12 carbon ring atoms (i.e., C6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C6-10 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not encompass or overlap in any way with heteroaryl, as defined below. When one or more aryl groups are fused to a heteroaryl, the resulting ring system is a heteroaryl. When one or more aryl groups are fused to a heterocyclyl, the resulting ring system is a heterocyclyl.

[0020] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl has 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0021] As used herein, "hydroxypropyl methylcellulose acetate succinate" may be referred to interchangeably as HPMCAS or hypromellose acetate succinate (e.g., Aquasolve™, Shin-Etsu AQOAT™, or other commercially available equivalents). HPMCAS is commercially available in a variety of grades (e.g., L, M, or H) having various molecular weights (e.g., 10,000-500,000 da) and differing degrees of substitution of acetyl and succinoyl groups as well as particle size (e.g., F or G). For example, the L grade of Aquasolve™ is commercially available and comprises an acetyl content of 5-9%, a succinoyl content of 14-18%, a methoxyl content of 20-24%, and a hydroxypropoxy content of 5-9%. For example, Aquasolve™ M grade is commercially available and comprises an acetyl content of 7-11%, a succinoyl content of 10-14%, a methoxyl content of 21-25%, and a hydroxypropoxy content of 5-9%. For example, Aquasolve™ S grade is commercially available and comprises an acetyl content of 10-14%, a succinoyl content of 4-8%, a methoxyl content of 22-26%, and a hydroxypropoxy content of 6-10%. Each grade is available in fine (F) and granular (G) particle sizes. In some cases, the fine (F) type has an average particle size of 10 microns or less, and the granular (G) type has an average particle size of 20 microns or less.

[0022] The term "optionally" or "optionally" means that the next described event or circumstance may or may not occur, and the description includes cases where said event or circumstance occurs and cases where said event or circumstance does not occur. Also, the term "optionally substituted" refers to any one or more hydrogen atoms on a specified atom or group may or may not be replaced with a non-hydrogen moiety.

[0023] Some of the compounds may exist as tautomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium between the tautomers, one skilled in the art will understand that the compound comprises both amide and imidic acid tautomers. Thus, amide-containing compounds are understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include their amide tautomers.

[0024] Any formula or structure shown herein is also intended to represent unlabeled form of the compound as well as isotopically labeled form.Isotopically labeled compounds have the structure shown by the formula given herein, except that one or more atoms are replaced by an atom with selected atomic mass or mass number.Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, 2H (deuterium, D), 3H (tritium), 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl and 125I.Various isotopically labeled compounds of the present disclosure, such as compounds incorporating radioisotopes such as 3H and 14C. Such isotopically labeled compounds may be useful for detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) including metabolism studies, reaction kinetics studies, drug or substrate tissue distribution assays, or for radiotherapy of patients.

[0025] The present disclosure also includes "deuterated analogs" of compounds of formula I in which one to n hydrogens attached to a carbon atom are replaced with deuterium, where n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful for extending the half-life of compounds of formula I when administered to mammals, particularly humans. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, e.g., using starting materials in which one or more hydrogens have been replaced with deuterium.

[0026] The deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties related to distribution, metabolism and excretion (ADME). Substitution with heavy isotopes such as deuterium may provide certain therapeutic advantages resulting from higher metabolic stability, such as extended in vivo half-life, reduced dose requirements, and / or improved therapeutic index. 18F-labeled compounds may be useful for PET or SPECT studies. The isotopically-labeled compounds of the present disclosure and their prodrugs can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations below, replacing non-isotopically labeled reagents with readily available isotopically labeled reagents. It is understood that deuterium in this context is considered as a substituent in the compound of formula I.

[0027] The concentration of such heavy isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, an atom that is not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise noted, when a position is specifically designated as "H" or "hydrogen", that position is understood to have hydrogen at its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, an atom specifically designated as deuterium (D) is meant to represent deuterium.

[0028] In many cases, the compounds of the present disclosure may form acid and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto. "Salts" may be derived from inorganic acids, inorganic bases, organic acids, or organic bases. Salts derived from inorganic acids include salts from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include those from acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, mandelic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, tetrahydrofuran carboxylic acid, and the like. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines.

[0029] Also provided are compositions comprising pharma- ceutically acceptable salts, hydrates, solvates, and tautomeric forms of Compound I, as described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0030] The term "pharmaceutical acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutical acceptable salt" or "physiologically acceptable salt" includes, for example, salts with inorganic acids and salts with organic acids. Furthermore, when a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, an addition salt, particularly a pharmaceutical acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare non-toxic pharmaceutical acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include those from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts from organic acids include those from acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Similarly, pharma-ceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts.Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(alkenyl)2), tri(substituted alkenyl)amines (i.e., N(substituted alkyl)3), Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0031] The free base, salt or pharma- ceutically acceptable salt provided herein may be a "solvate" formed by the interaction of a solvent and a compound. The solvate of the salt and free base of compound I described herein is provided. When the solvent is water, the solvate is a hydrate. The salt or pharma- ceutically acceptable salt provided herein may be a hydrate. Also provided is the "hydrate" of the free base of compound I described herein. In some embodiments, the hydrate is a monohydrate.

[0032] composition As used herein, the formula: [ka] or a pharma- ceutically acceptable salt or solvate thereof, and a water soluble polymer.

[0033] In some embodiments, the water-soluble polymer is polyvinylpyrrolidone / vinyl acetate (PVPVA), hydroxypropyl methylcellulose (HPMC), or any grade of hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the water-soluble polymer is HPMCAS. In some embodiments, the HPMCAS is grade L and comprises an acetyl content of 5-9%, a succinoyl content of 14-18%, a methoxyl content of 20-24%, and a hydroxypropoxy content of 5-9%. In some embodiments, the HPMCAS is grade M and comprises an acetyl content of 7-11%, a succinoyl content of 10-14%, a methoxyl content of 21-25%, and a hydroxypropoxy content of 5-9%. In some embodiments, the HPMCAS is grade S and comprises an acetyl content of 10-14%, a succinoyl content of 4-8%, a methoxyl content of 22-26%, and a hydroxypropoxy content of 6-10%. In any of these embodiments, the HPMCAS has a fine particle size, such as the F particle size commercially available as Aquasolve™. In any of these embodiments, the HPMCAS has a granular particle size, such as the G particle size commercially available as Aquasolve™.

[0034] In some embodiments, the composition comprises a free base hydrate of Compound I. In some or any of the embodiments provided herein, the composition comprises a free base monohydrate of Compound I. In some or any of the embodiments provided herein, the composition comprises Form B of Compound I as described in WO2018 / 193410.

[0035] Further provided herein is a compound of the formula: [ka] or a pharma- ceutically acceptable salt or solvate thereof, Compound I, or a pharma- ceutically acceptable salt or solvate thereof, is molecularly dispersed within a polymer matrix comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS); A solid dispersion is provided.

[0036] In some embodiments, Compound I, or a pharma- ceutically acceptable salt or solvate thereof, is present in the solid dispersion in an amount of about 10% to about 50% by weight of the solid dispersion. In other words, in some embodiments, for 100 g of solid dispersion, 10 to 50 g of the total weight of the solid dispersion is derived from the weight of Compound I, or a pharma- ceutically acceptable salt or solvate thereof, and 90 to 50 g of the total weight of the solid dispersion is derived from HPMCAS. In some embodiments, Compound I, or a pharma- ceutically acceptable salt or solvate thereof, is present in the solid dispersion in an amount of about 20% to about 50% by weight of the solid dispersion. In some embodiments, Compound I, or a pharma- ceutically acceptable salt or solvate thereof, is present in the solid dispersion in an amount of about 20% to about 30% by weight of the solid dispersion.

[0037] In some embodiments, compound I, or a pharma- ceutically acceptable salt or solvate thereof, is substantially amorphous. In some embodiments, in the solid dispersion, at least 98% of compound I, or a pharma- ceutically acceptable salt or solvate thereof, is in amorphous form. In some embodiments, in the solid dispersion, at least 95% of compound I, or a pharma- ceutically acceptable salt or solvate thereof, is in amorphous form. In some embodiments, in the solid dispersion, at least 90% of compound I, or a pharma- ceutically acceptable salt or solvate thereof, is in amorphous form. In some embodiments, in the solid dispersion, compound I is a free base or a solvate thereof. In some embodiments, in the solid dispersion, compound I is a free base hydrate.

[0038] In some embodiments, the weight ratio of compound I or a pharma- ceutically acceptable salt or solvate thereof to HPMCAS in the solid dispersion is about 1:1 to about 1:5. In some embodiments, the weight ratio of compound I or a pharma- ceutically acceptable salt or solvate thereof to HPMCAS is about 1:2 to about 1:4. In some embodiments, the weight ratio of compound I or a pharma- ceutically acceptable salt or solvate thereof to HPMCAS is about 1:3. In some embodiments, the weight ratio of compound I or a pharma- ceutically acceptable salt or solvate thereof to HPMCAS is about 1:2. In some embodiments, the weight ratio of compound I or a pharma- ceutically acceptable salt or solvate thereof to HPMCAS is about 1:1.

[0039] In some embodiments, HPMCAS is present in an amount greater than about 50% by weight of the solid dispersion. In some embodiments, HPMCAS is present in an amount greater than about 60% by weight of the solid dispersion. In some embodiments, HPMCAS is present in an amount greater than about 70% by weight of the solid dispersion.

[0040] In some embodiments, HPMCAS is present in an amount of about 60% to about 80% by weight of the solid dispersion. In some embodiments, HPMCAS is present in an amount of about 70% to about 80% by weight of the solid dispersion.

[0041] In some embodiments, HPMCAS is present in an amount of about 50% by weight of the solid dispersion. In some embodiments, HPMCAS is present in an amount of about 60% by weight of the solid dispersion. In some embodiments, HPMCAS is present in an amount of about 70% by weight of the solid dispersion. In some embodiments, HPMCAS is present in an amount of about 75% by weight of the solid dispersion.

[0042] In some embodiments, HPMCAS is present in an amount of about 50% by weight of the solid dispersion and Compound I or a pharma- ceutically acceptable salt or solvate thereof is present in an amount of about 50% by weight of the solid dispersion. In some embodiments, HPMCAS is present in an amount of about 60% by weight of the solid dispersion and Compound I or a pharma- ceutically acceptable salt or solvate thereof is present in an amount of about 40% by weight of the solid dispersion. In some embodiments, HPMCAS is present in an amount of about 70% by weight of the solid dispersion and Compound I or a pharma- ceutically acceptable salt or solvate thereof is present in an amount of about 30% by weight of the solid dispersion. In some embodiments, HPMCAS is present in an amount of about 75% by weight of the solid dispersion and Compound I or a pharma- ceutically acceptable salt or solvate thereof is present in an amount of about 25% by weight of the solid dispersion.

[0043] In some or any embodiments, the HPMCAS in the solid dispersion has an acetyl content ranging from about 5 to about 14% by weight of the HPMCAS, and a succinoyl content ranging from about 5 to about 20% by weight of the HPMCAS, hi some embodiments, the HPMCAS in the solid dispersion has an acetyl content ranging from about 7 to about 11% by weight of the HPMCAS, and a succinoyl content ranging from about 10 to about 14% by weight of the HPMCAS.

[0044] In some tablet embodiments, the solid dispersion comprises about 40-70% by weight of the tablet. In some tablet embodiments, the solid dispersion comprises about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70% by weight of the tablet. In some tablet embodiments, the solid dispersion comprises about 60% by weight of the tablet.

[0045] Provided herein is a pharmaceutical composition comprising a solid dispersion as described herein. In some embodiments, the composition is formulated as a tablet. In some embodiments, the composition is formulated as a tablet comprising an inner granular layer and an outer granular layer. In some such embodiments, the solid dispersion is in the inner granular layer, and the inner granular layer further comprises an additional excipient as described herein. In some such embodiments, the solid dispersion is in the outer granular layer, and the outer granular layer further comprises an additional excipient as described herein. In some such embodiments, the solid dispersion is in the inner granular layer and the outer granular layer, and the inner granular layer and / or the outer granular layer further comprise an additional excipient as described herein.

[0046] In some embodiments of the pharmaceutical composition formulated as a tablet, the inner granular layer of the tablet comprises about 8-18%, about 10-18%, or about 12-18% by weight of microcrystalline cellulose. In some embodiments of the pharmaceutical composition formulated as a tablet, the inner granular layer of the tablet further comprises about 8-18%, about 10-18%, or about 12-18% by weight of lactose. In some embodiments, the lactose is lactose monohydrate. In some embodiments, the lactose monohydrate is agglomerated lactose monohydrate (e.g., Tablettose®). In some embodiments of the pharmaceutical composition formulated as a tablet, the inner granular layer of the tablet further comprises about 2-8%, about 4-8%, or about 6-8% by weight of croscarmellose sodium. In some embodiments of the pharmaceutical composition formulated as a tablet, the inner granular layer of the tablet further comprises about 0.5-2%, or about 0.5-1.5% by weight of non-fumed silica. In some embodiments of the pharmaceutical composition formulated as a tablet, the inner granular layer of the tablet further comprises about 0.1-0.5% or about 0.2-0.4% by weight magnesium stearate.

[0047] In some embodiments of the pharmaceutical composition formulated as a tablet, the inner granular layer of the tablet comprises: about 8-18% by weight of microcrystalline cellulose; about 8-18% by weight lactose monohydrate; about 2-8% by weight of croscarmellose sodium; about 0.5 to 2 weight percent non-fumed silica; and Approximately 0.1 to 0.5% by weight of magnesium stearate The present invention relates to a method for producing a semiconductor device comprising the steps of:

[0048] In some embodiments, the weight percent amounts of microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, non-fumed silica and / or magnesium stearate in the inner granular layer are as described in any of the above embodiments or examples section. In some of these embodiments, the solid dispersion is in the inner granular layer. In some of these embodiments, the solid dispersion is in the outer granular layer. In some of these embodiments, the solid dispersion is in the inner granular layer and the outer granular layer.

[0049] In some embodiments of the pharmaceutical composition formulated as a tablet, the outer granular layer of the tablet comprises about 0-14%, or about 5-14% by weight of microcrystalline cellulose. In some embodiments, the solid dispersion is in the inner granular layer and the outer granular layer does not comprise microcrystalline cellulose. In some embodiments of the pharmaceutical composition formulated as a tablet, the outer granular layer of the tablet comprises about 0-14%, or about 5% to about 10% by weight of lactose. In some embodiments, the lactose is lactose monohydrate. In some embodiments, the lactose is agglomerated lactose monohydrate (e.g., Tablettose®). In some embodiments, the solid dispersion is in the inner granular layer and the outer granular layer does not comprise lactose.

[0050] In some embodiments of the pharmaceutical composition formulated as a tablet, the outer granular layer of the tablet comprises about 2-8%, or about 3-5% by weight of croscarmellose sodium. In some embodiments of the pharmaceutical composition formulated as a tablet, the outer granular layer of the tablet comprises about 0.5-2%, or about 0.5-1.5% by weight of non-fumed silica. In some embodiments of the pharmaceutical composition formulated as a tablet, the outer granular layer of the tablet comprises about 0.1-0.5%, or about 0.2-0.4% by weight of magnesium stearate.

[0051] In some embodiments of the pharmaceutical composition formulated as a tablet, the outer granular layer of the tablet comprises: about 0-14% by weight microcrystalline cellulose; about 0-14% by weight lactose monohydrate; about 2-8% by weight of croscarmellose sodium; about 0.5 to 2 weight percent non-fumed silica; and Approximately 0.1 to 0.5% by weight of magnesium stearate The present invention relates to a method for producing a semiconductor device comprising the steps of:

[0052] In some embodiments of the pharmaceutical composition formulated as a tablet, the outer granular layer of the tablet comprises: about 2-8% by weight of croscarmellose sodium; about 0.5 to 2 weight percent non-fumed silica; and Approximately 0.1 to 0.5% by weight of magnesium stearate The present invention relates to a method for producing a semiconductor device comprising the steps of:

[0053] In some embodiments, the weight percent amounts of microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, non-fumed silica and / or magnesium stearate in the outer granular layer are as described in any of the above embodiments or examples section. In some of these embodiments, the solid dispersion is in the inner granular layer. In some of these embodiments, the solid dispersion is in the outer granular layer. In some of these embodiments, the solid dispersion is in the inner granular layer and the outer granular layer.

[0054] In some embodiments of the pharmaceutical composition formulated as a tablet, the tablet is coated with a film. In some embodiments, the film coat comprises a polymer, a plasticizer, and / or a pigment. Examples of polymers in tablet film coatings include, but are not limited to, polyvinyl alcohol (PVA), polyvinylpyrrolidone (copovidone), hydroxypropylmethylcellulose (HPMC), methacrylic acid copolymers, methylcellulose, ethylcellulose, or any other suitable film-forming polymer. Examples of plasticizers in tablet film coatings include, but are not limited to, hydroxypropylmethylcellulose (HPMC), polyethylene glycol, triacetin, stearic acid, citric acid, phthalate esters, or any other suitable plasticizer. In some embodiments, the film coating is OPADRY II®.

[0055] In one aspect, the present disclosure comprises a solid dispersion, the solid dispersion comprising a compound having the formula: [ka] or a pharma- ceutically acceptable salt or solvate thereof, Compound I, or a pharma- ceutically acceptable salt or solvate thereof, is molecularly dispersed within a polymer matrix comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS); and the ratio by weight of Compound I, or a pharma- ceutically acceptable salt or solvate thereof, in the solid dispersion to the weight of HPMCAS in the solid dispersion is about 1:3. Tablets are provided. In some other embodiments of the tablets, the ratio of the weight of Compound I or a pharma- ceutically acceptable salt or solvate thereof in the solid dispersion to the weight of HPMCAS in the solid dispersion is about 1:2, or about 1:1.

[0056] In some embodiments of the tablet, compound I, or a pharma- ceutically acceptable salt or solvate thereof, is substantially amorphous. In some embodiments of the tablet, at least 98% of compound I, or a pharma- ceutically acceptable salt or solvate thereof, is in amorphous form. In some embodiments of the tablet, at least 95% of compound I, or a pharma- ceutically acceptable salt or solvate thereof, is in amorphous form. In some embodiments of the tablet, at least 90% of compound I, or a pharma- ceutically acceptable salt or solvate thereof, is in amorphous form. In some embodiments of the tablet, compound I is a free base or a solvate thereof. In some embodiments of the tablet, compound I is a free base hydrate.

[0057] In some embodiments, provided herein is a compound of the formula: [ka] or a pharma- ceutically acceptable salt or solvate thereof, a solid dispersion of about 40-80% by weight of Compound I, or a pharma- ceutically acceptable salt or solvate thereof, and HPMCAS, wherein Compound I, or a pharma- ceutically acceptable salt or solvate thereof, is substantially amorphous and molecularly dispersed in a polymer matrix comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS), and the ratio by weight of Compound I, or a pharma- ceutically acceptable salt or solvate thereof in the solid dispersion to the weight of HPMCAS in the solid dispersion is about 1:3; about 8-18% by weight of microcrystalline cellulose; about 8-18% by weight lactose monohydrate; about 2-8% by weight of croscarmellose sodium; about 0.5 to 2 weight percent non-fumed silica; and Approximately 0.1 to 0.5% by weight of magnesium stearate An inner granule portion comprising about 2-8% by weight of croscarmellose sodium; about 0.5 to 2 weight percent non-fumed silica; and Approximately 0.1 to 0.5% by weight of magnesium stearate; An outer granule portion comprising A tablet composition is provided comprising:

[0058] In another aspect, the present specification provides a method for producing a composition comprising: formula: [ka] or a pharma- ceutically acceptable salt or solvate thereof, a solid dispersion of about 60% by weight of Compound I, or a pharma- ceutically acceptable salt or solvate thereof, and HPMCAS, wherein Compound I, or a pharma- ceutically acceptable salt or solvate thereof, is substantially amorphous and molecularly dispersed in a polymer matrix comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS), and the ratio by weight of Compound I, or a pharma- ceutically acceptable salt or solvate thereof in the solid dispersion to the weight of HPMCAS in the solid dispersion is about 1:3; about 14% by weight microcrystalline cellulose; about 13.5% by weight lactose monohydrate; about 6% by weight of croscarmellose sodium; About 1% by weight of non-fumed silica; and Approximately 0.25% by weight of magnesium stearate An inner granule portion comprising about 4% by weight of croscarmellose sodium; About 1% by weight of non-fumed silica; and Approximately 0.25% by weight of magnesium stearate An outer granule portion comprising A tablet composition is provided comprising:

[0059] In some embodiments of the tablet composition of Compound I, or a pharma- ceutically acceptable salt or solvate thereof, the HPMCAS has an acetyl content ranging from about 7% to about 11% by weight of the HPMCAS, and a succinoyl content ranging from about 10% to about 14% by weight.

[0060] Provided herein is the use of the compositions described herein for treating cancer.

[0061] Also provided is a method of treating cancer comprising administering to an individual in need thereof a composition of Compound I, or a pharma- ceutically acceptable salt or solvate thereof, as described herein.

[0062] Provided herein is a process for preparing a solid dispersion of Compound I, or a pharma- ceutically acceptable salt or solvate thereof, comprising spray drying a solution of Compound I, or a pharma- ceutically acceptable salt or solvate thereof, and HPMCAS in a solvent, the solution having a solid loading of up to about 20% by weight. In some embodiments, the solution has a solid loading of about 5% to about 15%, or about 10%. In some embodiments, the solvent is methanol. In some embodiments, the solvent is acetone. In some embodiments, the solvent is a mixture of methanol and acetone. In some embodiments of this process, Compound I is a free base. In some embodiments of this process, Compound I is a free base monohydrate. In some embodiments, Compound I is Form B as described in WO2018 / 193410, where Form B is a free base monohydrate of Compound I.

[0063] Provided herein is a process for preparing a solid dispersion of Compound I, or a pharma- ceutically acceptable salt or solvate thereof, comprising spray drying a solution of Compound I, or a pharma- ceutically acceptable salt or solvate thereof, and HPMCAS in acetone, wherein the solution in acetone has a solids loading of up to about 10% by weight. In some embodiments, the solution in acetone has a solids loading of about 5% to about 10%. In some embodiments of this process, Compound I is a free base. In some embodiments of this process, Compound I is a free base hydrate.

[0064] Compound I of the present disclosure, or a pharma- ceutically acceptable salt or solvate thereof, can be prepared from readily available starting materials using common methods and procedures described, for example, in WO2017 / 068412. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be recognized that other process conditions can also be used unless otherwise noted. Optimal reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one of ordinary skill in the art by routine optimization procedures. EXAMPLES

[0065] The following examples are included to illustrate certain embodiments of the present disclosure. Those skilled in the art should understand that the techniques disclosed in the following examples represent techniques that work well in the implementation of the present disclosure and therefore can be considered to constitute certain modes for its implementation. However, those skilled in the art should understand in light of the present disclosure that many changes can be made in the specific embodiments disclosed and still obtain the same or similar results without departing from the spirit and scope of the present disclosure. Where available, reagents can be purchased commercially, for example from Sigma Aldrich or other chemical suppliers.

[0066] Example 1-1: Preparation of a solid dispersion of Compound I:HPMCAS 1:3 The amorphous solid dispersion comprises Compound I:HPMCAS (Shin-Etsu Chemical, M grade, G particle size) in a ratio of 1:3. The solid dispersion was prepared by spray drying a solution of 2 grams of Compound I free base hydrate crystalline form B and 6 grams of HPMCAS from acetone at a solid loading of 10% w / w, or optionally at a loading of about 4% w / w to about 10% w / w. Compound I free base monohydrate crystalline form B was prepared as described in WO2018 / 193410. The solid dispersion was prepared using a spray drying process. The spray drying process included three steps: preparation of the feed solution, spray drying, and secondary drying. To prepare the feed solution, 90% of the total acetone volume was added to the reactor, and then Compound I was added to the reactor. The mixture was stirred at room temperature until the solids were dissolved. HPMCAS (Shin-Etsu Chemical, M grade, G particle size) was added, and the mixture was stirred at room temperature until most of the solids were dissolved. The remaining amount of acetone was added to the reactor and stirring was continued for an additional period of time (>30 min) until the solids were dissolved. For spray drying, the spray dryer (Bend BLD-35) was stabilized with nitrogen gas, then the solution was introduced and the wet spray was collected in a bag, then the collected wet spray dried was secondary dried in a vacuum tray until the residual solvent was 1500 ppm or less. The spray dried material was an amorphous white to off-white solid with a yield of 86.8%.

[0067] Example 1-2: Preparation of a 1:1 solid dispersion of Compound I:HPMCAS The amorphous solid dispersion comprises Compound I:HPMCAS (Shin-Etsu Chemical, M grade, G particle size) in a ratio of 1:1. The solid dispersion was prepared by spray drying 4 grams of Compound I free base hydrate crystal form B and 4 grams of HPMCAS using the same procedure as in Example 1-1.

[0068] Examples 1-3: Preparation of Compound I:HPMC 1:3 solid dispersion The amorphous solid dispersion comprises Compound I:HPMC (JRS PHARMA, Grade E3) in a ratio of 1:3. The solid dispersion was prepared by spray drying 2 grams of Compound I free base hydrate crystal form B and 6 grams of HPMC using a procedure similar to that of Example 1-1, except that 90% methanol (9:1 methanol:water) was used as the solvent for the spray drying solution.

[0069] Example 2: Preparation of tablets comprising a solid dispersion Tablet dosage forms were developed using a dry granulation process using 60% w / w amorphous solid dispersion and other excipients. The amorphous solid dispersion, microcrystalline cellulose, lactose monohydrate, silicon dioxide, and croscarmellose sodium were each de-lumped and blended. Magnesium stearate was de-lumped by sieving and blended. This constituted the intragranular blend. The intragranular blend was rotary compressed and milled to form granules. The granules, microcrystalline cellulose, lactose monohydrate, silicon dioxide, and croscarmellose sodium were each de-lumped and blended. Magnesium stearate was de-lumped by sieving and blended with the blend obtained from the previous unit operation. This constituted the tablets prepared at 12 kg scale using the weight proportions shown in Table 2 below. The tablet blend was compressed on a rotary tablet press to form tablet cores of the desired dose of drug. Tablet weights were varied to obtain different doses of drug. A different size and shape die was used for each dosage strength. The tablet cores were cosmetically coated in a pan coater.

[0070] Table 1 below shows the composition of a tablet composition of Compound I comprising the solid dispersion of Example 1.

[0071] [Table 1]

[0072] Example 3-1: Dissolution test The solid dispersions described in Example 1 were evaluated in two non-immersed dissolution tests to assess various aspects of the formulations and how they can be differentiated. The two dissolution tests evaluated include the gastric-to-intestinal (G-IB) transfer microcentrifugation dissolution test and the ultracentrifugation free drug test.

[0073] The Gastrointestinal Buffer (G-IB) transfer dissolution test is used to measure the degree of supersaturation of a drug over the solubility of the bulk drug when administered as a powder, initially in a medium with a lower pH to mimic the fasted stomach. After 30 minutes of exposure in the gastric medium, the sample is transferred to a medium with a higher pH to mimic the intestine. The drug concentration measured in this test is a mixture of free drug, drug in micelles, and drug suspended in solution as a drug / polymer colloid.

[0074] Ultracentrifugation free drug analysis is used to determine the dissolved drug species present in each formulation. This test is performed at several time points during the microcentrifugation test, namely 0, 30, 60 and 90 minutes, and consists of a centrifugation step at 300,000g which removes any colloidal species present, leaving only the free drug and drug species in micellar species. In combination with the microcentrifugation data, the content of both free drug and colloids can be determined at the time they are tested.

[0075] The G-IB dissolution test is performed similarly, but with a 30 min intragastric exposure before transfer to the intestinal medium. The intestinal medium for the G-IB dissolution test is doubly concentrated with respect to buffer and bile salts, so that after the gastric transfer step, the final pH is 6.5 and the SIF concentration is 0.5 wt%.

[0076] Microcentrifuge dissolution tests separate precipitate (undissolved drug) and total solubilized drug. Total solubilized drug consists of three solubilized species: free solubilized drug, drug associated with bile salt micelles, and drug associated with polymers (drug-polymer colloids). These three species have different activities in vivo and differentiate the formulations. Free solubilized drug is the smallest species and is the most available for absorption. Free solubilized drug can cross the unstirred mucosal boundary layer and be absorbed through the epithelium into the blood. Micelle-associated drug diffuses through the unstirred mucosal boundary layer and replenishes free drug as it is absorbed. Finally, drug-polymer colloids can also replenish free drug as it is absorbed and contribute to the effective diffusion rate. These colloids can be important depending on the rate-limiting step of absorption.

[0077] In both dissolution tests, the solid dispersion formulations exceeded the dissolution of Compound I alone with higher supersaturated solubility and better persistence.

[0078] Figures 1 and 2 show the results of the dissolution test. Figure 1 shows the dissolution data of the compositions, i.e., a solid dispersion (SD) of 1:3 Compound I free base hydrate:HPMCAS by weight (indicated as 25% HPMCAS); a solid dispersion (SD) of 1:1 Compound I free base hydrate:HPMCAS by weight (indicated as 50% HPMCAS); and a solid dispersion (SD) of 1:3 Compound I free base hydrate:HPMC by weight (indicated as hydroxypropyl methylcellulose, 25% HPMC), compared to Compound I free base hydrate alone. Error bars represent standard deviation. As shown in Figure 1, the solid dispersion of Compound I (25% HPMCAS) comprising Compound I and HPMCAS in a 1:3 weight ratio had a superior dissolution profile compared to the other compositions under these test conditions.

[0079] FIG. 2 shows the speciation data from the dissolution study. The solubility of amorphous Compound I was approximately 15 μg / mL. The free drug concentration of crystalline Compound I was comparable to that of amorphous Compound I. In contrast, the free drug concentration of Compound I in the solid dispersions ranged from 133 to 142 μg / mL. For this study, the potency of all samples was analyzed so that all formulations were tested at comparable concentrations. All solid dispersion formulations had improved free drug concentrations compared to crystalline Compound I.

[0080] Unexpectedly, it was also observed that the 25% Compound I:HPMCAS solid dispersion had a much higher concentration of drug in the form of drug-polymer colloid. In particular, a disproportionately high concentration of drug-polymer colloid in 25% Compound I:HPMCAS (529 μg / mL) was observed compared to the drug-polymer colloid concentration in 50% Compound I:HPMCAS (18 μg / mL). The colloidal species increased the drug concentration to 671 μg / mL, about 500 μg / mL higher than the free drug value. As mentioned above, it is known that drug-polymer colloids can resupply free drug as they are absorbed and contribute to the effective diffusion rate, and colloids can be important in some rate-limiting steps of absorption. Thus, it is believed that the surprisingly high concentration of drug in the form of drug-polymer colloid, in addition to the drug in free drug form, contributes to the bioavailability of Compound I.

[0081] Example 3-2: Dissolution test A solid dispersion comprising Compound I:HPMCAS in a 1:2 ratio ("33.3% HPMCAS") was prepared from 2.7 grams of Compound I free base hydrate crystal form B and 5.3 grams of HPMCAS (Shin-Etsu Chemical Co., L grade, F particle size (≦10 micron particle size)) using a procedure similar to that of Example 1. Briefly, 2 mg of test compound / mL in 0.9 mL of gastric buffer was transferred to a final dose of 1 mg / mL in 1.8 mL of 0.5% SIF in PBS, pH 6.5 at room temperature, resulting in a total volume of 1.8 mL of test solution. These samples were centrifuged at 15,800 g for 1 minute. At the designated time points, 50 μL aliquot samples were diluted 6-fold with 50 / 50 acetonitrile / water and assayed by HPLC.

[0082] The solid dispersions were evaluated using the G-IB dissolution test described in Example 3-1, along with a 25% Compound I:HPMCAS solid dispersion ("25% HPMCAS") and a 95.3% Compound I (free base hydrate, "crystalline API"), and the results are shown in Table 2.

[0083] [Table 2]

[0084] The results of the dissolution test are shown in Figure 3. Again, the solid dispersion of Compound I (25% HPMCAS) comprising Compound I and HPMCAS in a 1:3 weight ratio had a superior dissolution profile under these test conditions compared to the other compositions.

[0085] Example 4: Pharmacokinetic (PK) Study Compound I was orally administered to beagle dogs (n=3) at a dose of 10 mg / kg in various amorphous spray-dried dispersion formulations. Compound I was administered by oral gavage (PO) at a concentration of 25 mg / mL in 0.5% Methocel "A" suspension vehicle at a dose volume of 0.4 mL / kg to achieve a dose level of 10 mg / kg. "0.5% Methocel "A" suspension vehicle" was prepared by heating 30 mL of deionized water to approximately 90°C with stirring. After cooling, 0.5 g of Methocel "A" (Dow Methocel A4M Premium) was added to the water and stirred until well dispersed, followed by the addition of 70 mL of deionized water and further stirring in an ice bath. The vehicles were stored under refrigerated conditions for up to one week. Suspensions of Compound I were made by placing the solid dispersion in a mortar and adding 0.5% Methocel "A" suspension vehicle in increments, mixing with a pestle between additions. The suspension was transferred to a flask and stirred for 1 minute.

[0086] Blood samples (approximately 1.3 mL) were collected from the jugular vein into tubes containing potassium EDTA at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after dosing. Samples were centrifuged (10 min at 3,000 × g +4°C) and the resulting plasma was separated from the red blood cell pellet and stored at -20°C until biological analysis.

[0087] Compound I was extracted using protein precipitation. Plasma samples were thawed after storage at -20°C, and 50 μL aliquots were precipitated with 150 μL acetonitrile containing a suitable internal standard (IS), such as an analog of Compound I, such as a compound described in WO2017 / 068412. Calibration standards and quality controls were prepared in plasma and similarly extracted. All samples were centrifuged at 4700 rpm at +4°C for 20 minutes. The supernatant was analyzed using reversed-phase liquid chromatography mass spectrometry (LC-MS / MS).

[0088] Noncompartmental pharmacokinetic analysis was performed using Phoenix 6.3.0.395® (Certara USA, Inc.) software. Parameters calculated included clearance, time to maximum observed concentration (Tmax), maximum concentration (Cmax), terminal half-life, area under the curve (AUC) from time of administration to the last measurable concentration (AUC0-t), and extrapolated to infinity (AUC0-∞).

[0089] FIG. 4A shows the plasma concentration of compound I in the dog PK study of this example, and FIG. 4B shows the AUC of the test composition. The following Tables 3 and 4 show the results of the dog PK study described in this example. Table 3 summarizes the mean plasma pharmacokinetic parameters of compound I after oral administration at 10 mg / kg as a spray-dried dispersion formulation. Table 4 shows the bioequivalence of compound I after oral administration at 10 mg / kg as a spray-dried dispersion formulation in various formulations. TPGS refers to D-α-tocopheryl polyethylene glycol 1000 succinate. Comparative formulation is a non-solid dispersion formulation.

[0090] [Table 3]

[0091] [Table 4]

[0092] As shown in Table 3, the maximum exposure was obtained with the 25% HPMCAS-M batch, which showed comparable exposure to the 80% propylene glycol, 10% ethanol, 10% TPGS formulation. However, the 50% HPMCAS and 25% HPMC batches showed reduced oral exposure compared to the 25% HPMCAS-M batch and the 80% propylene glycol, 10% ethanol, 10% TPGS formulation (Table 3).

[0093] This study demonstrated that solid dispersions of Compound I comprising a 1:3 weight ratio of Compound I to HPMCAS had a desirable PK profile under these study conditions as demonstrated by plasma concentrations and AUC and C. Unexpectedly, the compositions also demonstrated smaller exposure variability as shown by the smaller error bars for the 25% HPMCAS composition compared to the 50% HPMCAS composition I in Figure 4B.

[0094] As shown in Figure 4C, the 50% HPMCAS-M and 25% HPMC test samples showed reduced oral exposure compared to both the 25% HPMCAS-M batch and the 33.33% HPMCAS-L batch. Test samples were dosed at 10 mg / Kg. Do was calculated as follows:

number

[0095] Example 5: Primate studies A total of six animals were used in a three-way (2+2+2) crossover design, with two animals receiving Compound I in powder-in-bottle (PiB) suspension in reconstitution vehicle (20 mg / kg), two animals receiving Compound I solid dispersion suspension (20 mg / kg) of Example 1, and two animals receiving Compound I in tablet form (20 mg / kg) of Example 2, on each of three dosing occasions. The reconstitution vehicle comprised propylene glycol USP 80.0% w / w; ethanol USP 10.0% w / w; vitamin E TPGS USP 10.0% w / w, totaling 100.0% w / w.

[0096] The dosing in this study was performed under fasting conditions. On the second and third dosing (days 8 and 15), the compound I formulation for administering to animals was reversed, respectively, so that all six animals finally received compound I in three different formulations (PiB in reconstitution vehicle, solid dispersion suspension, or tablet) after completing three oral doses. Solid dispersion suspension refers to a 5% suspension of the solid dispersion of Example 1 above in methocel.

[0097] Animals were closely observed for the first 12 hours after each dose and once daily on non-dosing days. Body weight was measured and recorded before dosing, and blood samples for pharmacokinetic profiling were taken for all animals at the designated time points. No clinical signs were observed as a result of compound I treatment. Compound I was orally administered three times at 20 mg / kg, 7 days apart, in the form of powder-in-bottle formulation, solid dispersion suspension, or tablet, and was well tolerated by monkeys. Prior to sample analysis, partial qualification of the method for determining the concentration of compound I in monkey plasma by LC-MS / MS was successfully performed in the dynamic assay range of 1 to 2,000 ng / mL. All plasma samples obtained in this study were analyzed by this method, and the plasma concentrations of compound I were expressed in ng / mL.

[0098] FIG. 5A shows the plasma concentration (AUClast) of Compound I in the primate PK study of this embodiment, FIG. 5B shows the plasma concentration (Cmax) of Compound I, and FIG. 5C shows the AUC (estimated) of the test composition. Error bars represent standard deviation. SD refers to solid dispersion. PiB refers to powder-in-bottle. Tablet refers to the tablet composition of Example 2 above. AUClast refers to the area under the concentration-time curve from administration (time 0) to the time of the last measured concentration (24 hours).

[0099] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0100] The invention illustratively described herein can be suitably implemented in the absence of any element or elements, or limitation or limitations not specifically disclosed herein. Thus, for example, terms such as "comprises", "includes", "contains", etc., shall be read expansively and without limitation. Furthermore, the terms and expressions employed herein are used as terms of description and not of limitation, and the use of such terms and expressions is not intended to exclude any equivalents of the features shown and described or portions thereof, and it is recognized that various modifications are possible within the scope of the invention as claimed.

[0101] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated herein by reference in their entirety to the same extent as if each was individually incorporated herein by citation. In the case of conflict, the present specification, including definitions, will control.

[0102] While the present disclosure has been described in conjunction with the above embodiments, it should be understood that the foregoing description and examples are intended to illustrate, but not limit, the scope of the present disclosure. Other aspects, advantages, and modifications within the scope of the present disclosure will be apparent to those skilled in the art to which the present disclosure pertains.

Claims

1. formula: 【Chemical 1】 or a pharmaceutically acceptable salt or solvate thereof, and a water-soluble polymer.

2. 2. The composition of claim 1, wherein the water-soluble polymer is polyvinylpyrrolidone / vinyl acetate (PVPVA), hydroxypropyl methylcellulose (HPMC), or hydroxypropyl methylcellulose acetate succinate (HPMCAS).

3. 2. The composition of claim 1, wherein the water-soluble polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS).

4. 10. The composition of claim 1 comprising Compound I free base hydrate.

5. 10. The composition of claim 1 comprising Compound I free base monohydrate.

6. formula: 【Chemistry 2】 or a pharmaceutically acceptable salt or solvate thereof, A solid dispersion in which Compound I, or a pharmaceutically acceptable salt or solvate thereof, is molecularly dispersed within a polymer matrix comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS).

7. 7. The solid dispersion of claim 6, wherein Compound I, or a pharmaceutically acceptable salt or solvate thereof, is present in the solid dispersion in an amount of about 20% to about 50% by weight of the solid dispersion.

8. 7. The solid dispersion of claim 6, wherein Compound I, or a pharmaceutically acceptable salt or solvate thereof, is present in the solid dispersion in an amount of about 20% to about 40% by weight of the solid dispersion.

9. 7. The solid dispersion of claim 6, wherein Compound I, or a pharmaceutically acceptable salt or solvate thereof, is present in the solid dispersion in an amount of about 20% to about 30% by weight of the solid dispersion.

10. 7. The solid dispersion of claim 6, wherein Compound I, or a pharmaceutically acceptable salt or solvate thereof, is substantially amorphous.

11. 7. The solid dispersion of claim 6, wherein at least 98% of Compound I, or a pharmaceutically acceptable salt or solvate thereof, is in amorphous form.

12. 7. The solid dispersion of claim 6, wherein Compound I is a free base or a solvate thereof.

13. 7. The solid dispersion of claim 6, wherein Compound I is a free base hydrate.

14. 7. The solid dispersion according to claim 6, wherein the weight ratio of Compound I or a pharmaceutically acceptable salt or solvate thereof in the solid dispersion to the weight of HPMCAS in the solid dispersion is from about 1:1 to about 1:

5.

15. 7. The solid dispersion according to claim 6, wherein the weight ratio of Compound I or a pharmaceutically acceptable salt or solvate thereof in the solid dispersion to the weight of HPMCAS in the solid dispersion is from about 1:2 to about 1:

4.

16. 7. The solid dispersion of claim 6, wherein the ratio of the weight of Compound I in the solid dispersion to the weight of HPMCAS in the solid dispersion is about 1:

3.

17. 17. The solid dispersion of any one of claims 6 to 16, wherein HPMCAS is present in an amount greater than about 50% by weight of the solid dispersion.

18. 17. The solid dispersion of any one of claims 6 to 16, wherein HPMCAS is present in an amount of about 60% to about 80% by weight of the solid dispersion.

19. A pharmaceutical composition comprising the solid dispersion according to any one of claims 6 to 16.

20. 20. The pharmaceutical composition of claim 19, wherein the composition is formulated as a tablet.

21. 20. The pharmaceutical composition of claim 19, wherein the composition is formulated as a tablet comprising an inner granular layer and an outer granular layer.

22. 21. The pharmaceutical composition of claim 20, wherein the solid dispersion comprises about 40% to 70% by weight of the tablet.

23. 21. The pharmaceutical composition of claim 20, wherein the solid dispersion comprises about 60% by weight of the tablet.

24. The inner granule layer of the tablet is about 8-18% by weight of microcrystalline cellulose; about 8-18% by weight lactose monohydrate; about 2-8% by weight of croscarmellose sodium; about 0.5 to 2% by weight of non-fumed silica; and Approximately 0.1 to 0.5% by weight of magnesium stearate 22. The pharmaceutical composition of claim 21, further comprising:

25. The outer granular layer of the tablet is about 0-14% by weight of microcrystalline cellulose; about 0-14% by weight of lactose monohydrate; about 2-8% by weight of croscarmellose sodium; about 0.5 to 2% by weight of non-fumed silica; and Approximately 0.1 to 0.5% by weight of magnesium stearate 22. The pharmaceutical composition of claim 21, comprising:

26. 21. The pharmaceutical composition of claim 20, wherein the tablet is film coated.

27. a solid dispersion comprising a compound of formula: 【Chemistry 3】 or a pharmaceutically acceptable salt or solvate thereof, A tablet, wherein Compound I, or a pharmaceutically acceptable salt or solvate thereof, is molecularly dispersed in a polymer matrix comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS); and the weight ratio of Compound I, or a pharmaceutically acceptable salt or solvate thereof, in the solid dispersion to the weight of HPMCAS in the solid dispersion is about 1:1 to about 1:

5.

28. 28. The tablet of claim 27, wherein the ratio by weight of Compound I or a pharmaceutically acceptable salt or solvate thereof in the solid dispersion to the weight of HPMCAS in the solid dispersion is from about 1:2 to about 1:

4.

29. 28. The tablet of claim 27, wherein the ratio of the weight of Compound I in the solid dispersion to the weight of HPMCAS in the solid dispersion is about 1:

3.

30. 28. The tablet of claim 27, wherein Compound I, or a pharmaceutically acceptable salt or solvate thereof, is substantially amorphous.

31. 28. The tablet of claim 27, wherein at least 98% of Compound I, or a pharmaceutically acceptable salt or solvate thereof, is in amorphous form.

32. 28. The tablet of claim 27, wherein Compound I is the free base or a solvate thereof.

33. 28. The tablet of claim 27, wherein Compound I is a free base hydrate.

34. 28. The tablet of claim 27, wherein Compound I is the free base monohydrate.

35. formula: 【Chemistry 4】 or a pharmaceutically acceptable salt or solvate thereof, a solid dispersion of about 60% by weight of Compound I, or a pharmaceutically acceptable salt or solvate thereof, and HPMCAS, wherein Compound I, or a pharmaceutically acceptable salt or solvate thereof, is substantially amorphous and molecularly dispersed in a polymer matrix comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS), and the ratio by weight of Compound I, or a pharmaceutically acceptable salt or solvate thereof, in the solid dispersion to the weight of HPMCAS in the solid dispersion is about 1:3; About 14% by weight of microcrystalline cellulose; About 13.5% by weight of lactose monohydrate; About 6% by weight of croscarmellose sodium; about 1% by weight of non-fumed silica; and Approximately 0.25% by weight of magnesium stearate an inner granule portion comprising About 4% by weight of croscarmellose sodium; about 1% by weight of non-fumed silica; and Approximately 0.25% by weight of magnesium stearate an outer granule portion comprising A tablet composition comprising:

36. 36. The tablet composition of claim 35, wherein the HPMCAS has an acetyl content ranging from about 7 to about 11% by weight of the HPMCAS, and a succinoyl content ranging from about 10 to about 14% by weight of the HPMCAS.

37. 10. Use of the composition of claim 1 for treating cancer.

38. 10. A method of treating cancer, comprising administering the composition of claim 1 to an individual in need thereof.

39. 7. A process for preparing the solid dispersion of claim 6, comprising spray drying a solution of Compound I, or a pharmaceutically acceptable salt or solvate thereof, and HPMCAS in a solvent, wherein the solution has a solids loading of up to about 25% by weight.

40. 40. The process of claim 39, wherein the solvent is acetone or methanol.

41. 40. The process of claim 39, wherein the solid dispersion is prepared by spray drying a solution of Compound I, or a pharmaceutically acceptable salt or solvate thereof, and HPMCAS in acetone, the acetone solution having a solids loading of up to about 10% by weight.

42. 40. The process of claim 39, wherein Compound I is a free base hydrate.

43. 40. The process of claim 39, wherein Compound I is the free base monohydrate.

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