Solid dispersion containing substituted groups and pharmaceutical composition and method of preparation and use thereof

Abstract

The present invention provides a solid dispersion comprising an HIF-2α inhibitor, a pharmaceutical composition comprising the solid dispersion, and a method for treating HIF-2α-mediated diseases and conditions.

Description

Technology Field

[0001] Cross-reference regarding related applications

[0002] This application claims the benefit of U.S. provisional application No. 62 / 752,685 filed on October 30, 2018, which is incorporated by reference into the disclosure of this application. Background Technology

[0003] Adequate oxygen supply to tissues is essential for maintaining mammalian cell function and physiology. Deficiency in oxygen supply to tissues is characteristic of many pathophysiological conditions where blood flow is insufficient to provide adequate oxygenation. A hypoxic environment in tissues activates signaling cascades that drive the induction or repression of transcription of numerous genes involved in events such as angiogenesis, glucose metabolism, and cell survival / apoptosis. The key to these hypoxic transcriptional responses lies in the transcription factor Hypoxia-Inducible Factor (HIF). HIF is dysregulated in a wide range of cancers through hypoxia-dependent and hypoxia-independent mechanisms, and its expression is associated with poor patient prognosis.

[0004] HIF consists of an oxygen-sensitive HIFα subunit and a constitutively expressed HIFβ subunit. When HIF is activated, the HIFα and HIFβ subunits assemble into a functional heterodimer (the α subunit heterodimerizes with the β subunit). Both HIFα and HIFβ possess two identical structural features: a basic helix-loop-helix (bHLH) and a PAS domain (PAS is an acronym for the first protein, PER, ARNT, SIM, where this motif is identified). Three oxygen-sensitive human HIFα subunits exist (HIF-1α, HIF-2α, and HIF-3α). Of the three subunits, HIF-1α is the most ubiquitously expressed in many cell and tissue types and is induced by low oxygen concentrations. HIF-2α is highly similar to HIF-1α in both structure and function, but exhibits more restricted cell and tissue-specific expression and can also be differentially regulated by nuclear translocation. HIF-3α also exhibits conservation with HIF-1α and HIF-2α in the HLH and PAS domains. HIF-1β (also referred to as ARNT - aryl hydrocarbon acceptor nuclear translocator), the dimerization partner of the HIFα subunit, is constitutively expressed in all cell types and is not regulated by oxygen concentration. List of literature disclosing background technology - Reference 1: International Publication WO2016 / 145045 A1 (September 15, 2016) - Reference 2: U.S. Patent Application Publication US2009 / 0143423 A1 (June 4, 2009) - Reference 3: U.S. Patent Application Publication US2016 / 0152565 A1 (June 2, 2016) - Reference 4: International Publication WO2010 / 068794 A2 (June 17, 2010)

[0005] In a particular aspect, the present disclosure provides a solid dispersion comprising a compound of formula (I):

[0006] .

[0007] In some embodiments, the solid dispersion further comprises a pharmaceutically acceptable polymer. The polymer may comprise hydrophobic and hydrophilic regions. In some embodiments, the polymer is selected from cellulose esters; cellulose ethers; polyalkylene oxides; polyvinyl chloride; polyvinyl alcohols; polyacrylates; polymethacrylates; homopolymers and copolymers of N-vinyl lactam, polyacrylamide, and vinyl acetate; graft copolymers of polyethylene glycol, polyvinyl caprolactam, and polyvinyl acetate; oligosaccharides; polysaccharides; and mixtures thereof. In some embodiments, the polymer is a cellulose ester or a cellulose ether. In some embodiments, the polymer is methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, cellulose acetate phthalate (CAP), hypromellose (HPMC), hydroxypropyl cellulose, hypromellose phthalate (HPMCP), hypromellose acetate succinate (HPMCAS), poly(ethylene glycol) methyl, poly-ethylene glycol vinyl acetate vinylcaprolactam (Soluplus), polyethylene glycol 6000 (PEG 6000), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone vinyl acetate (PVP-VA), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1 (e.g., Eudragit RS 100), methacrylic acid copolymer type B (e.g., Eudragit S 100), methacrylic acid copolymer type B, polyvinyl Acetate phthalate (e.g., Sureteric), polyoxyethylene-polyoxypropylene block copolymer (e.g., Pluronic F-68) and polyoxyethylene (20) sorbitan monooleate (Tween 80). In some embodiments, the polymer is selected from HPMCAS, CAP and poly-ethylene glycol vinyl acetate vinylcaprolactam (e.g., Soluplus).In some embodiments, the polymer is selected from HPMCAS-L, HPMCAS-M, and HPMCAS-H, e.g., HPMCAS-H.

[0008] In some embodiments, the compound of formula (I) is present in an amount of 1 wt% to 50 wt% of the solid dispersion. In some embodiments, the polymer is present in an amount of 50 wt% to 99 wt% of the solid dispersion. In some embodiments, the compound of formula (I) is present in an amount of 15 wt% to 35 wt% of the solid dispersion. In some embodiments, the polymer is present in an amount of 65 wt% to 85 wt% of the solid dispersion. In some embodiments, the compound of formula (I) is present in an amount of 22.5 wt% to 27.5 wt% of the solid dispersion. In some embodiments, the polymer is present in an amount of 72.5 wt% to 77.5 wt% of the solid dispersion. In some embodiments, the compound of formula (I) is present in an amount of about 25 wt% of the solid dispersion. In some embodiments, the polymer is present in an amount of about 75 wt% of the solid dispersion. In some embodiments, the weight ratio of the compound of formula (I) to the polymer is 1:99 to 1:1, e.g., 15:85 to 35:65. In some embodiments, the weight ratio of the compound of formula (I) to the polymer is 22.5:77.5 to 27.5:72.5, e.g., about 25:75.

[0009] In some embodiments, the solid dispersion is substantially amorphous. In some embodiments, the solid dispersion is amorphous. In some embodiments, the solid dispersion has a glass transition temperature (T) of 80 to 100°C, e.g., 82 to 92°C. g ) indicates. In some embodiments, the solid dispersion has a glass transition temperature (T) of about 87°C, e.g. 87 ± 3°C. g...represents ). In some embodiments, the solid dispersion contains less than 2 weight percent of impurities. In some embodiments, the solid dispersion contains less than 2 weight percent of impurities after storage at room temperature for 3 months. In some embodiments, the solid dispersion contains less than 2 weight percent of water. In some embodiments, the solid dispersion contains less than 2% of water after storage at room temperature for 3 months. In some embodiments, the solid dispersion contains less than 5000 ppm of acetone. In some embodiments, the excess rate of the enantiomer of the compound of formula (I) is at least 95%, e.g., at least 99%.

[0010] In some embodiments, the particle size distribution of the solid dispersion is less than 6 μm. 10 It is characterized by. In some embodiments, the particle size distribution of the solid dispersion is d of less than 18 μm. 50 It is characterized by. In some embodiments, the particle size distribution of the solid dispersion is d of less than 45 μm. 90 It is characterized by. In some embodiments, the solid dispersion is characterized by a bulk density of at least 0.20 g / mL. In some embodiments, the solid dispersion is characterized by a tap density of at least 0.35 g / mL. In some embodiments, the particle size distribution of the solid dispersion is d less than 15 μm. 10 It is characterized by. In some embodiments, the particle size distribution of the solid dispersion is d of less than 45 μm. 50 It is characterized by. In some embodiments, the particle size distribution of the solid dispersion is d of less than 90 μm. 90 It is characterized by. In some embodiments, the solid dispersion is characterized by a bulk density of at least 0.15 g / mL. In some embodiments, the solid dispersion is characterized by a tap density of at least 0.30 g / mL. In some embodiments, the solid dispersion is characterized by a C of at least 300 μgA / mL. max It features GB. In some embodiments, the solid dispersion has at least 400 μgA / mL of Cmax It is characterized by FaSSIF. In some embodiments, the solid dispersion is characterized by an AUC FaSSIF of at least 40,000 μgA / mL. In some embodiments, the solid dispersion is characterized by an AUC FaSSIF of at least 85,000 μgA / mL. In some embodiments, the solid dispersion is obtained by spray drying. In some embodiments, the solid dispersion is obtained by melting, solvent evaporation, spray drying, fusion, kneading, co-grinding, freeze-drying, hot melt extrusion, melt aggregation, or supercritical fluid technology.

[0011] In certain aspects, the present disclosure is based on weight relative to the total weight of the solid dispersion,

[0012] (a) 22.5% to 27.5% of the compound of formula (I):

[0013] ; and

[0014] (b) HPMCAS 72.5% to 77.5%

[0015] Provides an amorphous solid dispersion containing

[0016] In certain aspects, the present disclosure provides a pharmaceutical composition comprising the solid dispersion and pharmaceutically acceptable excipients described herein. In some embodiments, the pharmaceutical composition is a capsule or a tablet. In some embodiments, the pharmaceutical composition is formulated for oral delivery. In some embodiments, the pharmaceutically acceptable excipients include a binder, a filler, a disintegrant, a lubricant, a lubricant, or a combination thereof. In some embodiments, the solid dispersion is present in an amount of 15% to 50% by weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises, by weight relative to the total weight of the pharmaceutical composition: (a) 15% to 50% of the solid dispersion; (b) 20% to 50% of the binder; (c) 20% to 40% of the filler; (d) 1.0% to 5.0% of the disintegrant; and (e) 0.25% to 1.25% of the lubricant. In some embodiments, the binder is microcrystalline cellulose. In some embodiments, the filler is mannitol. In some embodiments, the disintegrant is sodium croscarmellose. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the pharmaceutical composition further comprises 0.1% to 1.25% by weight relative to the total weight of the pharmaceutical composition, optionally wherein the lubricant is colloidal silicon dioxide. In some embodiments, the pharmaceutical composition further comprises a coating, optionally wherein the coating is a poly(vinyl) alcohol polymer-based coating. In certain embodiments, the poly(vinyl) alcohol polymer-based coating in the pharmaceutical composition further comprises polyethylene glycol. In specific embodiments, the pharmaceutical composition has a coating that is OpaDry II.

[0017] In certain aspects, the present disclosure provides a packaged solid dispersion comprising the solid dispersion and a desiccant described herein. In some embodiments, the desiccant is SiO2. In some embodiments, the packaging comprises a low-water vapor permeable container.

[0018] In certain aspects, the present disclosure provides a method for treating VHL disease, comprising administering an effective amount of the solid dispersion or pharmaceutical composition described herein to a subject requiring treatment for VHL disease. In some embodiments, the subject also suffers from a hemangioma, a pheochromocytoma, a pancreatic neuroendocrine tumor, or a renal cell carcinoma, such as a renal cell carcinoma. The present disclosure also provides a method for treating renal cell carcinoma, comprising administering an effective amount of the solid dispersion or pharmaceutical composition described herein to a subject requiring treatment for renal cell carcinoma. In some embodiments, the renal cell carcinoma is a clear cell renal cell carcinoma.

[0019] In certain aspects, the present disclosure provides a method for treating an HIF-2α-mediated disease or condition, comprising administering a therapeutically effective amount of the solid dispersion or pharmaceutical composition described herein to a subject requiring treatment for the HIF-2α-mediated disease or condition. In some embodiments, the disease or condition is cancer. In some embodiments, the disease or condition is selected from renal cell carcinoma, von Hippel-Lindau disease, pulmonary arterial hypertension, glioblastoma, and colitis. The present disclosure also provides a method for inhibiting HIF-2α, comprising contacting HIF-2α with an effective amount of the solid dispersion or pharmaceutical composition described herein. The method described herein may further comprise administering a second therapeutic agent.

[0020] In a particular aspect, the present disclosure provides a method for preparing the solid dispersion described herein, comprising the steps of: (a) providing a solution of the compound of formula (I) and the polymer in a solvent; and (b) removing the solvent to provide a solid dispersion. In some embodiments, the solvent comprises acetone, methyl ethyl ketone, tetrahydrofuran, water, or a combination thereof. In some embodiments, the solvent comprises acetone. In some embodiments, the solvent comprises up to 5% water. In some embodiments, the solvent is removed by freeze-evaporation or spray drying. In some embodiments, the solvent is removed by spray drying. The method may further comprise drying the solid dispersion in a tray dryer to remove residual solvent. In some embodiments, the solution comprises 8% by weight to 14% by weight of solid.

[0021] In a particular aspect, the present disclosure provides a pharmaceutical solid dosage form for oral delivery of a compound of formula (I), and

[0022]

[0023] The solid dosage form comprises (a) a solid dispersion containing a compound of formula (I); and (b) one or more pharmaceutically acceptable excipients. In some embodiments, the solid dosage form is a capsule or a tablet. In some embodiments, the solid dosage form is a tablet. In some embodiments, one or more pharmaceutically acceptable excipients include a binder, a filler, a disintegrant, and a lubricant. In some embodiments, the solid dispersion is present in an amount of 15% to 50% by weight of the solid dosage form. In some embodiments, the solid dispersion contains a pharmaceutically acceptable polymer. In some embodiments, the pharmaceutically acceptable polymer is HPMCAS. In some embodiments, the polymer is present in an amount of 15% to 35% by weight of the solid dosage form. In some embodiments, the compound of formula (I) is present in an amount of 1% to 15% by weight of the solid dosage form. The solid dosage form may contain 5 mg to 100 mg of the compound of formula (I), for example, about 10 mg of the compound of formula (I) or about 40 mg of the compound of formula (I).

[0024] The solid dosage form of the present disclosure may contain a binder in an amount of 20% to 50% by weight of the solid dosage form, optionally the binder is microcrystalline cellulose. The solid dosage form may contain a filler in an amount of 20% to 40% by weight of the solid dosage form. In some embodiments, the solid dosage form comprises an intragranular filler and an extragranular filler, wherein the intragranular filler is present in an amount of 12% to 22% by weight of the solid dosage form, and the extragranular filler is present in an amount of 8% to 18% of the solid dosage form. In some embodiments, the filler is mannitol. The solid dosage form may contain a disintegrant in an amount of 1.0% to 5.0% by weight of the solid dosage form. In some embodiments, the solid dosage form comprises an intragranular disintegrant and an extragranular disintegrant, wherein the intragranular disintegrant is present in an amount of 0.9% to 3.0% by weight of the solid dosage form and the extragranular disintegrant is present in an amount of 0.1% to 2.0% of the solid dosage form. In some embodiments, the disintegrant is sodium croscarmellose. The solid dosage form may comprise a lubricant in an amount of 0.25% to 1.25% by weight of the solid dosage form. In some embodiments, the solid dosage form comprises an intragranular lubricant and an extragranular lubricant, wherein the intragranular lubricant is present in an amount of 0.15% to 0.75% by weight of the solid dosage form and the extragranular lubricant is present in an amount of 0.10% to 0.50% of the solid dosage form. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the solid dosage form contains a lubricant in an amount of 0.10% to 1.25% by weight of the solid dosage form. In some embodiments, the lubricant is colloidal silicon dioxide, e.g., CabOSil. In some embodiments, the solid dosage form contains a coating. In some embodiments, the coating is PVA-based, e.g., Opadry II.

[0025] The solid dosage form of the present disclosure may exhibit a hardness of 5 to 25 kP. In some embodiments, the weight of the solid dosage form is 50 to 750 mg, e.g., about 125 mg or about 500 mg. In some embodiments, the solid dosage form contains less than 2 weight percent impurities. In some embodiments, the solid dosage form contains less than 2 weight percent impurities after 6 months of storage at room temperature. In some embodiments, the solid dosage form contains less than 3 weight percent water. In some embodiments, the solid dosage form contains less than 3 weight percent water after 6 months of storage at room temperature. In some embodiments, the solid dosage form is characterized by a disintegration time of 1 to 5 minutes.

[0026] In certain aspects, the present disclosure provides a packaged solid dosage form comprising the solid dosage form described herein and a desiccant. In some embodiments, the desiccant is SiO2. In some embodiments, the packaging comprises a low-water vapor permeable container. The packaged dosage form may further comprise a cotton, rayon, or polyester coil. The present disclosure also provides a kit comprising the solid dosage form described herein and instructions for administering the solid dosage form to a subject who requires it.

[0027] In certain aspects, the present disclosure provides a method for treating VHL disease, comprising administering the solid dosage form described herein to a subject requiring treatment for VHL disease. In some embodiments, the subject also suffers from a hemangioma, a pheochromocytoma, a pancreatic neuroendocrine tumor, or a renal cell carcinoma, such as a renal cell carcinoma. The present disclosure also provides a method for treating renal cell carcinoma, comprising administering the solid dosage form described herein to a subject requiring treatment for renal cell carcinoma. In some embodiments, the renal cell carcinoma is a clear cell renal cell carcinoma.

[0028] In certain aspects, the present disclosure provides a method for treating an HIF-2α-mediated disease or condition, comprising administering the solid dosage form described herein to a subject requiring treatment for the HIF-2α-mediated disease or condition. In some embodiments, the disease or condition is cancer. In some embodiments, the disease or condition is selected from renal cell carcinoma, von Hippel-Lindau disease, pulmonary arterial hypertension, glioblastoma, and colitis. The present disclosure also provides a method for inhibiting HIF-2α, comprising bringing HIF-2α into contact with the solid dosage form described herein. Any of the target methods may further comprise administering a second therapeutic agent.

[0029] In a particular aspect, the present disclosure provides a method for producing a solid dosage form described herein, comprising: (a) mixing a compound of formula (I) and one or more pharmaceutically acceptable excipients to form milled granules; and (b) compressing the granules by applying a compressive force of 5 kN to 20 kN. The present disclosure also provides a method for producing a solid dosage form described herein, comprising: (a) blending a compound of formula (I), a binder, a filler, a disintegrant, and a lubricant to form a blended mixture; (b) granulating the blended mixture using optional roller presses to form a granulated mixture; (c) mixing a second filler, a second disintegrant, and a second lubricant with the granulated mixture to form a tablet mixture; and (d) compressing the tablet mixture into a tablet, wherein the filler and the second filler are the same or different; the disintegrant and the second disintegrant are the same or different; and the lubricant and the second lubricant are the same or different. In some embodiments, the method further comprises mixing a lubricant with the granulated mixture of (c). In some embodiments, the process further comprises coating the tablet, e.g., with Opadry II.

[0030] Include as a reference

[0031] All disclosures, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as specifically and individually specified that each individual disclosure, patent, or patent application is incorporated by reference. Brief explanation of the drawing

[0032] Figure 1 shows the XRPD pattern of a crystalline compound of chemical formula (I). Figure 2 shows an overlay of diffraction patterns of seven solid dispersions of the compound of formula (I), the crystalline compound of formula (I), and the spray-dried compound of formula (I). The two diffraction patterns of the latter are characterized by sharp and distinct peaks. Figure 3 shows an overlay of the diffraction patterns of three solid dispersions of the compound of formula (I) and the crystalline compound of formula (I). Figure 4 provides SEM images of the compound of formula (I) and solid dispersions of HPMCAS-H (left), CAP (middle), or Soluplus (right) at 5,000x magnification. Figure 5 shows three sets of overlays of XRPD patterns of a solid dispersion of the compound of formula (I) and the crystalline compound of formula (I). In each set, the upper wide curve represents a solid dispersion stored open for 4 weeks at 40°C and 75% RH, the middle wide curve represents a solid dispersion stored closed for 4 weeks under the same conditions, and the lower wide curve represents the solid dispersion before storage (t=0). The curve containing sharp and distinct peaks represents the crystalline compound of formula (I). Figure 6 shows the XRPD pattern of a solid dispersion of compound:HPMCAS-H of formula (I) in a 1:3 ratio. Figure 7 provides SEM images of a solid dispersion of compound (I) of formula 1:3:HPMCAS-H at magnifications of 500x (left) and 5,000x (right). Figure 8 shows the particle size distribution of a solid dispersion. Figure 9 shows HPLC traces of a blank (bottom trace), a compound of formula (I) (middle trace), and a solid dispersion of the compound of formula (I) and HPMCAS-H (top trace). Figure 10 shows the mDSC profile of a solid dispersion of compound of formula (I):HPMCAS-H at a 1:3 ratio after 24 hours of exposure to 33% humidity (upper curve), 50% humidity (middle curve), or 75% humidity (lower curve). Figure 11 provides XRPD patterns of wet solid dispersions maintained at room temperature for 1, 3, 5, or 7 days (top to bottom curves, respectively). Figure 12 provides the XRPD pattern of a solid dispersion of compound:HPMCAS-H of formula (I) in a 1:3 ratio. Figure 13 shows the particle size distribution of a solid dispersion. Figure 14 illustrates a process flow diagram for manufacturing a solid dosage form. Figure 15 shows the dissolution profiles of 10 and 40 mg tablets. Specific details for implementing the invention

[0033] Good manufacturing practices are typically required for the large-scale production of clinically useful drug candidates. A method for preparing a pharmaceutical composition comprising a compound of formula (I) is provided herein:

[0034] .

[0035] The compositions provided herein possess advantageous physical properties, which can provide benefits in processing, formulation, stability, bioavailability, storage, and handling, among other important pharmaceutical features. The methods described herein enable large-scale production in compliance with Good Manufacturing Practice (GMP) guidelines.

[0036] Unless otherwise specified, the compound referred to herein by the name 3-(((1S,2S,3R)-2,3-difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-indene-4-yl)oxy)-5-fluorobenzonitrile corresponds to the compound of the chemical formula (I) shown below.

[0037]

[0038] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a person skilled in the art to which this invention pertains.

[0039] The singular form used in the specification and claims includes the plural designation unless the context clearly indicates otherwise.

[0040] "Optional" or "opportunistically" means that the subsequently described event or situation may or may not occur, and that the description includes cases where the event or situation occurs and cases where it does not occur. For example, "opportunistically substituted aryl" means that the aryl group may or may not be substituted, and that the description includes both the substituted aryl group and the aryl group without substitution.

[0041] Compounds of formula (I) also include crystalline and amorphous forms of the compound, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, cocrystalline, polymorphic, pseudopolymorphic, solvate, hydrate, nonsolved polymorphic (including anhydride), stereomorphic, and amorphous forms of the compound, as well as mixtures thereof.

[0042] As used herein, the term “co-crystal” refers to a solid phase (which may or may not be crystalline) in which two or more different molecular and / or ionic components (generally in stoichiometric ratios) are held together by non-ionic interactions, including but not limited to hydrogen bonding, dipole-dipole interactions, dipole-quadripole interactions, or dispersion forces (van der Waals). There is no proton transfer between the different components, and the solid phase is neither a monosal nor a solvate. Discussions of co-crystals can be found, for example, in the literature [S. Aitipamula et al., Crystal Growth and Design. 2012, 12 (5), pp. 2147-2152].

[0043] As used herein, the term “solid form” refers to a compound that is not predominantly in a liquid or gaseous state. As used herein, the term “solid form” encompasses semi-solids. A solid form may be crystalline, amorphous, semicrystalline, semi-amorphous, or a mixture thereof. A “single-component” solid form containing a compound of formula (I) is essentially composed of the compound of formula (I). A “multi-component” solid form containing a compound of formula (I) contains one or more additional species, such as ions and / or molecules, within the solid form. For example, in a specific embodiment, an amorphous multi-component solid form containing a compound of formula (I) comprises one or more polymer(s) and a compound of formula (I) dispersed in a solid matrix containing the polymer(s).

[0044] The term "crystalline" means that, when used to describe a substance, compound, component, product, or form, the substance, compound, component, product, or form is substantially crystalline, as determined, for example, by X-ray diffraction.

[0045] The term “crystalline form” refers to a crystalline variant comprising a given material, including but not limited to single-component crystalline forms and multi-component crystalline forms, and including polymorphs, solvates, hydrates, co-crystals, other molecular complexes, salts, solvates of salts, hydrates of salts, co-crystals of salts, and other molecular complexes of salts, and their polymorphs. In some embodiments, the crystalline form of the material may substantially lack an amorphous form and / or other crystalline forms. In other embodiments, the crystalline form of the material may contain one or more amorphous form(s) and / or other crystalline form(s) in an amount of about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or less than 50% by weight. The crystalline form of the material may be obtained by a number of methods. These methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, recrystallization in a confined space, e.g., in a nanopore or capillary, recrystallization on a surface or on a template, e.g., on a polymer, recrystallization in the presence of additives, e.g., co-crystallized counter-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, grinding, and solvent-dropping grinding.

[0046] The terms “polymorph” and “polymorphic form” refer to two or more crystalline forms essentially composed of the same molecules, molecules, or ions. Different polymorphs may have different physical properties, such as melting temperature, heat of fusion, solubility, dissolution rate, and / or vibrational spectrum, as a result of different arrangements or stereotypes of molecules or ions within the crystal lattice. Differences in physical properties exhibited by polymorphs may affect pharmaceutical parameters, such as storage stability, compressibility, and density (important in formulation and product manufacturing), and dissolution rate (an important factor in bioavailability). Differences in stability may result from changes in chemical reactivity (e.g., differential oxidation, which causes a dosage form composed of one polymorph to discolor more rapidly than one composed of another polymorph), mechanical changes (e.g., tablets breaking during storage as a kinetically preferred polymorph transitions to a thermodynamically more stable polymorph), or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity). As a result of differences in solubility / dissolution, in extreme cases, some polymorphic transitions may result in a lack of efficacy, or in other extreme cases, toxicity. Additionally, the physical properties of the crystals can be important in processing; for example, one polymorph may be more likely to form solvates or may be difficult to filter and wash without impurities (for example, particle shape and size distribution may differ between polymorphs).

[0047] The terms “amorphous” and “amorphous form” are used herein to describe a material, component, or product that is not substantially crystalline as determined by X-ray diffraction. In certain embodiments, the amorphous form of a material may be substantially devoid of a crystalline form. In other embodiments, the amorphous form of a material may contain one or more crystalline forms in an amount of about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or less than 50% by weight. In other embodiments, the amorphous form of a material may include additional components or ingredients (e.g., additives, polymers, or excipients that may serve to further stabilize the amorphous form). In some embodiments, the amorphous form may be a solid solution. The amorphous form of a material may be obtained by a number of methods. These methods include, but are not limited to, heating, melt cooling, rapid melt cooling, solvent evaporation, rapid solvent evaporation, desolvation, sublimation, grinding, ball milling, cryogenic grinding, spray drying, and freeze drying.

[0048] Unless otherwise specified, the term “solid dispersion” refers to a solid state comprising at least two components, wherein one component is significantly evenly and homogeneously dispersed throughout the other components or components. This comprises a solid or glassy solution, that is, the dispersion of components exists in a manner that causes the composition to be chemically and physically homogeneous by property. In one embodiment, the first component is an active pharmaceutical ingredient (API), e.g., a compound of formula (I), and the second component is a matrix comprising a polymer, wherein the API is significantly and homogeneously dispersed within the matrix (polymer). The API may exist in an amorphous state or in a microcrystalline dispersion form. Additionally, the API may be available as a mixture of amorphous and crystalline forms. The solid dispersion may comprise more than two components. For example, two or more APIs may be dispersed in the matrix, and the matrix may comprise two or more polymers. Without limitation, solid dispersions may be physically classified as eutectic mixtures, solid solutions, glass solutions or suspensions, amorphous precipitates in glassy or crystalline carriers, composites, composite formations, or combinations of different systems. Additionally, solid dispersions may be prepared using various techniques known to those skilled in the art, for example, by co-dissolving API and a polymer in a solvent, followed by spray-drying, spray-condensing, evaporation, curing or microwavy, blending and direct compression, mechanical mixing at elevated but non-melting temperatures, wet granulation, extrusion-spheroidization, melt fusion, hot melt extrusion, etc. "Solid matrix" refers to a matrix that is solid.

[0049] The term "polymer" refers to a compound comprising repeating structural units (monomers) connected by covalent chemical bonds. Polymers may be further derivatized, crosslinked, grafted, or end-capped. Non-limiting examples of polymers include copolymers, terpolymers, quaternary polymers, and homologues. The term "polymer" refers to a polymer essentially composed of two or more different types of repeating structural units (monomers).

[0050] The terms “about” and “approximately,” when used in relation to quantity, refer to an amount within 30% of the specified amount, for example, within 20%, within 15%, within 10%, or within 5%.

[0051] The compounds described herein may represent their natural isotopic abundances, or one or more atoms may be artificially enriched with a specific isotope having the same atomic number but a different atomic mass or mass number from that which is predominantly found in nature. All isotopic variations of the compounds of this disclosure, whether radioactive or not, are encompassed within the scope of this disclosure. For example, hydrogen 1 H (light hydrogen), 2 H (deuterium), and 3 It has three naturally occurring isotopes, denoted by H (tritium). Deuterium is virtually the most abundant isotope of hydrogen. Deuterium enrichment can provide specific therapeutic benefits, such as increased in vivo half-life and / or exposure, or can provide compounds useful for investigating in vivo pathways of drug elimination and metabolism. Isotope-enriched compounds can be manufactured by conventional techniques widely known to those skilled in the art.

[0052] "Isomers" are different compounds having the same molecular formula. "Stereoisomers" are isomers that differ only in the way their atoms are arranged in space. "Enantiomers" are a pair of stereoisomers that are mirror images of each other and cannot be superimposed. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to designate racemic mixtures where appropriate. "Diastereoisomers" or "diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. If a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by R or S. Decomposed compounds whose absolute coordination is unknown may be designated as (+) or (-) depending on the direction in which they rotate plane polarization at the wavelength of the sodium D line (left-handed or right-handed). Specific compounds described herein contain one or more asymmetric centers and thus may produce enantiomers, diastereomers, and other stereoisomer forms, the asymmetric centers of which may be defined as (R)- or (S)- in terms of absolute stereochemistry. The chemicals, pharmaceutical compositions, and methods of the present invention are intended to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers, and mixtures of intermediates. Optically active (R)- and (S)-isomers may be prepared using chiral synthetic monomers or chiral reagents, or may be decomposed using conventional techniques. The optical activity of a compound can be analyzed through any suitable method, including but not limited to chiral chromatography and polarimetry, and the dominance of one stereoisomer over another isomer can be determined.

[0053] The isolation and purification of the chemicals and intermediates described herein may, if desired, be carried out by any suitable separation or purification procedure, such as filtration, extraction, crystallization, column chromatography, thin-layer chromatography, or thick-layer chromatography, or a combination thereof. Specific examples of suitable separation and isolation procedures may be referenced in the examples below. However, other equivalent separation or isolation procedures may also be used.

[0054] The terms "salt" or "pharmaceutical acceptable salt" refer to salts derived from various organic and inorganic counterions that are widely known in the relevant art. Pharmaceutically acceptable acid addition salts may be formed from inorganic acids and organic acids. Inorganic acids from which salts may be derived include, for example, hydrochloric acid, hydrobromide, sulfuric acid, nitric acid, phosphoric acid, etc. Organic acids from which salts may be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvate, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Pharmaceutically acceptable base addition salts may be formed from inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Specifically, they include, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0055] The term “pharmaceutical acceptable excipients” includes, but is not limited to, any ajuvant, carrier, excipient, binder, filler, disintegrant, lubricant, lubricant, sweetener, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration for use in humans or livestock.

[0056] The terms “effective dose” or “therapeutic effective dose” refer to an amount of the compound described herein sufficient to produce an intended application, including but not limited to the treatment of a disease as defined below. The therapeutic effective dose may vary depending on the intended therapeutic use (in vivo) or the subject and disease state to be treated, e.g., the subject’s body weight and age, the severity of the disease state, the method of administration, etc., which can be readily determined by a person skilled in the art. The above terms also apply to a dose that induces a specific response in target cells, e.g., a reduction in platelet adhesion and / or cell migration. The specific dose will vary depending on the specific compound selected, the subsequent administration regimen, whether it is administered in combination with other compounds, the timing of administration, the tissue to be administered, and the physical delivery system to be performed.

[0057] As used herein, “treatment” or “treating” refers to an approach to obtain a beneficial or intended result in relation to a disease, disorder, or medical condition, including but not limited to therapeutic benefits and / or preventive benefits. A therapeutic benefit means the eradication or improvement of the underlying disorder to be treated. Additionally, a therapeutic benefit is achieved by the eradication or improvement of one or more physiological symptoms associated with the underlying disorder such that improvement is observed in the subject, even though the subject may still suffer from the underlying disorder. In certain embodiments, for a preventive benefit, the composition is administered to a subject at risk of developing a specific disease, or to a subject in whom one or more physiological symptoms of such disease have been reported, even if a diagnosis of the disease may not have been made.

[0058] As used herein, the term "therapeutic effect" encompasses therapeutic benefits and / or preventive benefits as described above. Preventive effects include the delay or elimination of the onset of a disease or condition, the delay or elimination of the onset of symptoms of a disease or condition, the slowing, cessation, or reversal of the progression of a disease or condition, or any combination thereof.

[0059] As used herein, the terms “co-administration,” “administered in combination with,” and their grammatical equivalents encompass the administration of two or more agents to an animal, including humans, such that both the agent and / or its metabolite are simultaneously present in the subject. Co-administration includes simultaneous administration of individual compositions, administration of individual compositions at different times, or administration of a composition in which both agents are present.

[0060] The terms "antagonist" and "inhibitor" are used interchangeably and refer to compounds having the ability to inhibit the biological functions (e.g., activity, expression, binding, protein-protein interactions) of a target protein or enzyme (e.g., HIF-2α). Accordingly, the terms "antagonist" and "inhibitor" are defined in relation to the biological role of the target protein. A desirable antagonist specifically includes, within this definition, a compound that interacts specifically with the target (e.g., binds to it) but inhibits the biological activity of the target protein by interacting with another member of a signaling pathway of which the target protein is a member. The desirable biological activity inhibited by the antagonist is associated with inflammation.

[0061] As used herein, the term "agonist" refers to a compound having the ability to initiate or enhance the biological function of a target protein by inhibiting the activity or expression of the target protein. Accordingly, the term "agonist" is defined in relation to the biological role of the target polypeptide. A preferred agonist is also specifically included within this definition a compound that specifically interacts with the target (e.g., binds thereto) but initiates or enhances the biological activity of the target polypeptide by interacting with another member of a signaling pathway of which the target polypeptide is a member.

[0062] "Signal transduction" is the process by which stimulating or inhibitory signals are transmitted into and within a cell to elicit an intracellular response. Modulators of a signal transduction pathway refer to compounds that modulate the activity of one or more cellular proteins mapped to the same specific signal transduction pathway. Modulators can increase (agonists) or inhibit (antagonists) the activity of signal transduction molecules.

[0063] As used herein, the term "heteromerization" refers to a complex formed by the non-covalent bonding of HIF-2α to HIF-1β (ARNT). Heteromerization of HIF-2α with HIF-1β (ARNT) is required for HIF-2α DNA binding and transcriptional activity, which is mediated by the HLH and PAS-B domains. Transcriptional activity following the heteromerization of HIF-2α with HIF-1β (ARNT) can affect five groups of target genes, including angiogenesis factors, glucose transporters and glycolytic enzymes, stem-cell factors, survival factors, and invasion factors.

[0064] The term "HIF-2α" refers to a monomeric protein containing, in addition to a C-terminal regulatory region, three conserved structuring domains: a basic helix-loop-helix (bHLH), and two Per-ARNT-Sim (PAS) domains designated as PAS-A and PAS-B. "HIF-2α" is also known by several other alternative names in the scientific literature, most commonly known as Endothelial PAS Domain-Containing Protein 1 (EPAS-1) encoded by the EPAS1 gene. Alternative names include Basic-Helix-Loop-Helix-PAS Protein (MOP2). As a member of the bHLH / PAS family of transcription factors, "HIF-2α" forms an active heteromeric transcription factor complex by binding to the ARNT (also known as HIF-1β) protein through non-covalent interactions.

[0065] The term "HIF-2α PAS-B domain cavity" refers to an internal cavity within the PAS-B domain of HIF-2α. The crystal structure of the PAS-B domain may contain a large cavity (approximately 290 Å) in its core. However, in the solution structure, the amino acid side chains are dynamic. For example, such side chains may tend to intrude deeper into the core, which can contract the cavity into one or two smaller cavities or even expand the cavity. The cavity is surrounded by amino acid residues including PHE-244, SER-246, HIS-248, MET-252, PHE-254, ALA-277, PHE-280, TYR-281, MET-289, SER-292, HIS-293, LEU-296, VAL-302, VAL-303, SER-304, TYR-307, MET-309, LEU-319, THR-321, GLN-322, GLY-323, ILE-337, CYS-339, and ASN-341 of the HIF-2α PAS-B domain. The numbering system is from a known structure reported in the RCSB Protein Data Bank under PDB code 3H7W. Other numbering systems of PDB can define the same amino acids expressed above surrounding the cavity.

[0066] The term "cell proliferation" refers to the phenomenon in which the number of cells changes as a result of division. This term also encompasses cell growth in which the cell shape changes (e.g., increased size) in accordance with proliferative signals.

[0067] The term "selective inhibition" or "to selectively inhibit" refers to the ability of a biological agent to preferentially reduce target signaling activity compared to off-target signaling activity through direct or indirect interaction with a target.

[0068] "Subject" refers to an animal, e.g., a mammal, e.g., a human. The method described herein may be useful for both human treatment and veterinary application. In some embodiments, the subject is a mammal, and in some embodiments, the subject is a human. "Mammal" includes humans, and livestock of both laboratory animals and domestic pets (e.g., cats, dogs, pigs, cattle, sheep, goats, horses, rabbits), and non-livestock, e.g., wild animals.

[0069] The term "in vivo" refers to events occurring within the subject's body.

[0070] The term "in vitro" refers to events occurring outside the body of a subject. For example, in vitro tests encompass any test performed outside the subject. In vitro tests include cell-based tests where living or dead cells are used. In vitro tests also include cell-free tests where undamaged cells are not used.

[0071] The disclosure is also intended to encompass the in vivo metabolic products of the disclosed compound. These products may be produced primarily by enzymatic processes, for example, from the oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound. Accordingly, the disclosure includes compounds produced by a method comprising administering the compound of the disclosure to a mammal for a period sufficient to produce its metabolic products. These products are typically identified by administering the radiolabeled compound of the disclosure to an animal, e.g., a rat, mouse, guinea pig, monkey, or human, at a detectable dose, allowing sufficient time for metabolism to occur, and isolating its transformed products from urine, blood, or other biological samples.

[0072] The term "Opadry II" refers to an aqueous film coating manufactured by Colorcon having the specifications summarized in the table below:

[0073]

[0074] The chemical nomenclature protocols and structural diagrams used herein are a modified form of the IUPAC nomenclature system using ChemDraw Professional 15.1 or the mol2nam application of OpenEye Scientific Software. For complex chemical names used herein, substituents are typically named before the group to which they are attached. For example, cyclopropylethyl comprises an ethyl backbone having a cyclopropyl substituent. All bonds are identified in the chemical structural diagrams of this invention, except for all bonds on some carbon atoms that are assumed to be bonded to hydrogen atoms sufficient to complete the valence, as described below.

[0075] solid dispersion

[0076] In certain aspects, the present disclosure relates to a compound of formula (I):

[0077]

[0078] Or provides a solid dispersion containing a salt that is permitted under his constraints.

[0079] In some embodiments, the solid dispersion further comprises a pharmaceutically acceptable polymer. The compound of formula (I) may be dispersed in a solid matrix containing the polymer. In some embodiments, the polymer comprises hydrophobic regions and hydrophilic regions. In some embodiments, the polymer is a water-soluble polymer.

[0080] Polymers suitable for use in the target solid dispersion include, but are not limited to, cellulose esters; cellulose ethers; polyalkylene oxides; polyacrylates; polymethacrylates; homopolymers and copolymers of N-vinyl lactam, polyacrylamide, and vinyl acetate polymers; graft copolymers of polyethylene glycol, polyvinyl caprolactam, and polyvinyl acetate; oligosaccharides; polysaccharides; and mixtures thereof.

[0081] In some embodiments, the polymer is a cellulose ether polymer. For example, the polymer may be selected from methyl cellulose, ethyl cellulose, (hydroxyalkyl)cellulose (e.g., hydroxyethyl cellulose (HEC) or hydroxypropyl cellulose (HPC)), or (hydroxyalkyl)alkyl-cellulose (e.g., hydroxypropyl methyl cellulose (HPMC or hypromellose)). In some embodiments, the polymer is methyl cellulose. In some embodiments, the polymer is ethyl cellulose. In some embodiments, the polymer is HEC. In some embodiments, the polymer is HPC. In some embodiments, the polymer is HPMC.

[0082] In some embodiments, the polymer is a cellulose ester polymer. In some embodiments, the polymer is a cellulose phthalate (e.g., cellulose acetate phthalate or hypromellose phthalate (HPMCP)) or a cellulose succinate (e.g., hypromellose succinate (HPMCS) or hypromellose acetate succinate (HPMCAS)). In some embodiments, the polymer is HPMCP. In some embodiments, the polymer is HPMCAS.

[0083] The cellulose polymers described herein may be further defined by specific grades. For example, the HPMC polymer may be selected from HPMC E3, HPMC E5, HPMC E6, HPMC E15, HPMC K3, HPMC A4, or HPMC A15. In some embodiments, HPMCAS is HPMCAS-L, HPMCAS-M, HPMCAS-H, HPMCAS-LF, HPMCAS-MF, HPMCAS-HF, HPMCAS-LG, HPMCAS-MG, or HPMCAS-HG. In some embodiments, HPMCP is HPMCP 50 or HPMCP 55. In some embodiments, the polymer is HPMCP. In some embodiments, the polymer is HPMCP 50. In some embodiments, the polymer is HPMCAS-L, HPMCAS-M, or HPMCAS-H. In some embodiments, the polymer is HPMCAS-H. In some embodiments, the polymer is HPMCAS-HG.

[0084] In some embodiments, the polymer is polyalkylene oxide. In some embodiments, the polymer is high molecular weight polyalkylene oxide. In some embodiments, the polymer is polyethylene oxide (PEG or PEO) or a copolymer of ethylene oxide and propylene oxide (poloxamer). Suitable PEGs include, but are not limited to, PEG 400, PEG 600, PEG 1450, PEG 3350, PEG 4000, PEG 6000, PEG 8000, PEG 20000, and mixtures thereof. Suitable poloxamers include, but are not limited to, poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, and mixtures thereof. In one embodiment, the polymer is poly(ethylene glycol) methyl. In some embodiments, the polymer is polyethylene glycol 6000 (PEG 6000).

[0085] In some embodiments, the polymer is a polyacrylate or a polymethacrylate. In some embodiments, the polymer is a methacrylic acid / ethyl acrylate copolymer, a methacrylic acid / methyl methacrylate copolymer, a butyl methacrylate / 2-dimethylaminoethyl methacrylate copolymer, a poly(hydroxyalkyl acrylate), or a poly(hydroxyalkyl methacrylate). Suitable polyacrylates or polymethacrylates include, but are not limited to, those sold under the trade name Eudragit™ of Rohm GmbH as Eudragit RS 100, Eudragit L 100, Eudragit L 100-55, and Eudragit S 100, products from other manufacturers equivalent thereto, and mixtures thereof. In one embodiment, the polymer is Eudragit RS 100. In some embodiments, the polymer is Eudragit S 100.

[0086] In some embodiments, the polymer is a homopolymer or copolymer of N-vinyl lactam. In some embodiments, the polymer is a homopolymer or copolymer of N-vinylpyrrolidone. In some embodiments, the polymer is a homopolymer or copolymer of polyvinylpyrrolidone (PVP or povidone) (e.g., comprising monomers of N-vinylpyrrolidone and vinyl acetate (copovidone) or N-vinylpyrrolidone and vinyl propionate). Suitable povidones include, but are not limited to, those having a K-value (a measure of the viscosity of an aqueous solution of povidone) of about 12, about 15, about 17, about 25, about 30, or about 90, and mixtures thereof. In some embodiments, the polymer is polyvinylpyrrolidone K30. In some embodiments, the polymer is poly(1-vinylpyrrolidone-co-vinyl acetate).

[0087] In some embodiments, the polymer is polyacrylamide. In some embodiments, the polymer is a vinyl acetate polymer (e.g., a copolymer of vinyl acetate and crotonic acid, polyvinyl acetate, polyvinyl alcohol, or partially hydrolyzed polyvinyl acetate). In some embodiments, the polymer is a graft copolymer of polyethylene glycol, polyvinyl caprolactam, and polyvinyl acetate (e.g., BASF's Soluplus™ or an equivalent product). In some embodiments, the polymer is an oligo- or polysaccharide (e.g., carrageenan, galactomannan, or xanthan gum).

[0088] In some embodiments, the polymer is methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, cellulose acetate phthalate (CAP), hypromellose (HPMC), hydroxypropyl cellulose, hypromellose phthalate (HPMCP), hypromellose acetate succinate (HPMCAS), poly(ethylene glycol) methyl, poly-ethylene glycol vinyl acetate vinylcaprolactam (e.g., Soluplus), polyethylene glycol 6000 (PEG 6000), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone vinyl acetate (PVP-VA), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1 (Eudrazit RS 100), methacrylic acid copolymer type B (Eudrazit S 100), Sureteric, Pluronic F-68, and polyoxyethylene (20) sorbitan It is selected from monooleate (Tween 80). Preferably, the polymer is selected from HPMCAS, CAP, and Soluplus, e.g., HPMCAS. In some embodiments, the polymer is selected from HPMCAS Grade L (HPMCAS-L), HPMCAS Grade M (HPMCAS-M), and HPMCAS Grade H (HPMCAS-H). In some embodiments, the polymer is HPMCAS-H.

[0089] In some embodiments, the compound of formula (I) is 1 wt% to 50 wt% of the solid dispersion, for example, 1 wt% to 45 wt%, 1 wt% to 40 wt%, 1 wt% to 35 wt%, 1 wt% to 30 wt%, 5 wt% to 50 wt%, 5 wt% to 45 wt%, 5 wt% to 40 wt%, 5 wt% to 35 wt%, 5 wt% to 30 wt%, 10 wt% to 50 wt%, 10 wt% to 45 wt%, 10 wt% to 40 wt%, 10 wt% to 35 wt%, 10 wt% to 30 wt%, 15 wt% to 50 wt%, 15 wt% to 45 wt%, 15 wt% to 35 wt%, 15 wt% to 30 wt%, 15 wt% to 40 wt%, 15 wt% to 30 wt%, 15 wt% to 30 wt%, 15 wt% to 30 wt%, 15 wt% to 40 wt%, 15 wt% to 35 wt%, 15 wt% to 30 wt%, 15 wt% to 30 wt%, 15 wt% to 30 wt%, 15 wt% to 40 wt%, 15 wt% to 340 wt%, 15 wt% to 30 wt It is present in an amount of weight%, 20 weight% to 50 weight%, 20 weight% to 45 weight%, 20 weight% to 40 weight%, 20 weight% to 35 weight%, 20 weight% to 30 weight%, 22.5 weight% to 50 weight%, 22.5 weight% to 45 weight%, 22.5 weight% to 40 weight%, 22.5 weight% to 35 weight%, 22.5 weight% to 30 weight%, 22.5 weight% to 27.5 weight%, 25 weight% to 50 weight%, 25 weight% to 45 weight%, 25 weight% to 40 weight%, 25 weight% to 35 weight%, 25 weight% to 30 weight%, or 25 weight% to 27.5 weight%. In some embodiments, the compound of formula (I) is present in at least 1 wt% of a solid dispersion, e.g., at least 2 wt%, at least 3 wt%, at least 4 wt%, at least 5 wt%, at least 7.5 wt%, at least 10 wt%, at least 12.5 wt%, at least 15 wt%, at least 17.5 wt%, at least 20 wt%, at least 22.5 wt%, at least 25 wt%, at least 27.5 wt%, at least 30 wt%, at least 32.5 wt%, at least 35 wt%, at least 37 wt% of a solid dispersion.It is present in an amount of 5 wt%, at least 40 wt%, at least 42.5 wt%, at least 45 wt%, at least 47.5 wt%, or at least 50 wt%.

[0090] In some embodiments, the compound of formula (I) is present in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 7.5 wt%, about 10 wt%, about 12.5 wt%, about 15 wt%, about 17.5 wt%, about 20 wt%, about 22.5 wt%, about 25 wt%, about 27.5 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, or about 50 wt% of the solid dispersion.

[0091] In some embodiments, the compound of formula (I) is present in an amount of 1% to 50% by weight of the solid dispersion. In some embodiments, the compound of formula (I) is present in an amount of 15% to 35% by weight of the solid dispersion. In some embodiments, the compound of formula (I) is present in an amount of at least 22.5% to 27.5% by weight of the solid dispersion. In some embodiments, the compound of formula (I) is present in an amount of about 25% by weight of the solid dispersion.

[0092] In some embodiments, the polymer comprises 50% to 99% by weight of the solid dispersion, for example, 55% to 99% by weight, 60% to 99% by weight, 65% to 99% by weight, 70% to 99% by weight, 50% to 95% by weight, 55% to 95% by weight, 60% to 95% by weight, 65% to 95% by weight, 70% to 95% by weight, 50% to 90% by weight, 55% to 90% by weight, 60% to 90% by weight, 65% to 90% by weight, 70% to 90% by weight, 50% to 85% by weight, 55% to 85% by weight, 60% to 85% by weight, 65% to 85% by weight, 70% to 85 wt%, 50 wt% to 80 wt%, 55 wt% to 80 wt%, 60 wt% to 80 wt%, 65 wt% to 80 wt%, 70 wt% to 80 wt%, 50 wt% to 77.5 wt%, 52.5 wt% to 77.5 wt%, 55 wt% to 77.5 wt%, 57.5 wt% to 77.5 wt%, 62.5 wt% to 77.5 wt%, 65 wt% to 77.5 wt%, 67.5 wt% to 77.5 wt%, 70 wt% to 77.5 wt%, 72.5 wt% to 77.5 wt%, 50 wt% to 75 wt%, 52.5 wt% to 75 wt%, 55 wt% to 75 wt%, 57.5 The polymer is present in an amount of 60% to 75% by weight, 62.5% to 75% by weight, 65% to 75% by weight, 67.5% to 75% by weight, 70% to 75% by weight, or 72.5% to 75% by weight. In some embodiments, the polymer is present in at least 50% by weight of the solid dispersion, e.g., at least 55% by weight, at least 57.5% by weight, at least 60% by weight, at least 62.5% by weight, at least 65% by weight, or at least 67% by weight of the solid dispersion.It is present in an amount of 5 weight%, at least 70.5 weight%, at least 72.5 weight%, or at least 75 weight%.

[0093] In some embodiments, the polymer is present in an amount of about 60 wt%, about 62.5 wt%, about 65 wt%, about 67.5 wt%, about 70 wt%, about 72.5 wt%, about 75 wt%, about 77.5 wt%, about 80 wt%, about 82.5 wt%, about 85 wt%, about 87.5 wt%, or about 90 wt% of the solid dispersion.

[0094] In some embodiments, the polymer is present in an amount of 50% to 99% by weight of the solid dispersion. In some embodiments, the polymer is present in an amount of 65% to 85% by weight of the solid dispersion. In some embodiments, the polymer is present in an amount of at least 72.5% to 77.5% by weight of the solid dispersion. In some embodiments, the polymer is present in an amount of about 75% by weight of the solid dispersion.

[0095] In some embodiments, the weight ratio of the compound of formula (I) to the polymer is 1:99 to 1:1, e.g., 5:95 to 1:1, 10:90 to 1:1, 15:85 to 1:1, 20:80 to 1:1, 25:75 to 1:1, 1:99 to 35:65, 5:95 to 35:65, 10:90 to 35:65, 15:85 to 35:65, 20:80 to 35:65, 25:75 to 35:65, 1:99 to 27.5:72.5, 5:95 to 27.5:72.5, 10:90 to 27.5:72.5, 15:85 to 27.5:72.5, 20:80 to It is 27.5:72.5, or 22.5:77.5 to 27.5:72.5. In some embodiments, the weight ratio of the compound of formula (I) to the polymer is 1:99 to 1:1. In some embodiments, the weight ratio of the compound of formula (I) to the polymer is 15:85 to 35:65. In some embodiments, the weight ratio of the compound of formula (I) to the polymer is 22.5:77.5 to 27.5:72.5. In some embodiments, the weight ratio of the compound of formula (I) to the polymer is about 25:75.

[0096] The solid dispersion disclosed herein may be characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), modified differential scanning calorimetry (mDSC), scanning electron microscopy (SEM), Karl Fischer water titration (KF), residual solvent, particle size, bulk density, tap density, chiral high-pressure liquid chromatography (HPLC), and achiral HPLC.

[0097] XRPD can be used to evaluate the degree of crystallinity of a solid dispersion, for example, to determine whether the solid dispersion is crystalline, semicrystalline, or amorphous. In some embodiments, the solid dispersion is substantially amorphous. In some embodiments, about 20% or less, about 15% or less, about 10% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, or about 1% or less of the solid dispersion is crystalline as observed by X-ray powder diffraction. In some embodiments, the solid dispersion is amorphous. The XRPD pattern of an amorphous solid dispersion is typically characterized by a broad background signal, that is, a pattern lacking distinct peaks found in crystalline materials. Preferably, XRPD is performed using a Bruker D2 Phaser X-ray diffractometer with scan-type coupling θ / 2θ (where the voltage is set to 30 kV and the current is set to 10 mA), at a rotation of 15 rpm maintained by a Zero-Background Cup, with a slit width of 1.0 mm and a knife-edge width of 1.0 mm.

[0098] Glass transition temperature of solid dispersions (T g ) and melting temperature (T m ) can be measured using any suitable technique, e.g., mDSC. In some embodiments, the solid dispersion is at T 70 to 110°C, e.g., 75 to 105°C, 80 to 100°C, 80 to 95°C, 82 to 92°C, or 83 to 89°C. g It represents. In some embodiments, the solid dispersion is at about 87°C, e.g., 87.0 ± 2.0°C T gIt represents. Preferably, mDSC analysis is performed on a TA Q2000, RCS 90 instrument at a heating rate of 1.5°C per minute in a temperature range of 0 to 250°C, wherein the scanning mode is adjusted to a frequency of 60 seconds and an amplitude of 1°C. In some embodiments, the solid dispersion is at T 60 to 145°C, e.g. 65 to 140°C, 70 to 135°C, 75 to 130°C, 77.5 to 120°C, 80 to 110°C, 82.5 to 100°C, or 85 to 90°C. g It represents.

[0099] The morphology of the solid dispersion can be visually characterized using SEM imaging. In some embodiments, the solid dispersion includes complete spheres and collapsed spheres. The surface of the spheres may be smooth. In some embodiments, no crystalline material is detected in the SEM image of the solid dispersion. Preferably, SEM is performed using an FEI Quanta 200 SEM equipped with a Polaron E5200 Au / Pd target sputter coater, at a voltage of 15 kV, a spot size of 3.0 mA, a filament current of 2.52 A, and an emission current of 96 μA.

[0100] The water content of a solid dispersion can be characterized using KF. In some embodiments, the solid dispersion contains less than 2 weight percent water. In some embodiments, the solid dispersion contains less than 2% water after storage at room temperature for 3 months. The solid dispersion of the present disclosure may be hygroscopic. In some embodiments, exposure of the solid dispersion to humidity, e.g., 33%, 50%, or 75% humidity, causes the T of the solid dispersion g Reduces. In some embodiments, T of the solid dispersion gIt decreases by more than 10% when exposed to 33% relative humidity for 24 hours. While we do not wish to be bound by any specific theory, the effect of humidity on the glass transition temperature may indicate that molecular mobility is possible at room temperature when humidity exceeds 33%, which may enable the ability of the compound of formula (I) to nucleate and / or crystallize. Preferably, the solid dispersion of the present disclosure is stored under conditions maintaining a relative humidity level of less than 50%, e.g., less than 33%. In some embodiments, the solid dispersion is packaged with a desiccant, e.g., SiO2. In some embodiments, the solid dispersion is packaged in a low-vapor permeable container, e.g., Mylar or LDPE bag, optionally in an HDPE drum. In some embodiments, the solid dispersion is packaged and stored with a desiccant in a low-vapor permeable container.

[0101] The residual solvent level in the solid dispersion of the present disclosure can be determined using gas chromatography headspace (GCHS) analysis. For example, a sample can be analyzed using the following method parameters with an Agilent 6890A / 7694 GC / HS instrument equipped with a 30 m x 0.32 mm, 1.8 μm, JW Scientific DB-624 column: sample temperature, 105°C; loop temperature, 110°C; transfer line temperature, 115°C; GC cycle time, 45 min; vial equilibration time, 30 min; injection loop size, 1 mL; vial pressure time, 20 sec; carrier gas pressure, 7 psi; and vial pressure, 15 psi. In some embodiments, the solid dispersion contains residual solvent. In some embodiments, the solid dispersion contains less than 25,000 ppm of acetone. In some embodiments, the solid dispersion contains less than 5,000 ppm of acetone.

[0102] Laser light scattering may be performed on powder, e.g., the solid dispersion disclosed herein, to determine the particle size distribution. For example, a sample may be analyzed using a Malvern Aero S dry particle size analyzer with a 3 mm hopper height at a feed rate of 40% at a pressure of 0.7 bar. Preferably, the sample is analyzed in triplicate for 10 seconds. A refractive index of 1.681 and a density of 0.5 g / mL may be used for analysis using a non-spherical algorithm and sample shielding of 0.1 to 15%. In some embodiments, the particle size distribution is average d 10, d 50 and d 90 It is reported using values, where 10% of the particles in the solid dispersion by mass is d 10 Having a diameter less than the value, 50% of the particles in the solid dispersion by mass are d 50 Having a diameter less than the value, 90% of the particles in the solid dispersion by mass are d 90 It has a diameter less than the value. In some embodiments, the particle size distribution of the solid dispersion is less than 16 μm, e.g., less than 15 μm, less than 14 μm, less than 12 μm, less than 10 μm, less than 8 μm, or about less than 6 μm. 10 It is characterized by. In some embodiments, the particle size distribution of the solid dispersion is less than 50 μm, e.g., less than 45 μm, less than 40 μm, less than 35 μm, less than 30 μm, less than 28 μm, less than 25 μm, less than 23 μm, or less than about 18 μm. 50 It is characterized by. In some embodiments, the particle size distribution of the solid dispersion is less than 100 μm, e.g., less than 90 μm, less than 80 μm, less than 70 μm, less than 65 μm, less than 55 μm, or less than about 45 μm. 90 It is characterized by.

[0103] The bulk density of the solid dispersion of the present disclosure can be obtained by measuring the mass and volume of a sample of the solid dispersion. In some embodiments, the solid dispersion is characterized by a bulk density of at least 0.10 g / mL, e.g., at least 0.15 g / mL, at least 0.20 g / mL, at least 0.25 g / mL, or at least 0.30 g / mL.

[0104] The tap density of the solid dispersion of the present disclosure can be obtained by measuring the mass and volume of the sample of the solid dispersion after mechanically tapping the sample until little or no further volume change is observed. In some embodiments, the solid dispersion is characterized by a tap density of at least 0.20 g / mL, e.g., at least 0.25 g / mL, at least 0.30 g / mL, at least 0.35 g / mL, at least 0.40 g / mL, at least 0.45 g / mL, or at least 0.50 g / mL.

[0105] The purity of the solid dispersion of the present disclosure can be evaluated by high-pressure liquid chromatography (HPLC). For example, the following method parameters are used on an Agilent 1220 instrument equipped with a Kinetex, C18, 4.6 x 100 mm, 2.6 μm column: mobile phase A, 0.1% formic acid in water; mobile phase B, 0.1% formic acid in acetonitrile; gradient consisting of 95% A (0 min), 60% A (6 min), 5% A (12 min), 95% A (15.1 min), and the remainder being mobile phase B; flow rate, 0.8 mL / min; column temperature, 40°C; sample temperature, room temperature; injection volume, 5 μL; detection wavelength, 240 nm; and run time, 18.5 min. In some embodiments, the solid dispersion contains less than 5 wt% impurities, e.g., less than 2 wt% impurities. In some embodiments, the solid dispersion contains less than 2% by weight of impurities after storage at room temperature for 3 months. In some embodiments, the enantiomer excess rate of the compound of formula (I) is at least 95%. In some embodiments, the enantiomer excess rate of the compound of formula (I) is at least 99%. In some embodiments, the enantiomer excess rate of the compound of formula (I) is at least 99.5%.

[0106] The solubility performance of the solid dispersion can be tested by measuring the solubility of the compound of formula (I) in a biocompatible intestinal medium (FaSSIF) after 30 minutes of exposure to a low-pH environment (SGF) in a non-sink solubility test. SGF (C max GB) and SIF (C max The maximum concentration of the compound of formula (I) in FaSSIF, as well as the area under the curve after transfer (AUC FaSSIF), can be obtained from the dissolution profile.

[0107] In some embodiments, C of the solid dispersion maxGB is at least 100 μgA / mL, e.g., at least 150, at least 200, at least 250, at least 300, at least 350, at least 400, at least 450, at least 500, or at least 550 μgA / mL. Preferably, C max GB is at least 300 μgA / mL. In some embodiments, C max GB is 100 to 600 μgA / mL, e.g. 150 to 600, 200 to 550, 250 to 500, 300 to 450, 350 to 450, 400 to 450, or 375 to 425 μgA / mL. Preferably, C max GB is 375 to 425 μgA / mL. In some embodiments, C max GB is approximately 409 μgA / mL, e.g. 410 ± 10 μgA / mL.

[0108] In some embodiments, C of the solid dispersion max FaSSIF is at least 50 μgA / mL, e.g., at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, at least 400, at least 450, at least 500, at least 550, at least 600, at least 650, at least 700, at least 750, or at least 800 μgA / mL. Preferably, C max FaSSIF is at least 300 μgA / mL. In some embodiments, C max FaSSIF is 50 to 900 μgA / mL, e.g. 150 to 800, 250 to 700, 350 to 600, or 350 to 575 μgA / mL. Preferably, C max FaSSIF is 350 to 575 μgA / mL. In some embodiments, C max FaSSIF is about 545 μgA / mL, e.g. 545 ± 50 μgA / mL, or about 435 μgA / mL, e.g. 435 ± 50 μgA / mL.

[0109] In some embodiments, the AUC FaSSIF of the solid dispersion is at least 10,000 μgA / mL, e.g., at least 20,000, at least 30,000, at least 40,000, at least 50,000, at least 60,000, at least 70,000, at least 80,000, at least 90,000, or at least 100,000 μgA / mL. Preferably, the AUC FaSSIF is at least 40,000 μgA / mL. In some embodiments, the AUC FaSSIF is 10,000 to 200,000 μgA / mL, e.g., 10,000 to 175,000, 15,000 to 150,000, 20,000 to 125,000, or 25,000 to 100,000 μgA / mL. In some embodiments, the AUC FaSSIF is about 90,000 μgA / mL, e.g., 90,000 ± 1,000 μgA / mL. In some embodiments, the AUC FaSSIF is about 65,000 μgA / mL, e.g., 65,000 ± 1,000 μgA / mL.

[0110] In some embodiments, the AUC enhancement of the solid dispersion is at least 3.0, e.g., at least 5.0, at least 10.0, at least 15.0, at least 20.0, at least 25.0, at least 30.0, at least 35.0, or at least 40.0, where the AUC enhancement represents the ratio of the AUC FaSSIF of the solid dispersion to the AUC FaSSIF of the compound of formula (I). Preferably, the AUC enhancement is at least 10. In some embodiments, the AUC enhancement is 3.0 to 50.0, e.g., 5.0 to 45.0, 10.0 to 40.0, 15.0 to 40.0, 20.0 to 40.0, or 25.0 to 45.0. In some embodiments, the AUC enhancement is about 35.0, e.g., 35.0 ± 3.0. In some embodiments, the AUC enhancement is about 25.0, e.g., 25.0 ± 3.0.

[0111] In some aspects, the present disclosure is based on weight relative to the total weight of the solid dispersion,

[0112] (a) 22.5% to 27.5% of the compound of formula (I):

[0113] ; and

[0114] (b) HPMCAS 72.5% to 77.5%

[0115] Provides an amorphous solid dispersion containing

[0116] In some aspects, the present disclosure is based on weight relative to the total weight of the solid dispersion,

[0117] (a) 20% to 30% of the compound of formula (I):

[0118] ; and

[0119] (b) 70% to 80% of a polymer selected from cellulose esters and cellulose ethers

[0120] The present invention provides an amorphous solid dispersion comprising, wherein the solid dispersion has a glass transition temperature (T) of 80 to 100°C. g ) represents, where the solid dispersion contains less than 2 weight percent of water.

[0121] In some aspects, the present disclosure is based on weight relative to the total weight of the solid dispersion,

[0122] (a) 1% to 50% of the compound of formula (I):

[0123] ; and

[0124] (b) 50% to 99% of a polymer selected from HPMCAS, CAP, and Soluplus

[0125] Provides an amorphous solid dispersion containing

[0126] In some aspects, the present disclosure is based on weight relative to the total weight of the solid dispersion,

[0127] (a) 10% to 30% of the compound of formula (I):

[0128] ; and

[0129] (b) HPMCAS 70% to 90%

[0130] The present invention provides an amorphous solid dispersion comprising, wherein the solid dispersion comprises less than 2 weight percent of water.

[0131] In some aspects, the present disclosure is based on weight relative to the total weight of the solid dispersion,

[0132] (a) 22.5% to 27.5% of the compound of formula (I):

[0133] ; and

[0134] (b) 72.5% to 77.5% of a polymer selected from HPMCAS-L, HPMCAS-M, and HPMCAS-H

[0135] Provides an amorphous solid dispersion comprising, wherein the excess ratio of the enantiomer of the compound of formula (I) is at least 95%.

[0136] In some embodiments, a solid dispersion comprising about 25 weight percent of the compound of Formula (I) dispersed in a solid matrix containing HPMCAS is provided herein. In some embodiments, the solid dispersion is provided as a powder. In some embodiments, the solid dispersion is provided as granules. In some embodiments, the solid dispersion is provided as a film. In some embodiments, the solid dispersion remains amorphous after storage for 4 weeks at 25°C and 60% RH or 40°C and 75% RH. In some embodiments, the solid dispersion remains amorphous after storage for 3 months at 2-8°C, 25°C and 60% RH, or 40°C and 75% RH. In some embodiments, the solid dispersion is moderately hygroscopic. In some embodiments, the solid dispersion exhibits increased solubility of the compound of Formula (I) in an aqueous medium compared to the pure compound of Formula (I). In some embodiments, the aqueous medium is water, artificial gastric juice (SGF), artificial intestinal juice (FaSSIF), or a 5% glycerin solution in water.

[0137] While we do not wish to be bound by any particular theory, the specific solid dispersions provided herein exhibit physical properties, e.g., stability, solubility, and / or dissolution rate, suitable for use in clinical and therapeutic dosage forms. In some embodiments, the specific solid dispersions provided herein are suitable for use in solid formulations for oral administration.

[0138] Crystalline form

[0139] The crystalline form of the compound of formula (I) is useful in the manufacture of at least pharmaceutical compositions.

[0140] One embodiment provides a crystalline form of a compound of formula (I):

[0141]

[0142] In this invention, the crystalline form represents the XRPD pattern of Fig. 1.

[0143] One embodiment provides a crystalline form of a compound of formula (I):

[0144]

[0145] Here, the crystalline form exhibits a Tm of approximately 209°C.

[0146] One embodiment provides a crystalline form of a compound of formula (I):

[0147]

[0148] Here, the crystalline form exhibits a Tg of about 80°C.

[0149] One embodiment provides a crystalline form of a compound of formula (I):

[0150]

[0151] Here, the crystalline form exhibits an XRPD pattern having at least one 2θ peak selected from 7.6, 15.0, 19.6, 22.9, 25.8, or 30.2.

[0152] One embodiment provides a crystalline form of a compound of formula (I):

[0153]

[0154] Here, the crystalline form exhibits an XRPD pattern having at least two 2θ peaks selected from 7.6, 15.0, 19.6, 22.9, 25.8, or 30.2.

[0155] One embodiment provides a crystalline form of a compound of formula (I):

[0156]

[0157] Here, the crystalline form exhibits an XRPD pattern having at least three 2θ peaks selected from 7.6, 15.0, 19.6, 22.9, 25.8, or 30.2.

[0158] One embodiment provides a crystalline form of a compound of formula (I):

[0159]

[0160] Here, the crystalline form exhibits an XRPD pattern having at least four 2θ peaks selected from 7.6, 15.0, 19.6, 22.9, 25.8, or 30.2.

[0161] One embodiment provides a crystalline form of a compound of formula (I):

[0162]

[0163] Here, the crystalline form exhibits an XRPD pattern having at least five 2θ peaks selected from 7.6, 15.0, 19.6, 22.9, 25.8, or 30.2.

[0164] Method for preparing a solid dispersion

[0165] In some aspects, the present disclosure provides a method for preparing the solid dispersion disclosed herein, comprising the steps of: (a) providing a solution of a compound of formula (I) and a polymer in a solvent; and (b) removing the solvent to provide a solid dispersion. The polymer may be selected from any suitable polymer described herein, such as HPMCAS.

[0166] In some embodiments, the solvent comprises acetone, methyl ethyl ketone, tetrahydrofuran, water, or a combination thereof. In some embodiments, the solvent comprises acetone. The solvent may comprise up to 5% water. In some embodiments, the solvent comprises acetone and up to 5% water. In some embodiments, the solvent is 95 to 99 volume% acetone and 1 to 5 volume% water. In some embodiments, the solvent is 90 to 99 volume% acetone and 1 to 10 volume% water.

[0167] In some embodiments, the solvent is removed by freeze-evaporation or spray drying. In some embodiments, the solid dispersion is obtained by melting, solvent evaporation, spray drying, fusion, kneading, co-grinding, freeze-drying, hot melt extrusion, melt agglomeration, or supercritical fluid technology. Preferably, the solvent is removed by spray drying. Solvent removal may further include drying the solid dispersion in a tray dryer to remove any residual solvent remaining after spray drying.

[0168] In some embodiments, the solution comprises 5% to 20% by weight of solid, e.g., 8% to 14% by weight of solid. In some embodiments, the solution comprises about 8% by weight of solid, e.g., 8 ± 2% by weight of solid.

[0169] In some embodiments, the provided step (a) comprises adding the compound of formula (I) to a solvent (e.g., acetone) and mixing the resulting mixture until the compound of formula (I) is completely dissolved or until a clear solution is obtained. The provided step (a) may further comprise adding a suitable polymer (e.g., HPMCAS-H) to the solution of the compound of formula (I) in acetone and then mixing. In some embodiments, the removing step (b) comprises spray-drying the solution of the compound of formula (I) and the polymer in the solvent. Spray-drying may be completed in any suitable dryer, such as an SPX Anhydro MicraSpray MS-150 spray-drying unit equipped with a 2-fluid nozzle. In some embodiments, spraying is completed in a closed-loop configuration. The atomization pressure of the spray-drying may be 2.0 to 3.5 bar, e.g., 2.5 to 2.8 bar. In some embodiments, the spray rate is 5.0 to 20.0 kg / hr, e.g., 7.5 to 12.5 kg / hr. In some embodiments, the inlet temperature is raised to, e.g., 65 to 85°C. The outlet temperature may also be raised to, e.g., 40 to 45°C. In some embodiments, the dry gas flow rate is 150 to 200 kg / hr. The condenser temperature of the spray drying unit is typically below freezing, e.g., -30 to -10°C.

[0170] Secondary drying is optionally used to remove residual solvent remaining after spray drying. Secondary drying may include, for example, tray drying in a despatch tray dryer. In some embodiments, the solid dispersion is loaded into the trays of the tray dryer to a depth of approximately 1 inch. The temperature of the dryer is typically raised, for example, from 30 to 50°C. In some embodiments, secondary drying has a duration of 1 to 24 hours, for example, 6 to 18 hours, 8 to 12 hours, or about 10 hours.

[0171] Secondary recovery is optionally used to recover residual solid dispersion from the spray nozzle, main chamber, and outlet after spray drying. In some embodiments, residual solid dispersion from the spray nozzle, main chamber, and / or outlet may be collected and added to the bulk material. Adding residual solid dispersion collected from one or more of the spray nozzle, main chamber, and outlet of the spray dryer to the bulk material may increase the overall yield of the solid dispersion by at least 10%, e.g., at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, or at least 40%.

[0172] In some aspects, the present disclosure provides a method for preparing a solid dispersion disclosed herein, comprising: (a) providing a solution of a compound of formula (I) and HPMCAS in a solvent, wherein the solution comprises 6% to 15% by weight of total solids; and (b) removing the solvent to provide a solid dispersion. The polymer may be selected from any suitable polymer described herein, such as HPMCAS.

[0173] Pharmaceutical composition

[0174] In some aspects, the present disclosure provides a pharmaceutical solid dosage form for oral delivery of a compound of formula (I), and

[0175]

[0176] Here, the solid dosage form comprises (a) a solid dispersion containing a compound of formula (I); and (b) one or more pharmaceutically acceptable excipients.

[0177] The solid dosage form may be a capsule or a tablet. In some embodiments, the solid dosage form is a tablet. In some embodiments, one or more pharmaceutically acceptable excipients include a binder, a filler, a disintegrant, and a lubricant. In some embodiments, one or more pharmaceutically acceptable excipients further include a lubricant and a coating. In some embodiments, one or more pharmaceutically acceptable excipients include a binder, a filler, a disintegrant, a lubricant, a lubricant, and a coating. In some embodiments, the solid dispersion is present in an amount of 15% to 50% by weight of the solid dosage form.

[0178] In some embodiments, the solid dispersion comprises a pharmaceutically acceptable polymer, such as HPMCAS. In some embodiments, the polymer is present in an amount of 15% to 35% by weight of the solid dosage form. In some embodiments, the compound of formula (I) is present in an amount of 1% to 15% by weight of the solid dosage form. In some embodiments, the solid dosage form comprises 5 mg to 100 mg of the compound of formula (I), such as 10 mg or 40 mg of the compound of formula (I).

[0179] In some embodiments, the solid dosage form comprises a binder in an amount of 20% to 50% by weight of the solid dosage form. The binder may be microcrystalline cellulose. In some embodiments, the solid dosage form comprises a filler in an amount of 20% to 40% by weight of the solid dosage form. The filler may be mannitol. In some embodiments, the solid dosage form comprises an in-granular filler and an extragranular filler, optionally wherein the in-granular filler is present in an amount of 12% to 22% by weight of the solid dosage form, and the extragranular filler is present in an amount of 8% to 18% by weight of the solid dosage form.

[0180] In some embodiments, the solid dosage form contains a disintegrant in an amount of 1.0% to 5.0% by weight of the solid dosage form. The solid dosage may include an intragranular disintegrant and an extragranular disintegrant, optionally wherein the intragranular disintegrant is present in an amount of 0.9% to 3.0% by weight of the solid dosage form and the extragranular disintegrant is present in an amount of 0.1% to 2.0% by weight of the solid dosage form. In some embodiments, the disintegrant is sodium croscarmellose.

[0181] In some embodiments, the solid dosage form contains a lubricant in an amount of 0.25 wt% to 1.25 wt% of the solid dosage form. The solid dosage form may include an intragranular lubricant and an extragranular lubricant, optionally wherein the intragranular lubricant is present in an amount of 0.15 wt% to 0.75 wt% of the solid dosage form and the extragranular lubricant is present in an amount of 0.10 wt% to 0.50 wt% of the solid dosage form. In some embodiments, the lubricant is magnesium stearate.

[0182] In some embodiments, the solid dosage form contains a lubricant in an amount of 0.1% to 1.25% by weight of the solid dosage form. The solid dosage form may include an intragranular lubricant and an extragranular lubricant, optionally wherein the intragranular lubricant is present in an amount of 0.05% to 0.75% by weight of the solid dosage form and the extragranular lubricant is present in an amount of 0.05% to 0.50% by weight of the solid dosage form. In some embodiments, the solid dosage form contains an extragranular lubricant in an amount of 0.2% to 0.5% by weight of the solid dosage form. In some embodiments, the lubricant is colloidal silicon dioxide, e.g., Cab-O-Sil.

[0183] In some embodiments, the solid dosage form comprises a coating. In some embodiments, the coating is PVA-based, e.g., Opadry II. In some embodiments, the coating is colored, optionally blue. The solid dosage form may comprise the coating in an amount of 1% to 5% by weight, e.g., about 3% by weight, of the solid dosage form.

[0184] In some embodiments, the hardness of the solid dosage form is 5 to 25 KP. The weight of the solid dosage form may be 50 to 750 mg, e.g., about 125 mg or about 500 mg. In some embodiments, the solid dosage form contains less than 2 weight percent of impurities.

[0185] In some embodiments, the solid dosage form contains less than 3% by weight of water. In some embodiments, the solid dosage form contains less than 3% by weight of water after storage at room temperature for 6 months. In some embodiments, the solid dosage form is characterized by a disintegration time of 1 to 5 minutes.

[0186] In some aspects, the present disclosure provides a pharmaceutical solid dosage form for oral delivery of a compound of formula (I), and

[0187]

[0188] Here, the solid dosage form comprises (a) a solid dispersion comprising a compound of formula (I) and a polymer selected from HPMCAS, CAP and Soluplus; and (b) one or more pharmaceutically acceptable excipients.

[0189] In some aspects, the present disclosure provides a pharmaceutical solid dosage form for oral delivery of a compound of formula (I), and

[0190]

[0191] Herein, the solid dosage form comprises (a) a solid dispersion comprising 5 to 100 mg of a compound of formula (I); and (b) one or more pharmaceutically acceptable excipients.

[0192] In some aspects, the present disclosure provides a pharmaceutical solid dosage form for oral delivery of a compound of formula (I), and

[0193]

[0194] Here, the solid dosage form is based on weight relative to the total weight of the pharmaceutical composition:

[0195] (a) 15% to 50% of a solid dispersion comprising a compound of formula (I);

[0196] (b) 20% to 50% binder;

[0197] (c) 20% to 40% filler;

[0198] (d) disintegrant 1.0% to 5.0%; and

[0199] (e) Contains 0.25% to 1.25% of a lubricant.

[0200] In some aspects, the present disclosure provides a pharmaceutical solid dosage form for oral delivery of a compound of formula (I), and

[0201]

[0202] Here, the solid dosage form is based on weight relative to the total weight of the pharmaceutical composition:

[0203] (a) 15% to 50% of a solid dispersion comprising a compound of formula (I) and HMPCAS;

[0204] (b) 20% to 50% microcrystalline cellulose;

[0205] (c) 20% to 40% mannitol;

[0206] (d) 1.0% to 5.0% sodium croscarmellose; and

[0207] (e) Contains 0.25% to 1.25% magnesium stearate.

[0208] In some aspects, the present disclosure provides a pharmaceutical solid dosage form for oral delivery of a compound of formula (I), and

[0209]

[0210] Here, the solid dosage form is based on weight relative to the total weight of the pharmaceutical composition:

[0211] (a) 15% to 50% of a solid dispersion comprising a compound of formula (I);

[0212] (b) 20% to 50% binder;

[0213] (c) 20% to 40% filler;

[0214] (d) Disintegrant 1.0% to 5.0%;

[0215] (e) 0.25% to 1.25% of lubricant;

[0216] (f) 0.1% to 1.25% of a lubricant; and

[0217] (g) Contains 1% to 5% of coating.

[0218] In some aspects, the present disclosure provides a pharmaceutical solid dosage form for oral delivery of a compound of formula (I), and

[0219]

[0220] Here, the solid dosage form is based on weight relative to the total weight of the pharmaceutical composition:

[0221] (a) 15% to 50% of a solid dispersion comprising a compound of formula (I) and HMPCAS;

[0222] (b) 20% to 50% microcrystalline cellulose;

[0223] (c) 20% to 40% mannitol;

[0224] (d) Croscarmellose sodium 1.0% to 5.0%;

[0225] (e) 0.25% to 1.25% magnesium stearate;

[0226] (f) 0.1% to 1.25% colloidal silicon dioxide; and

[0227] (g) Optionally includes a PVA-based coating.

[0228] In some aspects, the present disclosure provides a pharmaceutical solid dosage form for oral delivery of a compound of formula (I), and

[0229]

[0230] Herein, the solid dosage form comprises (a) a solid dispersion containing a compound of formula (I); and (b) one or more pharmaceutically acceptable excipients, wherein the weight of the solid dosage form is 50 to 750 mg.

[0231] In some aspects, the present disclosure provides a pharmaceutical solid dosage form for oral delivery of a compound of formula (I), and

[0232]

[0233] Here, the solid dosage form comprises (a) a solid dispersion containing a compound of formula (I); (b) one or more pharmaceutically acceptable excipients; and (c) less than 2 weight percent of impurities.

[0234] In some aspects, the present disclosure provides a pharmaceutical solid dosage form for oral delivery of a compound of formula (I), and

[0235]

[0236] Here, the solid dosage form comprises, after storage at room temperature for 6 months: (a) a solid dispersion containing a compound of formula (I); (b) one or more pharmaceutically acceptable excipients; and (c) less than 3% by weight of water.

[0237] The compounds or solid dispersions of the present disclosure may be formulated into any suitable pharmaceutical formulation. Pharmaceutical compositions of the present disclosure typically contain an active ingredient (e.g., a compound of formula (I), and one or more pharmaceutically acceptable excipients and / or carriers, including but not limited to inert solid diluents and fillers, binders, diluents, disintegrants, lubricants, lubricants, coatings, sterile aqueous solutions and various organic solvents, penetration promoters, solubilizers and ajuvants. The compounds or solid dispersions of the present disclosure may be formulated into any suitable pharmaceutical formulation. In some embodiments, pharmaceutically acceptable excipients are selected from microcrystalline cellulose, mannitol, sodium croscarmellose, and magnesium stearate. In some embodiments, pharmaceutically acceptable excipients are selected from microcrystalline cellulose, mannitol, sodium croscarmellose, magnesium stearate, and Cab-O-Sil. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable excipient selected from microcrystalline cellulose, mannitol, sodium croscarmellose, and magnesium stearate. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable excipient selected from microcrystalline cellulose, mannitol, sodium croscarmellose, magnesium stearate, and colloidal silicon dioxide. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), microcrystalline cellulose, mannitol, sodium croscarmellose, and magnesium stearate. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), microcrystalline cellulose, mannitol, sodium croscarmellose, magnesium stearate, Cab-O-Sil, and a PVA-based coating.

[0238] Pharmaceutical formulations may be provided in any suitable form that may depend on the route of administration. In some embodiments, the pharmaceutical composition disclosed herein may be formulated into a dosage form for administration to a subject. In some embodiments, the pharmaceutical composition is formulated for oral, intravenous, intra-arterial, aerosol, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, intranasal, intrapulmonary, transmucosal, inhalation, and / or intraperitoneal administration. In some embodiments, the dosage form is formulated for oral administration. For example, the pharmaceutical composition may be formulated in the form of pills, tablets, capsules, inhalers, liquid suspensions, liquid emulsions, gels, or powders. Preferably, the pharmaceutical composition is formulated in the form of pills, tablets, or capsules. In some embodiments, the pharmaceutical composition may be formulated into unit doses in the form of liquid, gel, semi-liquid, semi-solid, foam, or solid.

[0239] The amount of each compound administered will depend on the mammal being treated, the severity of the disorder or condition, the rate of administration, the batch of compounds, and the judgment of the prescribing physician. However, the effective dose may be in the range of about 0.001 to about 100 mg per kg body weight per day as a single or divided dose. In some embodiments, the dose is in the range of about 0.1 mg / kg to about 1.0 mg / kg body weight per dose. In some cases, a dose level below the lower limit of the aforementioned range may be more sufficient, whereas in other cases, a much larger dose may be used without causing any adverse side effects, for example by dividing this larger dose into several smaller doses for administration over a day.

[0240] In some embodiments, the disclosure provides a pharmaceutical composition comprising an amount of a compound of formula (I) formulated for administration to a subject in need thereof. In some embodiments, the pharmaceutical composition comprises about 0.1 to 1000 mg of a compound of formula (I), e.g., 0.1 to 500 mg, 1 to 250 mg, 5 to 125 mg, 5 to 100 mg, 5 to 75 mg, or 5 to 50 mg of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg or about more of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises 1 to 100 mg of the compound of formula (I) in a single dose, e.g., 5 to 50 mg of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 10 mg of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 40 mg of the compound of formula (I).

[0241] In some embodiments, a therapeutically effective amount of a compound of formula (I), which may be a daily amount administered over the course of a treatment period, may sufficiently provide one or more of the therapeutic effects described herein. For example, the therapeutically effective dose may be a compound of formula (I) in the range of about 0.001-100 mg / kg body weight, 0.001-50 mg / kg body weight, 0.01-50 mg / kg body weight, 0.01-25 mg / kg body weight, 0.01-10 mg / kg body weight, 0.01-5 mg / kg body weight, 0.01-4 mg / kg body weight, 0.01-3 mg / kg body weight, 0.01-2 mg / kg body weight, 0.01-1 mg / kg body weight, 0.01-0.75 mg / kg body weight, 0.1-5 mg / kg body weight, 0.1-4 mg / kg body weight, 0.1-3 mg / kg body weight, 0.1-2 mg / kg body weight, 0.1-1 mg / kg body weight, or 0.1-0.75 mg / kg body weight. In some embodiments, the therapeutic dose may be about 0.001 mg / kg body weight, 0.01 mg / kg body weight, 0.1 mg / kg body weight, 0.2 mg / kg body weight, 0.3 mg / kg body weight, 0.4 mg / kg body weight, 0.5 mg / kg body weight, 0.6 mg / kg body weight, 0.7 mg / kg body weight, 0.8 mg / kg body weight, 0.9 mg / kg body weight, 1 mg / kg body weight, 1.5 mg / kg body weight, 2 mg / kg body weight, 3 mg / kg body weight, 4 mg / kg body weight, 5 mg / kg body weight, 6 mg / kg body weight, 7 mg / kg body weight, 8 mg / kg body weight, 9 mg / kg body weight, or 10 mg / kg body weight or about more of the compound of formula (I). In some embodiments, the effective dose is at least about 0.01 mg / kg body weight of the compound of formula (I). In some embodiments, the effective amount is about 0.01-10 mg / kg body weight of the compound of formula (I).

[0242] In some embodiments, the composition is provided in one or more unit doses. For example, the composition may be administered in doses of 1, 2, 3, 4, 5, 6, 7, 14, 30, 60, or more. These amounts may be administered as individual doses daily, for example, once, twice, or three times or more per day. However, the doses mentioned herein on a daily basis should not be interpreted as requiring the administration of a daily dose each and every day. For example, if one of the agents is provided in a suitably slow-release form, two or more daily doses may be administered as a depot at a lower frequency, for example every two days to once a month or even more. Most typically and conveniently, for a subject, a compound of the inhibitor of formula (I) may be administered once a day, for example in the morning, evening, or during the day.

[0243] Unit doses may be administered simultaneously or sequentially. The composition may be administered for an extended treatment period. For example, the treatment period may be at least about 1 month, e.g., at least about 3 months, at least about 6 months, or at least about 1 year. In some cases, administration may continue substantially for the remainder of the subject's life.

[0244] Pharmaceutical composition for oral administration: In some embodiments, the disclosure provides a pharmaceutical composition for oral administration comprising at least one compound of the present disclosure and a pharmaceutical excipient suitable for oral administration. The composition may be in a solid, liquid, gel, semi-liquid, or semi-solid form. In some embodiments, the composition is in a solid form. In some embodiments, the composition further comprises a second agent.

[0245] In some embodiments, the present invention provides a solid pharmaceutical composition for oral administration comprising (i) a compound of formula (I); and (ii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further comprises (iii) a third agent or even a fourth agent. In some embodiments, each compound or agent is present in a therapeutically effective amount. In other embodiments, one or more compounds or agents are present in amounts less than therapeutic, and the compounds or agents act synergistically to provide a therapeutically effective pharmaceutical composition.

[0246] A pharmaceutical composition of the disclosed content suitable for oral administration may be provided in individual dosage forms, such as hard or soft capsules, cassettes, troches, lozenges, or tablets, or as a liquid or aerosol spray, a solution or suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a liquid-in-oil emulsion, or a dispersible powder or granule, or a syrup or elixir, each containing a predetermined amount of the active ingredient as a powder or granules. Preferably, the pharmaceutical composition for oral administration is provided as a tablet. Such dosage forms may be prepared by any pharmaceutical method, which typically comprises the step of associating the active ingredient(s) with an excipient. Generally, the composition is prepared by uniformly and intimately mixing the active ingredient(s) with a liquid excipient or a finely divided solid excipient, or both, and then, if necessary, molding the product into a desired shape. For example, tablets may be prepared by compression or molding with optionally one or more pharmaceutically acceptable excipients. Compressed tablets may be manufactured by compressing active ingredient(s) in a free-flowing form, such as powder or granules, mixed with optional excipients, such as binders, fillers, disintegrants, lubricants, and / or lubricants, in a suitable machine. Molded tablets may be manufactured by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0247] The present disclosure further covers anhydrous pharmaceutical compositions and dosage forms containing an active ingredient, as water can facilitate the degradation of some compounds. For example, water may be added as a means of simulating long-term storage to determine characteristics such as the shelf-life or stability of the formulation over time (e.g., 5%). The anhydrous pharmaceutical compositions and dosage forms of the disclosure may be prepared using anhydrous or low-moisture containing ingredients and low-moisture or low-humidity conditions. Pharmaceutical compositions and dosage forms of the disclosure containing lactose may be prepared anhydrous if substantial contact with moisture and / or humidity is expected during preparation, packaging, and / or storage. The anhydrous pharmaceutical compositions may be prepared and stored so that their anhydrous properties are maintained. Accordingly, the anhydrous compositions may be packaged using materials known to prevent exposure to water so that they can be included in suitable prescribed kits. Examples of suitable packaging include, but are not limited to, low-vapor permeable containers, airtight foil, plastics, unit dosage containers, blister packs, and strip packs.

[0248] The active ingredient may be combined with pharmaceutical excipients in an intimate mixture according to pharmaceutical formulation technology. Excipients may take on a wide variety of forms depending on the form of the formulation intended for administration. In the preparation of a composition for an oral administration form, any suitable pharmaceutical medium may be used as an excipient, such as, for example, water, glycol, oil, alcohol, flavoring agent, preservative, coloring agent, etc., in the case of an oral liquid formulation (e.g., suspension, solution, and elixir) or aerosol; or in the case of an oral solid formulation, in some embodiments not utilizing the use of lactose, excipients may be used, such as starch, sugar, microcrystalline cellulose, diluent, granulator, lubricant, lubricant, binder, and disintegrant. If desired, the tablet may be coated by standard aqueous or non-aqueous technology.

[0249] Binders suitable for use in the target pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanths, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof. In some embodiments, the binder is microcrystalline cellulose. In some embodiments, the microcrystalline cellulose is selected from microcrystalline cellulose PH101, microcrystalline cellulose PH105, microcrystalline cellulose PH112, microcrystalline cellulose PH113, microcrystalline cellulose PH200, microcrystalline cellulose PH301, and microcrystalline cellulose PH302. In some embodiments, the binder is microcrystalline cellulose PH101 or microcrystalline cellulose PH105. In some embodiments, the binder is microcrystalline cellulose PH101. In some embodiments, the binder is microcrystalline cellulose PH105. In some embodiments, the binder is present in an amount of at least 0.5 mg, at least 1 mg, at least 5 mg, at least 10 mg, at least 20 mg, at least 30 mg, at least 50 mg, at least 100 mg, at least 150 mg, at least 200 mg, at least 300 mg, or at least 500 mg.

[0250] Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrate, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. In some embodiments, the filler is mannitol. In some embodiments, mannitol is selected from mannitol M100, mannitol M200, and mannitol M300. In some embodiments, the filler is mannitol M100. In some embodiments, the filler is present in an amount of at least 0.5 mg, at least 1 mg, at least 5 mg, at least 10 mg, at least 20 mg, at least 30 mg, at least 50 mg, at least 100 mg, at least 150 mg, at least 200 mg, at least 300 mg, or at least 500 mg.

[0251] A disintegrant may be used in the composition of the present disclosure to provide a tablet that disintegrates upon exposure to an aqueous environment. Too much disintegrant may produce a tablet that disintegrates in a vial. Too little may be insufficient for disintegration to occur and may alter the rate and extent of release of the active ingredient(s) from the dosage form. A dosage form of the compound disclosed herein may be formed using a sufficient amount of disintegrant that is neither too little nor too much to adversely alter the release of the active ingredient(s). The amount of disintegrant used may vary based on the type of formulation and the mode of administration. About 0.5 to about 15 weight percent of disintegrant, for example about 1.0 to about 5.0 weight percent of disintegrant, may be used in the pharmaceutical composition. Disintegrants that may be used to form the pharmaceutical composition and dosage form of the disclosure include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, sodium croscarmellose, crospovidone, potassium polacrylin, sodium starch glycolate, potato or tapioca starch, other starch, pre-gelatinized starch, other starch, clay, other algin, other cellulose, gum, or mixtures thereof. In some embodiments, the disintegrant is sodium croscarmellose.

[0252] Lubricants that may be used to form the pharmaceutical composition and dosage form of the disclosure include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Additional lubricants include, for example, siloid silica gel, coagulated aerosol of synthetic silica, or mixtures thereof. The lubricant may optionally be added in an amount of less than about 1 weight percent of the pharmaceutical composition. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is present in an amount of at least 0.1 mg, at least 0.2 mg, at least 0.3 mg, at least 0.4 mg, at least 0.5 mg, at least 0.6 mg, at least 0.7 mg, at least 0.8 mg, at least 0.9 mg, at least 1 mg, or at least 5 mg.

[0253] Lubricants that may be used to form the pharmaceutical composition and dosage form of the disclosure include, but are not limited to, colloidal silicon dioxide, CAB-O-SIL® (Cabot Co., Boston, Massachusetts), asbestos-free talc, magnesium stearate, starch, and talc. In some embodiments, the lubricant is present in an amount of at least 0.1 mg, at least 0.2 mg, at least 0.3 mg, at least 0.4 mg, at least 0.5 mg, at least 0.6 mg, at least 0.7 mg, at least 0.8 mg, at least 0.9 mg, at least 1 mg, at least 1.1 mg, at least 1.2 mg, at least 1.3 mg, at least 1.4 mg, at least 1.5 mg, at least 2 mg, at least 3 mg, at least 4 mg, or at least 5 mg.

[0254] Where an aqueous suspension and / or elixir is preferred for oral administration, the active ingredient therein may be combined with various sweeteners or flavorings, colorings or dyes, and, if desired, emulsifiers and / or suspending agents, and diluents such as water, ethanol, propylene glycol, glycerin, and various combinations thereof.

[0255] The tablet may be uncoated or may be coated by known techniques to provide sustained action over a longer period by delaying disintegration and absorption in the gastrointestinal tract. For example, time-delaying agents, such as glyceryl monostearate or glyceryl distearate, may be used. The coating may further prevent or slow down water adsorption. Formulations for oral use may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a water or oil medium, such as peanut oil, liquid paraffin, or olive oil. The enteric coating comprises, but is not limited to, CAP, acrylate polymer, HPMCP, HPMC, PVAP, PVA, fatty acids, fats, phenyl salicylates, waxes, shellac, ammonified shellac, and cellulose acetate phthalate. Non-enteric coatings include, but are not limited to, HPMC, methyl hydroxyethyl cellulose (MHEC), EC, HPC, povidone, sodium carboxymethylcellulose (SCMC), PEG, and acrylate polymers. Sugar-coated tablets are compressed tablets surrounded by a sugar coating that may be beneficial for masking an unpleasant taste or odor and protecting the tablet from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart the same general characteristics as sugar coatings. In some embodiments, the coating is PVA-based, e.g., Opadry II. In some embodiments, the coating is colored. For example, the coating may include blue, green, red, purple, orange, silver, and / or yellow pigments. In some embodiments, the coating is Opadry II, e.g., Opadry II Blue. In some embodiments, the coating is at least 0.It is present in an amount of 5 mg, at least 1 mg, at least 2.5 mg, at least 5 mg, at least 7.5 mg, at least 10 mg, at least 12.5 mg, at least 15 mg, at least 17.5 mg, at least 20 mg, at least 25, or at least 30 mg.

[0256] Surfactants that can be used to form the pharmaceutical composition and dosage form of the disclosed invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be used, a mixture of lipophilic surfactants may be used, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be used.

[0257] Suitable hydrophilic surfactants generally have an HLB value of at least 10, whereas suitable lipophilic surfactants generally have an HLB value of about 10 or less. The experimental parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values ​​are more lipophilic or hydrophobic and have greater solubility in oil, whereas surfactants with higher HLB values ​​are more hydrophilic and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be compounds with an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is generally not applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds with an HLB value of about 10 or less. However, the HLB value of surfactants is merely an approximate guideline commonly used to enable the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0258] Hydrophilic surfactants may be ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides and polypeptides; glyceride derivatives of amino acids, oligopeptides and polypeptides; lecithin and hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin; phospholipids and their derivatives; lysophospholipids and their derivatives; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; sodium docusate; acyl lactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

[0259] Within the group mentioned above, ionic surfactants include, for example, lecithin, lysolecithin, phospholipids, lysophospholipids and their derivatives; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; sodium docusate; acyl acylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

[0260] Ionic surfactants include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactic acid esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono / diacetylated tartaric acid esters of mono / diglycerides, citric acid esters of mono / diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, It may be an ionized form of stearate, lauryl sulfate, terasecyl sulfate, docusate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and their salts and mixtures.

[0261] Hydrophilic non-ionic surfactants include alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers, such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols, such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters, such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters, such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of polyols and at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, their derivatives, and analogs; polyoxyethylated vitamins and their derivatives; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; It may include, but is not limited to, a polyethylene glycol sorbitan fatty acid ester, and a hydrophilic transesterification product of at least one member of the group consisting of a polyol and a triglyceride, vegetable oil, and hydrogenated vegetable oil. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or saccharide.

[0262] Other hydrophilic-nonionic surfactants include, but are not limited to, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, and PEG-30 glyceryl Laurate, PEG-20 Glyceryl Stearate, PEG-20 Glyceryl Oleate, PEG-30 Glyceryl Oleate, PEG-30 Glyceryl Laurate, PEG-40 Glyceryl Laurate, PEG-40 Palm Kernel Oil, PEG-50 Hydrogenated Castor Oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil, PEG-40 Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, PEG-60 Corn Oil, PEG-6 Caprate / Caprylate Glycerides, PEG-8 Caprate / Caprylate Glycerides, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG-25 Phytosterols, PEG-30 Soy Sterols, PEG-20 Trioleate, PEG-40 Sorbitan Oleate, PEG-80 Sorbitan Laureate, Polysorbate 20, Polysorbate 80, POE-9 Lauryl Ether, POE-23 Lauryl Ether, POE-10 Oleyl Ether, POE-20 Oleyl Ether, POE-20 Stearyl Ether, Tocopheryl PEG-100 Succinate, PEG-24 Cholesterol, Polyglyceryl-10 Oleate, Tween 40, Tween 60, Sucrose Monostearate, Sucrose Monolaurate, Sucrose Monopalmitate, PEG 10-100 Nonylphenol Series, PEG 15-100 Octylphenol Series,and includes poloxamer.

[0263] Suitable lipophilic surfactants include, by way of example: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of polyols and at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; oil-soluble vitamins / vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or hydrophobic transesterification products of polyols and at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0264] In one embodiment, the composition may include a solubilizing agent to ensure excellent solubilization and / or dissolution of the compound of the present disclosure and to minimize precipitation of the compound of the present disclosure. This may be particularly important for compositions intended for non-oral use, e.g., compositions for injection. The solubilizing agent may also be added to increase the solubility of hydrophilic drugs and / or other components, e.g., surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[0265] Examples of suitable solubilizers are alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrin and cyclodextrin derivatives; ethers of polyethylene glycol having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; Amides and other nitrogen-containing compounds, e.g., 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters, e.g., ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizing agents known in the relevant art, such as dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidone, monooctanoin, diethylene glycol monoethyl ether, and water, are included but not limited thereto.

[0266] A mixture of solubilizing agents may also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizing agents include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol, and propylene glycol.

[0267] The amount of solubilizer that may be included is not particularly limited. The amount of solubilizer given may be limited to a bioacceptable amount, which can be easily determined by a person skilled in the art. In some situations, for example, to maximize the concentration of the drug, it may be advantageous to include an amount of solubilizer that far exceeds the bioacceptable amount, whereby the excess solubilizer is removed using conventional techniques, such as distillation or evaporation, before administering the composition to the patient. Where present, the solubilizer may be present in a weight ratio of 10 wt%, 25 wt%, 50 wt%, 100 wt%, or up to about 200 wt% based on the combined weight of the drug and other excipients. If desired, very small amounts of solubilizer, such as 5%, 2%, 1%, or even less, may also be used. Typically, the solubilizer may be present in an amount of about 1 wt% to about 100 wt%, more typically about 5 wt% to about 25 wt%.

[0268] The composition may further include one or more pharmaceutically acceptable additives and excipients. These additives and excipients include, but are not limited to, detackifiers, defoamers, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, flow modifiers, flavoring agents, coloring agents, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0269] Additionally, acids or bases may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS), etc. In addition, bases that are salts of pharmaceutically permissible acids, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc., are suitable. Salts of polypolysaccharides, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate, may also be used. If the base is a salt, the cation may be any convenient and pharmaceutically permissible cation, such as ammonium, alkali metal, alkaline earth metal, etc. Examples may include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0270] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromide, hydroiodide, sulfuric acid, nitric acid, boric acid, phosphoric acid, etc. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc.

[0271] Where the method of the disclosure involves, for example, a combination therapy in which a secondary agent is co-administered with the compound of formula (I), the agents may be administered individually, simultaneously, or at different times of the day, or they may be administered as a single composition. In the combination therapy of the disclosure, each agent may be administered in an "immediate release" manner or in a "controlled release manner." Where the additional active agent is a corticosteroid, for example, any dosage form containing both active agents, such as both the compound of formula (I) and the corticosteroid, may provide immediate or controlled release of the corticosteroid and immediate or controlled release of the compound of formula (I). In other formulations of the disclosure, two or more additional active agents, which may or may not be drugs of the same class, may be present in combination with the compound of formula (I). In such cases, the effective amount of any one or each individual additional active agent present will generally be reduced compared to the amount required when only a single additive is used.

[0272] In some embodiments, the solid dispersion, solid dosage form, or pharmaceutical composition provided herein, or a composition comprising the solid dispersion, solid dosage form, or pharmaceutical composition provided herein is administered orally, parenterally, topically, or by mucosal contact. In some embodiments, the solid dispersion, solid dosage form, or pharmaceutical composition provided herein, or a composition comprising the solid dispersion, solid dosage form, or pharmaceutical composition provided herein is administered orally.

[0273] In some embodiments, the solid dispersion, solid dosage form, or pharmaceutical composition provided herein, or the composition comprising the solid dispersion, solid dosage form, or pharmaceutical composition provided herein, is administered at a dosage frequency of once, twice, three, or four times per day. In some embodiments, the solid dispersion, solid dosage form, or pharmaceutical composition provided herein, or the composition comprising the solid dispersion, solid dosage form, or pharmaceutical composition provided herein, comprises a compound of formula (I) in an amount of about 0.1 to about 100 mg, about 0.5 to about 75 mg, about 5 to about 50 mg, about 5 mg to about 45 mg, about 5 to about 15 mg, or about 35 to about 45 mg. In some embodiments, a single unit dosage form suitable for oral administration to humans is provided herein, comprising an amount of at least 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, or 100 mg of a compound of formula (I); and pharmaceutically acceptable excipients. In some embodiments, the amount of the active ingredient is about 10 mg. In some embodiments, the amount of the active ingredient is about 40 mg.

[0274] In some embodiments, the second activator is administered in amounts of about 1 to about 1000 mg, about 5 to about 500 mg, about 10 to about 350 mg, or about 50 to about 200 mg once or twice daily, every other day, once weekly, once every two weeks, or once every three weeks. In some embodiments, the second activator is administered orally or intravenously. The specific amount of the second activator will depend on the specific agent used, the type of disease to be treated or managed, the severity and stage of the disease, and the amount(s) of any optional additional activator co-administered with the compound provided herein and the patient.

[0275] As discussed elsewhere in this application, methods for reducing, treating, and / or preventing harmful or undesirable effects associated with conventional therapies, including but not limited to surgery, chemotherapy, radiation therapy, hormone therapy, biological therapy, and immunotherapy, are also covered. Solid dispersions comprising the compound of formula (I) and other active ingredients provided herein may be administered to a patient before, during, or after the occurrence of adverse effects associated with conventional therapies.

[0276] Method for preparing a pharmaceutical composition

[0277] In a particular aspect, the present disclosure provides a method for producing a solid dosage form comprising: (a) mixing a compound of formula (I) and one or more pharmaceutically acceptable excipients to form milled granules; and (b) compressing the granules by applying a compressive force of 5 kN to 20 kN.

[0278] In a particular aspect, the present disclosure provides a method for producing a solid dosage form comprising: (a) blending a compound of formula (I), a binder, a filler, a disintegrant, and a lubricant to form a blended mixture; (b) granulating the blended mixture using optional roller presses to form a granulated mixture; (c) mixing a second filler, a second disintegrant, and a second lubricant with the granulated mixture to form a tabletized mixture; and (d) compressing the tabletized mixture into a tablet, wherein the filler and the second filler are the same or different; the disintegrant and the second disintegrant are the same or different; and the lubricant and the second lubricant are the same or different. In some embodiments, the binder is microcrystalline cellulose, the filler is mannitol, the disintegrant is sodium croscarmellose, and the lubricant is magnesium stearate. In some embodiments, the second filler is mannitol, the second disintegrant is sodium croscarmellose, and the second lubricant is magnesium stearate. The process may further include mixing the lubricant with the granulated mixture. In some embodiments, the lubricant is colloidal silicon dioxide, e.g., Cab-O-Sil. In some embodiments, the process further includes coating the tablet. The coating may be a PVA-based coating, e.g., Opadry II.

[0279] In some embodiments, the process comprises pre-coating a blender shell with a binder, optionally wherein the binder is microcrystalline cellulose. Pre-coating the blender shell may comprise blending the binder, e.g., blending the binder for at least 1 minute. The process may further comprise mixing the granular components in the coated blender, optionally wherein the granular components comprise a compound of formula (I), a binder, a filler, a disintegrant, and optionally a lubricant. Mixing may comprise blending for at least 5 minutes, optionally at a speed of 15 rpm or more. In some embodiments, the process further comprises milling the blended granular components. The process may further comprise mixing the milled granular components in a blender, e.g., blending for at least 10 minutes at a speed of at least 15 rpm. In some embodiments, a lubricant, such as magnesium stearate, is added to a blender and mixed with the milled and blended granular components. This mixture may optionally be granulated using a roller press. Optionally, the process further comprises passing the granulated material through a mill. The process may further comprise transferring the milled granules to a blender and mixing them with non-granular components, optionally wherein the non-granular components include fillers and disintegrants. In some embodiments, the process further comprises adding a lubricant, such as magnesium stearate, to the mixture and mixing to form a tablet blend. In some embodiments, the process further comprises adding a lubricant, such as colloidal silicon dioxide, to the mixture and mixing to form a tablet blend. Optionally, the tablet blend is compressed using a roller press. In some embodiments, the process comprises compressing the tablet blend into tablets. In some embodiments, the tablets are elliptical in shape. In some embodiments, the pressing compressive force is 5 to 20 kN, for example, about 7.5 kN or about 15 kN.In some embodiments, the tablets consist of a blend of tablets of about 500 mg, e.g., 500 ± 25 mg. In some embodiments, the tablets consist of a blend of tablets of about 125 mg, e.g., 125 ± 10 mg.

[0280] Packaged composition and kit

[0281] In certain aspects, the present disclosure provides a packaged solid dispersion comprising the solid dispersion and a desiccant described herein. Suitable desiccants include silica gel, bentonite clay, or molecular sieves. In some embodiments, the packaging comprises a low-water vapor permeable container, such as an HDPE bottle, an LDPE bag, a double LDPE bag with the opening bent by a cable tie, an HDPE bottle sealed by a screw cap, an HDPE drum, or a combination thereof.

[0282] In certain aspects, the present disclosure provides a packaged solid dosage form comprising the solid dosage form described herein and a desiccant. Suitable desiccants include silica gel, sorbit, clariant, bentonite clay, or molecular sieves. In some embodiments, the packaging comprises a low-water vapor permeable container, such as an HDPE bottle, an LDPE bag, a double LDPE bag with the opening bent by a cable tie, an HDPE bottle sealed by a screw cap, an HDPE drum, a foil-foil blister, a cold-forming foil-foil blister, an aluminum-aluminum blister, a cold-forming aluminum-aluminum blister, a polyvinyl chloride (PVC) blister, a polyvinylidene chloride (PVDC) blister, an aclar blister, a poly-chloro-tri-fluoro-ethylene (PCTFE) blister, a plastic bottle, a multilayer bottle, or a combination thereof. The packaged solid dosage form may further comprise a cotton, rayon, or polyester coil. In some embodiments, the packaged solid dosage form comprises a solid dosage form, a desiccant, and a bottle, such as an HDPE bottle, containing optionally a cotton, rayon, or polyester coil. In some embodiments, the packaged solid dosage form comprises a solid dosage form, a desiccant, and a bottle, such as an HDPE bottle, containing a cotton, rayon, or polyester coil.

[0283] In certain aspects, the present disclosure provides a kit comprising the solid dosage form described herein and instructions for administering the solid dosage form to a subject requiring it. In some embodiments, the kit comprises a solid dosage form comprising a compound of formula (I) packaged in a low-water vapor permeable container together with a desiccant. Optionally, a label is on the container or associated with the container. For example, the label is on the container where the letters, numbers, or other symbols forming the label are attached, molded, or etched onto the container itself, and the label is associated with the container where it is present in a recipient or carrier, such as a box, that also holds the container, for example, as a package insert. Additionally, the label may be used to indicate that the contents should be used for a specific therapeutic purpose. In some embodiments, the label includes instructions for the use of the contents, for example, in the method described herein. In some embodiments, the pharmaceutical composition provided herein is provided in a pack or container containing one or more unit dosage forms comprising a compound of formula (I). The pack may contain metal or plastic foil, such as a blister pack. The pack or container may enclose instructions for administration in the unit dosage form. In some embodiments, the pack or container encloses instructions in a form prescribed by a government agency regulating the manufacture, use, or sale of the pharmaceutical, and the instructions reflect agency approval of the drug form for human or veterinary administration. Such instructions may be, for example, labeling approved by the U.S. Food and Drug Administration for the prescription of the drug, or approved product inserts. In some embodiments, a composition containing a compound of formula (I) is prepared, placed in a suitable container, and labeled for the treatment of the indicated condition.

[0284] Treatment methods

[0285] In one aspect, the present disclosure provides a method for treating a proliferative disorder in a subject requiring treatment for a proliferative disorder, comprising administering a solid dispersion, a solid dosage form, or a pharmaceutical composition provided herein to the subject requiring treatment for the proliferative disorder. In some embodiments, the proliferative disorder is a cancerous condition. In some additional embodiments, the cancerous condition is a cancer selected from the group consisting of lung cancer, head and neck squamous cell carcinoma, pancreatic cancer, breast cancer, ovarian cancer, renal cell carcinoma, prostate cancer, neuroendocrine cancer, gastric cancer, bladder cancer, and colon cancer. In some additional embodiments, the cancerous condition is renal cell carcinoma. In a specific aspect, the present disclosure provides a method for treating renal cell carcinoma, comprising administering an effective amount of a solid dispersion, a solid dosage form, or a pharmaceutical composition provided herein to a subject requiring treatment for renal cell carcinoma. In some embodiments, the renal cell carcinoma is clear cell renal cell carcinoma.

[0286] In some embodiments, the present disclosure provides a method for treating a cancerous condition, wherein the compound of formula (I) is effective for one or more of inhibiting the proliferation of cancer cells, inhibiting the metastasis of cancer cells, killing cancer cells, and reducing the severity or incidence of symptoms associated with the presence of cancer cells. In some other embodiments, the method comprises administering a therapeutically effective amount of the solid dispersion, solid dosage form, or pharmaceutical composition provided herein to cancer cells. In some embodiments, administration takes place in vitro. In other embodiments, administration takes place in vivo.

[0287] In some embodiments, the present invention provides a method for treating von Hippel-Lindau (VHL) disease, comprising administering the solid dispersion, solid dosage form, or pharmaceutical composition provided herein to a subject requiring treatment for VHL disease. In some embodiments, the subject also suffers from hemangioma, pheochromocytoma, pancreatic neuroendocrine tumor, or renal cell carcinoma. In some embodiments, the subject suffers from renal cell carcinoma. VHL disease is an autosomal dominant syndrome that predisposes patients not only to renal cancer (~70% lifetime risk) but also to hemangioma, pheochromocytoma, and pancreatic neuroendocrine tumor. VHL disease gives rise to tumors containing constitutively active HIF-α proteins, most of which are dependent on HIF-2α activity (Maher, et al., Eur. J. Hum. Genet. 19: 617-623, 2011). HIF-2α has been associated with cancers of the retina, adrenal gland, and pancreas through both VHL disease and activating mutations. Recently, function-acquired HIF-2α mutations have been identified in paragangliomas accompanied by erythrocytosis and polycythemia (Zhuang, et al., NEJM 367: 922-930, 2012; Percy, et al., NEJM 358: 162-168, 2008; and Percy, et al., Am. J. Hematol. 87: 439-442, 2012). In particular, a number of known HIF-2α targeted gene products (e.g., VEGF, PDGF, and Cyclin D1) have been found to play pivotal roles in cancers originating from the kidney, liver, colon, lung, and brain. Indeed, therapies targeted against VEGF, one of the major HIF-2α regulated gene products, have been approved for the treatment of these cancers.

[0288] The therapeutically effective amount of a solid dispersion, solid dosage form, or pharmaceutical composition used herein refers to an amount of a compound of formula (I) sufficient to perform an intended application, including but not limited to the treatment of a disease as defined herein. Additionally, the use of a compound of formula (I) in an amount less than the therapeutic amount is considered for treating the disease state intended in the target method.

[0289] The amount of solid dispersion, solid dosage form, or pharmaceutical composition administered may vary depending on the intended application (in vitro or in vivo) or the subject and disease state to be treated, e.g., the subject's body weight and age, the severity of the disease state, the method of administration, etc., and can be easily determined by a person skilled in the art.

[0290] Measuring the inhibition of the biological effects of HIF-2α may involve performing a test on biological samples, such as samples from a subject. Any variety of samples may be selected for the test. Examples of samples include, but are not limited to, blood samples (e.g., plasma or serum), exhaled condensate samples, bronchoalveolar lavage fluid, sputum samples, urine samples, and tissue samples.

[0291] A subject treated with the solid dispersion, solid dosage form, or pharmaceutical composition of the present disclosure may be monitored to determine the efficacy of the treatment, and the treatment regimen may be adjusted based on the subject's physiological response to the treatment. For example, if the inhibition of the biological effect of HIF-2α inhibition exceeds or falls below the threshold, the dosage or frequency of administration may be decreased or increased, respectively. The method may further include continuing the regimen if the regimen is determined to be effective. The method may include maintaining, decreasing, reducing, or stopping the dosage of the compound in the regimen if the regimen is determined to be effective. The method may include increasing the dosage of the compound in the regimen if the regimen is determined to be ineffective. Alternatively, the method may include stopping the regimen if the regimen is determined to be ineffective. In some embodiments, treatment with the compound of formula (I) is discontinued when the inhibition of the biological effect exceeds or falls below the threshold, e.g., in the event of a lack of response or an adverse reaction. The biological effect may be a change in any various physiological indicator.

[0292] Generally, HIF-2α inhibitors, such as compounds of formula (I), are compounds that inhibit one or more biological effects of HIF-2α. Examples of biological effects of HIF-2α include, but are not limited to, the heteromerization of HIF-2α with HIF-1β, HIF-2α target gene expression, VEGF gene expression, and VEGF protein secretion. In some embodiments, the HIF-2α inhibitor is selective for HIF-2α, so the inhibitor inhibits the heteromerization of HIF-2α with HIF-1β but does not inhibit the heteromerization of HIF-1α with HIF-1β. These biological effects may be inhibited by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more, or about more than that.

[0293] Hypoxia-inducible factors (HIFs), such as HIF-2α, are transcription factors that respond to changes in oxygen available in the cellular environment (e.g., a decrease in oxygen, or hypoxia). The HIF signaling cascade mediates the effects of hypoxia, a state of low oxygen concentration for cells. Hypoxia often prevents cell differentiation. However, hypoxia promotes angiogenesis and is important for the formation of vascular systems in embryonic and cancerous tumors. In wounds, hypoxia also promotes the migration of keratinocytes and epithelial recovery. A compound of formula (I) can be administered in an amount effective in reducing any one or more of these effects of HIF-2α activity.

[0294] HIF-2α activity can be inhibited by inhibiting the heteromerization of HIF-2α with HIF-1β (ARNT), for example, using a compound of formula (I). Various methods are available to measure HIF-2α dimerization. In some embodiments, the HIF-2α inhibitor binds to the PAS-B domain co of HIF-2α.

[0295] The inhibition of the heteromerization of HIF-2α with HIF-1β (ARNT) can also be determined by the reduction in HIF-2α target gene mRNA expression. mRNA quantification can be performed using real-time PCR technology. (Wong, et al., "Real-time PCR for mRNA quantitation", 2005. BioTechniques 39, l: ll.). Another method to determine the inhibition of the heteromerization of HIF-2α with HIF-1β (ARNT) is by co-immunoprecipitation.

[0296] As described herein, HIF-2α is a transcription factor that plays an important role in regulating the expression of target genes. Non-limiting examples of HIF-2α target genes include HMOX1, SFTPA1, CXCR4, PAI1, BDNF, hTERT, ATP7A, and VEGF. For example, HIF-2α is an activator of VEGF. Further non-limiting examples of HIF-2α target genes include HMOX1, EPO, CXCR4, PAI1, CCND1, CLUT1, IL6, and VEGF. The compound of formula (I) may be administered in an amount effective in reducing the expression of any one or more of the genes induced by HIF-2α activity. Various methods are available for detecting gene expression levels and include the detection of gene transcription products (polynucleotides) and translation products (polypeptides). For example, gene expression may be detected and quantified at the DNA, RNA, or mRNA level. Various methods used to quantify mRNA include in-situ hybridization techniques, fluorescent in-situ hybridization techniques, reporter genes, RNase protection assays, Northern blotting, reverse transcription (RT)-PCR, SAGE, DNA microarrays, tiling arrays, and RNA-seq. Examples of methods for detecting polynucleotides include, but are not limited to, selective colorimetric detection of polynucleotides based on the distance-dependent optical properties of gold nanoparticles, and solution-phase detection of polynucleotides using interaction fluorescent labeling and competitive hybridization. Examples of protein detection include, but are not limited to, microscopy and protein immunostaining, protein immunoprecipitation, immunoelectrophoresis, Western blot, BCA assay, spectrophotometry, mass spectrophotometry, and enzymatic assays.

[0297] In some embodiments, inhibition of HIF-2α is characterized by a decrease in VEGF gene expression. The decrease can be measured by any various method, such as those described herein. As an additional example, the mRNA expression level of VEGF can be measured by quantitative PCR (QT-PCR), microarrays, RNA-seq, and nanostrings. As yet another example, the level of VEGF protein secretion can be measured using an ELISA assay.

[0298] In certain aspects, the present disclosure provides a method for treating an HIF-2α-mediated disease or condition, comprising administering a therapeutically effective amount of the solid dispersion, solid dosage form, or pharmaceutical composition described herein to a subject requiring treatment for the HIF-2α-mediated disease or condition. In some embodiments, the disease or condition is cancer. In some embodiments, the disease or condition is selected from renal cell carcinoma, von Hippel-Lindau disease, pulmonary arterial hypertension, glioblastoma, and colitis.

[0299] In some embodiments, a method for inhibiting HIF-2α is provided herein, comprising contacting an effective amount of HIF-2α with the solid dispersion, solid dosage form, or pharmaceutical composition described herein. In some other embodiments, the target method is useful for treating disease states associated with HIF-2α. Any disease state caused directly or indirectly by abnormal activity or expression levels of HIF-2α may be the intended disease state. In some embodiments, the disease state is a proliferative disorder as described herein, including but not limited to cancer. The role of HIF-2α in tumorigenesis and tumor progression has been implicated in many human cancers. Constitutively active HIF-2α may result from defective VHL or low oxygen concentrations in cancer cells. Rapidly growing tumors are typically hypoxic due to poor vascularization, a condition that activates HIF-2α, which supports tumor cell survival and proliferation. Constitutively activated HIF-2α has emerged as a common topic in various human cancers, and consequently, agonists targeting HIF-2α have therapeutic value.

[0300] The data presented in the embodiments of the present invention below demonstrate the anticancer effect of the compound of formula (I). Therefore, the method is particularly useful for treating proliferative disorders, such as neoplastic conditions. Non-limiting examples of these conditions include acanthocarcinoma, acinar cell carcinoma, acoustic neuroma, acral lentigo melanoma, acral hidradenoma, acute eosinophilic leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute myeloid leukemia according to maturation, acute myeloid dendritic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, enameloma, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatous odontogenic tumor, adrenocortical carcinoma, adult T-cell leukemia, aggressive NK-cell leukemia, AIDS-associated cancer, AIDS-associated lymphoma, alveolar soft tissue sarcoma, enameloblastofibroma, anal cancer, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, appendiceal cancer, astrocytoma, atypical rhabdomyocytoma Tumor, Basal cell carcinoma, Basal-like carcinoma, B-cell leukemia, B-cell lymphoma, Bellini duct carcinoma, Biliary tract cancer, Bladder cancer, Bladder cancer, Bladder tumor, Bone cancer, Bone tumor, Brainstem glioma, Brain tumor, Breast cancer, Brenner tumor, Bronchial tumor, Bronchioloalveolar carcinoma, Brown tumor, Burkitt lymphoma, Carcinoid tumor, Carcinoma, Carcinosarcoma, Castleman disease, Central nervous system embryonic tumor, Cerebellar astrocytoma, Brain astrocytoma, Cervical cancer, Cholangiocarcinoma, Chondroma, Chondrosarcoma, Chordoma, Choriocarcinoma, Choroid plexus papilloma, Chronic lymphocytic leukemia, Chronic monocytic leukemia, Chronic myeloproliferative disorder, Chronic neutrophilic leukemia, Clear cell renal cell carcinoma, Clear-cell tumor, Colon cancer, Colorectal cancer, Craniopharyngioma, Cutaneous T-cell lymphoma, Dermatofibrosarcoma protuberance, Dermoid cyst, connective tissue-forming small round cell tumor, diffuse large B-cell lymphoma, embryogenic neuroepithelial tumor, embryonic carcinoma, endodermal sinus tumor, endometrial cancer, endometrial cancer, endometrioid tumor, enteropathy-associated T-cell lymphoma, ependymoma, ependymoma, epithelioid sarcoma, erythroleukemia, esophageal cancer,Sensory neuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic cholangiocarcinoma, extramammary Paget's disease, fallopian tube cancer, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, gallbladder cancer, ganglion glioma, ganglion neuroma, gastric cancer, gastric lymphoma, gastric cancer, gastric carcinoid tumor, gastric stromal tumor, germ cell tumor, germ cell tumor, gestational choriocarcinoma, gestational trophoblastoma, giant cell tumor of bone, glioblastoma pleomorphic, glioma, cerebral gliomatosis, glomus tumor, glucagonoma, germoma, granulosa cell tumor, hairy cell leukemia, head and neck cancer, heart cancer, hemangioma, perivascular cell tumor, angiosarcoma, hematological malignancy, hepatocellular carcinoma, hepatosplenic T-cell lymphoma, Hodgkin lymphoma, hypopharyngeal cancer, hypothalamic glioma, inflammatory breast cancer, intraocular melanoma, islet cell Carcinoma, Pediatric Myelomonocytic Leukemia, Kaposi Sarcoma, Kidney Cancer, Klatskin Tumor, Krukenberg Tumor, Laryngeal Cancer, Malignant Lentigon, Leukemia, Lip and Oral Cancer, Liposarcoma, Lung Cancer, Luteinoma, Lymphangioma, Lymphangiosarcoma, Lymphoidepithelialoma, Lymphocytic Leukemia, Lymphoma, Macroglobulinemia, Malignant Fibrohistiocytoma, Malignant Glioma, Malignant Mesothelioma, Malignant Peripheral Sheath Tumor, Malignant Rhabdomyocystoid Tumor, Malignant Triton Tumor, MALT Lymphoma, Mantle Cell Lymphoma, Mast Cell Leukemia, Mediastinal Germ Cell Tumor, Mediastinal Tumor, Medullary Thyroid Cancer, Medulloblastoma, Medulloepithelial Tumor, Melanoma, Meningioma, Merkel Cell Carcinoma, Mesothelioma, Potential Primary Metastatic Squamous Neck Cancer, Metastatic Urothelial Carcinoma, Mixed Müller Tumor, Monocytic Leukemia, Oral Cancer, Mucinous Tumor, Multiple Endocrine Neoplastic syndrome, multiple myeloma, mycosis fungoides, myelodysplastic disease, myeloid leukemia, myeloid sarcoma, myeloproliferative disorder, myxoma, nasal cavity cancer, nasopharyngeal cancer, neoplasm, schwannoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, non-Hodgkin lymphoma, non-melanoma skin cancer, non-small cell lung cancer, ocular tumor, oligodendroglioma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, ovarian epithelial carcinoma,Ovarian germ cell tumor, ovarian low-malignant potential tumor, Pancost tumor, pancreatic cancer, papillary thyroid cancer, papillomatosis, paraganglioma, sinus cancer, parathyroid cancer, penile cancer, perivascular epithelioid tumor, pharyngeal cancer, pheochromocytoma, intermediately differentiated pineal parenchymal tumor, pineal blastoma, pituitary cytomatosis, pituitary adenoma, pituitary tumor, plasma cell neoplasm, pleuropulmonary blastoma, multigermoma, precursor T-lymphoblastic lymphoma, primitive neuroectodermal tumor, prostate cancer, peritoneal pseudomyxoma, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyocystoma, rhabdomyosarcoma, Richter transformation, sacrococcygeal teratoma, salivary gland carcinoma, sarcoma, Schwann cytomatosis, sebaceous carcinoma, secondary neoplasm, seminoma, serous tumor, Serous tumor, Sertoli-Leydig cell tumor, sex cord-stromal tumor, three-digit Syndrome, signet cell carcinoma, skin cancer, small blue round cell tumor, small cell carcinoma, small cell lung cancer, small cell lymphoma, small intestine cancer, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, gastric cancer, superficial diffuse melanoma, supratentorial primitive neuroectodermal tumor, surface epithelial-stromal tumor, synovial sarcoma, T-cell acute lymphoblastic leukemia, T-cell megagranulocyte leukemia, T-cell leukemia, T-cell lymphoma, T-cell prelymphocytic leukemia, teratoma, acral lymphoma, testicular cancer, follicular membranoma, throat cancer, thymic carcinoma, thymoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, transitional cell carcinoma, urachal carcinoma, urethral cancer, genitourinary neoplasm, uterine sarcoma, uveal melanoma, vaginal cancer, Werner Morrison syndrome, Includes, but is not limited to, verrucous carcinoma, optic pathway glioma, vulvar cancer, Waldenström macrobulinemia, Warthin tumor, Wilms tumor, or any combination thereof.

[0301] In some embodiments, the method of administering the solid dispersion, solid dosage form, or pharmaceutical composition described herein is applied to the treatment of cancer of the adrenal gland, blood, bone marrow, brain, breast, cervical, colon, head and neck, kidney, liver, lung, ovary, pancreas, plasma cell, rectum, retina, skin, spine, throat, or any combination thereof.

[0302] Some embodiments of the present disclosure consider human subjects, e.g., subjects diagnosed with a proliferative disorder or at risk of developing or acquiring such a condition. Certain other embodiments consider non-human subjects, e.g., non-human primates, such as macaques, chimpanzees, gorillas, vervets, orangutans, baboons, or other non-human primates including such non-human subjects that may be known in the art as preclinical models. Certain other embodiments consider non-human subjects that are mammals, e.g., mice, rats, rabbits, pigs, sheep, horses, cattle, goats, gerbils, hamsters, guinea pigs, or other mammals. Other embodiments are also considered in which the subject or biological source may be a non-mammalian vertebrate, e.g., another higher vertebrate, or a bird, amphibian, or reptile species, or another subject or biological source. In certain embodiments of the present invention, transgenic animals are used. A transgenic animal is a non-human animal in which one or more of the animal's cells contain a non-endogenous (i.e., heterogeneous) nucleic acid, which is present as an extrachromosomal element in part of the cell or is stably integrated into the wiring DNA (i.e., within the genome sequence of most or all of the cell).

[0303] In some embodiments, therapeutic efficacy is measured based on the effect of treating proliferative disorders, e.g., cancer. Generally, regarding the treatment of proliferative disorders (e.g., benign or malignant cancer), the therapeutic efficacy of the methods and compositions of the present invention may be measured by the extent to which the methods and compositions promote the inhibition of tumor cell proliferation, inhibition of tumor angiogenesis, eradication of tumor cells, reduction of the tumor growth rate, and / or reduction of at least one tumor size. Several parameters considered in determining therapeutic efficacy are discussed herein. An appropriate combination of parameters for a specific situation may be established by a clinician. Progress of the methods of the present invention in cancer treatment (e.g., reduction of tumor size or eradication of cancerous cells) may be confirmed using any suitable method, such as methods currently used in clinics to track tumor size and cancer progression. The primary efficacy parameter used to evaluate the treatment of cancer by the methods and compositions of the present invention is preferably a reduction in tumor size. Tumor size may be indicated using any suitable technique, such as measurement of dimensions, or by using available computer software, such as FreeFlight software developed at Wake Forest University, which enables accurate estimation of tumor volume. Tumor size may be determined by tumor visualization using, for example, CT, ultrasound, SPECT, helical CT, MRI, photography, etc. In embodiments where the tumor is surgically resected after the completion of the treatment period, the presence of tumor tissue and tumor size may be determined by gross analysis of the tissue to be resected and / or by pathological analysis of the resected tissue.

[0304] In some embodiments, the growth of the tumor is stabilized as a result of the method and composition of the present invention (i.e., one or more tumors do not increase in size by more than 1%, 5%, 10%, 15%, or 20% and / or metastasize). In some embodiments, the tumor is stabilized for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 weeks or more. In some embodiments, the tumor is stabilized for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more. In some embodiments, the tumor is stabilized for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 years or more. Preferably, the method of the present invention reduces the size of the tumor by at least about 5% (e.g., at least about 10%, 15%, 20%, or 25%). More preferably, the tumor size is reduced by at least about 30% (e.g., at least about 35%, 40%, 45%, 50%, 55%, 60%, or 65%). Even more preferably, the tumor size is reduced by at least about 70% (e.g., at least about 75%, 80%, 85%, 90%, or 95%). Most preferably, the tumor is completely eliminated or reduced to a level below the detectable level. In some embodiments, the subject remains tumor-free (e.g., in remission) for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 weeks, or longer after treatment. In some embodiments, the subject remains tumor-free for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more after treatment. In some embodiments, the subject remains tumor-free for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 years or more after treatment.

[0305] In some embodiments, the efficacy of the method of the present disclosure in reducing tumor size may be determined by measuring the percentage of necrotic (i.e., dead) tissue of the surgically resected tumor after the completion of the treatment period. In some additional embodiments, treatment is therapeutically effective when the percentage of necrosis of the resected tissue is greater than about 20% (e.g., at least about 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%), more preferably about 90% or more (e.g., about 90%, 95%, or 100%). Most preferably, the percentage of necrosis of the resected tissue is 100%, that is, no tumor tissue is present or detectable.

[0306] The efficacy of the method of the present disclosure may be determined by a number of secondary parameters. Examples of secondary parameters include, but are not limited to, the detection of new tumors, the detection of tumor antigens or markers (e.g., CEA, PSA, or CA-125), biopsy, surgical stage reduction (i.e., the surgical transition of a tumor from unresectable to resectable), PET scan, survival, disease-free survival, time to disease progression, quality of life assessment, and, for example, assessment of clinical benefit response, all of which may indicate overall progression (or regression) of cancer in humans. Biopsy is particularly useful for detecting the eradication of cancerous cells within tissue. Radioimmunodetection (RAID) is used to localize and stage tumors using serum levels of markers (antigens) produced by or associated with the tumor ("tumor markers" or "tumor-associated antigens"), and may be useful as a diagnostic basis before treatment, an indicator of recurrence after treatment, and an indicator of therapeutic efficacy after treatment. Examples of tumor markers or tumor-associated antigens that can be evaluated as indicators of therapeutic efficacy include, but are not limited to, carcinoembryonic antigen (CEA), prostate-specific antigen (PSA), CA-125, CA19-9, ganglioside molecules (e.g., GM2, GD2, and GD3), MART-1, heat shock protein (e.g., gp96), sialyl Tn (STn), tyrosinase, MUC-1, HER-2 / neu, c-erb-B2, KSA, PSMA, p53, RAS, EGF-R, VEGF, MAGE, and gp100. Other tumor-associated antigens are known in the art. RAID technology combined with an endoscopic detection system can also efficiently distinguish small tumors from surrounding tissues (see, e.g., U.S. Patent No. 4,932,412).

[0307] In some embodiments, treatment of cancer in a human patient according to the method of the present invention is demonstrated by one or more of the following results: (a) complete eradication of the tumor (i.e., complete response), (b) a reduction in the size of the tumor by about 25% to about 50% over at least 4 weeks after the completion of the treatment period compared to the size of the tumor before treatment, (c) a reduction in the size of the tumor by at least about 50% over at least 4 weeks after the completion of the treatment period compared to the size of the tumor before treatment, and (d) a reduction in the level of specific tumor-associated antigen by at least 2% over 4 to 12 weeks after the completion of the treatment period compared to the level of tumor-associated antigen before treatment (e.g., a reduction of about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%). While a reduction of at least 2% in the level of tumor-associated antigen is preferred, any reduction in the level of tumor-associated antigen is evidence of treatment of cancer in a patient by the method of the present invention. For example, in the case of unresectable, locally advanced pancreatic cancer, treatment may be demonstrated by at least a 10% reduction in CA19-9 tumor-associated antigen levels 4 to 12 weeks after the completion of the treatment period compared to CA19-9 levels before the treatment period. Similarly, in the case of locally advanced rectal cancer, treatment may be demonstrated by at least a 10% reduction in CEA tumor-associated antigen levels 4 to 12 weeks after the completion of the treatment period compared to CEA levels before the treatment period.

[0308] In relation to quality of life assessment, e.g., clinical benefit response criteria, the therapeutic benefit of the treatment according to the present invention can be demonstrated in terms of pain intensity, analgesic consumption, and / or Karnovsky performance scale scores. Treatment of cancer in human patients, alternatively or additionally, (a) a reduction of at least 50% in pain intensity reported by the patient during any consecutive 4-week period within 12 weeks after completion of treatment compared to pain intensity reported by the patient prior to treatment (e.g., at least 60%, 70%, 80%, 90%, or 100% reduction), (b) a reduction of at least 50% in analgesic consumption reported by the patient during any consecutive 4-week period within 12 weeks after completion of treatment compared to analgesic consumption reported by the patient prior to treatment (e.g., at least 60%, 70%, 80%, 90%, or 100% reduction), and / or (c) an increase of at least 20 points in the Karnovsky Performance Scale score reported by the patient during any consecutive 4-week period within 12 weeks after completion of treatment compared to the Karnovsky Performance Scale score reported by the patient prior to treatment (e.g., at least 30 points, 50 points, It is proven by an increase of 70 points or 90 points.

[0309] Treatment of proliferative disorders (e.g., benign or malignant cancer) in human patients is preferably demonstrated by one or more of the above results (any combination), but alternative or additional results of the referenced test and / or other tests may demonstrate therapeutic efficacy.

[0310] In some embodiments, tumor size is preferably reduced as a result of the method of the present invention without significant adverse events in the subject. Adverse events are categorized or "graded" by the National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP), where Grade 0 indicates the least adverse event and Grade 4 indicates the most severe adverse event. Preferably, the method of the present invention is associated with the least adverse event as graded by CTEP / NCI, e.g., Grade 0, Grade 1, or Grade 2 adverse event. However, as discussed herein, a reduction in tumor size is desirable but not required, given that the actual size of the tumor cannot shrink despite the eradication of tumor cells. The eradication of cancerous cells is sufficient to realize a therapeutic effect. Likewise, any reduction in tumor size is sufficient to realize a therapeutic effect.

[0311] The detection, monitoring, and grading of various cancers in humans are further described in the literature [Cancer Facts and Figures 2001, American Cancer Society, New York, NY] and international patent application WO 01 / 24684. Accordingly, clinicians may use standard tests to determine the efficacy of various embodiments of the method of the present invention in treating cancer. However, in addition to tumor size and spread, clinicians may also consider the patient's quality of life and survival when evaluating therapeutic efficacy.

[0312] In one aspect, the disclosure provides a method for treating pulmonary arterial hypertension (PAH). In one embodiment, the method comprises administering an effective amount of the solid dispersion, solid dosage form, or pharmaceutical composition described herein to said subject. PAH is a life-threatening progressive disease of various origin characterized by pulmonary revascularization, which leads to increased pulmonary vascular resistance and pulmonary arterial pressure, most often resulting in right-sided heart failure. The most common symptom presented is dyspnea, and impaired exercise capacity is a characteristic of the disease. PAH includes idiopathic PAH, hereditary PAH (e.g., BMPR2, ALK1, endoglin), drug-induced PAH, toxin-induced PAH, and PAH associated with other conditions (e.g., connective tissue disease, HIV infection, portal hypertension, congenital heart disease, schistosomiasis, or chronic hemolytic anemia). Idiopathic PAH occurs in the absence of known risk factors and is the most common form of the disease. The PAH condition treated according to the present disclosure may include any of these PAH conditions.

[0313] Generally, the median survival time after diagnosis for PAH based on the early US National Institutes of Health Registry of prospective follow-up is less than 3 years for 194 untreated patients with idiopathic or hereditary PAH (formerly called primary pulmonary hypertension) with an average age of 36 years. Currently, the average survival after diagnosis in adults is estimated to be 5 to 7 years, and a similarly poor overall prognosis exists in children. In some embodiments, a solid dispersion, solid dosage form, or pharmaceutical composition is administered in an amount effective to increase the average survival among a population of treated subjects by, for example, about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 years, or more, or about more.

[0314] The pathological state of PAH may include pathological changes in the intima, media, and adventitia layers of the blood vessel wall. Both vascular endothelium and smooth muscle cells are characterized by abnormal growth with excessive cell proliferation and resistance to apoptosis. These abnormalities in resident blood vessel cells, combined with inflammation, excessive vasoconstriction, and intrasystem thrombosis, can contribute to physical stenosis of the distal pulmonary arterioles. Although not bound by any theory, this stenosis can cause an increase in pulmonary vascular resistance, which leads to a chronic and progressive elevation of pulmonary artery pressure. In some cases, PAH can be induced by hypoxia. In some embodiments, a solid dispersion, a solid dosage form, or a pharmaceutical composition is administered in an amount effective in delaying one or more of these symptoms associated with PAH, reducing their incidence, or reducing their severity.

[0315] Treating PAH involves treating subjects diagnosed with existing PAH as well as preventing PAH. In some embodiments, the amount of solid dispersion, solid dosage form, or pharmaceutical composition administered to a subject (as a single dose or over multiple doses) is effective in delaying the onset of one or more symptoms of PAH or reducing their incidence. The delay or reduction in incidence may be related to a reference population, e.g., subjects with PAH or a non-treated population of subjects with PAH who have been treated with another agent. The delay or reduction in the incidence of one or more symptoms of PAH may be about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or greater than or approximately greater than that. In some embodiments, a delay or reduction in incidence is measured by an increased time in disease progression, for example, between the appearance of one or more first symptoms and the appearance of one or more second symptoms. The delay may be about days, weeks, months, or years, or about longer than (e.g., 1, 2, 3, 4, 5, 6, 7 days, or longer than; 1, 2, 3, 4, 5, 6, 7, 8 weeks, or longer than; 1, 2, 3, 4, 5, 6 months, or longer than; or 1, 2, 3, 4, 5 years, or longer than). In the case of prevention, the subject may be an individual at risk of developing PAH.

[0316] In one embodiment, the amount of solid dispersion, solid dosage form, or pharmaceutical composition administered to a subject (as a single dose or over multiple doses) is effective in (a) stabilizing pulmonary artery pressure (PAP) compared to the PAP trend in the subject prior to treatment, or (b) reducing PAP compared to the starting level of PAP in the subject; wherein PAP is systolic pulmonary artery pressure (SPAP) or diastolic pulmonary artery pressure (DPAP). Various methods for measuring PAP are available. For example, PAP can be measured by inserting a catheter into the pulmonary artery. Typically, the mean pressure is 9–18 mmHg, and the wedge pressure measured in the left atrium may be 6–12 mmHg. Wedge pressure may be elevated in left heart failure, mitral stenosis, and other conditions, such as sickle cell disease.

[0317] PAP in the subject may stabilize at the level present at the start of treatment, for example, over several days, weeks, months, or years. In some embodiments, the starting level of PAP in the subject may be reduced by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more than that. In some embodiments, the rate of increase in PAP may be reduced by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more than that.

[0318] The amount of solid dispersion, solid dosage form, or pharmaceutical composition administered to a subject (as a single dose or over multiple doses) may be effective in reducing right ventricular hypertrophy, as measured by the Fulton index, compared to a non-treated group of subjects with PAH. The Fulton index is a measure of the ratio between the mass of the right ventricle and the combined mass of the left ventricle and septum (RV / (LV + S)). Mass may be measured directly (e.g., in relation to animal studies) or extrapolated from volume measurements of living subjects (e.g., as determined by echocardiography). The reduction may be relative to the non-treated group of subjects with PAH. For example, compared to a non-treated group of PAH subjects, the average reduction in the Fulton index among a group of PAH subjects treated with a compound of formula (I) may be about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or greater than or about greater than that. In some embodiments, the reduction in the Fulton index is at least about 20%.

[0319] In some embodiments, the amount of solid dispersion, solid dosage form, or pharmaceutical composition administered to a subject (as a single dose or over multiple doses) is effective in reducing physiological indicators of PAH. The reduction may be measured over a specified period, e.g., after the initiation of treatment (treatment may continue throughout the period), in terms of days of reduction (e.g., about 1, 2, 3, 4, 5, 6, 7 days, or more than that), weeks (e.g., 1, 2, 3, 4, 5, 6 weeks, or more than that), months (e.g., 1, 2, 3, 4, 5, 6, 8, 10 months, or more than that), or a longer period (e.g., 1, 2, 3, 4, 5 years, or more than that). Any various physiological indicators, such as pulmonary vascular resistance, pulmonary arterial pressure, systemic arterial pressure, mixed venous oxygen saturation, arterial oxygen saturation, cardiac index, pulmonary capillary wedge pressure, right atrial pressure, 6-minute walk distance, cerebral natriuretic peptide levels, and pulmonary diffusing capacity may be measured. For example, a solid dispersion, solid dosage form, or pharmaceutical composition may be present in an amount effective to (a) decrease one or more of pulmonary vascular resistance, pulmonary arterial pressure, systemic arterial pressure, pulmonary capillary wedge pressure, right atrial pressure, and cerebral natriuretic peptide levels; or (b) increase one or more of mixed venous oxygen saturation, arterial oxygen saturation, cardiac index, 6-minute walk distance, and pulmonary diffusing capacity. The amount of the solid dispersion, solid dosage form, or pharmaceutical composition may be effective to increase the time to death, increase the time to clinical deterioration, decrease the incidence of right heart failure, or promote favorable changes in WHO functional classes.

[0320] One physiological indicator of PAH is pulmonary vascular resistance (PVR). The baseline or reference PVR level is 200 dyn·sec / cm². 5 Above, 240 dyn·sec / cm 5 Above, 300 dyn·sec / cm 5Above, 400 dyn·sec / cm 5 Above, 500 dyn·sec / cm 5 Above, 600 dyn·sec / cm 5 Above, 700 dyn·sec / cm 5 Above, or 800 dyn·sec / cm 5 It may be greater than. In some embodiments, the treatment provided herein is such that after treatment begins, the subject's endpoint PVR level is 70 dyn·sec / cm from the baseline or reference PVR level. 5 Above, 100 dyn·sec / cm 5 Above, 130 dyn·sec / cm 5 Above, or 160 dyn·sec / cm 5 It is effective in cases where the amount has decreased.

[0321] Another physiological indicator of PAH is pulmonary artery pressure (PAP). Baseline or reference PAP levels may be greater than 20 mmHg, greater than 25 mmHg, greater than 30 mmHg, greater than 35 mmHg, greater than 40 mmHg, greater than 45 mmHg, greater than 50 mmHg, greater than 60 mmHg, or greater than 70 mmHg. In some embodiments, the treatment provided herein is effective when, after the initiation of treatment, the subject's endpoint PAP level decreases by greater than 0.5 mmHg, greater than 1 mmHg, greater than 1.5 mmHg, greater than 5 mmHg, greater than 10 mmHg, greater than 20 mmHg, greater than 30 mmHg, greater than 40 mmHg, or greater than 50 mmHg from the baseline or reference PAP level.

[0322] Another physiological indicator of PAH is the cardiac index (CI). The baseline or reference CI level is 5 L / min / m² 2 Below, 2.5 L / min / m 2 Below, 2 L / min / m 2 Below, 1.5 L / min / m 2 Less than, or 1 L / min / m 2It may be less than or equal to. In some embodiments, the treatment provided herein is effective when, after treatment is started, the endpoint CI level increases by 0.1 or more, 0.2 or more, 0.3 or more, 0.4 or more, 0.5 or more, 1 or more, or 2 or more from the baseline or reference CI level.

[0323] Another physiological indicator of PAH is pulmonary capillary wedge pressure (PCWP). Baseline or reference PCWP levels may be 36 mmHg or less, 24 mmHg or less, 18 mmHg or less, 10 mmHg or less, or 5 mmHg or less. In some embodiments, the treatment provided herein is effective when, after the start of treatment, the endpoint PCWP level increases by 0.2 mmHg or more, 0.3 mmHg or more, 0.4 mmHg or more, 0.5 mmHg or more, 0.6 mmHg or more, 1 mmHg or more, or 5 mmHg or more from the baseline or reference PCWP level.

[0324] Another physiological indicator of PAH is right atrial pressure (RAP). Baseline or reference RAP levels may be 4 mmHg or higher, 6 mmHg or higher, 8 mmHg or higher, 10 mmHg or higher, 12 mmHg or higher, 16 mmHg or higher, 20 mmHg or higher, or 25 mmHg or higher. In some embodiments, the treatment provided herein is effective when, after the initiation of treatment, the subject's endpoint RAP level decreases by 5 mmHg or higher, 2.5 mmHg or higher, 1 mmHg or higher, 0.5 mmHg or higher, or 0.2 mmHg or higher from the baseline or reference RAP level.

[0325] Another physiological indicator of PAH is the 6-minute walk distance (6 MWD). The baseline or reference 6 MWD may be 50 m or less, 100 m or less, 200 m or less, 300 m or less, 400 m or less, or 500 m or less. In some embodiments, the treatment provided herein is effective when, after the start of treatment, the subject's endpoint 6 MWD increases by 10 m or more, 15 m or more, 20 m or more, 25 m or more, 30 m or more, or 50 m or more from the baseline or reference 6 MWD; or when the subject's endpoint 6 MWD increases by 3% or more, 4% or more, 5% or more, 10% or more, or 20% or more from the baseline level.

[0326] Another physiological indicator of PAH is brain natriuretic peptide (BNP) levels. Baseline or reference BNP levels may be greater than 60 pg / mL, greater than 80 pg / mL, greater than 100 pg / mL, greater than 120 pg / mL, greater than 140 pg / mL, greater than 200 pg / mL, greater than 500 pg / mL, or greater than 1000 pg / mL. In some embodiments, the treatment provided herein is effective when the subject's endpoint BNP level decreases from the baseline or reference BNP level after the start of treatment. For example, the subject's endpoint BNP level may decrease by greater than 1 pg / mL, greater than 2 pg / mL, greater than 5 pg / mL, greater than 10 pg / mL, greater than 20 pg / mL, greater than 100 pg / mL, greater than 500 pg / mL, or greater than 1000 pg / mL.

[0327] Diffusion of lung volume (DLCO) or CO diffusing capacity may also be used as a physiological indicator of PAH. The baseline or reference DLCO may be 90% or less, 80% or less, 70% or less, 50% or less, 45% or less, or 40% or less. In some embodiments, the treatment provided herein is effective when the endpoint DLCO increases from the baseline level after the start of treatment. For example, the endpoint DLCO may increase by 1% or more, 5% or more, 10% or more, 15% or more, 20% or more, or 50% or more from the baseline or reference DLCO.

[0328] Mean survival rate may be used as a parameter to determine efficacy in a population of one or more subjects. The reference mean survival rate may be 95% or less, 93% or less, 90% or less, 86% or less, 82% or less, or 78% or less. The mean survival rate may be the mean 1-year survival rate. In some embodiments, the treatment provided herein is effective when the mean survival rate increases after the initiation of treatment in a population of one or more subjects. For example, the mean survival rate may increase by 1% or more, 2% or more, 5% or more, 10% or more, or 20% or more from the reference mean survival rate.

[0329] In one aspect, the disclosure provides a method for treating glioblastoma in a subject requiring treatment for glioblastoma (including glioblastoma pleomorphic or GBM). In one embodiment, the method comprises administering an effective amount of the solid dispersion, solid dosage form, or pharmaceutical composition described herein to said subject. Gliomas are typically heterologous tumors composed of glioma cancer stem cells (GSCs) and tumor cells that promote self-renewal, proliferation, and survival. These stem cell populations may preferentially express HIF-2α-regulated genes, such as VEGF, Oct4, Glut-1, NOTCH, and prostate acid phosphatase (PAP). GSC populations tend to reside within perivascular depressions to support vascular function and tumor growth, and to exhibit resistance to radiation. The effects of aggressive glioma growth and stem cell-like phenotypes may be mediated by signaling pathways upstream of HIF, such as PI3K / AKT / mTOR, and a general increase in HIF-2α activity. The histopathological features of GBM include invasive invasion into the brain parenchyma, significant lesions of pelvic necrosis, and extensive patterns of microvascular proliferation. In some embodiments, a solid dispersion, solid dosage form, or pharmaceutical composition is administered in an amount effective to delay the progression of one or more of these features associated with glioblastoma or other features as described herein, or to reduce the incidence or severity thereof. In some embodiments, a solid dispersion, solid dosage form, or pharmaceutical composition is administered (as a single dose or over multiple doses) in an amount effective to increase the mean survival among a population of treated subjects by, for example, about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 years, or more than that, or about more.

[0330] Treating glioblastoma includes treating subjects diagnosed with existing glioblastoma, as well as preventing glioblastoma in subjects at risk of developing glioblastoma, for example. In some embodiments, the amount of solid dispersion, solid dosage form, or pharmaceutical composition administered to a subject (as a single dose or over multiple doses) is effective for one or more of inhibiting the growth of glioblastoma cells, inhibiting the metastasis of glioblastoma cells, killing glioblastoma cells, reducing tumor size, and reducing the severity or incidence of symptoms associated with the presence of glioblastoma cells. The degree of one or more of these therapeutic effects may be about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or greater than or about that. In some embodiments, therapeutic efficacy is measured by a delay in disease progression, for example, between the appearance of one or more first symptoms and the appearance of one or more second symptoms, or between two or more occurrences of the same symptom. The delay may be about days, weeks, months, or years, or about more than (e.g., 1, 2, 3, 4, 5, 6, 7 days, or more than; 1, 2, 3, 4, 5, 6, 7, 8 weeks, or more than; 1, 2, 3, 4, 5, 6 months, or more than; or 1, 2, 3, 4, 5 years, or more than). For prevention, the subject may be an individual at risk of developing glioblastoma, for example, a subject who is in remission and / or has a family history and / or has some other predisposition. The degree of therapeutic efficacy may be compared to the subject's starting state (e.g., tumor size, growth rate, metastasis rate, severity or incidence of one or more symptoms) or to a reference group (e.g., a non-treated group or a group treated with a different agent).

[0331] The efficacy of glioblastoma treatment can be verified using any suitable method, such as methods currently used in the clinic to track tumor size and cancer progression. Measuring tumor size is one method to determine whether growth has slowed, stopped, or reversed (e.g., in the case of killing glioblastoma cells). Tumor size can be indicated using any suitable technique, such as the measurement of dimensions, or using available computer software, such as FreeFlight software developed at Wake Forest University, which enables the accurate estimation of tumor volume. Tumor size can be determined by tumor visualization using, for example, CT, ultrasound, SPECT, helical CT, MRI, imaging, etc. In embodiments where the tumor is surgically resected after the completion of the treatment period, the presence of tumor tissue and tumor size can be determined by a gross analysis of the tissue to be resected and / or by a pathological analysis of the resected tissue.

[0332] Preferably, tumor growth is stabilized as a result of treatment (i.e., one or more tumors do not increase in size by more than 1%, 5%, 10%, 15%, or 20% and / or metastasize). In some embodiments, the tumor is stabilized for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 weeks or more. In some embodiments, the tumor is stabilized for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more. In some embodiments, the tumor is stabilized for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 years or more. Preferably, the method of the present invention reduces the size of the tumor by at least about 5% (e.g., at least about 10%, 15%, 20%, or 25%). More preferably, the tumor size is reduced by at least about 30% (e.g., at least about 35%, 40%, 45%, 50%, 55%, 60%, or 65%). Even more preferably, the tumor size is reduced by at least about 70% (e.g., at least about 75%, 80%, 85%, 90%, or 95%). Most preferably, the tumor is completely eliminated or reduced to a level below the detectable level. In some embodiments, the subject remains tumor-free (e.g., in remission) for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 weeks, or longer after treatment. In some embodiments, the subject remains tumor-free for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more after treatment. In some embodiments, the subject remains tumor-free for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 years or more after treatment. When the tumor is subjected to surgical resection after the completion of the treatment period, the efficacy of the method of the present invention in reducing tumor size can be determined by measuring the percentage of necrotic resected tissue.In some embodiments, treatment is therapeutically effective when the percentage of necrosis of the resected tissue is greater than about 20% (e.g., at least about 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%), more preferably about 90% or more (e.g., about 90%, 95%, or 100%). Most preferably, the percentage of necrosis of the resected tissue is 100%, that is, no tumor tissue is present or undetectable. In some embodiments, the growth rate of the glioblastoma (e.g., the rate of change in tumor size) is reduced by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more, or about more than that, including the complete cessation of glioblastoma growth. In some embodiments, about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more than that of the identified glioblastoma cells (e.g., as in a tumor mass) are killed.

[0333] Treatment efficacy can be determined using multiple secondary parameters. Examples of secondary parameters include, but are not limited to, the detection of new tumors, detection of tumor antigens or markers, biopsy, surgical stage reduction (e.g., surgical progression of a tumor from unresectable to resectable), PET scans, survival, disease-free survival, time to disease progression, quality of life assessment, and, for example, assessment of clinical benefit response; all of these may indicate overall progression (or regression) of cancer in humans. Biopsy is particularly useful for detecting the eradication of cancerous cells within tissue. Radioimmunodetection (RAID) is used to localize and stage tumors using serum levels of markers (antigens) produced by or associated with the tumor ("tumor markers" or "tumor-associated antigens"), and can be useful as a diagnostic basis before treatment, an indicator of recurrence after treatment, and an indicator of treatment efficacy after treatment. Examples of glioblastoma markers that can be evaluated as indicators of therapeutic efficacy include, but are not limited to, ABCC3, GPNMB, NNMT, and SEC61γ (see, for example, US7115265).

[0334] As an additional example of a method for evaluating therapeutic efficacy, the expression of biomarkers for a disease, e.g., glioblastoma, can be compared over time between subjects with or at risk of having the disease and the expression of the same biomarkers in subjects. In some cases, the expression of the same set of biomarkers can be compared between subjects with or at risk of having the disease and one or more normal subjects. In evaluating disease outcomes or the effects of a treatment, a population of patients, all of whom have the disease, may be tracked for a specified period. The level of biomarker expression can be established by evaluating the expression of the biomarker in a sample from one patient, evaluating the expression in additional samples obtained later from the same patient, and comparing the expression of the biomarker from the later samples with the initial samples. This method may be used, for example, in the case of biomarkers indicating disease progression or worsening, lack of efficacy of the therapeutic regimen, disease remission, or the efficacy of the therapeutic regimen. In addition, therapeutic efficacy in the subject may be evaluated by various methods including, but not limited to, physical examination, biopsy, or any of a number of imaging techniques, such as ultrasound, computed tomography, magnetic resonance imaging, magnetic resonance spectroscopy, or positron emission tomography.

[0335] Glioblastoma is associated with a variety of symptoms. Common symptoms of the disease include seizures, nausea and vomiting, headaches, memory loss and hemiparesis, and progressive memory, personality, or neurological deficits resulting from temporal and frontal lobe involvement. In some cases, the tumor may begin to produce symptoms rapidly, but sometimes it remains asymptomatic until it reaches a massive size. Therapeutic efficacy can be measured in terms of a reduction in one or more of these, for example, in terms of frequency or severity. In some embodiments, the reduction in symptoms, when measured using an appropriate scale, is about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or greater than or approximately greater than that.

[0336] In relation to quality of life assessments, such as clinical benefit-response criteria, the therapeutic benefit of treatment can be demonstrated in terms of pain intensity, analgesic consumption, and / or Karnovsky Performance Scale scores. The Karnovsky Performance Scale allows patients to be classified according to their functional impairment. The Karnovsky Performance Scale is scored from 0 to 100. Generally, lower Karnovsky scores predict a poor survival prognosis. In some embodiments, treatment of glioblastoma in human patients comprises, alternatively or additionally, (a) a reduction of at least 50% (e.g., at least 60%, 70%, 80%, 90%, or 100% reduction) in pain intensity reported by the patient during any consecutive 4-week period within 12 weeks after completion of treatment, compared to pain intensity reported by the patient prior to treatment; (b) a reduction of at least 50% (e.g., at least 60%, 70%, 80%, 90%, or 100% reduction) in analgesic consumption reported by the patient during any consecutive 4-week period within 12 weeks after completion of treatment, compared to analgesic consumption reported by the patient prior to treatment; and / or (c) an increase of at least 20 points (e.g., at least 30 points) in the Karnovsky Performance Scale score reported by the patient during any consecutive 4-week period within 12 weeks after completion of treatment, compared to the Karnovsky Performance Scale score reported by the patient prior to treatment. It is proven by an increase of 50, 70, or 90 points.

[0337] In one aspect, the present disclosure provides a method for treating an inflammatory disease of the digestive system in a subject requiring treatment of an inflammatory disease of the digestive system. In some embodiments, the method comprises administering an effective amount of the solid dispersion, solid dosage form, or pharmaceutical composition provided herein to the subject. In one aspect, the present disclosure provides a method for reducing inflammation of the digestive system in a subject requiring reduction of inflammation of the digestive system, comprising administering an effective amount of the solid dispersion, solid dosage form, or pharmaceutical composition provided herein to the subject requiring reduction of inflammation of the digestive system. In some embodiments, the solid dispersion, solid dosage form, or pharmaceutical composition is administered in an amount effective in delaying the progression of one or more features associated with inflammation or an inflammatory disease, reducing their incidence, or reducing their severity. In some embodiments, the solid dispersion, solid dosage form, or pharmaceutical composition is administered as a single dose or over multiple doses in an amount effective in inducing remission of inflammation or an inflammatory disease.

[0338] The digestive system consists of the gastrointestinal tract plus auxiliary digestive organs including the tongue, salivary glands, esophagus, stomach, pancreas, liver, gallbladder, small intestine, large intestine, colon, anus, and rectum. Some embodiments of the present disclosure specifically refer to the lower gastrointestinal tract including the small intestine and large intestine. The term “small intestine” encompasses the duodenum, jejunum, and ileum, and the term “large intestine” includes the cecum, appendix, colon, ascending colon, right curvature of the colon, transverse colon, left curvature of the colon, descending colon, sigmoid colon, rectum, anal canal, and anus.

[0339] The present disclosure provides both a method for reducing inflammation of the digestive system and a method for treating an inflammatory disease of the digestive system. As used herein, the term “inflammation” refers to a general term for the local accumulation of fluid, plasma proteins, and / or leukocytes initiated by an autoimmune reaction, physical injury, infection, vascular disease, chemical exposure, radiation, or a local immune response. Generally, inflammation is characterized by one or more signs, including, for example, redness, pain, fever, swelling, and / or loss of function. Inflammation may be associated with a chronic (long-term) inflammatory disease or disorder or an acute (short-term) inflammatory disease or disorder.

[0340] In carrying out any target method, a solid dispersion, solid dosage form, or pharmaceutical composition may reduce inflammation of the digestive system, such as inflammation of one or more of the tongue, salivary glands, esophagus, stomach, pancreas, liver, gallbladder, small intestine, large intestine, colon, anus, and rectum. In some embodiments, the solid dispersion, solid dosage form, or pharmaceutical composition reduces inflammation of the lower gastrointestinal tract, such as inflammation of the small intestine, large intestine, or colon. In some exemplary embodiments, the solid dispersion, solid dosage form, or pharmaceutical composition reduces inflammation of the colon. Inflammation may be characterized as enteritis, gastritis, gastroenteritis, colitis, enterocolitis, duodenitis, jejunitis, ileitis, proctitis, or appendicitis. Inflammation may be acute or chronic. In some preferred embodiments, inflammation is classified as colitis.

[0341] Under physiological conditions, the gastrointestinal tract can be characterized by a steep oxygen gradient. Chronic inflammatory bowel disease is typically characterized by the active consumption of O2 by mobilized inflammatory cells, including macrophages, dendritic cells, and neutrophils. The resulting imbalance between oxygen consumption and supply makes the inflamed intestinal mucosa severely hypoxic. This "inflammatory hypoxia" typically leads to elevated levels of hypoxia-inducible factors 1α and 2α (HIF-1α and HIF-2α) in the intestinal epithelium of subjects with gastrointestinal inflammation, including those with inflammatory bowel disease, and in murine models of colitis. In inflammatory bowel disease, HIF-1α and HIF-2α have been found to play opposing roles in disease progression. Elevated HIF-1α expression has been found to be protective during inflammatory bowel disease, including epithelial cell survival, protection of various barriers and induction of tight junction proteins, increase in antimicrobial β-defensin, and prevention of excessive immune responses through the upregulation of CD39 / CD73 and T regulatory cells. Chronic expression of HIF-2α can lead to robust spontaneous intestinal inflammation and damage in inflammatory bowel disease, including epithelial cell apoptosis, barrier protection and dysregulation of tight junction proteins, increased pro-inflammatory cytokines, and excessive immune responses. HIF-2α has been shown to facilitate the progression of inflammation and inflammation-mediated colon cancer by regulating the mobilization and function of myeloid cells, including neutrophils and macrophages. Recently, HIF-1α has been reported to act as an inflammation driver in a colitis model when knocked down in myeloid cell lineages.

[0342] Although we do not wish to be bound by any specific theory, the inventors hypothesized that HIF-2α expression in colon epithelial and bone marrow cells is a major driver of the initiation, progression, and maintenance of chronic inflammation. Blocking HIF-2α is expected to reduce or inhibit the mobilization of inflammatory cell types and their pro-inflammatory products, particularly in subjects suffering from Crohn's disease and ulcerative colitis, which is expected to lead to the regression or prevention of inflammation in the digestive system.

[0343] Subjects exhibiting inflammation of the digestive system may suffer from inflammatory bowel disease, Crohn's disease, colitis, celiac disease, eosinophilic enteropathy, or appendicitis. As used herein, the term "inflammatory bowel disease" refers to a pathological condition characterized by an inflammatory state of the colon and / or small intestine. Crohn's disease and colitis are two types of inflammatory bowel disease.

[0344] In some embodiments, inflammatory bowel disease includes colitis, e.g., ulcerative colitis. “Colitis” is inflammation of the colon. Colitis may be acute or chronic. As used herein, colitis includes ulcerative colitis, microscopic colitis, lymphocytic colitis, collagenous colitis, transformative colitis, chemical colitis, ischemic colitis, infectious colitis, pan-colitis, left-sided colitis, extensive colitis, segmental colitis, microscopic colitis, radiation-induced colitis, drug-induced colitis, and proctitis. “Ulcerative colitis” is a chronic inflammatory disease affecting the colon. It is characterized by inflammation of the mucosa of the colon. Symptoms can range from mild to severe and may include bloody stools, diarrhea, bloody diarrhea, rectal urgency, tenesmus, incontinence, fatigue, increased bowel motility, mucosal secretions, nocturnal bowel movements, abdominal discomfort, fever, weight loss, paradoxical constipation, anemia, and abdominal tenderness. Ulcerative colitis is an intermittent disease, and most patients have a disease course of relapses and remissions, accompanied by periodic acute exacerbations. The terms "acute exacerbation" or "relapse" refer to an increase in symptoms of ulcerative colitis, such as increased bowel frequency, increased rectal bleeding, and / or abnormal mucosal appearance as evidenced by endoscopy. Although symptoms of ulcerative colitis may decrease without intervention, the disease typically requires treatment for remission.

[0345] As used herein, the term “active” ulcerative colitis refers to biologically active ulcerative colitis. Patients with active disease may be symptomatic and may exhibit one or more signs or symptoms of ulcerative colitis, e.g., rectal bleeding, increased bowel frequency, mucosal inflammation, or abnormal laboratory tests (e.g., elevated ESR or CRP values ​​or decreased hemoglobin). In relation to a specific therapy, “refractory” ulcerative colitis refers to active ulcerative colitis or ulcerative colitis that relapses or acutely exacerbates despite being treated with such therapy.

[0346] As used herein, the term "Crohn's disease" refers to a type of inflammatory bowel disease characterized by inflammation of the lining of the gastrointestinal tract. Symptoms may include diarrhea, abdominal pain, fever, fatigue, bloody stools, and weight loss.

[0347] When ulcerative colitis is suspected in a patient, the initial diagnosis is generally based on a combination of symptoms, endoscopic findings, and histology. Diagnosis typically involves stool samples, urinalysis, and tests for anemia, iron deficiency, leukocytosis, and / or thrombocytosis. Markers of inflammation, such as erythrocyte sedimentation rate (ESR) and C-reactive protein, may be elevated depending on the severity of the disease. However, endoscopy with a biopsy is generally considered the only definitive method for establishing a diagnosis of ulcerative colitis. Endoscopic findings supporting a diagnosis of ulcerative colitis may include erythema, loss of normal vascular patterns, erosion, hemorrhage, granularity, discontinuity, ulceration, and pseudopolyps. A biopsy may also be taken during an endoscopy to differentiate ulcerative colitis from Crohn's disease. Biopsy samples were examined for distortion of the crypt architecture, inflammation of the crypts, shortening of the crypts, increased lymphocytes and plasma cells in the lamina propria, crypt abscess, mucin depletion, and hemorrhage or inflammation in the lamina propria.

[0348] Ulcerative colitis may affect a portion of the colon or substantially the entire colon. Ulcerative colitis may be proctitis, wherein the ulcerative colitis is limited to the inner wall of the anus and rectum. Ulcerative colitis may be left-sided colitis, wherein the colitis is limited to a portion of the colon distal to the curvature of the spleen, more specifically, an ulcerative colitis extending from the rectum and extending proximal to the curvature of the spleen. Ulcerative colitis may be extensive colitis in which substantially the entire colon is affected. Accordingly, in some embodiments, the present disclosure provides a method for reducing inflammation in a subject suffering from ulcerative colitis, including proctitis, left-sided colitis, and extensive colitis.

[0349] Ulcerative colitis is generally further characterized by the severity of the disease, e.g., remission, mild, moderate, or severe ulcerative colitis. The methods of the present disclosure may be applied to the treatment of mild, moderate, or severe ulcerative colitis, or ulcerative colitis in a remission state. For example, an effective amount of a solid dispersion, solid dosage form, or pharmaceutical composition provided herein may be administered to a subject suffering from mild ulcerative colitis. A solid dispersion, solid dosage form, or pharmaceutical composition may be administered to a subject suffering from moderate ulcerative colitis. A solid dispersion, solid dosage form, or pharmaceutical composition may be administered to a subject suffering from severe ulcerative colitis. A solid dispersion, solid dosage form, or pharmaceutical composition may be administered to a subject suffering from mild or moderate ulcerative colitis. Solid dispersions, solid dosage forms, or pharmaceutical compositions may be administered to subjects suffering from moderate or severe ulcerative colitis. Solid dispersions, solid dosage forms, or pharmaceutical compositions may be administered to subjects suffering from ulcerative colitis in a remission state.

[0350] There are multiple indices for assessing the severity of ulcerative colitis, including the Mayo score, the Lichtiger score, and the simple clinical colitis activity index. These indices typically include subscores of the Mayo score or endoscopic subscores, such as the ulcerative colitis endoscopic severity index, as factors. Typical histological classifications include the Robarts histopathology index and the Nancy index. Composite criteria may be used to assess disease severity, including one or more of these indices, the impact of the disease on the subject's quality of life, measurable markers of disease activity and severity, and the overall disease course, such as extraintestinal signs, intestinal injury, and the frequency of acute exacerbations.

[0351] In some embodiments, the method described herein further comprises administering a second therapeutic agent. The second agent may be administered intravenously or subcutaneously. In some embodiments, the second agent is administered once or twice daily, every other day, weekly, every two weeks, or every three weeks. The second agent may be administered in amounts of about 1 to about 1000 mg, about 5 to about 500 mg, about 10 to about 350 mg, or about 50 to about 200 mg. In one embodiment, the second activator is administered orally once or twice daily, every other day, once a week, once every two weeks, or once every three weeks in an amount of about 1 to about 1000 mg, about 5 to about 500 mg, about 10 to about 350 mg, about 10 to about 200 mg, about 10 to about 100 mg, or about 20 to about 50 mg. The specific amount of the second activator will depend on the specific agent used, the type of disease to be treated or managed, the severity and stage of the disease, and the amount of any optional additional activator co-administered to the patient with the compound of formula (I).

[0352] Examples

[0353] The following examples are provided for the purpose of illustrating various embodiments of the present invention and are not intended to limit the disclosure in any way. Together with the methods described herein, these examples represent currently preferred embodiments, are illustrative, and are not intended to limit the scope of the invention. Variations and other uses encompassed within the spirit of the invention as defined by the scope of the claims will be made by those skilled in the art.

[0354] Characterization method

[0355] X-ray powder diffraction

[0356] XRPD was performed using a Bruker D2 phasor X-ray diffractometer with scan-type coupling θ / 2θ (where the voltage was set to 30 kV and the current to 10 mA), at a rotation of 15 rpm maintained by a zero-background cup, with a slit width of 1.0 mm and a knife-edge width of 1.0 mm.

[0357] Adjusted differential scanning calorimetry

[0358] MDSC was performed using a TA Instruments Q2000 differential scanning calorimeter equipped with a TA Instruments 90 refrigerated cooling system. Using MDSC, the glass transition temperature (T g ) and melting temperature (T m ) (if present) was measured. The temperature range was adjusted from 0-250℃ at a heating rate of 1.5℃ / min. The scanning mode was adjusted, where the adjustment frequency was 60 seconds and the adjustment amplitude was 1℃.

[0359] Gas chromatography head-space

[0360] Residual solvent levels were determined using Gas Chromatography Headspace (GCHS) analysis. For example, samples were analyzed using the following method parameters with an Agilent 6890A / 7694 GC / HS instrument equipped with a 30 m x 0.32 mm, 1.8 μm, JW Scientific DB-624 column: sample temperature, 105 °C; loop temperature, 110 °C; transfer line temperature, 115 °C; GC cycle time, 45 min; vial equilibration time, 30 min; injection loop size, 1 mL; vial pressure time, 20 sec; carrier gas pressure, 7 psi; and vial pressure, 15 psi.

[0361] High-pressure liquid chromatography

[0362] HPLC was performed on an Agilent 1220 instrument equipped with a Kinetex, C18, 4.6 x 100 mm, 2.6 μm column using the following method parameters: mobile phase A, 0.1% formic acid in water; mobile phase B, 0.1% formic acid in acetonitrile; gradient consisting of 95% A (0 min), 60% A (6 min), 5% A (12 min), 95% A (15.1 min), and the remainder being mobile phase B; flow rate, 0.8 mL / min; column temperature, 40°C; sample temperature, room temperature; injection volume, 5 μL; detection wavelength, 240 nm; and run time, 18.5 min.

[0363] Scanning electron microscopy

[0364] SEM imaging was performed using an FEI Quanta 200 SEM equipped with a polaron automatic coating machine E5200 Au / Pd target sputter coating machine, with a voltage of 15 kV, a spot size of 3.0 mA, a filament current of 2.52 A, and an emission current of 96 μA.

[0365] Example 1: Characterization of 3-(((1S,2S,3R)-2,3-difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-indene-4-yl)oxy)-5-fluorobenzonitrile.

[0366] 3-(((1S,2S,3R)-2,3-difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-indene-4-yl)oxy)-5-fluorobenzonitrile, melting temperature (T) of the compound of formula (I) m ) and glass transition temperature (T g ) was measured by mDSC and confirmed to be 209.2°C and 79.9°C, respectively. The diffraction pattern of the compound of formula (I) was captured using XRPD (Fig. 1), which indicated a crystalline material.

[0367] The solubility of the compound of formula (I) was measured twice in acetone and an acetone / H2O mixture. The first measurement was performed over 30 minutes at room temperature while completing the mixing by spinning in a centrifuge tube. The observed solubility is presented in Table 1.

[0368] Table 1

[0369]

[0370] The second measurement was completed to further evaluate the acetone / H2O combination with 1% H2O increments. The solubility presented in Table 2 was observed after allowing the samples to equilibrate at room temperature for 48 hours.

[0371] Table 2

[0372]

[0373] Example 2: Solid dispersion screening.

[0374] Seven polymer dispersion formulations containing the compound of formula (I) were prepared and spray-dried in 95:5 acetone:H2O in a 25:75 ratio of the compound of formula (I) to the polymer according to the parameters provided in Table 3.

[0375] Table 3

[0376]

[0377] Residual solvent was removed after the initial spray drying using a secondary tray drying process. In this step, the "wet" solid dispersion was heated to 40°C and stored in a convection tray oven for 26 hours. The secondary step treatment by temperature increase removed residual acetone from the solid dispersion. Residual solvent remaining in the solid dispersion after secondary drying was measured using gas chromatography (GC) headspace analysis. Among the various formulations, residual acetone was determined to be significantly lower than the 5000 ppm limit for acetone set by the International Conference on Harmonisation (ICH). Total yield of each solid dispersion, measured T gThe , and residual acetone content are presented in Table 4.

[0378] Table 4

[0379]

[0380] LOQ: Limit of Quantity

[0381] Thermal analysis of solid dispersions by mDSC shows that all dispersions are a single T g It was indicated that it possesses, which represents an intimately mixed amorphous solid dispersion with excellent homogeneity. T of the solid dispersion g The values ​​ranged from 70°C to 140°C (Table 4). These relatively high T g The value indicates excellent physical stability, for example, that the compound of formula (I) has a low tendency to recrystallize during long-term storage. To ensure long-term physical stability, the solid dispersion is T g It was stored at a temperature below to ensure low mobility of the compound of formula (I) in the glass dispersion. A solution containing 100% of the compound of formula (I) in acetone was spray-dried, and T g As evidenced by the absence of and the XRPD pattern, it was recovered in a crystalline form. Characterization by XRPD indicated that the solid dispersion is consistent with an amorphous structure due to the absence of crystalline peaks observed in the diffraction pattern of the solid dispersion (Fig. 2).

[0382] The surface morphology of the solid dispersion was evaluated using SEM. The solid dispersion was observed to contain perfect spheres and collapsed spheres with smooth surfaces. No crystalline material was observed in the solid dispersion samples.

[0383] The solubility performance of the solid dispersion was tested in a non-sink solubility test. The solubility test was used to measure the supersaturation of the drug exceeding the solubility of the bulk crystalline compound of formula (I) in a biocompatible intestinal medium (FaSSIF) after 30 minutes of exposure to a low-pH environment (SGF). During the test, samples were transferred from SGF [Theoretical Cmax = 2000 μgA / mL] to FaSSIF [Theoretical Cmax = 1000 μgA / mL].

[0384] The observed Cmax GB, Cmax FaSSIF, AUC FaSSIF, and AUC enhancements are provided in Table 5. HPMCAS-H, CAP, and Soluplus-based solid dispersions provided approximately 30-fold enhancement of the solubilized drug compared to the bulk crystalline drug, as presented in Table 5 (AUC 고체 분산물 / AUC 화학식 (I)의 화합물 All three solid dispersions provided a substantial increase in Cmax while simultaneously maintaining the supersaturation limit over at least 180 minutes of FaSSIF exposure. These three solid dispersions demonstrated superior performance in gastric delivery dissolution tests and were expected to significantly enhance the bioavailability of the compound of formula (I) compared to the bulk crystalline drug.

[0385] Table 5

[0386]

[0387] Example 3: Additional screening of solid dispersions.

[0388] Three solid dispersion formulations containing the compound of Formula (I) in a ratio of 25:75 to HPMCAS-H, CAP, or Soluplus were prepared for in vivo testing. All formulations were spray-dried using parameters similar to those used in Example 2. After the initial spray drying, a secondary tray drying process was used to remove residual solvent. In this step, the "wet" solid dispersion was heated to 40°C and stored in a convection tray oven for 24 hours. The secondary treatment by increasing the temperature removed residual acetone spray solvent from the solid dispersion material. Residual solvent remaining in the solid dispersion material after secondary drying was measured using Gas Chromatography Headspace (GCHS) analysis. For all three formulations, residual acetone was well below the 5000 ppm limit for acetone provided by the International Conference on Harmonisation (ICH), and the HPMCAS-H and Soluplus formulations were below the LOQ of the test (<200 ppm). The CAP formulations were dried for an additional 24 hours, and after retesting, it was determined to be < LOQ. Table 6 shows the residual solvent results for the two formulations. HPLC calibration and purity analysis were performed after the second drying, and it was confirmed that the manufacturing process did not introduce any impurities or decompose the compound of formula (I).

[0389] Table 6

[0390]

[0391] LOQ: Limit of Quantity

[0392] Cmax GB, Cmax FaSSIF, and AUC FaSSIF values ​​were obtained and reported in Table 7. HPMCAS-H, CAP, and Soluplus solid dispersions provided a 10 to 30-fold enhancement of the solubilized drug compared to the bulk crystalline drug (AUC 고체 분산물 / AUC 화학식 (I)의 화합물All three solid dispersions provided a substantial increase in Cmax while simultaneously maintaining the supersaturation limit over at least 180 minutes of FaSSIF exposure. These three solid dispersions demonstrated superior performance in gastric delivery dissolution tests and were expected to significantly enhance the bioavailability of the compound of formula (I) compared to the bulk crystalline drug.

[0393] Table 7

[0394]

[0395] Thermal analysis performed via mDSC showed that all dispersions were a single T g It was indicated that it contains, which represents an intimately mixed amorphous solid dispersion with excellent homogeneity. Relatively high T g The value indicates excellent physical stability, for example, that the compound of formula (I) has a low tendency to recrystallize during long-term storage. To ensure long-term physical stability, the solid dispersion is T g By storing at a temperature below this level, the mobility of the compound of formula (I) in the glass dispersion was reduced.

[0396] Solid-state characterization by XRPD indicated that the solid dispersion was an amorphous dispersion because no crystalline peaks were observed in the diffraction pattern of the solid dispersion (Fig. 3).

[0397] The surface morphology of the solid dispersion particles was characterized using scanning electron microscopy. SEM images (Fig. 4) show the compound of formula (I) at 5,000x magnification, and solid dispersions of HPMCAS-H, CAP, or Soluplus from left to right. The solid dispersions were observed to include complete spheres and collapsed spheres with smooth surfaces. No crystalline material was observed in the solid dispersion samples.

[0398] Example 4: Administration of suspension.

[0399] The suspension stability of the solid dispersion was evaluated at a suspension concentration of 10 mg of the compound of formula (I) per 1 mL in a 1 wt% 1:1 methyl-cellulose:Twin 80 solution. The performance of each solid dispersion suspension was monitored 4 and 24 hours after preparation using the SGF / FaSSIF dissolution test as a comparative measurement method.

[0400] For the suspension of the solid dispersion formulation prepared at 10 mgA / mL in the standard administration vehicle, stable solubility performance within 4 hours (when stored at room temperature to 21°C under stirring at 750 rpm) was observed, which will allow sufficient time for in vivo administration after the formulation of the suspension. The suspension stability solubility profiles for the solid dispersion formulation maintained for 4 or 24 hours can be found in Tables 8 and 9, respectively. The solubility test was administered at 2.0 mgA / mL in SGF and reduced to 1.0 mgA / mL upon delivery to FaSSIF. The solid dispersion suspension is expected to be maintained for up to 4 hours prior to administration.

[0401] Table 8

[0402]

[0403] Table 9

[0404]

[0405] Example 5: Stability of solid dispersion.

[0406] To rapidly evaluate the physical and chemical stability of the solid dispersion formulation of the compound of formula (I), the dispersion was aged for 4 weeks in both open and closed packaging in the presence of a desiccant at 25°C / 60% RH and 40°C / 75% RH. The solid dispersion was evaluated for its amorphous physical state by XRPD, chemical purity by HPLC, and changes in particle morphology by SEM.

[0407] XRPD analysis of the aged solid dispersion samples indicated that, as shown in Figure 5, all solid dispersion formulations remained amorphous after 4 weeks without any detectable crystalline material. The surface morphology of the aged solid dispersion particles was characterized using scanning electron microscopy. SEM images revealed that the solid dispersions consisted of complete spheres and collapsed spheres with smooth surfaces, with the exception of the Soluplus formulation under 40 / 75 open conditions, which appeared as glassy aggregated spheres but remained amorphous as confirmed by XRPD. Purity analysis of the aged solid dispersions was performed for the HPMCAS-H and CAP formulations at 2 and 4 weeks under both 40 / 75 open and closed conditions. No substantial impurities were detected.

[0408] Example 6: Lipid vehicle formulation.

[0409] Five formulations of the compound of formula (I) and lipid vehicles were prepared. Size 0 gelatin capsules were filled with the formulations at 60°C. Each capsule had a total weight of 500 ± 50 mg and contained 5.0 ± 0.3 wt% of the compound of formula (I), and approximately 95 wt% of a lipid vehicle selected from (1) 1:4 TPGS-1000:Gellucir 44 / 14; (2) 2:3 TPGS-1000:Gellucir 44 / 14; (3) 1:4 TPGS-1000:Gellucir 50 / 13; (4) 2:3 TPGS-1000:Gellucir 50 / 13; and (5) 1:1:1 TPGS-1000:Gellucir 44 / 14:Gellucir 50 / 13.

[0410] Cmax GB, Cmax FaSSIF, and AUC FaSSIF values ​​were calculated for each formulation and reported in Table 10. The 2:3 TPGS-1000:Gellucir 44 / 14-based formulation provided a 4-fold increase in solubilized drug compared to the bulk crystalline drug.

[0411] Table 10

[0412]

[0413] Approximately 35 capsules containing 25 mg A (25 mg of the compound of formula (I)) in 2:3 TPGS-1000:Gellucir 44 / 14 were prepared for in vivo and accelerated stability tests. HPLC assays and purity analyses were performed. No degradation of the compound of formula (I) was observed in the presence or absence of capsule excipients.

[0414] Lipid capsules were aged for 4 weeks at 25°C / 60% RH (closed) and 40°C / 75% RH (open or closed packaging). The lipid capsules were evaluated for changes in chemical purity by HPLC. Purity analysis of the aged lipid capsules was performed at 2 and 4 weeks in both 40 / 75 open and closed conditions, in the presence and absence of capsule excipients. Compound-related degradation of Formula (I) was not observed after 4 weeks under any conditions. The peak due to gelatin grew from 0.30% of the total peak area for all configurations to 0.9–1.3% of the total peak area after 4 weeks, while the peak associated with TPGS-1000 remained static throughout the study.

[0415] Example 7: Solid dispersion containing HPMCAS-H.

[0416] Acetone (23.0 kg) was followed by the compound of Formula (I) (0.5 kg) in a 75 L tank equipped with a pneumatic stirrer. The resulting suspension was mixed at room temperature for 6 minutes; at this point, a clear solution was obtained, indicating that all of the compound of Formula (I) had dissolved. Subsequently, HPMCAS-H polymer (1.5 kg) was added, and the resulting solution was mixed at room temperature for 14 hours. Acetone was removed by spray-drying the solution using an SPX AnhydroMicrospray MS-150 spray-drying unit equipped with a 2-fluid nozzle. Spraying was completed in a closed-loop configuration using the following parameters: nozzle, spray system 2-fluid; solvent, acetone; total solids, 2.0 kg; solution composition, 8% solids; total solution weight, 25.0 kg; spraying pressure, 2.5-2.8 bar; spray rate, 10.0 kg / hr; Inlet temperature, 74.9-77.0℃; outlet temperature, 42.0-42.9℃; dry gas flow rate, 174 kg / hr; condenser temperature, -17.6 to -17.1℃.

[0417] Secondary drying at Despatch 4 ft 3 The residual acetone remaining after spray drying was removed by completing the process in a tray dryer. The bed depth of the solid dispersion was approximately 1 inch on the tray, and the dryer temperature setpoint was 40°C. The solid dispersion was confirmed to exhibit rapid removal of acetone at 40°C, and drying was completed in nearly 5 hours after loading into the dryer. The dried solid dispersion met the 5000 ppm ICH Option 1 limit for acetone.

[0418] After the completion of spray drying, the solid dispersion was observed to contain electrostatic charge. As a result, there was some accumulation of the solid dispersion in the MS-150 drying chamber, but the material remained loose and did not aggregate together. The overall yield was only 64%, which was likely due to the retention in the chamber. A minimal amount (~100 g) of solid dispersion was observed inside the baghouse, an accumulation (~400 g) was observed on the main chamber walls, and a moderate accumulation (~25 g) was observed on the outlet processing pipe.

[0419] The retention time was evaluated for both the spray solution and the wet solid dispersion prior to secondary drying. The total impurities observed by HPLC for the retained spray solution and the retained wet solid dispersion were recorded in Table 11. Both the spray solution and the wet solid dispersion were retained at room temperature for the times indicated in the table. The stability data for the spray solution indicated an approximate growth of 0.05% of impurities per day. The stability data for the wet solid dispersion indicated an approximate growth of 0.02% of impurities per day.

[0420] Table 11

[0421]

[0422] The dried solid dispersion was characterized by XRPD, mDSC, SEM, KF, residual solvent, particle size, bulk / tap density, and HPLC (chiral and achiral). Figure 6 shows the XRPD pattern of the solid dispersion. With the absence of crystalline peaks in the diffraction pattern, the solid dispersion was found to be virtually amorphous. Weight percentage measurements of water and residual solvent indicated that the solid dispersion contained 0.75 wt percent H2O according to KF and that the residual acetone was below LOQ (<200 ppm).

[0423] The glass transition temperature of the solid dispersion was measured by mDSC. The data is T gIt indicates that it is approximately 86°C. The only single thermal event (T g ...was observed, suggesting that a homogeneous glassy solution was obtained from the spray drying process. SEM analysis (Fig. 7) indicated that the solid dispersion consisted of complete spheres and collapsed spheres with smooth surfaces at magnifications of 500x (left) and 5,000x (right). No crystalline material was observed in the sample.

[0424] As shown in Fig. 8, the particle size distribution was determined by performing laser light scattering on the solid dispersion powder. A Malvern Aero S dry particle size analyzer was used at a pressure of 0.7 bar, a feed rate of 40%, and a hopper height of 3 mm. The samples were analyzed in triplicate over 10 seconds. A refractive index of 1.681 and a density of 0.5 g / mL were used for the analysis using a non-spherical algorithm. Sample shielding ranged from 0.1 to 15%. Particle size measurements showed that the solid dispersion exhibited a monomodal distribution, and the average d 10 is 4.9 μm, and the average d 50 is 15.6 μm, and the average d 90 It was determined to be 41.5 μm.

[0425] Bulk and tap densities were also measured. The bulk density was confirmed to be 0.25 g / mL, and the tap density was confirmed to be 0.41 g / mL. Fluidity was calculated using a Kars index of 44.35 and a Hausner ratio of 1.80.

[0426] The solid dispersion was analyzed by HPLC and confirmed to contain 24.6% of the compound of formula (I). The chromatographs of the solid dispersion (top line), the compound of formula (I) (middle line), and the blank (bottom line) are presented in Fig. 9. According to HPLC, the compound of formula (I) and the solid dispersion showed minimal differences in impurities. Chiral purity analysis was also performed on the solid dispersion, which showed a 99.8% excess of the enantiomer of the compound of formula (I).

[0427] T g The effect of relative humidity on solid dispersions was investigated. Solid dispersions were exposed to humidity levels of 33%, 50%, or 75% for 24 hours. After exposure, samples were capped in airtight DSC pans for analysis. The temperature logs of each sample are shown in Fig. 10. As RH increased, the dispersion... g It showed a decrease, which is likely due to the hygroscopic nature of the material. As presented, T g The temperature dropped to 71°C and 51°C upon exposure to 33% and 75% RH, respectively. The effect of humidity (water content) on the glass transition temperature of the solid dispersion suggests that when humidity is > 33%, molecular mobility is theoretically possible at room temperature (25°C), which implies that the compound of formula (I) can nucleate and consequently crystallize. The solid dispersion was packaged in a package that maintains an RH value of <33% during long-term storage.

[0428] The water adsorption of solid dispersions was determined using dynamic vapor adsorption (DVS). The dispersions were subjected to rising humidity from 5–95% RH and subsequently exposed to decreasing humidity from 95–5% RH to determine the adsorption / desorption of water. The DVS results indicate that the solid dispersions are moderately non-hygroscopic and adsorb up to 5.5 wt% of H2O at 90% RH.

[0429] Samples of the retention material collected from the spray dryer chamber were analyzed for particle morphology by SEM, amorphous characteristics by XRPD, and impurities by HPLC. All tests showed equivalence between the retention chamber material and the collected solid dispersion, demonstrating that the retention chamber material and the collected solid dispersion can be combined.

[0430] The solid dispersion was packaged in double LDPE bags and placed in HDPE drums. A 2-gram lot of the solid dispersion was packaged in double LDPE bags, and each opening was bent and sealed with a cable tie. The samples in the bags were stored in 75 cc HDPE bottles and sealed with screw-stop enclosures. Subsequently, the stability of the packaged solid dispersion was tested under ICH conditions. No significant changes were observed in appearance, color, associated material, amorphous characteristics, or thermal analysis after 3 months of storage at 2–8°C, 25°C / 60% RH, or 40°C / 75% RH. At 40°C / 75% RH, moisture increased from 0.75% at T0 to 2.42% at 3 months. Adding a desiccant to the packaging is expected to prevent this increase in moisture. The stability data collected for the solid dispersion is summarized in Table 12.

[0431] Table 12

[0432]

[0433] Example 8: Preparation of a solid dispersion.

[0434] Compound of Formula (I) (2.25 kg) was mixed with acetone (103.5 kg) at room temperature for 15 minutes until a clear solution was obtained. HPMCAS-H polymer (6.75 kg) was added, the resulting mixture was mixed for 8 hours, and kept overnight under ambient conditions. The resulting solution was spray-dried using an Anhydro MS-150 spray dryer equipped with a Spray Systems 2-fluid nozzle. The following spray parameters were used and monitored throughout the spray-drying process: inlet temperature, 76.0 ± 20.0°C; outlet temperature, 42.0 ± 5.0°C; cooler setpoint, -30.0°C; condenser temperature, -17.0 ± 10.0°C; solution feed rate, 10.0 ± 2.0 kg / hr; dry gas flow rate, 170.0 ± 20.0 kg / hr; atomization pressure, 2.5 ± 0.5 bar; Chamber pressure, 34 cmWC; cyclone ΔP, 150 mmWC; and baghouse ΔP, 70 mmWC. After spray drying, the solid dispersion was loaded onto a tray and dried at 40°C for approximately 14 hours. A total of 8.2 kg of dried solid dispersion was recovered with an overall yield of 92%, of which 1.3 kg was from the chamber collection. The solid dispersion was packed in double 4-mil LDPE bags, 20 packets of 5-gram silica gel desiccant were placed between the bags, then placed in 15-gal HDPE drums and stored at 2-8°C.

[0435] The solid dispersion was packed in 2-gram batches in double LDPE bags, and 0.5 grams of desiccant was added between the LDPE bags. Each opening was bent and sealed with a cable tie. Each sample was stored in a 75 cc HDPE bottle and sealed with a screw-stop enclosure. The samples were stored for 3 months at 2–8°C, 25°C and 25% relative humidity, or 40°C and 75% relative humidity, and then characterized to evaluate the stability of the solid dispersion. Under any conditions from time 0, no significant changes were observed other than a slight increase in KF. XRPD analysis revealed no crystallization.

[0436] This batch of solid dispersion was characterized against approved specifications. Analysis including appearance, HPLC purity, chiral HPLC purity, KF, residual solvent, XRPD, and mDSC is shown in Table 13.

[0437] Table 13

[0438]

[0439] Example 9: Evaluation of solid loading in spray drying.

[0440] The solution viscosity and precipitation behavior of the compound of formula (I) and the HPMCAS-H formulation were evaluated among various solvent compositions. As shown in Table 14, it was confirmed that the viscosity in acetone increases with increasing solid loading. The 97:3 acetone / H2O solution exhibited a viscosity similar to pure acetone at a solid loading of 14 wt%. These values ​​indicate that each of these formulations can be present as a spray solution by a standard solution pump.

[0441] Table 14

[0442]

[0443] The precipitation behavior of the three types of solutions was visually evaluated. No precipitation of the compound or polymer of formula (I) was observed after 3 days at room temperature. The spray solution appeared slightly cloudy after 3 days due to HPMCAS-H, and the viscosity increased as the polymer dissolved.

[0444] The compound of formula (I) was formulated with hypromellose acetate succinate HG grade (HPMCAS-H) at a 1:3 ratio (i.e., 25% drug load). Spray drying was performed on a 100 g scale using a 12 wt% solid loading in 97 / 3 acetone / H2O, and secondary drying was completed using a tray convection dryer. Characterization of the solid dispersion was performed using XRPD, SEM, mSDC, GC-HS, achiral HPLC, and particle size measurement. In addition, spray solution stability and wet solid dispersion stability were also evaluated.

[0445] 97 / 3 acetone / H2O (733.3 g) was added to a flask containing a magnetic stirrer, followed by the compound of formula (I) (25 g). After mixing at room temperature, a clear solution was obtained, which indicated that the compound of formula (I) was dissolved. Subsequently, HPMCAS-H polymer (75 g) was added to the solution and mixed at room temperature until a clear solution was obtained.

[0446] Spray drying to remove the acetone / H2O solvent and provide an amorphous solid dispersion was completed on a Buchi B-290 spray drying unit equipped with a 2-fluid nozzle. Spraying was completed in a recirculation configuration by a high-efficiency cyclone.

[0447] The yield of the wet solid dispersion was confirmed to be 93% (excluding solution samples taken for stability analysis). Secondary drying was completed in a tray dryer to remove residual acetone and water remaining after spray drying. The dryer temperature setpoint was 40°C, and the solid dispersion was dried for 24 hours. After drying, a dry solid dispersion yield of 79% was obtained, excluding samples taken for residual solvent analysis.

[0448] The solid dispersion exhibited rapid removal of acetone at 40°C. After loading into a dryer, drying was completed in approximately 5 hours. The solid dispersion met the 5000 ppm ICH Option 1 limit for acetone. The water content was confirmed to be 0.74 wt% after a 24-hour drying period.

[0449] To establish the retention times for both the spray solution and the wet solid dispersion prior to secondary drying, additional information was collected regarding the solid dispersion during spray drying. Table 15 shows the total HPLC impurities in the spray solution and the wet solid dispersion after retention at room temperature for 7 days. The wet solid dispersion contained ~21,000 ppm acetone.

[0450] Table 15

[0451]

[0452] The spray solution stability data showed no change in impurities. From this data, it was determined that the acetone / H2O spray solution could be used (i.e., spray-dried) 7 days after preparation when maintained at room temperature. The wet solid dispersion stability data indicated that no impurities grew over 7 days. From this data, it was determined that the wet solid dispersion could be maintained at room temperature for several days if necessary.

[0453] The wet solid dispersion was also evaluated for crystallization by XRPD and mDSC analysis. Figure 11 shows the XRPD patterns of the solid dispersion over 7 days at room temperature. As evidenced by the XRPD patterns, the wet solid dispersion remained amorphous without evidence of crystallization after 7 days of storage. As reported in Table 15, T g It was confirmed that the temperature ranged from 58 to 62°C over the maintenance period, and no crystallization events were observed.

[0454] The dried solid dispersion was characterized by XRPD, mDSC, SEM, KF, residual solvent, particle size, and achiral HPLC. Figure 12 shows the XRPD pattern for the solid dispersion. Crystalline peaks were absent in the diffraction pattern, and thus the solid dispersion was found to be virtually amorphous.

[0455] Weight percentage measurements of water and residual solvent indicated that the solid dispersion contained 0.75 weight percent H2O according to KF and that residual acetone was less than LOQ (<200 ppm).

[0456] T of solid dispersion g The temperature was confirmed to be approximately 84°C by mDSC. A single thermal event was observed, suggesting that a homogeneous glassy solution was obtained from the spray drying process. SEM analysis indicated that the solid dispersion consisted of complete spheres and collapsed spheres with smooth surfaces. No crystalline material was observed in the sample.

[0457] As shown in Fig. 13, the particle size distribution was determined by performing laser light scattering on the solid dispersion. A Malvern Aero S dry particle size analyzer was used at a pressure of 0.7 bar, a feed rate of 40%, and a hopper height of 3 mm. The samples were analyzed in triplicate over 10 seconds. A refractive index of 1.681 and a density of 0.5 g / mL were used for the analysis using a non-spherical algorithm. Sample shielding ranged from 0.1 to 15%. Particle size measurements showed that the solid dispersion exhibited a monomodal distribution, and the average d 10 is 1.9 μm, and the average d 50 is 9.8 μm, and the average d 90 It was determined to be 26.6 μm. The distribution was cut off at 200 μm due to large ~1 mm aggregates that were not dispersed in the particle size analyzer.

[0458] HPLC analysis confirmed that the concentration of the compound of formula (I) in the solid dispersion was 25.6%. The compound of formula (I) and the solid dispersion showed minimal differences in impurities according to HPLC (0.90% and 0.92%, respectively).

[0459] Example 10: Tablet formulation.

[0460] An 80-gram batch of a solid dispersion containing the compound of formula (I):HPMCAS-H in a 1:3 ratio was prepared according to the general procedure summarized in Examples 3 and 8. Three tablet formulations using this solid dispersion were prepared on a single-station press using slug, mill, blend, and compression methodologies. Tablets were prepared with a 32.00% solid dispersion load (8% active) to provide 40 mg active tablets compressed into modified capsule tools (~16.499 mm x 8.498 mm) with a total weight of 500 mg. Tables 16, 17, and 18 summarize the compositions of the three tablet formulations.

[0461] Table 16

[0462]

[0463] Table 17

[0464]

[0465] Table 18

[0466]

[0467] Each formulation was first compressed to a target solid fraction (~0.7) of 1 / 2-inch flat slugs. The slugs were milled through a 30-mesh screen. Excipients other than granules were added, and the resulting mixture was compressed into tablets. A target hardness of 15 kiloponds (KP) was achieved for the formulations in Tables 16 and 18 using a pressure of approximately 90 MPa. A similar hardness was achieved for the formulation in Table 17 using a compression force of approximately 150 MPa. Disintegration of the tablets prepared from the formulations in Tables 16 and 18 occurred within less than 1 minute, whereas the disintegration time of the tablets prepared from the formulation in Table 17 was approximately 1.5 minutes.

[0468] Additional tablets were prepared with a hardness of approximately 10 kP and tested for dissolution in 0.1 N HCl (900 mL) at 37°C using a USP Device II (Paddle). The paddle speed was maintained at 75 rpm for the first 60 minutes and then increased to 250 rpm for the last 15 minutes of the test. 10 mL samples were taken at each time point, filtered through a 10 μm polyethylene filter, diluted, and analyzed by HPLC. The dissolution test showed no differences in release profiles among the three formulations.

[0469] Example 11: Preparation and Characterization of Tablets.

[0470] Additional tablets were prepared using the formulations listed in Tables 16 and 18, and their stability, pharmacokinetics (PK), and solubility in an optimized medium were evaluated. The general preparation method described in Example 10 was followed. The compressed tablets exhibited a white appearance. A granular solid fraction of 0.7 and a target tablet hardness of 14 KP (1.61 MPa tensile strength) were used. The efficacy and total impurities of the tablets were evaluated by HPLC after compression (Table 19).

[0471] Table 19

[0472]

[0473] The expected efficacy of the tablets was confirmed by HPLC. No significant differences were observed among the formulations in total impurities.

[0474] The solubility of the crystalline compound of formula (I) as well as the 1:3 solid dispersion of compound of formula (I):HPMCAS-H in typical solubility media at pH 2 and 6.8 was tested. The sink factor was calculated using a 900 mL medium volume along with the solubility and purification dose content, and is presented in Table 20.

[0475] Table 20

[0476]

[0477] Potential outliers

[0478] The pharmacokinetics of the compound of formula (I) were evaluated in two different tablet formulations, tablet formulation 1 (Table 16) and tablet formulation 3 (Table 18) (Table 21). Each formulation was administered to a group of fasted male dogs (n=4 / group) (i.e., each dog was provided with a single oral dose containing 40 mg of the compound of formula (I)). Blood samples were collected at specified time intervals after administration to analyze plasma concentrations of the compound of formula (I) over time. For comparison purposes, the pharmacokinetics of tablet formulations 1 and 3 were compared with the pharmacokinetics of a solid dispersion (compound of formula (I) in a 1:3 ratio:HPMCAS-H) administered as a suspension.

[0479] Table 21

[0480]

[0481] The average PK parameter estimates are presented in Table 21. The AUC of the compound of formula (I) 0-t (The area under the plasma concentration curve from time = 0 to the last time point collected) was used for comparisons across groups. Dose-normalized mean AUC 0-t The values ​​were 10.8 ± 3.2 and 8.9 ± 1.4 (μg*hr / mL) / (mg / kg) for tablet formulations 1 and 3, respectively, which were similar to the 1:3 suspension formulation of compound (I):HPMCAS-H (within 20%). Dose-normalized mean C values ​​in plasma. max It was confirmed to be similar between the two tablet formulations and slightly higher than the suspension formulation. The observed t max The values ​​suggested that tablet formulation 1 was absorbed faster than tablet formulation 3.

[0482] Tablet formulations 1 and 3 were left open under accelerated stability conditions (40°C / 75% RH) and tested for chemical purity and efficacy at 2 and 4 weeks. Under accelerated conditions, for tablet formulation 1, a decrease in efficacy from 99.3% to 96.7% was observed, while total impurities increased from 1.24% at time 0 to 2.02% after 4 weeks. For tablet formulation 3, a decrease in efficacy from 100.1% to 96.2% was observed, while total impurities increased from 1.25% at time 0 to 1.77% after 4 weeks.

[0483] Example 12: Tablet formulation, preparation, and characterization.

[0484] Tablet formulation 1, with an active content of 40 mg, was prepared in advance with a solid fraction of 0.70, and the tablet hardness was 14.1 KP and the tensile strength was 1.61 MPa (see Examples 10 and 11). This tablet exhibited a disintegration time of 33 seconds. Additional tablets were prepared with a reduced solid fraction of 0.6 (granules) to allow for additional tablet compressibility. Subsequently, the granules were compressed within a tablet hardness range of 11.6 to 39.7 KP (tensile strength of 1.2–4.7 MPa), and disintegration was measured. The disintegration time for these tablets was approximately 30 seconds. Subsequently, the formulation was modified by removing all granules, ac-di-sol, and mannitol and replacing them with MCC. The tablets were then compressed to a hardness of 20.7 KP (tensile strength of 2.1 MPa), and disintegration was confirmed to be 27 seconds. The granular blend alone was also compressed to 17.9 KP (2.1 MPa tensile strength). The disintegration time for the granular blend alone was confirmed to be 26 seconds.

[0485] Since small changes to the formulation had no effect and compression of the granular blend alone exhibited very rapid disintegration, attention was turned to investigating the effect of grade change of MCC from pH 101 to pH 105 on disintegration time. This change would more closely match the particle size of the solid dispersion with MCC, the main compression aid, and thus provide more intimate contact with the particles, enabling increased bonding during roller compression.

[0486] Next, a 40 mg active tablet (from granules with a solid fraction of 0.59) in which the pH 101 grade MCC of tablet formulation 1 was replaced with a pH 105 grade MCC was compressed to a hardness of 27 KP. The resulting tablet was found to exhibit a disintegration time of 1:40 min and a wear rate of 0.03%. As the disintegration time increased, a 10 mg active tablet was also compressed, which was found to exhibit a hardness of 10 KP and a disintegration time of 2:21 min.

[0487] A conventional blend of tablet formulation 4 having the composition provided in Table 22 was prepared, and then 10 mg active and 40 mg active tablets were compressed. The tool selected for compression was a standard concave circular 0.25" for the 10 mg tablet and a modified elliptical 0.2750" x 0.5500" for the 40 mg tablet. The conventional blend was prepared in a scale of approximately 1.25 kg using 480 g of solid dispersion. From the conventional blend, it was divided into portions for compression of both 10 and 40 mg tablets. The compositions of the 10 and 40 mg active tablet formulations are presented in Table 22. The composition of the coated 40 mg active tablet formulation is presented in Table 23.

[0488] Table 22

[0489]

[0490] Table 23

[0491]

[0492] The main equipment used for granulation and tablet manufacturing was a bin blender equipped with a 5 L shell, a 40 mesh sieve, a Quadrocomil U5 mill, a Vector TFC Lab-micro roller compressor, and a Piccola-B rotary tablet press. Briefly, the granulation and tablet manufacturing process involves blending the granular components, removing lumps, roller pressing, blending the granular components, removing lumps, and compressing into both 10 and 40 mg active tablets. A process flowchart is presented in Fig. 14.

[0493] More specifically, the manufacturing process comprises the following steps: (1) pre-coating the blender shell with microcrystalline cellulose (1 minute at 20 rpm); (2) mixing the granular components in the coated blender (5 minutes at 20 rpm); (3) milling the granular components (screen 032R, 4000 rpm); (4) mixing the granular components in the blender (15 minutes at 20 rpm); (5) adding 40-mesh sieved magnesium stearate to the blender and mixing (4 minutes at 20 rpm); (6) granulating the mixture using a roller press (screw speed 40 rpm, roll speed 3 rpm, pressure 10 mPA); (7) passing the dried granulated material through a mill (screen 050G, 2000 rpm); (8) The milled granules were transferred to a blender, the extragranular components excluding magnesium stearate were added and mixed (at 20 rpm for 10 minutes); (9) The mixture was lubricated by adding magnesium stearate sieved at 40 mesh, and then mixed (at 20 rpm for 4 minutes); (10) Tablets (containing 10 mg and 40 mg) were compressed using a tablet press with a suitable tool (weight, thickness, and hardness were tested during the compression process).

[0494] A standard blend was prepared on a 1.25 kg scale using roller compression, aiming for a ribbon bulk density of approximately 0.8 g / mL (~0.6 solid fraction). Processing was completed at room temperature (approx. 25.2°C) under 26% relative humidity. After milling, bulk and tap densities (Table 24) were measured in addition to the granule particle size.

[0495] Table 24

[0496]

[0497] The in-granulation blend exhibited the lowest bulk density and the highest Hausner ratio. After granulation, the bulk density improved to 0.5 g / mL and the Hausner ratio decreased, suggesting improved flowability. The addition of excipients did not alter the bulk characteristics of the granules but slightly improved flowability, as indicated by a lower Hausner ratio.

[0498] The particle size distribution indicated that most of the granules (48.7%) were retained on a 250–595 μm sieve, and the remaining bulk material was collected in a pan. 31% of fine particles (particles smaller than 74 μm) were observed. The overall yield was 96.1%, and a total of 1.2 kg of final blend was collected.

[0499] The granules were divided between 10 and 40 mg tablet compressions. 949.95 g of granules were used to prepare 40 mg active tablets. Tool descriptions, as well as the number of stations, target filling weight, and tablet hardness are presented in Table 25.

[0500] Table 25

[0501]

[0502] The Piccola press was operated at a paddle speed of 5 rpm at 20 rpm. The compression force was dialed to 15 kN, and the pre-compression force was 480-600 N. The ejection force during operation was confirmed to be 181 N. During the compression operation, a total of 1,736 tablets were recovered with a yield of 91.4%. Process characteristics of the tablets showed a hardness range of 16.9-22.8 KP, with most tablets being approximately 20 KP. Tablet thickness was approximately 5.7-5.8 mm, and weight was concentrated at 500 mg. The disintegration test showed an average of 1:37, and the abrasion rate was 0.14%.

[0503] The remaining granules, approximately 257.05 g, were used for compressing 10 mg tablets. The Piccola press was operated at a paddle speed of 4 rpm at 20 rpm. The compression force was dialed to 7.5 kN, and the initial compression force was 280 N. The ejection force during the operation was confirmed to be 80-89 N. During the compression process, a total of 1,561 tablets were recovered with a yield of 75.9%. Process characteristics of the tablets showed a hardness range of 8.8-10.5 KP, with most tablets being approximately 10 KP. Tablet thickness was approximately 3.9 mm, and weight was concentrated at 126 mg. The disintegration test showed an average of 2.04, and the abrasion rate was 0.01%.

[0504] The tablets were characterized for appearance, confirmation by HPLC, calibration and impurities, content uniformity, water content, and solubility. A summary of the test results is provided in Table 26.

[0505] Table 26

[0506]

[0507] The tablets were white in appearance, no speckles or spot formation were observed, and the efficacy by HPLC was nearly 100%. Total impurities were similar to those in solid dispersions, and content uniformity passed USP standards. Water content was similar between the two tablets. Solubility analysis was performed in 0.01N HCl (pH 2) containing 0.5% SLS medium (900 mL) at 37°C at a paddle speed of 75 rpm. Data acquisition was completed at 5, 15, 30, 45, and 60 minutes. 10 mL samples were taken at each time point, filtered through a 10 μm polyethylene filter, diluted, and analyzed by HPLC. Figure 15 shows the combined solubility plots for the 10 and 40 mg tablets.

[0508] Complete dissolution within 15 minutes was observed for both tablet contents. The standard deviation for all time points was 1-3%, and the RSD was also in the 1-3% range, indicating that dissolution was very similar between units. The dissolution profile meets USP / FDA criteria for immediate-release formulations for poorly soluble drugs, where 85% dissolution is achieved after 30 and / or 45 minutes.

[0509] Bulk tablets were packaged in double LDPE bags containing SiO2 desiccant between the bags, and then placed in an HDPE drum.

[0510] Example 13: Pharmacokinetics of the tablet.

[0511] The pharmacokinetics of the 40 mg tablet described in Example 12 were evaluated in both fasted and fed dogs. The formulation was administered to groups of fasted male dogs (n=4 / group) and fed male dogs (n=4 / group), where each dog was provided with a single oral dose of 40 mg. Blood samples were collected at specified time intervals after dose administration to analyze plasma concentrations of the compound of formula (I) over time. Estimates of the mean PK parameters are presented in Table 27.

[0512] Table 27

[0513]

[0514] Capacity-normalized mean AUC 0-t The values ​​were 8.6 and 9.4 (μg*hr / mL) / (mg / kg) for the feeding and fasting tablet evaluations, respectively, and were similar between the groups (within 20%). Exposure variability among feeding animals was lower than when the tablet was administered on the stomach while fasting. Dose-normalized mean Cmax in plasma max It was confirmed to be slightly higher in the case of fasting stomach. The observed t max The value suggested that the tablet formulation was absorbed more quickly in a fasting state, and the fasting state was faster t max and a slightly higher C max It represented. AUC 0-t The values ​​were similar, indicating that there may be no substantial effect of food on the tablet formulation.

[0515] Example 14: Stability of tablets.

[0516] The stability of both the 10 and 40 mg active tablets described in Example 12 was evaluated. The 10 mg tablets were stored in 30 cc HDPE bottles with 0.5 g SiO2 desiccant and 9 g pure coiled polyester (30 tablets per bottle). The 40 mg tablets were stored in 60 cc HDPE bottles with 0.5 g SiO2 desiccant and 9 g pure coiled polyester (30 tablets per bottle). All bottles were sealed with foil heat-induction seals. The bottles were placed in stability chambers at 2–8°C, 25°C / 60% RH, and 40°C / 75% RH for 6 months. A brief summary of the results for the 10 and 40 mg tablets at the 6-month time point is provided in Tables 28 and 29, respectively.

[0517] Table 28

[0518]

[0519] Table 29

[0520]

[0521] Over a course of six months, no significant differences were observed in the physical or chemical properties of the tablets, even under accelerated storage conditions.

[0522] Example 15: HIF-2α scintillation proximity test (SPA)

[0523] The total assay volume was approximately 100 μL with the following composition: 2 μL of compound in 100% DMSO, 88 μL of buffer with protein and probe, and 10 μL of SPA beads. The compound was diluted in a master plate with a 10-point dose reaction using a 3-fold compound dilution from 100 μM to 5 nM. The assay was performed on a 96-well plate, where one column designated as a high-signal control contained DMSO without the compound, and another column designated as a low-signal control contained no protein. Before plating the compounds, a buffer solution consisting of 25 mM Tris pH 7.5 (Sigma), 150 mM NaCl (Sigma), 15% glycerol (Sigma), 0.15% BSA (Sigma), 0.001% Tween-20 (Sigma), 150 nM N-(3-chlorophenyl-4,6-t2)-4-nitrobenzo[c][1,2,5]oxadiazole-5-amine, and 100 nM HIF-2α HIS TAG-PASB domain was prepared and allowed to equilibrate for 30 minutes. Subsequently, the compounds to be tested were plated onto 96-well white clear-bottom isoplate-96 SPA plates (Perkin Elmer). 88 μL of buffer solution was added to the compound, the plate was covered with a plastic cover and aluminum foil, placed on a shaker, and equilibrated for 1 hour. After equilibration, 10 μL of a 2 mg / mL solution of YSi Cu His-tagged SPA beads (PerkinElmer) was added to each well of the plate, covered, and equilibrated for an additional 2 hours. Subsequently, the plate was removed from the shaker and placed into a 1450 LSC and a MicroBeta Trilux emission counter (PerkinElmer) to measure the degree of probe displacement. Percent inhibition was determined, and the IC was calculated using the Dotmatics system based on the following equation. 50The value was calculated: % inhibition = [(High control - Sample) / (High control - Low control)] x 100. The compound of formula (I) has an IC50 of less than 50 nM in the SPA test. 50 It was confirmed to have.

[0524] Example 16: VEGF ELISA assay

[0525] On day 1, approximately 7,500 786-O cells were seeded into each well of a 96-well, white, clear-bottom plate (07-200-566, Fisher Scientific) in 180 μL of growth medium. After 4 hours, serial dilutions of the 10x compound stock solution were prepared in the growth medium from the 500x DMSO stock solution, and 20 μL of such 10x stock solution was added to each well to prepare the following final concentrations (μM): 20, 6.67, 2.22, 0.74, 0.25, 0.082, 0.027, 0.009, 0.003, 0.001, and 0. Each concentration was plated in duplicate. After approximately 20 hours, the medium was removed by aspiration, and 180 μL of growth medium was supplied to each well. Approximately 20 μl of the freshly prepared 10x compound stock solution was added to each well. After about 24 hours, the cell culture medium was removed, and VEGF concentrations were determined according to the manufacturer's suggested method using an ELISA kit purchased from R&D Systems. EC 50...was calculated using the dose-response-inhibition (4-parameter) equation via GraphPad Prism. Subsequently, 50 μL of Celtiter-Glow reagent was added to each well, and the plate was shaken at 550 rpm for 8 minutes (Thermomixer R, Eppendorf). The cell-seeded plate was then subjected to the Celtiter-Glow luminescence cell viability assay (Promega) by immediately reading the luminescence signal using a plate reader (3-second delay, 0.5-second / well integration time, Synergy 2 multi-detection microplate reader). The compound of Formula (I) showed an EC of less than 50 nM in the VEGF ELISA assay. 50 It was confirmed to have.

[0526] Example 17: Luciferase test

[0527] 786-O-Hif-Luc monoclonal cells were obtained by infecting 786-O cells (ATCC® CRL-1932™) with a commercial lentivirus (Cignal Lenti HIF Reporter (luc): CLS-007L, Qiagen) delivering a luciferase gene driven by multiple HIF-reactive factors at an infection multiplicity (MOI) of 25 for 24 hours. Cells were supplemented with fresh medium (Dulbeco Modified Eagle Medium (DMEM, D5796, Sigma) supplemented with 10% FBS (F6178, Sigma), 100 units of penicillin, and 100 μg streptomycin / mL (P4333, Sigma)) for an additional 24 hours. Subsequently, a pool of infected cells was selected for 10 days with 2 μg / mL puromycin (P8833, Sigma), and then a single clone was selected by limiting the dilution. The clones were tested for their response to HIF-2 inhibitors, and the one exhibiting the largest dynamic range (786-0-Hif-Luc) was expanded and used for the luciferase assay. For the luciferase assay, approximately 7,500 786-0-Hif-Luc cells in 90 μL of growth medium were seeded into each well of a 96-well white opaque plate (08-771-26, Fisher Scientific) the day before treatment.

[0528] On the treatment day, serial dilutions of the 10x compound stock solution were prepared in growth medium from the 500x DMSO stock solution, and 10 μL of the 10x stock solution was added to each well to prepare the following final concentrations (μM): 20, 6.67, 2.22, 0.74, 0.25, 0.08, 0.027, 0.009, 0.003, 0.001, and 0. Each concentration was tested in triplicate. After approximately 24 hours, luciferase activity was determined using the ONE-GLO luciferase assay reagent (E6110, Promega) according to the manufacturer's recommended procedure. EC 50...was calculated using Dotmatics software. The compound of formula (I) has an EC of less than 50 nM in the luciferase assay. 50 It was confirmed to have.

[0529] Example 18: Screening of spray-dried dispersion (SDD) scale-up process parameters.

[0530] A solution of compound of formula (I):HPMCAS-H in acetone was prepared by mixing all components in a 50 L tank under top-mounted stirring until the solid became visually transparent. The solution composition and mixing time are as follows:

[0531]

[0532] The preparation of spray-dried dispersions (SDDs) of the compound of formula (I) was examined by investigating various processing parameters and the bulk characteristics produced from the above-prepared solution. The following processing ranges were investigated on an open-loop spray dryer with a drying gas capacity of 200 kg / hr:

[0533] - Outlet temperature: 35 - 46℃

[0534] - Solution feed rate: 340 - 455 g / min

[0535] - Calculated outlet relative saturation: 7 - 11%

[0536] A range of generated bulk characteristics was observed as a function of the various thermodynamic conditions and nozzle sizes used:

[0537] - Particle D (v 0.5): 33 - 67 μm

[0538] - Bulk density: 0.16 - 0.20 g / mL

[0539] Proof deployment

[0540] Leading conditions were prepared prior to the demonstration batch using an L:G ratio of 0.121 and an outlet temperature of 42°C. These conditions produced SDDs with acceptable stability, performance, and yield. The following spray drying conditions were selected for the preparation of 25% of the compound of formula (I):HPMCAS-H SDD.

[0541]

[0542] Based on the drying curve generated for the demonstration batch, the following secondary drying conditions using a convection tray dryer were selected.

[0543]

[0544] Although preferred embodiments of the present invention have been presented and described herein, it will be apparent to those skilled in the art that such embodiments are provided merely as examples. Many modifications, variations, and substitutions will now be made by those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be used to practice the invention. The following claims define the scope of the invention and are intended to encompass methods, structures, and equivalents within the scope of these claims.

Claims

Claim 1 As a pharmaceutical solid dosage form for oral delivery of a compound of chemical formula (I), The above solid dosage form comprises a solid dispersion comprising a compound of formula (I), a pharmaceutically acceptable polymer selected from the group consisting of hypromellose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), and polyethylene glycol vinyl acetate vinylcaprolactam, and one or more pharmaceutically acceptable excipients, and is a capsule or tablet. Claim 2 In paragraph 1, a solid dosage form that is a tablet. Claim 3 A solid dosage form according to claim 1, wherein one or more pharmaceutically acceptable excipients comprise a binder, a filler, a disintegrant, and a lubricant. Claim 4 A solid dosage form according to paragraph 3, wherein one or more pharmaceutically acceptable excipients additionally include a lubricant. Claim 5 A solid dosage form according to claim 1, wherein the solid dispersion is present in an amount of 15% to 50% by weight of the solid dosage form. Claim 6 In paragraph 1, a solid dosage form in which the pharmaceutically acceptable polymer is hypromellose acetate succinate. Claim 7 A solid dosage form according to claim 1, wherein a pharmaceutically acceptable polymer is present in an amount of 15% to 35% by weight in the solid dosage form. Claim 8 A solid dosage form according to claim 1, wherein the compound of formula (I) is present in an amount of 1% to 15% by weight in the solid dosage form. Claim 9 In claim 1, a solid dosage form comprising 5 mg to 100 mg of a compound of formula (I). Claim 10 In claim 1, a solid dosage form comprising about 10 mg of a compound of formula (I). Claim 11 In claim 1, a solid dosage form comprising about 40 mg of a compound of formula (I). Claim 12 In claim 1, a solid dosage form for use in treating von Hippel-Lindau (VHL) disease in a subject. Claim 13 In Clause 12, a solid administration form in which the subject also suffers from hemangioma, pheochromocytoma, pancreatic neuroendocrine tumor or renal cell carcinoma. Claim 14 In Clause 12, a solid administration form in which the subject suffers from renal cell carcinoma. Claim 15 In claim 1, a solid dosage form for use in treating renal cell carcinoma in a subject. Claim 16 In item 15, a solid dosage form in which the renal cell carcinoma is a clear cell renal cell carcinoma. Claim 17 A method for producing a solid dosage form of claim 1, comprising: (a) mixing a compound of formula (I) and one or more pharmaceutically acceptable excipients to form milled granules; and (b) compressing the granules by applying a compressive force of 5 kN to 20 kN. Claim 18 A method for producing a solid dosage form of claim 1, comprising: (a) a step of blending a compound of formula (I), a binder, a filler, a disintegrant, and a lubricant to form a blended mixture; (b) a step of granulating the blended mixture to form a granulated mixture; (c) a step of mixing a second filler, a second disintegrant, and a second lubricant with the granulated mixture to form a tablet mixture; and (d) a step of compressing the tablet mixture into a tablet, wherein the filler and the second filler are the same or different; the disintegrant and the second disintegrant are the same or different; and the lubricant and the second lubricant are the same or different. Claim 19 delete Claim 20 delete Claim 21 delete Claim 22 delete Claim 23 delete Claim 24 delete Claim 25 delete Claim 26 delete Claim 27 delete Claim 28 delete Claim 29 delete Claim 30 delete Claim 31 delete Claim 32 delete Claim 33 delete Claim 34 delete Claim 35 delete Claim 36 delete Claim 37 delete Claim 38 delete Claim 39 delete Claim 40 delete Claim 41 delete Claim 42 delete Claim 43 delete Claim 44 delete Claim 45 delete Claim 46 delete Claim 47 delete Claim 48 delete Claim 49 delete Claim 50 delete Claim 51 delete Claim 52 delete Claim 53 delete Claim 54 delete Claim 55 delete Claim 56 delete Claim 57 delete Claim 58 delete Claim 59 delete Claim 60 delete Claim 61 delete Claim 62 delete Claim 63 delete Claim 64 delete Claim 65 delete Claim 66 delete Claim 67 delete Claim 68 delete Claim 69 delete Claim 70 delete Claim 71 delete Claim 72 delete Claim 73 delete Claim 74 delete Claim 75 delete Claim 76 delete Claim 77 delete Claim 78 delete Claim 79 delete Claim 80 delete Claim 81 delete Claim 82 delete Claim 83 delete Claim 84 delete Claim 85 delete Claim 86 delete Claim 87 delete Claim 88 delete Claim 89 delete Claim 90 delete Claim 91 delete Claim 92 delete Claim 93 delete Claim 94 delete Claim 95 delete Claim 96 delete Claim 97 delete Claim 98 delete Claim 99 delete Claim 100 delete Claim 101 delete Claim 102 delete Claim 103 delete Claim 104 delete Claim 105 delete Claim 106 delete Claim 107 delete Claim 108 delete

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