Benceritinib formulations

Abstract

The present disclosure relates to beceritinib formulations, methods of making such formulations, and methods of using such formulations to treat conditions, diseases, or disorders that would benefit from modulation of c-Kit protein kinases and / or mutant c-Kit protein kinases.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 476,812, filed on December 22, 2022, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] The present disclosure relates to novel dosage forms comprising 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide. The novel dosage forms exhibit improved properties, including allowing for increased dosage. Background Art

[0003] Receptor protein tyrosine kinases (RPTKs) regulate key signal transduction cascades that control cell growth and proliferation. The stem cell factor (SCF) receptor, C-Kit, is a type III transmembrane RPTK that consists of five extracellular immunoglobulin (IG) domains, a single transmembrane domain, and a split cytoplasmic kinase domain separated by a kinase insert. C-Kit (also known as KIT, CD117, and stem cell factor receptor) plays an important role in the development of melanocytes, mast cells, germ cells, and hematopoietic cells.

[0004] Abnormal expression and / or activation of c-Kit and / or mutant forms of c-Kit are associated with a variety of pathological conditions (Roskoski, 2005, Biochemical and Biophysical Research Comm. 338: 1307-1315). For example, evidence of the contribution of c-Kit to tumor pathology includes its association with leukemia and mast cell tumors, small cell lung cancer, testicular cancer, and some cancers of the gastrointestinal tract and central nervous system. In addition, c-Kit has been implicated in the carcinogenesis of female genital tract sarcomas of neuroectodermal origin and in the formation of Schwann cell tumors associated with neurofibromatosis. Mast cells have been found to be involved in altering the tumor microenvironment and enhancing tumor growth (Yang et al., J Clin Invest. 2003, 112: 1851-1861; Viskochil, J Clin Invest. 2003, 112: 1791-1793).

[0005] Therefore, pharmaceutical formulations comprising c-Kit inhibitors would have high therapeutic value in treating patients with diseases or conditions such as acute myeloid leukemia (AML), gastrointestinal stromal tumors (GIST), mast cell leukemia (MCL), and mastocytosis. Oral formulations of c-Kit inhibitors are urgently needed because oral drug delivery is a popular route of administration due to its versatility, ease of administration, and patient compliance. Summary of the Invention

[0006] The following aspects and embodiments thereof described below are intended to be exemplary and illustrative, not limiting in scope.

[0007] In one aspect, the present disclosure relates to a pharmaceutical formulation comprising 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (Compound (I)) and a pharmaceutically acceptable polymer. In one aspect, Compound (I) is dispersed in a polymer matrix formed by the pharmaceutically acceptable polymer.

[0008] In one aspect of the present disclosure, the pharmaceutical formulation comprises a spray-dried solid dispersion.

[0009] In one aspect of the present disclosure, the Compound (I) and the pharmaceutically acceptable polymer are in a spray-dried solid dispersion.

[0010] In one aspect of the present disclosure, the compound (I) is in an amorphous form.

[0011] In one aspect of the present disclosure, the compound (I) is in the free base form.

[0012] In one aspect of the present disclosure, the pharmaceutically acceptable polymer is hypromellose acetate succinate (HPMCAS).

[0013] In one aspect of the present disclosure, the pharmaceutically acceptable polymer is hypromellose acetate succinate grade H (HPMCAS-H).

[0014] In various aspects of the disclosure, the spray-dried solid dispersion comprises at least about 1 wt% to at least about 25 wt% of Compound (I).

[0015] The spray-dried solid dispersions of the present disclosure comprise at least about 75% by weight to at least about 99% by weight of the pharmaceutically acceptable polymer.

[0016] In the spray-dried solid dispersion of the present disclosure, the weight ratio of the compound (I) to the pharmaceutically acceptable polymer is from about 1:3 to about 1:99.

[0017] The spray-dried solid dispersion of the present disclosure may further comprise a solvent. The solvent is a combination of water and tetrahydrofuran. The volume ratio of water to tetrahydrofuran is from about 1:2 to about 1:99.

[0018] The present disclosure also relates to a tablet comprising a spray-dried solid dispersion comprising compound (I), a pharmaceutically acceptable polymer, and one or more pharmaceutically acceptable ingredients, wherein compound (I) is dispersed in a polymer matrix formed by the pharmaceutically acceptable polymer, and the one or more pharmaceutically acceptable ingredients are selected from one or more binders, one or more buffers, one or more diluents, one or more disintegrants, one or more fillers, one or more film coatings, one or more lubricants, one or more glidants, and one or more surfactants.

[0019] Tablets according to the present disclosure contain one or more pharmaceutically acceptable ingredients, such as, but not limited to, colloidal silicon dioxide, croscarmellose sodium, sodium stearyl fumarate, mannitol, and microcrystalline cellulose.

[0020] The present disclosure also provides a tablet comprising compound (I) dispersed in a polymer matrix formed by the pharmaceutically acceptable polymer, and one or more pharmaceutically acceptable ingredients, wherein the one or more pharmaceutically acceptable ingredients are selected from one or more binders, one or more buffers, one or more diluents, one or more disintegrants, one or more fillers, one or more film coatings, one or more lubricants, one or more glidants and one or more surfactants.

[0021] In the tablet of the present disclosure, Compound (I) dispersed in the polymer matrix formed of the pharmaceutically acceptable polymer is a spray-dried solid dispersion.

[0022] In the tablets of the present disclosure, the compound (I) is in amorphous and free base form, and the pharmaceutically acceptable polymer is hypromellose acetate succinate (HPMCAS).

[0023] In the tablets of the present disclosure, the compound (I) is in amorphous and free base forms, and the pharmaceutically acceptable polymer is hypromellose acetate succinate grade H (HPMCAS-H).

[0024] The tablets of the present disclosure contain at least about 1% by weight to at least about 20% by weight of Compound (I).

[0025] The tablets of the present disclosure further comprise at least about 10% by weight to at least about 90% by weight of the pharmaceutically acceptable polymer.

[0026] In various aspects of the present disclosure, the tablet comprises at least about 3% by weight to at least about 65% by weight of the one or more pharmaceutically acceptable ingredients selected from one or more binders, one or more buffers, one or more diluents, one or more disintegrants, one or more fillers, one or more lubricants, one or more glidants, and one or more surfactants.

[0027] In a specific aspect, the tablets of the present disclosure comprise at least about 1% by weight to at least about 20% by weight of Compound (I), at least about 10% by weight to at least about 90% by weight of hypromellose acetate succinate grade H (HPMCAS-H), and at least about 3% by weight to at least about 65% by weight of one or more pharmaceutically acceptable ingredients selected from one or more binders, one or more buffers, one or more diluents, one or more disintegrants, one or more fillers, one or more lubricants, one or more glidants, and one or more surfactants.

[0028] The present disclosure also relates to a method of treating a subject having a disease or condition comprising orally administering to the subject a tablet as disclosed herein.

[0029] In some aspects, the method further comprises administering a therapeutic agent other than Compound (I) in combination with the tablet. In various aspects of the disclosure, the therapeutic agent other than Compound (I) is a receptor tyrosine kinase (RTK) inhibitor, such as sunitinib malate.

[0030] In various aspects of the present disclosure, diseases or conditions treated by oral administration of the tablets disclosed herein include, but are not limited to, acute myeloid leukemia (AML), gastrointestinal stromal tumors (GIST), and mastocytosis.

[0031] In various aspects of the present disclosure, the mastocytosis treated by oral administration of the tablets disclosed herein is advanced systemic mastocytosis (AdvSM), non-advanced systemic mastocytosis (NonAdvSM), indolent systemic mastocytosis (ISM), and smoldering systemic mastocytosis (SSM).

[0032] In other aspects of the present disclosure, the tablets disclosed herein are taken once daily, twice daily, or continuously over a 28-day cycle.

[0033] In another aspect, the methods of the present disclosure result in a target area under the curve (AUC) of 500 to 80,000 (ng.h / mL) in increments of 500 ng.h / mL following a single oral dose in a subject.

[0034] In another aspect, the methods of the present disclosure result in a maximum plasma concentration (C max ) is 100 to 800 (ng / mL) in increments of 100 ng / mL.

[0035] In various aspects of the disclosed methods, when a 600 mg dose of bezuclastinib is co-administered with 37.5 mg of sunitinib malate, the once daily steady-state target area under the curve (AUC) is 30,000 to 50,000 (ng.h / mL) in increments of 500 ng.h / mL.

[0036] In other aspects of the methods of the present disclosure, when a 600 mg dose of bezulatinib is co-administered with 37.5 mg of sunitinib malate, the maximum plasma concentration (C max ) is 1,500 to 2,500 (ng / mL) in increments of 500 ng.h / mL. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 Is displayed using Technology, diagram for polymer screening using API.

[0038] Figure 2 is a microcentrifuge assay showing the non-sink total drug dissolution testing results of SDD samples compared to crystalline API in simulated intestinal fluid at pH 6.5 and 37°C with 0.5% bile salt concentration.

[0039] Figure 3 is an ultracentrifugation assay showing non-sink free drug dissolution testing results of SDD samples compared to crystalline API in simulated intestinal fluid at pH 6.5 and 37°C with 0.5% bile salt concentration.

[0040] Figure 4 is a graph showing the results of non-sink total drug dissolution testing of SDD samples with 10%, 15% and 20% drug loading at 37°C for gastric delivery.

[0041] Figure 5 is a graph showing the results of non-sink free drug dissolution testing of SDD samples loaded with 10%, 15% and 20% drug for gastric delivery at 37°C.

[0042] Figure 6 is a process flow diagram showing the steps for preparing Formulations A and B.

[0043] Figure 7 Shown are the plasma concentration-time profiles of tablets prepared with SDD and KSD amorphous dispersions in nonhuman primates.

[0044] Figure 8 Shown are the areas under the curve for tablets prepared with SDD and KSD amorphous dispersions in nonhuman primates.

[0045] Figure 9 Plasma concentration time profiles of Formulations A and B at various doses over 336 hours are shown.

[0046] Figure 10 Plasma concentration time profiles over 24 hours are shown for Formulations A and B at various doses.

[0047] Figure 11 The C of formulations A and B at different doses was compared. max .

[0048] Figure 12 The area under the curve (AUC) of Formulations A and B at different doses were compared.

[0049] Figure 13 The C of formulations A and B at different doses was compared. max As well as the geometric mean and 90% confidence interval of the area under the curve. Detailed description

[0050] The present disclosure relates to spray-dried solid dispersions and tablets comprising 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (Compound I). The chemical structure of compound (I) is shown below.

[0051] Compound (I) is also referred to by its international nonproprietary name, bezulatinib.

[0052] Compound (I) described herein is a kinase modulator active against c-Kit protein kinase or mutant c-Kit protein kinase. The synthesis of Compound (I) and methods for treating diseases and conditions associated with abnormal activity of c-Kit protein kinase and / or mutant c-Kit protein kinase have previously been disclosed in US Pat. Nos. 9,676,748, B2 and 10,301,280, the entire contents of which are incorporated herein by reference.

[0053] Compound (I) was first disclosed in US9,676,748B2 and US10,301,280B2. In the past 10 years, it has been proven that compound (I) is difficult to prepare into a tablet form suitable for commercial development. In particular, compound (I) has a very high melting point (>365 ° C) and is almost insoluble in aqueous conditions (0.32 ug / mL at pH 7.0) and most organic solvents. In addition, no suitable salt or co-crystal of compound (I) has been found, which itself is easy to crystallize when forming a tablet. Finally, the existing tablet form of compound (I) allows a relatively small proportion of API to be loaded into the tablet form, requiring repeated administration of many tablets, thereby potentially endangering patient compliance.

[0054] The applicant has surprisingly discovered a method for solving the low solubility of compound (I) and preparing a tablet containing compound (I). In this method, compound (I) is in an amorphous form and a free base form. The method has the advantages of being concise, rapid, economical, time-saving and industrially convenient.

[0055] The low solubility problem of Compound (I) is overcome by preparing a spray-dried dispersion (SDD). Specifically, by dissolving Compound (I) and a polymer in a solvent system such as THF and water, and then spray-drying the solution, an amorphous molecular dispersion of Compound (I) in a polymer matrix such as Hydroxypropyl Methylcellulose Acetate Succinate H Grade (HPMCAS-H) is produced. This formulation surprisingly allows a larger amount of Compound (I) to be loaded into the tablet than previous formulations, and also delivers more Compound (I) to the blood of human subjects compared to previous formulations.

[0056] Thus, the present disclosure relates to tablets comprising a spray-dried dispersion of Compound (I) having a desired dissolution profile and desired stability. I. Definition

[0057] For convenience, certain terms used in the specification, examples, and claims are summarized here. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0058] Where a numerical range is provided, it is intended that every intervening value between the upper and lower limits of that range and any other stated or intervening value in the stated range be encompassed within the disclosure. For example, if a range of 1 mg to 8 mg is recited, it is intended that 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, and 7 mg, as well as a numerical range greater than or equal to 1 mg and a numerical range less than or equal to 8 mg, are also specifically disclosed.

[0059] As used herein, the terms "active agent," "active pharmaceutical ingredient," or "API" refer to a pharmaceutically active agent or drug. Additionally, these terms may also refer to "Compound (I)" or "bezulatinib." All of these terms may also be used interchangeably.

[0060] The term "amorphous" as used herein refers to a solid form of Compound (I) that is not crystalline. An amorphous solid does not exhibit a defined X-ray diffraction pattern with sharp maxima; it is a thermodynamically non-equilibrium material that does not exhibit long-range periodicity.

[0061] As used herein, the terms "approximately" and "about" refer to values ​​similar to the reference value. In certain embodiments, the terms "approximately" or "about" refer to a numerical range that falls within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction (greater than or less than) of the reference value, unless otherwise stated or otherwise apparent from the context (unless such a number would exceed 100% of the possible value).

[0062] "Combination therapy" is a treatment that includes administering two or more therapeutic agents, such as compound (I) and a receptor tyrosine kinase (RTK) inhibitor, such as, but not limited to, sunitinib malate, to a patient. The two or more therapeutic agents can be delivered simultaneously, for example, in separate pharmaceutical compositions or in the same pharmaceutical composition, or they can be delivered at different times. For example, they can be delivered simultaneously or during overlapping time periods, and / or one therapeutic agent can be delivered before or after the other therapeutic agent. Treatment with combination therapy optionally includes treatment with any single agent before or after treatment with two agents simultaneously for a period of time. However, it is expected that over a period of time, an effective amount of two or more therapeutic agents will be present in the patient's body.

[0063] The term "Compound (I)" as used herein refers to 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide.

[0064] As used herein, the terms "disease" and "disorder" may be used interchangeably, or may be distinct in that a particular disease or disorder may not have a known etiology (and therefore the etiology has not been elucidated) and therefore is not yet recognized as a disease, but only as an undesirable condition or syndrome in which clinicians have identified a more or less specific group of symptoms.

[0065] As used herein, the term "excipient" includes any substance used as a vehicle for delivering the active ingredient to the subject, as well as any substance added to the active ingredient, for example to improve its handling properties or to allow the resulting composition to form an orally deliverable unit dose with the desired shape and consistency. As an illustration and not limitation, an excipient may include a filler, a binder, a surfactant, a disintegrant, a glidant, a lubricant, or a combination thereof, a substance added to improve the appearance of the dosage form, and any other substance other than the active ingredient conventionally used to prepare an oral dosage form. The term "excipient" includes inert substances and functional excipients that can result in the beneficial properties of the composition. Exemplary excipients include, but are not limited to, polymers, glidants, sugars, lubricants, salts, buffers, fats, fillers, disintegrants, binders, surfactants, high surface area substrates, flavorings, carriers, matrix materials, etc.

[0066] The term "in vitro" as used herein refers to events that occur in an artificial environment, such as in a test tube or reaction vessel, in a cell culture, in a petri dish, etc., rather than within an organism (such as an animal, plant, or microorganism).

[0067] As used herein, the term "in vivo" refers to events that occur within an organism (eg, an animal, plant, or microorganism, or a cell or tissue thereof).

[0068] As used herein, the term "mammal" includes humans as well as domestic animals such as laboratory animals and household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits) and non-domestic animals such as wild animals, etc.

[0069] As used herein, the term "pharmaceutically acceptable" refers to those compounds, salts, compositions, dosage forms, etc. that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and / or other mammals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio. In some aspects, "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia, for use in mammals (e.g., animals), more particularly humans.

[0070] As used herein, the term "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the United States Food and Drug Administration as acceptable for use in humans or veterinary medicine.

[0071] As used herein, the term "pharmaceutical composition" refers to a composition comprising an API and a pharmaceutically acceptable excipient for oral delivery of the API to a mammal.

[0072] As used herein, the term "spray-dried solid dispersion" or "spray-dried dispersion" (SDD) refers to a dispersion comprising a drug and a polymer, wherein the drug is non-crystalline and amorphous. Amorphous dispersions of drugs can be prepared by various manufacturing methods, such as spray drying, coprecipitation, or hot melt extrusion. In embodiments of the present disclosure, a spray drying procedure is used. A spray-dried dispersion (SDD) is a single-phase, amorphous molecular dispersion of a drug in a polymer matrix; it is an amorphous solid in which the drug is "dissolved" in the solid matrix at the molecular level. Spray-dried dispersions can be prepared by dissolving the drug and polymer in an organic solvent to produce a solution and then spray drying the solution. Techniques for preparing solid dispersions of amorphous drugs in polymers are disclosed, for example, in U.S. Patent Nos. 9,095,585 and 9,468,604, the contents of each of which are incorporated herein by reference in their entirety. Solid dispersions are also described, for example, in U.S. Patent No. 8,263,128.

[0073] As used herein, the terms "subject," "individual," or "patient" are used interchangeably and include any animal to which a composition according to the present disclosure can be administered, e.g., for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include animals, such as, but not limited to, mammals, such as, but not limited to, mice, rats, rabbits, non-human primates, and humans.

[0074] The term "stable" as used herein refers to an amorphous form of Compound (I) that does not convert to any other solid form and contains less than 5% (wt / wt) (or, for example, less than 4% w / w, less than 3% w / w, less than 2% w / w) total other forms when stored at temperatures up to about 40°C and a relative humidity of about 25% to about 75% for at least about three months.

[0075] As used herein, the term "therapeutic agent" or "prophylactic agent" refers to any agent that has a therapeutic, diagnostic and / or prophylactic effect and / or induces a desired biological and / or pharmacological effect when administered to a subject. Therapeutic agents are also referred to as "active substances" or "active agents."

[0076] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a composition that, when administered to a mammal (preferably a human), is sufficient to achieve treatment in a mammal (preferably a human). The amount of the composition that constitutes a "therapeutically effective amount" will vary depending on the condition and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art based on their own knowledge and this disclosure.

[0077] The term "oral formulation" as used herein refers to a composition or medium for administering a compound disclosed herein (e.g., Compound (I)) to a subject in need thereof by oral administration. Typically, oral formulations are administered by mouth, however, "oral formulations" as used herein are intended to encompass any substance that is administered to a subject and absorbed by a membrane (e.g., mucosa) of the gastrointestinal tract (including, for example, the mouth, esophagus, stomach, small intestine, large intestine, and colon). In some embodiments, the oral formulation is a pharmaceutical composition. In some embodiments, the oral formulation is a pharmaceutical composition that is administered orally to a subject in need thereof.

[0078] As used herein, the term "solid dispersion" refers to any solid composition having at least two components. In certain embodiments, a solid dispersion as disclosed herein comprises an active ingredient (e.g., Compound (I)) dispersed in at least one other component (e.g., a polymer (e.g., HPMCAS-H)).

[0079] As used herein, the terms "treating" or "treatment" as used herein encompass treating a disease or condition of interest in a mammal (preferably a human) suffering from the disease or condition of interest, and include preventing the disease or condition from occurring in a mammal, particularly when such mammal is susceptible to the condition but has not yet been diagnosed as having the condition, inhibiting the disease or condition, i.e., arresting its development, alleviating the disease or condition, i.e., causing regression of the disease or condition, or relieving the symptoms caused by the disease or condition, i.e., relieving pain without resolving the underlying disease or condition. The term "treating" also includes any effect that results in an improvement of a condition, disease, disorder, etc., such as alleviating, reducing, modulating, or eliminating.

[0080] Typically, solid-state forms, such as crystalline or amorphous forms, can be characterized by modulated differential scanning calorimetry (mDSC), powder X-ray diffraction (PXRD), near-infrared spectroscopy (NIR), or any other standard analytical technique. For example, mDSC assesses the thermal properties of SDD; for amorphous SDD, analysis by mDSC will yield a single glass transition temperature. mDSC can also detect crystalline phase separation, as the crystalline phase will exhibit a unique thermal signature. PXRD uses x-rays to identify crystalline forms in solid powders and can be used to analyze SDD, for example, to confirm that the SDD is a single amorphous phase with no measurable crystalline material. As is well known in the art, graphical data potentially provides additional technical information to further define the corresponding solid-state form (a so-called "fingerprint") that is not necessarily described solely by reference to numerical values ​​or peak positions. In any case, one skilled in the art will understand that such graphical representations of data may undergo small variations, such as variations in relative peak intensities and peak positions, due to factors such as, but not limited to, variations in instrument response and variations in sample concentration and purity, as is well known to one skilled in the art. Crystals are composed of atoms arranged periodically in 3D space, while in amorphous materials, atoms are randomly distributed in 3D space. As a result, the X-ray diffraction pattern of a crystalline material will show narrow peaks of high intensity, due to the fact that the X-rays are scattered only in certain directions (due to the periodic arrangement of the atoms). In contrast, the X-ray diffraction pattern of an amorphous material typically shows broad peaks of low intensity (halo patterns) because the X-rays are scattered in many different directions, resulting in large bumps distributed over a wide range (2θ).

[0081] The disclosed compositions can comprise, consist essentially of, or consist of the disclosed components.

[0082] All percentages, parts and ratios are based upon the total weight of the composition and all measurements made are at about 25°C, unless otherwise specified.

[0083] All ranges described herein are inclusive of the endpoints, including those describing a range "between" two values. The terms "substantially" and "about" should be interpreted as modifying a term or value so that it is not absolute. This includes at least the degree of expected experimental, technical, and instrumental error for the given technique used to measure the value.

[0084] Less than the entirety of the present disclosure may be claimed for any reason by reserving the right to limit or exclude any individual member of any such group, including any subrange or combination of subranges within that group (which may be claimed as a range or in any similar manner). In addition, less than the entirety of the present disclosure may be claimed for any reason by reserving the right to limit or exclude any individual excipient, polymer, compound, group thereof, or any member of a claimed group.

[0085] Throughout this disclosure, various patents, patent applications, and publications are cited. The disclosures of these patents, patent applications, and publications are incorporated herein by reference in their entirety to more fully describe the prior art known to those skilled in the art as of the date of this disclosure. In the event of any inconsistency between the cited patents, patent applications, and publications and this disclosure, the present disclosure will prevail. II. Spray-dried dispersions

[0086] Dispersions of active agents and pharmaceutically acceptable polymers as described herein are prepared by a spray drying process. As used herein, the term "spray-dried dispersion" or "spray-dried powder dispersion" refers to the product of a spray drying process, wherein the product comprises a dispersion of at least one active agent and at least one excipient (e.g., a polymer).

[0087] In some embodiments, the active agent is 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (Compound I). In some embodiments, the polymer is a pharmaceutically acceptable polymer, such as hypromellose acetate succinate grade H (HPMCAS-H).

[0088] In the spray drying method, activating agent and polymer are dissolved in a common solvent. "Common" refers to that a solvent (which can be a mixture of compounds) will dissolve both activating agent and polymer. After activating agent and polymer are dissolved, the solvent is quickly removed by evaporation in a spray drying device, resulting in the formation of a substantially uniform solid dispersion. In such a dispersion, the activating agent is evenly dispersed throughout the polymer as much as possible and can be considered to be a solid solution of the activating agent dispersed in the polymer. In aspects of the present disclosure, activating agent and polymer are dissolved in a solvent, and the solvent is a combination of water and tetrahydrofuran (THF).

[0089] Solvent is removed by spray drying process. The term "spray drying" is conventionally used and refers broadly to a method of breaking a liquid mixture into small droplets (atomization) and rapidly removing the solvent from the mixture in a spray drying apparatus, wherein there is a strong driving force for evaporating the solvent from the droplets. Spray drying methods and spray drying equipment are generally described in Perry's Chemical Engineers' Handbook, pp. 20-54 to 20-57 (Sixth Edition 1984). More details about spray drying methods and equipment are summarized in Marshall's "Atomization and Spray-Drying", 50 Chem. Eng. Prog. Monogr. Series 2 (1954) and Masters' Spray Drying Handbook (4th Edition 1985). In addition, other methods and spray drying techniques and equipment are generally described in U.S. Patent Nos. 8,343,550 and 7,780,988, the contents of which are incorporated herein by reference in their entirety for all purposes. A strong driving force for solvent evaporation is typically provided by maintaining the solvent partial pressure in the spray drying apparatus well below the vapor pressure of the solvent at the temperature of the drying droplets. This is achieved by (1) maintaining the pressure in the spray drying apparatus at a partial vacuum (e.g., 0.01 to 0.50 atm); or (2) mixing the droplets with a warm drying gas; or (3) both (1) and (2). In addition, a portion of the heat required to evaporate the solvent can be provided by heating the spray solution.

[0090] The drying gas can be virtually any gas, but to minimize the risk of fire or explosion due to ignition of flammable vapors and to minimize undesirable oxidation of the drug, enriched polymer, or other materials in the dispersion, an inert gas such as nitrogen, nitrogen-enriched air, or argon is used. The temperature of the drying gas at the gas inlet of the apparatus is typically from about 60° C. to about 300° C. The temperature of the product particles, drying gas, and evaporated solvent at the outlet or distal end of the collecting cone is typically in the range of from about 0° C. to about 100° C.

[0091] The solvent suitable for the spray drying method can be any organic compound in which the active agent and the polymer are mutually soluble. The solvent should have relatively low toxicity and be removed from the dispersion to a level acceptable according to the guidelines of The International Committee on Harmonization (ICH). Removing the solvent to this level may require subsequent processing steps, such as tray drying or secondary drying. In some embodiments, the solvent comprises tetrahydrofuran (THF). A mixture of solvent and water is suitable as long as the polymer and API are sufficiently soluble to make the spray drying method feasible. In some embodiments, the water: solvent mixture is water:THF. In some embodiments, the solvent is 100% THF.

[0092] The composition of the solvent-containing feed will depend on the desired ratio of drug to polymer in the dispersion and the solubility of the drug and polymer in the solvent. Generally, it is desirable to use as high a combined concentration of drug and polymer as possible in the solvent-containing feed, provided that the drug and polymer are soluble in the solvent within the temperature range of the process, to reduce the total amount of solvent that must be removed to form the solid amorphous dispersion.

[0093] The average residence time of the particles in the drying chamber should be at least 10 seconds, preferably at least 20 seconds. Typically, after solidification, the powder formed stays in the spray drying chamber for about 5 to 60 seconds, thereby causing the solvent to evaporate further. The final solvent content of the solid dispersion when it leaves the dryer should be low because this reduces the mobility of the drug molecules in the dispersion, thereby improving its stability. Typically, the solvent content when the dispersion leaves the spray drying chamber should be less than about 10% by weight. In some embodiments, the solvent content when the dispersion leaves the spray drying chamber is less than about 9wt%. In some embodiments, the solvent content when the dispersion leaves the spray drying chamber is less than about 8wt%. In some embodiments, the solvent content when the dispersion leaves the spray drying chamber is less than about 7wt%. In some embodiments, the solvent content when the dispersion leaves the spray drying chamber is less than about 6wt%. In some embodiments, the solvent content when the dispersion leaves the spray drying chamber is less than about 5wt%. In some embodiments, the solvent content when the dispersion leaves the spray drying chamber is less than about 4wt%. In some embodiments, the solvent content when the dispersion leaves the spray drying chamber is less than about 3wt%. In some embodiments, the solvent content when the dispersion leaves the spray drying chamber is less than about 2wt%. In some embodiments, the dispersion has a solvent content of less than about 1 wt % when it exits the spray drying chamber. Subsequent processing steps, such as tray drying, can be used to remove the solvent to this level.

[0094] In one aspect, provided herein is a spray-dried solid dispersion (SDD) comprising: (a) 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (Compound (I)), (b) a pharmaceutically acceptable polymer, and wherein Compound (I) is dispersed in a polymer matrix formed by the pharmaceutically acceptable polymer.

[0095] In one aspect, Compound (I) is in amorphous form in SDD. In one aspect, Compound (I) is in free base form in SDD.

[0096] In one aspect, in the spray-dried solid dispersion, the pharmaceutically acceptable polymer is hypromellose acetate succinate (HPMCAS).

[0097] In one aspect, in the spray-dried solid dispersion, the pharmaceutically acceptable polymer is hypromellose acetate succinate grade H (HPMCAS-H).

[0098] The spray-dried solid dispersion of the present disclosure comprises at least about 1 wt% to at least about 25 wt% 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (Compound I).

[0099] In some aspects, the spray-dried solid dispersion comprises at least about 1% to at least about 5% Compound I by weight.

[0100] In some aspects, the spray-dried solid dispersion comprises at least about 1% by weight to at least about 10% by weight of Compound I.

[0101] In some aspects, the spray-dried solid dispersion comprises at least about 1% to at least about 15% Compound I by weight.

[0102] In some aspects, the spray-dried solid dispersion comprises at least about 1% to at least about 20% Compound I by weight.

[0103] The spray-dried solid dispersions of the present disclosure comprise at least about 75% by weight to at least about 99% by weight of the pharmaceutically acceptable polymer.

[0104] In some aspects, the spray-dried solid dispersion comprises at least about 80% by weight to at least about 99% by weight of the pharmaceutically acceptable polymer.

[0105] In some aspects, the spray-dried solid dispersion comprises at least about 85% by weight to at least about 99% by weight of the pharmaceutically acceptable polymer.

[0106] In some aspects, the spray-dried solid dispersion comprises at least about 90% by weight to at least about 99% by weight of the pharmaceutically acceptable polymer.

[0107] In some aspects, the spray-dried solid dispersion comprises at least about 95% by weight to at least about 99% by weight of the pharmaceutically acceptable polymer.

[0108] In aspects of the present disclosure, the spray-dried solid dispersion comprises hypromellose acetate succinate (HPMCAS) as the pharmaceutically acceptable polymer.

[0109] In aspects of the present disclosure, the spray-dried solid dispersion comprises hypromellose acetate succinate grade H (HPMCAS-H) as the pharmaceutically acceptable polymer.

[0110] In the spray-dried solid dispersion of the present disclosure, the weight ratio of 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (Compound I) to the pharmaceutically acceptable polymer is about 1:3 to about 1:99.

[0111] In one aspect, the spray-dried solid dispersion comprises a solvent. The solvent is a combination of water and tetrahydrofuran (THF). The volume ratio of water to tetrahydrofuran is from about 1:2 to about 1:99. In one aspect, the solvent is THF. III. Pharmaceutical Preparations

[0112] In one aspect, provided herein are pharmaceutical compositions comprising Compound (I) and one or more pharmaceutically acceptable carriers, excipients, or diluents. In one aspect, provided herein are pharmaceutical compositions comprising a spray-dried dispersion (SDD) comprising Compound (I) and a pharmaceutically acceptable polymer.

[0113] In some aspects, Compound (I) in the pharmaceutical composition is in amorphous and free base form.

[0114] In some aspects, the pharmaceutically acceptable polymer in the pharmaceutical composition is hypromellose acetate succinate grade (HPMCAS).

[0115] In some aspects, the pharmaceutically acceptable polymer in the pharmaceutical composition is hypromellose acetate succinate grade H (HPMCAS-H).

[0116] In one aspect, provided herein is a pharmaceutical composition comprising an amorphous form of Compound (I) having no more than 5% (w / w) of any crystalline form or no detectable amount of any crystalline form and one or more pharmaceutically acceptable carriers, excipients, or diluents.

[0117] For example, such pharmaceutical compositions can be any oral dosage form, such as, but not limited to, tablets, capsules, pills, powders, liquids, suspensions, emulsions, granules, sustained release formulations, solutions and suspensions. In a preferred embodiment, the pharmaceutical composition is an oral formulation, such as a tablet suitable for single administration of an accurate dose. Such dosage forms should allow the pharmaceutical composition to reach the target cells. Other factors are well known in the art and include considerations such as toxicity and delaying the dosage form of the pharmaceutical composition to exert its effect. Techniques and formulations are generally found in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams and Wilkins, Philadelphia, Pa., 2005 (hereby incorporated herein by reference).

[0118] The methods and pharmaceutical compositions will generally be used in the therapy of human subjects. However, they may also be used to treat similar or identical indications in other animal subjects.

[0119] The pharmaceutical compositions of the present disclosure may be combined with one or more excipients. When granulation is used, the excipients may be added prior to granulation (thus intragranular) and / or may be added after granulation (thus extragranular).

[0120] Excipients used in pharmaceutical compositions can impart good powder flow and compression properties to the compressed material. It should be noted that excipients can serve multiple functions. Desirable features of excipients may include high compressibility to allow for the preparation of strong tablets under low compression forces; good powder flow properties, which can improve the powder flow of other excipients in the composition; and cohesiveness, for example, to prevent tablets from breaking during processing, transportation, and handling. These properties are imparted to these excipients through pretreatment steps, such as, but not limited to, dry granulation (e.g., by rolling, briquetting), wet granulation, or spray drying spheronization (e.g., spray-dried dispersions, solid nanodispersions). They can be classified according to the role they play in the final tablet. Other excipients that impart physical properties to the finished tablet are colorants and flavorings (e.g., in the case of chewable tablets). Examples of excipients are described, for example, in Handbook of Pharmaceutical Excipients (5th edition), edited by Raymond C. Rowe, Paul J. Sheskey, and Sian C. Owen, published by Pharmaceutical Press.

[0121] In some embodiments, the pharmaceutical composition will comprise a pharmaceutically acceptable carrier or excipient, such as a filler, binder, disintegrant, glidant, lubricant, complexing agent, solubilizer and surfactant, which can be selected to facilitate administration of the compound by a particular route. Examples of carriers include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose or sucrose, various types of starch, cellulose derivatives, gelatin, lipids, liposomes, nanoparticles, and the like. Carriers also include physiologically compatible liquids as solvents or for suspensions, including, for example, sterile solutions of water for injection (WFI), saline solutions, dextrose solutions, Hank's solutions, Ringer's solutions, vegetable oils, mineral oils, animal oils, polyethylene glycols, liquid paraffin, and the like. Excipients may also include, for example, colloidal silicon dioxide, silica gel, talc, magnesium silicate, calcium silicate, sodium aluminosilicate, magnesium trisilicate, powdered cellulose, microcrystalline cellulose, carboxymethyl cellulose, croscarmellose sodium, sodium benzoate, calcium carbonate, magnesium carbonate, stearic acid, aluminum stearate, calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, syloid, stearowet C, magnesium oxide, starch, sodium starch glycolate, glyceryl monostearate, glyceryl dibehenate, glyceryl palmitostearate, hydrogenated vegetable oil, hydrogenated cottonseed oil, castor seed oil, mineral oil, polyethylene glycol (e.g., PEG 4000-8000), polyoxyethylene glycol, poloxamer, povidone, crospovidone, croscarmellose sodium, alginic acid, casein, divinylbenzene methacrylate copolymer, docusate sodium, cyclodextrin (e.g., 2-hydroxypropyl-delta-cyclodextrin); polysorbates (e.g., polysorbate 80), cetyltrimonium bromide, TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate), magnesium lauryl sulfate, sodium lauryl sulfate, polyethylene glycol ethers, difatty acid esters of polyethylene glycol, or polyoxyalkylene sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan esters ), polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, for example sorbitan fatty acid esters from fatty acids such as oleic acid, stearic acid or palmitic acid, mannitol, xylitol, sorbitol, maltose, lactose, lactose monohydrate or spray-dried lactose, sucrose, fructose, calcium phosphate, calcium hydrogen phosphate, tricalcium phosphate, calcium sulfate, dextrates, dextran, dextrin, dextrose, cellulose acetate, maltodextrin, simethicone, polydextran, chitosan, gelatin, HPMC (hydroxypropyl methylcellulose), HPC (hydroxypropyl cellulose), hydroxyethyl cellulose, and the like.

[0122] The pharmaceutical compositions provided herein can contain one or more fillers, which are added to, for example, increase the bulk weight of the blend, thereby producing the actual size for compression. Useful fillers include one or more calcium salts (e.g., calcium hydrogen phosphate) and sugars (e.g., lactose, sucrose, dextrose, microcrystalline cellulose (MCC), mannitol, and maltodextrin). Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to, confectionery sugar, compressible sugar, dextrose, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose, and talc. In some embodiments, the filler is microcrystalline cellulose, which can be manufactured by controlled hydrolysis of alpha-cellulose. Suitable microcrystalline cellulose will have an average particle size of about 20 nm to about 200 nm. Suitable microcrystalline cellulose may include PH-101, PH-102, PH-103, PH-105, PH-113 and PH-200, which is manufactured, for example, by FMC Corporation. In some embodiments, the one or more fillers include PH-113 microcrystalline cellulose and M 100 (mannitol).

[0123] The pharmaceutical composition may also include one or more lubricants. As used herein, the term "lubricant" is typically added to prevent tabletting material from adhering to the punch, minimizes friction during tablet compression, and allows compressed tablets to be taken out from the die. Examples of lubricants include, but are not limited to, colloidal silicon dioxide, magnesium trisilicate, talc, magnesium carbonate, magnesium oxide, glycerylbehaptate, polyethylene glycol, ethylene oxide polymers (such as Carowax), sodium lauryl sulfate, magnesium stearate, aluminum stearate, calcium stearate, sodium stearyl fumarate, stearic acid, lauryl magnesium stearate, and a mixture of magnesium stearate and sodium lauryl sulfate. Exemplary lubricants include calcium stearate, magnesium stearate and sodium stearyl fumarate. In some embodiments, one or more lubricants include sodium stearyl fumarate.

[0124] The pharmaceutical compositions provided herein may also contain one or more glidants. As used herein, the term "glidant" is a substance added to a powder that can improve its flowability, for example, by reducing interparticle friction. Exemplary glidants include, but are not limited to, colloidal silicon dioxide, colloidal silicon oxide, fumed silica, M-5P, AEROSIL, talc, Starch and magnesium aluminum silicate.In some embodiments, the one or more glidants include colloidal silicon dioxide.

[0125] One or more disintegrants can be present in the pharmaceutical compositions provided herein in an amount required to accelerate dissolution (e.g., increase the tablet disintegration rate). The term "disintegrant" as used herein refers to an excipient that can resist the physical forces that bind the particles in a tablet or capsule when the oral formulation is placed in an aqueous environment. Disintegrants include starch derivatives and salts of carboxymethyl cellulose. Examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches such as sodium starch glycolate, pregelatinized starch; clays; celluloses; alginates; gums; cross-linked polymers such as cross-linked polyvinyl pyrrolidone (e.g., povidone-polyvinylpyrrolidone) and polyvinylpyrrolidone (e.g., polyvinylpyrrolidone). TM , polyvinylpolypyrrolidone, crospovidone), cross-linked carboxymethylcellulose calcium and cross-linked carboxymethylcellulose sodium (croscarmellose sodium); and soy polysaccharides. In some embodiments, one or more disintegrants include Croscarmellose sodium, which aids in disintegration and drug dissolution of the tablets of the present disclosure.

[0126] Also provided herein is a pharmaceutical composition comprising a spray-dried solid dispersion comprising an amorphous form of Compound (I) and a pharmaceutically acceptable polymer, wherein the 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (Compound I) is dispersed in a polymer matrix formed by the pharmaceutically acceptable polymer. In some embodiments, the pharmaceutically acceptable polymer is hypromellose acetate succinate grade H (HPMCAS-H). IV. Tablets

[0127] The pharmaceutical composition can also be provided as a tablet. Tablets can be uncoated, film-coated, sugar-coated, bisected, embossed, plain, layered, or sustained-release. They can be made in a variety of sizes, shapes, and colors. Tablets can be swallowed, chewed, or dissolved in the mouth or under the tongue.

[0128] In one embodiment, described herein are tablets comprising a spray-dried solid dispersion comprising 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (Compound 1) and a pharmaceutically acceptable polymer such as hypromellose acetate succinate grade H (HPMCAS-H) and one or more pharmaceutically acceptable ingredients selected from one or more binders, one or more buffers, one or more diluents, one or more disintegrants, one or more fillers, one or more film coatings, one or more lubricants, one or more glidants, and one or more surfactants.

[0129] In the tablet of the present disclosure, the one or more pharmaceutically acceptable ingredients include colloidal silicon dioxide, croscarmellose sodium, sodium stearyl fumarate, mannitol and microcrystalline cellulose.

[0130] The tablets of the present disclosure contain at least about 1% by weight to at least about 20% by weight of 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (Compound I).

[0131] In some aspects, the tablet comprises at least about 5% to at least about 20% Compound I by weight.

[0132] In some aspects, the tablet comprises at least about 15% to at least about 20% Compound I by weight.

[0133] The tablets of the present disclosure contain at least about 10% by weight to at least about 90% by weight of the pharmaceutically acceptable polymer.

[0134] The tablets of the present disclosure contain at least about 20% by weight to at least about 90% by weight of the pharmaceutically acceptable polymer.

[0135] The tablets of the present disclosure contain at least about 30% by weight to at least about 90% by weight of the pharmaceutically acceptable polymer.

[0136] In some aspects, the tablet comprises at least about 40% by weight to at least about 90% by weight of the pharmaceutically acceptable polymer.

[0137] In some aspects, the tablet comprises at least about 50% by weight to at least about 90% by weight of the pharmaceutically acceptable polymer.

[0138] In some aspects, the tablet comprises at least about 60% by weight to at least about 90% by weight of the pharmaceutically acceptable polymer.

[0139] In some aspects, the tablet comprises at least about 70% by weight to at least about 90% by weight of the pharmaceutically acceptable polymer.

[0140] In some aspects, the tablet comprises at least about 80% by weight to at least about 90% by weight of the pharmaceutically acceptable polymer.

[0141] In the tablets of the present disclosure, the pharmaceutically acceptable polymer is hypromellose acetate succinate grade (HPMCAS).

[0142] In the tablet of the present disclosure, the pharmaceutically acceptable polymer is hypromellose acetate succinate grade H (HPMCAS-H).

[0143] The tablets of the present disclosure comprise at least about 3% by weight to at least about 65% by weight of the one or more pharmaceutically acceptable ingredients selected from one or more binders, one or more buffers, one or more diluents, one or more disintegrants, one or more fillers, one or more lubricants, one or more glidants, and one or more surfactants.

[0144] The tablets of the present disclosure comprise at least about 5% by weight to at least about 65% by weight of the one or more pharmaceutically acceptable ingredients selected from one or more binders, one or more buffers, one or more diluents, one or more disintegrants, one or more fillers, one or more lubricants, one or more glidants, and one or more surfactants.

[0145] In some aspects, the tablet comprises at least about 10% by weight to at least about 65% by weight of the one or more pharmaceutically acceptable ingredients selected from one or more binders, one or more buffers, one or more diluents, one or more disintegrants, one or more fillers, one or more lubricants, one or more glidants, and one or more surfactants.

[0146] In some aspects, the tablet comprises at least about 15% by weight to at least about 65% by weight of the one or more pharmaceutically acceptable ingredients selected from one or more binders, one or more buffers, one or more diluents, one or more disintegrants, one or more fillers, one or more lubricants, one or more glidants, and one or more surfactants.

[0147] In some aspects, the tablet comprises at least about 20% by weight to at least about 65% by weight of the one or more pharmaceutically acceptable ingredients selected from one or more binders, one or more buffers, one or more diluents, one or more disintegrants, one or more fillers, one or more lubricants, one or more glidants, and one or more surfactants.

[0148] In some aspects, the tablet comprises at least about 25% by weight to at least about 65% by weight of the one or more pharmaceutically acceptable ingredients selected from one or more binders, one or more buffers, one or more diluents, one or more disintegrants, one or more fillers, one or more lubricants, one or more glidants, and one or more surfactants.

[0149] In some aspects, the tablet comprises at least about 30% by weight to at least about 65% by weight of the one or more pharmaceutically acceptable ingredients selected from one or more binders, one or more buffers, one or more diluents, one or more disintegrants, one or more fillers, one or more lubricants, one or more glidants, and one or more surfactants.

[0150] In some aspects, the tablet comprises at least about 35% by weight to at least about 65% by weight of the one or more pharmaceutically acceptable ingredients selected from one or more binders, one or more buffers, one or more diluents, one or more disintegrants, one or more fillers, one or more lubricants, one or more glidants, and one or more surfactants.

[0151] In some aspects, the tablet comprises at least about 40% by weight to at least about 65% by weight of the one or more pharmaceutically acceptable ingredients selected from one or more binders, one or more buffers, one or more diluents, one or more disintegrants, one or more fillers, one or more lubricants, one or more glidants, and one or more surfactants.

[0152] In some aspects, the tablet comprises at least about 45% by weight to at least about 65% by weight of the one or more pharmaceutically acceptable ingredients selected from one or more binders, one or more buffers, one or more diluents, one or more disintegrants, one or more fillers, one or more lubricants, one or more glidants, and one or more surfactants.

[0153] In some aspects, the tablet comprises at least about 50% by weight to at least about 65% by weight of the one or more pharmaceutically acceptable ingredients selected from one or more binders, one or more buffers, one or more diluents, one or more disintegrants, one or more fillers, one or more lubricants, one or more glidants, and one or more surfactants.

[0154] In some aspects, the tablet comprises at least about 55% by weight to at least about 65% by weight of the one or more pharmaceutically acceptable ingredients selected from one or more binders, one or more buffers, one or more diluents, one or more disintegrants, one or more fillers, one or more lubricants, one or more glidants, and one or more surfactants.

[0155] In some aspects, the tablet comprises at least about 60% by weight to at least about 65% by weight of the one or more pharmaceutically acceptable ingredients selected from one or more binders, one or more buffers, one or more diluents, one or more disintegrants, one or more fillers, one or more lubricants, one or more glidants, and one or more surfactants.

[0156] The present disclosure also relates to a tablet comprising at least about 1% by weight to at least about 20% by weight of 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (Compound I), at least about 10% by weight to at least about 90% by weight of hypromellose acetate succinate grade H (HPMCAS-H), and at least about 3% by weight to at least about 65% by weight of one or more pharmaceutically acceptable ingredients selected from one or more binders, one or more buffers, one or more diluents, one or more disintegrants, one or more fillers, one or more lubricants, one or more glidants, and one or more surfactants.

[0157] The tablet can be present in a unit dosage form containing a predetermined amount of active ingredient per unit dose. Such a unit can contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of compound (I), depending on the condition being treated, route of administration, and age, weight, and condition of the patient. Preferred unit dose formulations are those containing daily doses, weekly doses, monthly doses, sub-doses, or appropriate portions thereof of the active ingredient. In addition, such pharmaceutical preparations can be prepared by any method known to the pharmaceutical field.

[0158] In some aspects, the tablets of the present disclosure are taken once daily.

[0159] In other aspects, the tablets of the present disclosure are taken twice daily.

[0160] In another aspect, the tablets of the present disclosure are taken continuously in 28-day cycles.

[0161] The unit dose to be administered can be determined by standard procedures, taking into account, for example, the activity of the API (in vitro, e.g., relative to the target, IC of the compound, 50 , or in vivo activity in animal efficacy models), pharmacokinetic results in animal models (e.g., biological half-life or bioavailability), age, size, and weight of the subject, and factors such as the disease associated with the subject. The importance of these and other factors is well known to those of ordinary skill in the art. Generally, dosages range from about 0.01 to 50 mg / kg, and additionally about 0.1 to 20 mg / kg of the subject being treated. Multiple doses may be used.

[0162] The pharmaceutical compositions described herein can also be used in combination with other therapies for treating the same disease. Such combined use includes administering the compound and one or more other therapeutic agents at different times, or co-administering the compound and one or more other therapies. In some embodiments, the dosage of the pharmaceutical compositions of the present disclosure or other therapeutic agents used in combination can be modified by methods well known to those of ordinary skill in the art, such as reducing the dosage relative to the compound or therapy used alone.

[0163] It should be understood that use in combination includes use with other therapies, drugs, medical procedures, etc., wherein the other therapies or procedures can be administered at a different time than the pharmaceutical compositions described herein (e.g., within a short period of time, such as within a few hours (e.g., 1, 2, 3, 4-24 hours), or over a longer period of time (e.g., 1-2 days, 2-4 days, 4-7 days, 1-4 weeks)), or administered simultaneously with the pharmaceutical compositions described herein. Use in combination also includes use with a therapy or medical procedure (e.g., surgery) that is administered once or infrequently, and a pharmaceutical composition described herein that is administered before or after the other therapy or procedure, either within a short period of time or over a longer period of time. In some embodiments, the present disclosure provides for the delivery of a pharmaceutical composition described herein and one or more other drug therapeutics delivered by different routes of administration or by the same route of administration. Use in combination for any route of administration includes delivering a pharmaceutical composition described herein and one or more other drug therapeutics delivered by the same route of administration together in any formulation, including formulations in which the two compounds are chemically linked in a manner such that their therapeutic activity is maintained upon administration. In one aspect, other drug therapies can be co-administered with a pharmaceutical composition described herein. The combined use of co-administration includes administering a co-formulation or a chemically linked compound, or administering two or more compounds in a short period of time (e.g., within 1 hour, 2 hours, 3 hours, up to 24 hours) in separate formulations of each other, which are administered by the same or different routes. The co-administration of separate formulations includes administering via a device (e.g., the same inhalation device, the same syringe, etc.), or administering from separate devices of each other in a short period of time. The co-formulation of a compound as described herein and one or more other drug therapies delivered by the same route includes preparing the materials together so that they can be administered by a device, including separate compounds combined in a preparation, or modified so that they are chemically linked but still retain their biological activity. This chemically linked compound can have a key that is substantially maintained in vivo, or the key can be decomposed in vivo, thereby separating the two active components.

[0164] Provided herein is an embodiment of a method of treating a subject having a disease or condition selected from acute myeloid leukemia (AML), gastrointestinal stromal tumor (GIST), mast cell leukemia (MCL), and mastocytosis, the method comprising orally administering to the subject a tablet of the present disclosure.

[0165] In another embodiment, provided herein is a use of the pharmaceutical composition or tablet described herein in the preparation of a medicament for treating a disease or condition selected from acute myeloid leukemia (AML), gastrointestinal stromal tumor (GIST), mast cell leukemia (MCL) and mastocytosis. Disease indications and regulation of Vc-Kit kinase A. Exemplary Diseases Associated with c-Kit or Mutated Forms of c-Kit

[0166] The formulations described herein can be used to treat disorders associated with c-Kit, such as diseases associated with unregulated kinase signaling, including, among others, cell proliferative disorders, fibrotic disorders, and metabolic disorders. As described in more detail below and in US20040002534 to Lipson et al. (U.S. application Ser. No. 10 / 600,868, filed Jun. 23, 2003), which is incorporated herein by reference in its entirety, cell proliferative disorders that can be treated by the present disclosure include cancer and mast cell proliferative disorders.

[0167] The presence of c-Kit or mutant c-Kit has also been associated with many different types of cancers, diseases and conditions, as described below. Furthermore, the association between abnormalities in c-Kit and disease is not limited to cancer. Thus, c-Kit has been associated with malignancies including mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors (GIST), metastatic GIST, glioblastoma, astrocytoma, neuroblastoma, female genital tract cancer, sarcomas of neuroectodermal origin, colorectal cancer, carcinoma in situ, Schwann cell neoplasia associated with neurofibromatosis, acute myeloid leukemia (AML), acute lymphoblastic leukemia, chronic myeloid leukemia, mastocytosis, melanoma (mucosal and cutaneous), thyroid cancer, breast cancer, germ cell tumors including mixed germ cell tumors, ovarian germ cell tumors, dysgerminomas, seminoma, large cell neuroendocrine carcinoma, prostate cancer and canine mast cell tumors, as well as inflammatory diseases including asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis , inflammatory bowel syndrome, transplant rejection, eosinophilia, urticaria pigmentosa (UP), telangiectasia bullosa permanganate (TMEP), systemic mastocytosis, advanced systemic mastocytosis (AdvSM), systemic mastocytosis with hematologic neoplasm (SM-AHN), non-advanced systemic mastocytosis (NonAdvSM), indolent systemic (ISM), cutaneous mastocytosis (CM), smoldering systemic mastocytosis (SSM), aggressive systemic mast cell leukemia, mast cell sarcoma, mast cell activation syndrome (MCAS), maculopapular cutaneous mastocytosis / urticaria pigmentosa, chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), myelofibrosis, and sinonasal lymphoma. The presence of mutated forms of c-Kit has been associated with diseases or conditions such as gastrointestinal stromal tumors (GIST), mast cell leukemia, germ cell tumors, T-cell lymphoma, mastocytosis, acute lymphoblastic leukemia, and seminoma. B. Exemplary malignancies associated with c-Kit

[0168] Abnormal expression and / or activation of c-Kit and / or mutant forms of c-Kit are associated with a variety of cancers (Roskoski, 2005, Biochemical and biophysical Research Comm. 338: 1307-1315). Evidence for the contribution of c-Kit to tumor pathology includes its association with leukemia and mast cell tumors, small cell lung cancer, testicular cancer, and some cancers of the gastrointestinal tract and central nervous system. In addition, c-Kit has been implicated in carcinogenesis of the female reproductive tract (Inoue, et al., 1994, Cancer Res. 54(11): 3049-3053), sarcomas of neuroectodermal origin (Ricotti, et al., 1998, Blood 91: 2397-2405), and Schwann cell neoplasia associated with neurofibromatosis (Ryan, et al., 1994, J. Neuro. Res. 37: 415-432). Mast cells have been found to be involved in altering the tumor microenvironment and enhancing tumor growth (Yang et al., 2003, J Clin Invest. 112: 1851-1861; Viskochil, 2003, J Clin Invest. 112: 1791-1793). Therefore, c-Kit is a useful target for the treatment of neurofibromatosis and malignant tumors.

[0169] Small cell lung cancer: c-Kit kinase receptor has been found to be abnormally expressed in many small cell lung cancer (SCLC) cells (Hibi, et al., 1991, Oncogene 6:2291-2296). Therefore, as an example, inhibition of c-Kit kinase may be beneficial in the treatment of SCLC, for example, to improve the long-term survival of SCLC patients.

[0170] Leukemia: SCF binding to c-Kit protects hematopoietic stem and progenitor cells from apoptosis (Lee, et al., 1997, J. Immunol. 159: 3211-3219), thereby promoting colony formation and hematopoiesis. Expression of c-Kit is frequently observed in acute myeloid leukemia (AML) and in some cases acute lymphoblastic leukemia (ALL) (for review, see Sperling, et al., 1997, Haemat 82: 617-621; Escribano, et al., 1998, Leuk. Lymph. 30: 459-466). Although c-Kit is expressed in most AML cells, its expression does not appear to be a predictor of disease progression (Sperling, et al, 1997, Haemat 82: 617-621). However, SCF protects AML cells from apoptosis induced by chemotherapeutic agents (Hassan, et al., 1996, Acta. Hem. 95:257-262). Inhibition of c-Kit by the present disclosure will enhance the efficacy of these agents and may induce apoptosis in AML cells.

[0171] It was found that the clonal growth of cells from patients with myelodysplastic syndrome (Sawada, et al., 1996, Blood 88: 319-327) or chronic myeloid leukemia (CML) (Sawai, et al., 1996, Exp. Hem. 2: 116-122) was significantly enhanced by the combination of SCF and other cytokines. CML is characterized by the expansion of Philadelphia chromosome-positive cells in the bone marrow (Verfaillie, et al., Leuk. 1998, 12: 136-138), which seems to be mainly caused by the inhibition of apoptotic death (Jones, Curr. Opin. Onc. 1997, 9: 3-7). It has been reported that the product of the Philadelphia chromosome, p210 BCR-ABL Mediates inhibition of apoptosis (Bedi, et al., Blood 1995, 86: 1148-1158). Since both p210BCR-ABL and c-Kit inhibit apoptosis, and p62dok has been suggested to be a substrate (Carpino, et al., Cell 1997, 88: 197-204), clonal expansion mediated by these kinases may occur through a common signaling pathway. However, c-Kit has also been reported to be involved in the clonal expansion of p210BCR-ABL and p62dok. BCR-ABL c-Kit has a direct interaction with CML (Hallek, et al., Brit. J Haem. 1996, 94:5-16), suggesting that c-Kit plays a more potent pathogenic role in CML pathology. Therefore, inhibition of c-Kit could be used to treat these diseases.

[0172] Gastrointestinal cancer: Normal colorectal mucosa does not express c-Kit (Bellone, et al., 1997, J. Cell Physiol. 172: 1-11). However, c-Kit is frequently expressed in colorectal cancer (Bellone, et al., 1997, J. Cell Physiol. 172: 1-11), and an autocrine loop between SCF and c-Kit has been observed in several colon cancer cell lines (Toyota, et al., 1993, Turn Biol 14: 295-302; Lahm, et al., 1995, Cell Growth & Differ 6: 1111-1118; Bellone, et al., 1997, J. Cell Physiol. 172: 1-11). Furthermore, disruption of the autocrine loop by the use of neutralizing antibodies (Lahm, et al., 1995, Cell Growth & Differ. 6: 1111-1118) and downregulation of c-Kit and / or SCF significantly inhibited cell proliferation (Lahm, et al., 1995, Cell Growth & Differ 6: 1111-1118; Bellone, et al., 1997, J. Cell Physiol. 172: 1-11).

[0173] An SCF / c-Kit autocrine loop has been observed in gastric cancer cell lines (Turner, et al., 1992, Blood 80:374-381; Hassan, et al., 1998, Digest. Dis. Science 43:8-14), and constitutive c-Kit activation appears to be important for gastrointestinal stromal tumors (GISTs) as well. GISTs are the most common mesenchymal tumors of the digestive system. More than 90% of GISTs express c-Kit, consistent with the putative origin of these tumor cells from interstitial cells of Cajal (ICCs) (Hirota, et al., 1998, Science 279:577-580). ICCs are thought to regulate contractions of the gastrointestinal tract, and patients lacking c-Kit in their ICCs exhibit a myopathic form of chronic idiopathic intestinal pseudo-obstruction (Isozaki, et al., 1997, Amer. J. of Gast. 9 332-334). It has been observed that c-Kit expressed in GISTs from several different patients has mutations in the intracellular juxtamembrane domain, resulting in constitutive activation of c-Kit (Hirota, et al., 1998, Science 279:577-580). Therefore, inhibition of c-Kit kinase would be an effective means of treating these cancers.

[0174] Overexpression or constitutive activation of KIT mutations is implicated in and associated with gastrointestinal stromal tumors (GISTs), and most GISTs harbor oncogenic KIT receptor or PDGFRα receptor tyrosine kinase mutations (Miettinen et al., 2006, Arch Pathol Lab Med, 130:1466-1478; Fletcher et al., 2007, Current Opinion in Genetics & Development, 17:3-7; and Frost et al., 2002, Molecular Cancer Therapeutics, 1:1115-1124). Frost et al., 2002, have shown that the D816V KIT mutation confers resistance to imatinib, making other types of c-Kit inhibitors useful. Many GISTs harbor activating mutations in just one membrane region of KIT (Lux et al., 2000, American Journal Pathology, 156:795). Constitutive activation of the Kit receptor tyrosine kinase is a central pathogenic event in most GISTs and is often caused by oncogenic point mutations (Heinrich, et al. 2002, Human Pathology, 33: 484-495). Inhibition of wild-type KIT and / or certain mutant KIT isoforms with small molecule tyrosine kinase inhibitors has become the standard of care for patients with metastatic GIST (Schittenhelm, et al. 2006, Cancer Res., 66: 473-481). Therefore, inhibition of c-Kit kinase and / or mutant c-Kit kinase would be an effective means of treating GIST.

[0175] Testicular cancer: Male germ cell tumors are histologically divided into seminomas that retain germ cell characteristics and non-seminomas that may show embryonic differentiation characteristics. Both seminomas and non-seminomas are thought to begin from a pre-invasive stage called carcinoma in situ (CIS) (Murty, et al., 1998, Sem. Oncol. 25: 133-144). Both c-Kit and SCF have been reported to be required for normal gonadal development during embryogenesis (Loveland, et al., 1997, J. Endocrinol 153: 337-344). Loss of the receptor or ligand results in a lack of germ cells in the animal. In the postnatal testis, c-Kit has been found to be expressed in Leydig cells and spermatogonia, while SCF is expressed in Sertoli cells (Loveland, et al., 1997, J. Endocrinol 153: 337-344). In transgenic mice expressing the human papillomavirus 16 (HPV16) E6 and E7 oncogenes, testicular tumors develop at a high frequency from Leydig cells (Kondoh, et al., 1991, J. Virol. 65:3335-3339; Kondoh, et al., 1994, J. Urol. 152:2151-2154). These tumors express both c-Kit and SCF, and an autocrine loop can contribute to tumorigenesis associated with cellular loss of functional p53 and retinoblastoma gene products through association with E6 and E7 (Kondoh, et al., 1995, Oncogene 10:341-347) (Dyson, et al., 1989, Science 243:934-937; Werness, et al., 1990, Science 248:76-79; Scheffner, et al., 1990, Cell 63:1129-1136). Signaling mutants defective in SCF (Kondoh, et al., 1995, Oncogene 10:341-347) or c-kit (Li, et al., 1996, Canc. Res. 56:4343-4346) inhibited the formation of testicular tumors in mice expressing HPV 16 E6 and E7. Activation of c-kit kinase is critical for tumorigenesis in these animals, and thus modulation of the c-kit kinase pathway by the present disclosure will prevent or treat such conditions.

[0176] Expression of c-kit in germ cell tumors indicates that this receptor is expressed by the majority of carcinomas in situ and seminomas, but c-kit is expressed only in a minority of non-seminomas (Strohmeyer, et al., 1991, Canc. Res. 51:1811-1816; Rajpert-de Meyts, et al., 1994, Int. J. Androl. 17:85-92; Izquierdo, et al., 1995, J. Pathol. 177:253-258; Strohmeyer, et al., 1995, J. Urol. 153:511-515; Bokenmeyer, et al., 1996, J. Cancer Res. Clin. Oncol. 122:301-306; Sandlow, et al., 1996, J. Androl. 17:403-408). Therefore, inhibition of c-kit kinase offers a method for treating these diseases.

[0177] CNS cancer: SCF and c-kit are expressed throughout the CNS of developing rodents, and the expression pattern indicates a role in the growth, migration and differentiation of neuroectodermal cells. Expression of both receptors and ligands in the adult brain has also been reported (Hamel, et al., 1997, J. Neuro-Onc. 35: 327-333). Expression of c-kit has also been observed in normal human brain tissue (Tada, et al. 1994, J. Neuro 80: 1063-1073). Glioblastomas and astrocytomas define most intracranial tumors and are caused by neoplastic transformation of astrocytes (Levin, et al., 1997, Principles & Practice of Oncology: 2022-2082). Expression of c-kit has been observed in glioblastoma cell lines and tissues (Berdel, et al., 1992, Canc. Res. 52:3498-3502; Tada, et al. 1994, J. Neuro 80:1063-1073; Stanulla, et al., 1995, Act Neuropath 89:158-165).

[0178] Cohen, et al., 1994, Blood 84: 3465-3472 reported that all 14 neuroblastoma cell lines examined contained a c-kit / SCF autocrine loop, and expression of both the receptor and ligand was observed in 45% of the tumor samples examined. In two cell lines, anti-c-kit antibodies inhibited cell proliferation, indicating that the SCF / c-kit autocrine loop contributes to growth (will Cohen, et al., 1994, Blood 84: 3465-3472). Therefore, c-kit kinase inhibitors may be useful in treating these cancers. C. Exemplary Mast Cell Disorders Involving c-Kit

[0179] Overactivation of c-kit is also associated with diseases caused by an excess of mast cells. Mastocytosis is a term used to describe a heterogeneous group of diseases characterized by excessive proliferation of mast cells (Metcalfe, 1991, J. Invest. Derm 93: 2S-4S; Golkar, et al., 1997, Lancet 349: 1379-1385). It has been reported that c-kit expression is elevated on mast cells from patients with aggressive mastocytosis (Nagata, et al., 1998, Leukemia 12: 175-181).

[0180] In addition, mast cells and eosinophils represent key cells involved in allergy, inflammation and asthma (Thomas, et al., 1996, Gen. Pharmacol 27: 593-597; Metcalfe, et al., 1997, Physiol Rev 77: 1033-1079; Naclerio, et al., 1997, JAMA 278: 1842-1848; Costa, et al., 1997, JAMA 278: 1815-1822). SCF and therefore c-kit directly and indirectly regulate the activation of both mast cells and eosinophils, thereby affecting primary cells involved in allergy and asthma through multiple mechanisms. Due to this mutual regulation of mast cell and eosinophil function, and the role that SCF may play in this regulation, inhibition of c-kit may be used to treat allergy-related chronic rhinitis, inflammation and asthma.

[0181] Mastocytosis: SCF (also known as mast cell growth factor) has been reported to stimulate c-kit is necessary for the growth and development of mast cells (Hamel, et al., 1997, J. Neuro-Onc. 35: 327-333; Kitamura, et al., 1995, Int. Arch. Aller. Immunol. 107: 54-56). Mice with c-kit mutations that reduce their signaling activity exhibit significantly fewer mast cells in their skin (Tsujimura, 1996, Pathol Int 46: 933-938). Overactivation of c-kit may be associated with diseases caused by an excess of mast cells.

[0182] Mastocytosis is limited to the skin in most patients, but other organs may be involved in 15-20% of patients (Valent, 1996, Wein / Klin Wochenschr 108:385-397; Golkar, et al., 1997, Lancet 349:1379-1385). Even in patients with systemic mastocytosis, the disease ranges from having a relatively benign prognosis to aggressive mastocytosis and mast cell leukemia (Valent, 1996, Wein / Klin Wochenschr 108:385-397; Golkar, et al., 1997, Lancet 349:1379-1385). C-kit has been observed on malignant mast cells from canine mast cell tumors (London, et al., 1996, J. Compar. Pathol. 115:399-414), as well as on mast cells from patients with aggressive systemic mastocytosis (Baghestanian, et al., 1996, Leuk.: 116-122; Castells, et al., 1996, J. Aller. Clin. Immunol. 98:831-840).

[0183] SCF has been shown to be expressed on stromal cells as a membrane-bound protein, and its expression can be induced by fibrogenic growth factors such as PDGF. It has also been shown to be expressed on keratinocytes as a membrane-bound protein in normal skin. However, increased amounts of soluble SCF have been observed in the skin of patients with mastocytosis (Longley, et al., 1993, New Engl. J. Med. 328:1302-1307).

[0184] It is reported that mast cell chymotrypsin cleaves membrane-associated SCF into a soluble and biologically active form. This mast cell-mediated process can generate a feedback loop to enhance mast cell proliferation and function (Longley, et al., 1997, Proc. Natl. Acad. Sci. 94: 9017-9021) and may be important for the etiology of mastocytosis. Transgenic mice that overexpress a form of SCF that cannot be proteolytically released from keratinocytes do not develop mastocytosis, while similar animals expressing normal SCF in keratinocytes exhibit a phenotype similar to human skin mastocytosis (Kunisada, et al., 1998, J. Exp. Med. 187: 1565-1573). The formation of large amounts of soluble SCF in some patients can contribute to the pathology associated with mastocytosis, and the present disclosure can treat or prevent such conditions by regulating the interaction between SCF and c-kit kinase. Several different mutations of c-kit that result in constitutive kinase activity have been found in human and rodent mast cell tumor cell lines (Furitsu, et al., 1993, J. Clin. Invest. 92:1736-1744; Tsujimura, et al., 1994, Blood 9:2619-2626; Tsujimura, et al., 1995, Int. Arch. Aller. Immunol 106:377-385; Tsujimura, 1996, Pathol Int 46:933-938). In addition, activating mutations in the c-kit gene have been observed in peripheral mononuclear cells isolated from patients with mastocytosis and related hematological disorders (Nagata, et al., 1998, Mastocytosis Leuk 12: 175-181) and in mast cells from patients with urticaria pigmentosa and aggressive mastocytosis (Longley, et al., 1996, Nat. Gen. 12: 312-314). Therefore, inhibition of c-kit kinase would prove to have excellent therapeutic effects in the treatment of these diseases.

[0185] In some patients, activating mutations of c-kit may be the cause of the disease pathogenesis, and these patients can be treated or their disease can be prevented by regulating the interaction of SCF with c-kit kinase. It has been shown that SCF activation of c-kit prevents mast cell apoptosis, which may be critical for maintaining skin mast cell homeostasis (Iemura, et al., 1994, Amer. J. Pathol 144: 321-328; Yee, et al., 1994, J. Exp. Med. 179: 1777-1787; Mekori, et al., 1994, J. Immunol 153: 2194-2203; Mekori, et al., 1995, Int. Arch. Allergy Immunol. 107: 137-138). Inhibiting mast cell apoptosis can lead to mast cell accumulation associated with mastocytosis. Thus, the observation that c-kit activation results from overexpression of the receptor, excess formation of soluble SCF, or mutations in the c-kit gene that constitutively activate its kinase provides a rationale that inhibition of c-kit's kinase activity would reduce the number of mast cells and provide benefit to patients with mastocytosis.

[0186] For cells with activating c-kit mutations, inhibitors of c-kit were found to inhibit or even kill the cells (Ma et al., 2000, J Invest Dermatol. 114: 392-394), particularly for mutations in the regulatory region (Ma et al., 2002, Blood 99: 1741-1744). Ma et al., 2002 also showed that for mutations in the catalytic region, the inhibitors STI571 (Gleevec) and SU9529 did not inhibit the cells, making other types of c-kit inhibitors useful. Therefore, c-kit inhibitors can be used to combat wild-type c-kit as well as c-kit with mutations (e.g., activating mutations in the regulatory region and / or catalytic region).

[0187] It has been shown that mastocytosis is characterized by a pathological increase in mast cells in tissues associated with mutations in KIT (Metcalfe, 2008, Blood, 112:946-956; and Ma, et al., 2002). The D816 mutation of c-kit has been detected in patients with mastocytosis (Taylor, et al., 2001, Blood, 98:1195-1199; and Longley, et al. 1999, Proc. Natl. Acad. Sci. 96:1609-14). Inhibition of the KIT oncoprotein KITD816V with small molecule tyrosine kinase inhibitors can treat patients with systemic mastocytosis (Shah, et al., 2006, Blood, 108:286-291). Therefore, c-kit inhibitors can be used to treat patients with mastocytosis.

[0188] Asthma and Allergy: Mast cells and eosinophils represent key cells in parasitic infection, allergy, inflammation, and asthma (Thomas, et al., 1996, Gen. Pharmacol 27:593-597; Metcalfe, et al., 1997, Physiol Rev 77:1033-1079; Holgate, 1997, CIBA Found. Symp.; Naclerio, et al, 1997, JAMA 278:1842-1848; Costa, et al., 1997, JAMA 778:1815-1822). SCF has been shown to be required for mast cell development, survival, and growth (Kitamura, et al., 1995, Int. Arch. Aller. Immunol. 107:54-56; Metcalfe, et al., 1997, Physiol Rev 77:1033-1079). In addition, SCF synergizes with the eosinophil-specific regulator IL-5 to increase the development of eosinophil progenitor cells (Metcalf, et al., 1998, Proc. Natl. Acad. Sci., USA 95:6408-6412). It has also been reported that SCF induces mast cells to secrete factors that promote eosinophil survival (Okayama, et al., 1997, Int. Arch. Aller. Immunol. 114: 75-77; Okayama, et al., 1998, Eur. J. Immunol. 28: 708-715) (Kay, et al., 1997, Int. Arch. Aller. Immunol. 113: 196-199), which may contribute to chronic eosinophil-mediated inflammation (Okayama, et al., 1997, Int. Arch. Aller. Immunol. 114: 75-77; Okayama, et al., 1998, Eur. J. Immunol. 28: 708-715). In this regard, SCF directly and indirectly regulates the activation of both mast cells and eosinophils.

[0189] SCF induces the release of mediators from mast cells, triggering IgE-induced degranulation of these cells (Columbo, et al., 1992, J. Immunol 149:599-602) and sensitizing them to eosinophil-derived granular major basic protein (Furuta, et al., 1998, Blood 92:1055-1061). Factors released by activated mast cells include IL-5, GM-CSF, and TNF-α, which affect eosinophil protein secretion (Okayama, et al., 1997, Int. Arch. Aller. Immunol. 114:75-77; Okayama, et al., 1998, Eur. J. Immunol. 28:708-715). In addition to inducing histamine release from mast cells (Luckacs, et al., 1996, J. Immunol. 156:3945-3951; Hogaboam, et al., 1998, J. Immunol. 160:6166-6171), SCF also promotes mast cell production of the eotaxin chemoattractant factor, eotaxin (Hogaboam, et al., 1998, J. Immunol. 160:6166-6171) and eosinophil infiltration (Luckacs, et al., 1996, J. Immunol. 156:3945-3951).

[0190] SCF also directly affects the adhesion of both mast cells (Dastych, et al., 1994, J. Immunol. 152:213-219; Kinashi, et al., 1994, Blood 83:1033-1038) and eosinophils (Yuan, et al., 1997, J. Exp. Med. 186:313-323), which in turn regulate tissue infiltration. Thus, SCF can affect primary cells involved in allergy and asthma through multiple mechanisms. Currently, corticosteroids are the most effective treatment for chronic rhinitis and inflammation associated with allergies (Naclerio, et al., 1997, JAMA 278:1842-1848; Meltzer, 1997, Aller. 52:33-40). These agents act through a variety of mechanisms, including a reduction in circulating and infiltrating mast cells and eosinophils, and a reduction in eosinophil survival associated with inhibition of cytokine production (Meltzer, 1997, Aller. 52: 33-40). Steroids have also been reported to inhibit SCF expression in fibroblasts and resident connective tissue cells, which leads to reduced mast cell survival (Finotto, et al., 1997, J. Clin. Invest. 99 1721-1728). Due to the reciprocal regulation of mast cell and eosinophil function, and the role of SCF in this regulation, inhibition of c-kit kinase would provide a means of treating chronic rhinitis, inflammation, and asthma associated with allergic reactions.

[0191] Inflammatory arthritis (eg, rheumatoid arthritis): Because mast cells have been implicated in the arthritic process (Lee et al., 2002, Science 297:1689-1692), c-kit provides a useful target for preventing, delaying, and / or treating inflammatory arthritis (eg, rheumatoid arthritis).

[0192] Multiple sclerosis: Mast cells have been shown to play a broad role in autoimmune diseases, as demonstrated in mouse models of multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). Mast cells have been shown to be required for the full manifestation of the disease. Secor et al., 2000, J Exp Med 191:813-821. Therefore, c-kit also provides a useful target for preventing, delaying, and / or treating multiple sclerosis. VI. Methods of Treating Conditions Mediated by c-Kit Kinase

[0193] In another aspect, the present disclosure provides a method for treating a subject having or at risk of a disease or condition mediated by c-kit and / or mutant c-kit protein kinase, comprising orally administering to the subject an effective amount of a tablet disclosed herein.

[0194] In some embodiments, the mutant c-kit kinase has a mutation selected from D816F, D816H, D816N, D816Y, D816V, K642E, Y823D, Del 550-558, Del 557-561, N822K, V654A, N822H, Del 550-558+V654A, Del557-561+V654A, Ins503AY, V560G, 558NP, Del 557-558, Del W559-560, F522C, Del 579, R634W, K642E, T801I, C809G, D820Y, N822K, N822H, Y823D, Y823C, or T670I, or a combination thereof. In one embodiment, the mutant c-kit has an activating D816 mutation. In one embodiment, the mutant c-kit has an activating D816V mutation. In another embodiment, the mutant c-kit has a V560G mutation. In yet another embodiment, the mutant c-kit has activating D816V and V560G mutations. In certain embodiments, the method involves administering to a subject an effective amount of a tablet as described herein in combination with one or more other therapies for the disease or condition.

[0195] In some embodiments, the present disclosure provides a method for inhibiting the undesirable proliferation of tumor cells expressing D816 (such as D816F, D816H, D816N, D816Y or D816V) and / or V560G mutant c-kit protein kinase. The method comprises contacting tumor cells expressing D816 (e.g., D816F, D816H, D816N, D816Y or D816V) and / or V560G mutant c-kit protein kinase with an effective amount of a tablet as described herein. In some cases, the tumor cells express D816V and / or V560G mutant c-kit kinase.

[0196] In certain embodiments, the present disclosure provides a method for treating patients who are positive for c-kit protein kinase D816 (such as D816F, D816H, D816N, D816Y or D816V) and / or V560G mutations. The method comprises administering an effective amount of a tablet as described herein to a patient in need thereof. In some embodiments, the patient is positive for the D816V mutation. In other embodiments, the patient is positive for the V560G mutation. In some embodiments, the patient is positive for both D816V and V560G mutations. In some cases, the patient suffers from gastrointestinal stromal tumor (GIST) and / or mastocytosis.

[0197] In some embodiments, diseases or conditions that can be treated with the compounds of the present disclosure include, but are not limited to, multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease, seizures, and epilepsy; neoplastic diseases, including, but not limited to, melanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma, sarcoma, carcinoma (e.g., gastrointestinal cancer, liver cancer, biliary tract cancer, bile duct (cholangiocarcinoma), colorectal cancer, lung cancer, gallbladder cancer, breast cancer, pancreatic cancer, thyroid cancer, kidney cancer, ovarian cancer, adrenocortical carcinoma, prostate cancer), lymphoma (e.g., histiocytic lymphoma), neurofibromatosis, gastrointestinal stromal tumors, acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuroendocrine tumors such as medullary thyroid carcinoma, carcinoid tumor, small cell lung cancer, Kaposi's sarcoma, and pheochromocytoma; neuroendocrine tumors, including, but not limited to, glioma, glioblastoma multiforme, pilocytic astrocytoma, sarcoma, carcinoma (e.g., thyroid carcinoma), colorectal cancer, lung cancer, gallbladder cancer, breast cancer, pancreatic cancer, thyroid cancer, kidney cancer, ovarian cancer, adrenocortical carcinoma, prostate cancer), lymphoma (e.g., histiocytic lymphoma), neurofibromatosis, gastrointestinal stromal tumors, acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuroendocrine tumors such as medullary thyroid carcinoma, carcinoid tumor, small cell lung cancer, Kaposi's sarcoma, and pheochromocy Pain of an indolent or inflammatory origin, including but not limited to acute pain, chronic pain, cancer-related pain, and migraine; cardiovascular disease, including but not limited to heart failure, ischemic stroke, cardiac hypertrophy, thrombosis (e.g., thrombotic microangiopathy syndrome), atherosclerosis, and reperfusion injury; inflammatory and / or proliferative conditions, including but not limited to psoriasis, eczema, arthritis and autoimmune diseases and disorders, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic conditions, rheumatoid arthritis, inflammatory bowel disease (IBD); immunodeficiency disorders, including but not limited to organ transplant rejection, graft-versus-host disease, and HIV-associated Kaposi's sarcoma; renal, cystic, or prostate disease, including but not limited to diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostatic hyperplasia, polycystic liver disease, tuberous sclerosis, Von Hippel-Lindau disease, and inflammatory bowel disease (IBD). HippelLindau disease), medullary cystic kidney disease, renal tuberculosis, and cystic fibrosis; metabolic disorders, including but not limited to obesity; infections, including but not limited to Helicobacter pylori, hepatitis and influenza viruses, fever, HIV, and sepsis; pulmonary diseases, including but not limited to chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS); genetic developmental disorders, including but not limited to Noonan syndrome, Costello syndrome (faciocutaneous skeletal syndrome), Leopard skin syndrome, cardio-faciocutaneous syndrome (CFC), and neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair, and endocrine disorders;and diseases associated with muscle regeneration or degeneration, including, but not limited to, sarcopenia, muscular dystrophy (including, but not limited to, Duchenne muscular dystrophy, Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic muscular dystrophy, oculopharyngeal muscular dystrophy, distal and congenital muscular dystrophy), motor neuron disease (including, but not limited to, amyotrophic lateral sclerosis, infantile progressive spinal muscular atrophy, moderate spinal muscular atrophy, juvenile spinal muscular atrophy, spinal bulbar muscular atrophy, and adult spinal muscular atrophy), inflammatory myopathies (including, but not limited to, dermatomyositis, polymyositis, and inclusion body myositis), diseases of the neuromuscular junction (including, but not limited to, myasthenia gravis, Lambert-Eaton syndrome, and congenital myasthenic syndromes), myopathies due to endocrine abnormalities (including but not limited to hyperthyroid myopathy and hypothyroid myopathy), peripheral nerve diseases (including but not limited to Charcot-Marie-Tooth disease, Dejerine-Sottas disease and Friedreich's ataxia), other myopathies (including but not limited to myotonia congenita, paramyotonia congenita, central core disease, nematode myopathy, myotubular myopathy and periodic paralysis), and muscle metabolic diseases (including but not limited to phosphorylase deficiency, acid maltase deficiency, phosphofructokinase deficiency, debranching enzyme deficiency, mitochondrial myopathies, carnitine deficiency, carnitine palmitoyltransferase deficiency, phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency and myoadenylate deficiency). In one embodiment, the disease or condition is selected from melanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma, sarcoma, liver cancer, biliary tract cancer, bile duct cancer, colorectal cancer, lung cancer, gallbladder cancer, breast cancer, pancreatic cancer, thyroid cancer, kidney cancer, ovarian cancer, adrenocortical cancer, prostate cancer, histiocytic lymphoma, neurofibromatosis, gastrointestinal stromal tumor, acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, medullary thyroid carcinoma, carcinoid tumor, small cell lung cancer, Kaposi's sarcoma, pheochromocytoma, acute pain, chronic pain, and polycystic kidney disease. In a preferred embodiment, the disease or condition is selected from melanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma, colorectal cancer, thyroid cancer, lung cancer, ovarian cancer, prostate cancer, liver cancer, gallbladder cancer, gastrointestinal stromal tumor, biliary tract cancer, bile duct cancer, acute pain, chronic pain, and polycystic kidney disease.

[0198] In other embodiments, diseases or conditions that can be treated with the compounds of the present disclosure include, but are not limited to, ischemic stroke, cerebrovascular ischemia, multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, dementia, chorea, Huntington's disease, neoplastic diseases, complications of neoplastic diseases, chemotherapy-induced hypoxia, gastrointestinal stromal tumors, prostate tumors, mast cell tumors, canine mast cell tumors, acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, multiple myeloma, melanoma, mastocytosis, glioma, glioblastoma, astrocytoma, neuroblastoma, sarcoma, sarcoma of neuroectodermal origin, Leiomyosarcoma, lung cancer, breast cancer, pancreatic cancer, colon cancer, hepatocellular carcinoma, kidney cancer, female genital tract cancer, squamous cell carcinoma, carcinoma in situ, lymphoma, histiocytic lymphoma, non-Hodgkin lymphoma, MEN2 syndrome, neurofibromatosis, Schwann cell neoplasia, myelodysplastic syndrome, leukemia, tumor angiogenesis, thyroid cancer, liver cancer, bone cancer, skin cancer, brain cancer, central nervous system cancer, pancreatic cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, colon cancer, bladder cancer, prostate cancer, gastrointestinal cancer, endometrial cancer, fallopian tube cancer, testicular cancer, ovarian cancer, pain of neuropathic origin, pain of inflammatory origin, acute pain, chronic pain, migraine, cardiovascular disease, heart failure, cardiomegaly, blood Thrombosis, thrombotic microangiopathy syndrome, atherosclerosis, reperfusion injury, ischemia, cerebrovascular ischemia, hepatic ischemia, inflammation, polycystic kidney disease, age-related macular degeneration, rheumatoid arthritis, allergic rhinitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, Sjögren's syndrome, Wegener's granulomatosis, psoriasis, scleroderma, chronic thyroiditis, Graves' disease, myasthenia gravis, multiple sclerosis, osteoarthritis, endometriosis, skin scarring, tissue scarring, vascular restenosis, fibrotic disorders, eosinophilia, CNS inflammation, pancreatitis, nephritis, atopic dermatitis, hepatitis, immunodeficiency disorders, severe combined immunodeficiency, organ transplant rejection, graft-versus-host disease , kidney disease, prostate disease, diabetic nephropathy, nephrosclerosis, glomerulonephritis, interstitial nephritis, lupus nephritis, prostatic hyperplasia, chronic renal failure, tubular necrosis, diabetes-related renal complications, related renal hypertrophy, type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity, hepatic steatosis, insulin resistance, hyperglycemia, lipolytic obesity, infection, Helicobacter pylori infection, influenza virus infection, fever, sepsis, lung disease, chronic obstructive pulmonary disease, acute respiratory distress syndrome, asthma, allergies, bronchitis, emphysema, pulmonary fibrosis, genetic developmental diseases, Noonan syndrome, Cruzon syndrome, acrolein-syndactyly syndrome type I, Pfeiffer's syndrome, Jackson-Weiss syndrome,Costello syndrome, faciocutaneous skeletal syndrome, leopard skin syndrome, cardiofaciocutaneous syndrome, neural crest syndrome causing cardiovascular, skeletal, intestinal, skin, hair, or endocrine disorders, disorders of bone structure or mineralization, osteoporosis, increased risk of fractures, hypercalcemia, bone metastases, Graves' disease, Hirschsprung's disease, lymphedema, selective T-cell deficiency, X-linked agammaglobulinemia, diabetic retinopathy, alopecia, erectile dysfunction, and tuberous sclerosis.

[0199] In some embodiments, the disease is selected from mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors (GIST), metastatic GIST, glioblastoma, astrocytoma, neuroblastoma, female genital tract cancer, sarcoma of neuroectodermal origin, colorectal cancer, carcinoma in situ, Schwann cell neoplasia associated with neurofibromatosis, acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, mastocytosis, urticaria pigmentosa (UP), permanent bullous telangiectasia (TMEP), systemic mastocytosis, indolent systemic, smoldering systemic, aggressive systemic, mast cell leukemia, mast cell sarcoma melanoma, and canine mast cell tumor, and inflammatory diseases including asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, inflammatory bowel syndrome, transplant rejection, and eosinophilia. In some cases, the disease is c-kit and / or c-kit mutants, such as D816F, D816H, D816N, D816Y, D816V, K642E, Y823D, Del 550-558, Del 557-561, N822K, V654A, N822H, Del550-558+V654A, Del 557-561+V654A, Ins503AY, V560G, 558NP, Del 557-558, Del W559-560, F522C, Del In one embodiment, the disease is a disease mediated by a D816 (such as D816F, D816H, D816N, D816Y or D816V) mutant. In another embodiment, the disease is a disease mediated by a D816V mutant. In another embodiment, the disease is a disease mediated by a V560G mutant. In another embodiment, the disease is a disease mediated by a D816V and V560G mutant. In one embodiment, the disease is cancer, which is preferably selected from melanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma, colorectal cancer, thyroid cancer, lung cancer, ovarian cancer, prostate cancer, liver cancer, gallbladder cancer, gastrointestinal stromal tumors, biliary tract cancer and bile duct cancer. In one embodiment, the cancer is melanoma, colorectal cancer, thyroid cancer or lung cancer.

[0200] In some embodiments, the present disclosure provides a method for treating a disease or condition selected from the group consisting of urticaria pigmentosa (UP), telangiectasia bullosa permanganate (TMEP), systemic mastocytosis, indolent systemic mastocytosis, smoldering systemic mastocytosis, aggressive systemic mastocytosis, mast cell leukemia, mast cell sarcoma, GIST, and metastatic GIST. The method involves orally administering to a subject in need thereof an effective amount of a tablet as described herein.

[0201] In some embodiments, the present disclosure provides a method for treating any c-kit protein kinase-mediated disease or condition (including any c-kit mutant kinase-mediated disease or condition) in an animal subject in need thereof, wherein the method involves administering to the subject an effective amount of any one or more compounds as described herein. In certain embodiments, the method involves orally administering to the subject an effective amount of a tablet as described herein in combination with one or more other therapies for the disease or condition.

[0202] In some embodiments, the present disclosure provides methods for treating any of c-kit D816F, D816H, D816N, D816Y, D816V, K642E, Y823D, Del 550-558, Del 557-561, N822K, V654A, N822H, Del550-558+V654A, Del 557-561+V654A, Ins503AY, V560G, 558NP, Del 557-558, Del W559-560, F522C, Del 579, R634W, K642E, T801I, C809G, D820Y, N822K, N822H, Y823D, Y823C or T670I mutant protein kinase mediated disease or condition, wherein the method involves administering to the subject an effective amount of a tablet as described herein. In certain embodiments, the method involves administering to the subject an effective amount of a tablet as described herein in combination with one or more other therapies for the disease or condition. In some embodiments, the c-kit mutant protein kinase is a c-kit D816 (such as D816F, D816H, D816N, D816Y or D816V) mutant kinase. In one embodiment, the c-kit mutant protein kinase is a c-kit D816V mutant. In another embodiment, the c-kit mutant protein kinase is a c-kit V560G mutant. In another embodiment, the c-kit mutant protein kinase is a c-kit D816V / V560G mutant.

[0203] In some embodiments, the tablet comprising Compound (I) as described herein is a c-kit and / or mutant c-kit kinase inhibitor, and IC 50 Less than 500 nM, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a generally accepted c-kit kinase activity assay. In some embodiments, the IC of a compound as described herein relative to c-kit, c-kit D816V mutant, c-kit V560G mutant, or D816V / V560G mutant is less than 500 nM, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM, as determined in a generally accepted c-kit kinase activity assay. 50 Less than 500 nM, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM. In some embodiments, the compounds as described herein will selectively inhibit one or more mutant c-kit kinases relative to one or more other mutant c-kit kinases.

[0204] In some embodiments, the present disclosure provides a method for inhibiting c-kit mutant protein kinase, such as D816V, V560G or D816V / V560G mutant protein kinase. The method comprises contacting a tablet comprising compound (I) as described herein with cells or c-kit mutant protein kinase in vitro or in vivo.

[0205] In certain embodiments, the present disclosure provides for the preparation of a medicament for treating a disease or condition as described herein. In other embodiments, a tablet as described herein is used to treat a disease or condition as described herein.

[0206] In a specific aspect, the disease or condition treated by oral administration of the tablet of the present disclosure is acute myeloid leukemia (AML).

[0207] In a specific aspect, the disease or condition treated by oral administration of the tablet of the present disclosure is gastrointestinal stromal tumor (GIST).

[0208] In a specific aspect, the disease or condition treated by oral administration of the tablet of the present disclosure is mastocytosis.

[0209] In a specific aspect, the disease or condition treated by oral administration of the tablet of the present disclosure is advanced systemic mastocytosis (AdvSM).

[0210] In a specific aspect, the disease or condition treated by oral administration of the tablet of the present disclosure is non-advanced systemic mastocytosis (NonAdvSM).

[0211] In specific aspects, the disease or condition treated by oral administration of the tablets of the present disclosure is indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM). Example

[0212] The following examples are offered for illustrative purposes only and are not intended to limit the scope of the claims presented herein.

[0213] Example 1: Properties of Zulatinib

[0214] The chemical and physical properties of bezuratinib are provided in Table 1. Bezuratinib has a high melting point and is insoluble in aqueous and most organic solvents. No suitable salts or cocrystals have been found.

[0215] Table 1: Properties of Bezulatinib nature illustrate Molecular weight Free base: 331.38 Daltons Melting point >365℃ Polymorph crystallization Pka 2.86 (weak base) LogD 3.46 Water-soluble 0.31 μg / mL at pH 7.0

[0216] Example 2: Solubility Study

[0217] Solubility studies were performed during the development of formulations containing the active pharmaceutical ingredient (API), bezulatinib. The studies were conducted in IV fluids, organic solvents, aqueous systems, and biorelevant media. Studies were also conducted using spray-dried dispersions (SDDs).

[0218] 2.1 Solubility in biorelevant media

[0219] The solubility of bezuracinib was studied in biologically relevant media at 37°C. The biologically relevant media included 0.01N hydrochloric acid, fasting state simulated intestinal fluid (FaSSIF) with and without bile salts, simulated intestinal fluid (SIF) with various concentrations of bile salts (0, 0.5% and 1%), and fasting state simulated gastric fluid (FaSSGF). Saturated suspensions were prepared in each medium and the samples were stirred overnight using a magnetic stirrer. The free drug concentration was determined by subjecting the samples to 470,000× gravity in an ultracentrifuge for 7 minutes. 100 μL aliquots were taken and diluted 5× in DMSO and methanol and tested by the HPLC method described in Table 2. Six (6) replicates were performed in each culture medium. In all cases, bezuracinib was almost insoluble (free drug concentration ≤ 1.2 μg / mL).

[0220] Table 2: HPLC method

[0221] 2.2 Solubility in organic solvents

[0222] The solubility of bezuracinib was studied in organic solvents at 21 °C (Table 3). Saturated suspensions were prepared in each solvent and the samples were stirred overnight using a magnetic stirrer. The free drug concentration was determined by subjecting the samples to 470,000× gravity in an ultracentrifuge for 7 minutes. 100 μL aliquots were removed and diluted 5× in DMSO and methanol and tested by the HPLC method. Three (3) replicates were performed in each solvent. With the exception of DMSO (free drug concentration <20 mg / mL), bezuracinib had poor solubility (free drug concentration <5.0 mg / mL).

[0223] Table 3: Organic solvents used to determine API solubility medium acetone Acetic acid Acetonitrile DCM Ether DMF DMSO Ethyl acetate Isopropyl alcohol Methanol 2,2,2-Trifluoroethanol water ethanol 85 / 15THF / water dimethylacetamide NMP Formic acid 2-MethylTHF

[0224] 2.3 Effect of pH on solubility

[0225] The effect of pH on the solubility of bezuracinib was studied in simulated intestinal fluid containing 0.5% bile salts at 37°C, pH 4.0, 5.5 and 6.0. Saturated bezuracinib suspensions were prepared in each medium and the samples were stirred overnight using a magnetic stirrer. Total drug concentration was determined by subjecting the samples to 19,500× gravity for 3 minutes in a microcentrifuge. Free drug concentration was determined by subjecting the samples to 470,000× gravity for 7 minutes in an ultracentrifuge. 100 μL aliquots were removed and diluted 5× in DMSO and methanol and tested by HPLC method. Six (6) replicates were performed in each medium. Under all conditions, bezuracinib was poorly soluble (free drug concentration <20 μg / mL).

[0226] Example 3: Study on amorphous solid dispersion preparation

[0227] Due to the poor aqueous solubility and lipophilicity of bezulatinib, amorphous dispersion technology was investigated to improve bioavailability.

[0228] In ASD, the solubility of the drug substance is improved by disordering its crystal lattice to produce an amorphous form in a higher energy state. Through drug-polymer interactions, polymers also play a key role in improving the solubility and bioavailability of amorphous APIs. As shown below in this Example 3, many amorphous solid dispersion technologies were tried to address the known low solubility of bezulatinib in lipophilic substances. The applicant was surprised to find that specific polymers, and even polymer grades, produced unexpectedly excellent results. Polymers can stabilize ASD and prevent drug crystallization, and provide improved physical stability under various accelerated stability conditions (such as elevated temperature and relative humidity). Under this approach, the following studies were conducted.

[0229] 3.1.

[0230] is a fusion-based method for making amorphous solid dispersions ("KSD"), Ellenberger et al. (AAPS PharmSciTech, 2018), which is incorporated herein by reference. The method is applied to API in an effort to produce optimal amorphous solid dispersions. technology, using API for initial polymer screening, such as Figure 1 Hydroxypropyl methylcellulose (HPMC) and hypromellose acetate succinate (HPMCAS) polymers were found to be promising, although several polymers appeared to perform well in vitro.

[0231] The system was designed and manufactured by DisperSol Technologies LLC (Georgetown, TX, USA). Bezulatinib KSD was prepared using a small-scale compounder (Formulator II) and a large-scale compounder (batch compounder, GMP Gen 1 continuous / batch compounder). Prior to compounding, the API and polymer / oligomer excipients were accurately weighed and blended to prepare a physical mixture (PM). These physical mixtures were loaded into Inside the compounder chamber, a shaft with protruding blades rotates at varying incremental speeds without the addition of external heat, applying friction and shear forces to the sample material. An infrared probe monitors the material temperature. When the molten material reaches the target temperature, it is quickly ejected, collected, and pressed between two stainless steel plates to rapidly quench the sample. The setpoint range is 3,000 rpm to 7,2000 rpm, and the setpoint temperature range is 180°C to 250°C.

[0232] The samples were ground using a laboratory-scale rotor mill (i.e., IKA Tube Mill 100 (IKA Works GmbH & Co. KG, Staufen, Germany)). The quenched material obtained after treatment. For grinding, the fragments of the quenched material are loaded into a 20 mL grinding chamber, which is operated at a grinding speed of 10,000 to 20,000 rpm for 30-60 s. The ground material is then passed through a #60 mesh sieve (≤250 μm). With the same parameters, the material retained above the sieve (i.e., >250 μm) is circulated through the grinder. The grinding and sieving process is repeated until all the material passes through the sieve. The resulting material (<250 μm) is labeled KSD.

[0233] Four batches of formulations (polymer (% w / w): HPMCAS-LMP (85); HPMCAS-LMP (80); HPMCAS-LMP (5); and HPMC E5 (68)) were selected to complete stability studies. The formulations were found to be physically and chemically stable under accelerated conditions for four weeks when in closed packaging. Animal studies in rats and dogs showed that the HPMCAS E5 and HPMCAS LMP based formulations provided increased bioavailability compared to other formulations (including spray dried solid dispersions used as controls). However, low levels of impurities and greater than 2% total impurities were formed during processing. In addition, the appearance of the dispersions was dark, indicating that possible polymer degradation was observed. Therefore, the formulations were abandoned. method.

[0234] 3.2. Microprecipitated Bulk Powder (“MBP”)

[0235] MBP is a solvent-controlled coprecipitation method in which the API is dissolved in DMSO along with the polymer and then precipitated in an antisolvent (acidified cold water) to produce a polymer-stabilized amorphous solid dispersion. Methods for preparing samples for this MBP process can be found in Shah, et al. (Journal of Pharmaceutical Sciences, Vol. 102, No. 3, 2013) and US 9,447,089 B2, which are incorporated herein by reference.

[0236] As shown in Table 4, MBP samples were prepared using two grades of HPMCAS polymer at 20% and 15% drug loading. The API polymer solution to antisolvent ratio was 1:10, the antisolvent pH was 2.5, and the antisolvent temperature was 2-5°C. The precipitate was collected and washed once with chilled antisolvent, then washed with chilled purified water, and then dried at 30°C. X-ray powder diffraction (XRPD) was used to analyze the MPB samples.

[0237] A crystalline peak associated with the API was present in each MBP sample. After storage for 1 week at 40°C and 75% relative humidity, the intensity of the crystalline peak in the MBP samples increased under these storage conditions. Therefore, the MBP approach was abandoned because a completely amorphous dispersion could not be achieved.

[0238] Table 4: Formulations used for the MBP method

[0239] 3.3. Thermal Processing Spray Drying

[0240] The spray drying process is disclosed in WO 2010 / 111132 A2, which is incorporated herein by reference. In this study, a "hot process" spray drying technique was used, in which the feed suspension was fed through a heat exchanger to dissolve the drug in a pressurized line in order to increase the solubility of the active substance before entering the drying chamber.

[0241] API-SDD prototype fabrication involved the following polymers and drug loadings for this study, including 10% drug-loaded HPMCAS-L, -H; 20% drug-loaded HPMCAS-H; 30% drug-loaded HPMCAS-L, -H; 30% drug-loaded PVPVA64; and 20% drug-loaded HPMCP.

[0242] All SDD from this thermal process showed partial crystallinity by XRPD. The chemical stability of the thermal process SDD was assessed by HPLC. The efficacy of most SDD was off-target due to manufacturing issues where the API precipitated and was captured in the in-line filter. Low levels of impurities (<0.16) were formed during the thermal process spray drying. Due to manufacturing issues with precipitation in the process, thermal process spray drying was abandoned.

[0243] Spray drying

[0244] Screening methods for developing spray-dried amorphous solid dispersions have been evaluated in Duarte, et al., Pharm Res (2015) 32: 222-237, the entire contents of which are incorporated herein by reference. Spray-dried dispersions (SDDs) of low-solubility drugs prepared using the polymer hydroxypropyl methylcellulose acetate succinate (HPMCAS) have been described in Friesen, et al., Molecular Pharmaceutics, 2008, Vol. 5, No. 6, 1003-1019, the entire contents of which are incorporated herein by reference. The interaction between the preparation method, formulation parameters, physical structure and performance of solid dispersions regarding stability and drug release characteristics has been studied in Paudel, et al., Int. J. Pharmaceutics, 2013, 453, 253-284, the entire contents of which are incorporated herein by reference. The level of complexity that can be achieved in the field of particle engineering by spray drying is described in Vehring, Pharmaceutical Research, 2008, Vol. 25, the entire contents of which are incorporated herein by reference.

[0245] A method for preparing uniform spray-dried solid amorphous dispersions of drugs using a pressure nozzle is disclosed in US Pat. No. 7,780,988 B2, the entire contents of which are incorporated herein by reference.

[0246] Methods and compositions for improving the bioavailability of active agents and achieving rapid dissolution of drugs from spray-dried dispersions in capsules are disclosed in US 2018 / 0161269 A1, the entire contents of which are incorporated herein by reference.

[0247] A spray drying process is disclosed in WO 2019 / 162688 A1, which is incorporated herein by reference in its entirety, and is characterized by the continuous preparation and immediate spray drying of a solution comprising an API, an excipient, and a solvent.

[0248] US Patent No. 8,216,495 B2, the entire contents of which are incorporated herein by reference, discloses the preparation of poorly soluble drugs in solid dispersions by spray drying.

[0249] A spray drying process for forming a pharmaceutical composition comprising a solid amorphous dispersion of a low solubility drug and a polymer is disclosed in US 2005 / 0031692 A1, the entire contents of which are incorporated herein by reference.

[0250] Due to the limited solubility of the API in volatile organic solvents, a THF and water solvent system was used to prepare the spray dried dispersions (SDDs).

[0251] API-SDD prototypes were fabricated using the following polymers and drug loadings for this study: 10% drug-loaded HPMCAS-L, -H; 15% drug-loaded HPMCAS-H; 20% drug-loaded HPMCAS-L, -M, -H; 20% drug-loaded CAP; 20% drug-loaded Eudagrit L100; and 20% drug-loaded HPMCP. SDD samples were examined by XRPD at a scan rate of 2° / min from 3 to 40 2θ. For the 20% drug-loaded composition, all SDDs appeared amorphous by XRPD.

[0252] 3.4.1. Non-sink dissolution test

[0253] Non-sink dissolution testing is used to determine the kinetic solubility of amorphous dispersions and the degree and duration of supersaturation. Figure 2-5 Spray-dried samples were examined under non-sink dissolution testing conditions in . Non-sink testing was performed in biorelevant media, including simulated intestinal fluid at pH 6.5 and FaSSIF at pH 6.5, at various bile salt concentrations with and without gastric diversion. Total and free drug concentrations were determined as described in Example 2.

[0254] Figure 2-5Determinations from non-sink dissolution testing are shown. Generally speaking, HPMCAS performed best in non-sink dissolution testing. Grade H maintained free drug to a greater extent than other polymers. The results also show that 10% drug loading outperformed 20% drug loading. In terms of free drug retention, 20% HPMCAS-H SDD outperformed 10% HPMCAS-LSDD. Physical mixing of HPMCAS-H with 20% HPMCAS-L SDD had no effect.

[0255] Figure 2 Shown are the results of non-sink total drug dissolution testing of SDD samples compared to a crystalline API in simulated intestinal fluid with 0.5% bile salts at pH 6.5 and 37°C. Samples were loaded at a concentration of 1 mg API / mL medium. The SDDs tested were 10% and 20% drug-loaded HPMCAS-L SDDs, 20% HPMCAS-H, and 20% HPMCAS-L, with the addition of 5 mg / mL HPMCAS-H.

[0256] Figure 3 Shown are the results of non-sink drug dissolution testing of SDD samples compared to a crystalline API in simulated intestinal fluid with 0.5% bile salts at pH 6.5 and 37°C. Samples were loaded at a concentration of 1 mg API / mL medium. The SDDs tested were 10% and 20% drug-loaded HPMCAS-L SDDs, 20% HPMCAS-H, and 20% HPMCAS-L, with the addition of 5 mg / mL HPMCAS-H.

[0257] The total drug (determined by microcentrifugation) and free drug (determined by ultracentrifugation) concentrations are shown in Table 5.

[0258] Table 5: Preparations used for microcentrifugation and ultracentrifugation assays

[0259] All SDDs outperformed the crystalline API in terms of total and free drug. At 10% drug loading in HPMCAS-L, total and free drug concentrations were higher than those of the 20% loaded SDD within 60 minutes. However, at the 6-hour time point, 20% HPMCAS-H produced the highest total and free drug concentrations. 20% HPMCAS-H also produced the highest area under the curve for free drug concentration, while 10% HPMCAS-L produced the highest area under the curve for total drug concentration.

[0260] Figure 4Results of non-leaky, total drug dissolution testing of SDD samples loaded with 10%, 15%, and 20% drug at 37°C are shown. Samples were loaded at a concentration of 3 mg API / mL in 0.01N HCl (pH 2) for 30 minutes and then diluted to 1 mg API / mL in simulated intestinal fluid (pH 6.5) containing 0.224% bile salts. Total drug concentrations at the 60-minute time point are presented in Table 6.

[0261] Figure 5 Shown are the results of non-leaky, free drug dissolution testing of SDD samples loaded with 10%, 15% and 20% drug for gastric transit at 37° C. The free drug concentrations and total concentrations at the 60 minute time point are given in Table 6.

[0262] Table 6: SDD preparations for microcentrifugation and ultracentrifugation assays

[0263] The results from Table 6 indicate that all HPMCAS-H SDDs showed significant improvements in free drug and maintenance compared to HPMCAS-L SDD. The 15% API-85% HPMCAS-H SDD appeared to perform as well as the 10% API-90% HPMCAS-H SDD, and both outperformed the 20% API-80% HPMCAS-H SDD.

[0264] 10% API-90% HPMCAS-L SDD formed colloids and the free drug values ​​indicated that precipitation had occurred. 15% and 20% API-HPMCAS-L SDD formed very little colloids and had poor supersaturation maintenance.

[0265] 3.4.2.4 Week Stability Test

[0266] SDD samples were placed in open containers at 40°C and 75% relative humidity, and in closed containers at ambient humidity at 40°C to evaluate their physical stability by XRPD and their glass transition temperature by differential scanning calorimetry (DSC). The chemical stability of SDD was evaluated by HPLC.

[0267] HPMCAS-H and HPMCAS-L SDD samples were analyzed by XRPD to confirm that they were amorphous prior to stability studies. After 4 weeks of exposure to these conditions in a closed container, very slight crystallinity was observed in the 20% API 80% HPMCAS-L formulation. All other SDDs appeared to have no crystals observed by XRPD.

[0268] After four weeks of exposure to these conditions in an open container, samples with 15% and 20% drug loading were found to have crystal formation. Crystals appeared absent from the two SDDs with 10% drug loading. The 20% API 80% HPMCAS-L SDD appeared to have more pronounced crystallization than the 20% API 80% HPMCAS-H SDD.

[0269] Glass transition temperatures were measured using modulated differential scanning calorimetry (3°C / min ramp from 25-375°C, adjusted at 1°C / min). mDSC analysis was performed on the SDD from the stability study. All formulations exhibited changes in glass transition temperature, indicating that physical changes occurred under these conditions. The chemical stability and impurities of the SDD were analyzed by HPLC. Minimal impurity growth was observed in the HPMCAS-H batch after 4 weeks under stability conditions. More impurity growth was observed in the HPMCAS-L batch compared to the HPMCAS-H batch, and impurities increased with increasing drug load.

[0270] Example 4: Evaluation of SDD and KSD Amorphous Solid Dispersions (ASD) in Rats

[0271] As described below, SDD and KSD amorphous solid dispersions (ASD) were evaluated in a single-dose pharmacokinetic study in male Sprague Dawley rats. Six rats were administered an amorphous dispersion in 0.5% methylcellulose (Methocel A4M) in water by oral gavage at a dose of 100 mg / kg. At the start of dosing, the rats were 8 to 14 weeks old and weighed 275 to 325 grams. The animals were fasted overnight before oral dosing and then fed ~4 hours after dosing. Water was available ad libitum, and each animal was acclimated to its laboratory environment for a minimum of one day before the study.

[0272] Serial blood samples (approximately 0.3 ml each) were obtained from each animal via jugular vein catheter at the following time points: pre-dose and 2, 4, 6, 8, and 24 hours post-dose.

[0273] The area under the curve (AUC) and C for SDD and KSD formulations are provided in Table 7. max For all amorphous dispersions, 10% HPMCAS-L KSD produced the highest AUC and C max Among the SDDs, 10% HPMCAS-H SDD produced the highest AUC and C max .

[0274] Table 7: Summary of Rat TK Data - SDD and KSD Amorphous Solid Dispersions

[0275] Example 5: Development of tablet formulation

[0276] Tablets containing API are manufactured by roller compaction / dry granulation (RCDG) process. Arndt et al. studied the effect of binder properties on dry granules and tablets in PowderTech.2018, 337, 68-77, the entire contents of which are incorporated herein by reference. Herting et al., Pharmaceutical Devel.and Tech.2007, 12: 5, 525-532 evaluated the suitability of different dry binders for roller compaction / dry granulation, the entire contents of which are incorporated herein by reference. Herting et al., International J. of Pharmaceutics 2007, 338, 110-118 studied the effect of raw material particle size on granule and tablet properties, the entire contents of which are incorporated herein by reference. The compaction behavior of dry granulation binary mixtures was studied by Gandarillas et al., Powder Tech.2015, 285, 62-67, the entire contents of which are incorporated herein by reference.

[0277] Direct compression failed to produce quality tablets due to low drug load in SDD.Wet granulation is generally not used for amorphous dispersions as it causes recrystallization.

[0278] Tablets were formulated using 2 different methods. Tablets developed by method A resulted in Formulation A. Tablets developed by method B resulted in Formulation B.

[0279] 5.1. Tablet Formulation: Method A - Formulation A

[0280] After spray drying using HPMCAS-L as the polymer, HPMCAS-L SDD was blended with colloidal silicon dioxide and magnesium stearate. The blend was roller compacted to form granules. The granules were mixed with copovidone, crospovidone, croscarmellose sodium, mannitol, sodium lauryl sulfate, poloxamer 407, sodium chloride, and sodium bicarbonate.

[0281] The blend was lubricated with additional magnesium stearate and compressed into tablets with a target weight of 950.1 mg and containing 50 mg of API. The uncoated tablet compositions are provided in Table 8 and Figure 6 A process flow diagram is provided in .

[0282] Table 8: Tablet Formulation A - 50 mg Dose

[0283] As described below, Method A and its formulation were abandoned after analysis of human pharmacokinetic data compared to the formulation obtained by Method B.

[0284] 5.2. Tablet Formulation: Method B - Formulation B

[0285] After spray drying using HPMCAS-H as the polymer, HPMCAS-H SDD was blended with microcrystalline cellulose, mannitol, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate.

[0286] The blend was roller compacted to form granules. The granules were mixed with croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate. The blend was compressed into tablets with a target weight of 715 mg containing 50 mg of API and tablets with a target weight of 1,072.5 mg containing 75 mg of API. The uncoated tablet compositions are provided in Tables 9 and 10, and the process flow diagram is provided in Figure 6 middle.

[0287] Table 9: Tablet Formulation B - 50 mg Dose

[0288] Table 10: Tablet Formulation B - 75 mg Dosage

[0289] Example 6: Evaluation of Formulation B in Non-Human Primates (NHPs)

[0290] SDD and KSD amorphous dispersions were formulated into tablets as Formulation B and evaluated in a single-dose pharmacokinetic study in non-human primates (cynomolgus monkeys). For each composition, three monkeys were administered tablets at doses of 25-50 mg / kg.

[0291] Animals were fasted for 2 hours before oral administration and then fed approximately 2 hours after administration. Water was available ad libitum. Serial blood samples (approximately 0.5 ml each) were obtained from each animal by direct venipuncture through the femoral vein, saphenous vein, or other available vein at the following time points: before administration and 2, 4, 6, 8, and 24 hours after administration. The results are presented in Table 11.

[0292] Table 11: Summary of Non-Human Primate TK Data - SDD and KSD Amorphous Dispersions

[0293] Figure 7Shown are the plasma concentration-time profiles of tablets prepared with SDD and KSD amorphous dispersions in nonhuman primates.

[0294] Figure 8 Shown are the areas under the curve for tablets prepared with SDD and KSD amorphous dispersions in nonhuman primates.

[0295] For all amorphous dispersions, 10% HPMCAS-L KSD produced the highest AUC / dose and C max Among the SDDs, 10% HPMCAS-H SDD produced the highest AUC and C max Lower bezuratinib exposure was observed in the SDDs with 15% and 20% drug loading compared to the SDD with 10% drug loading.

[0296] Example 7: Evaluation of Formulations A and B in Humans

[0297] This example summarizes a single-center, open-label, phase 2, randomized, crossover study of bezulatinib formulations A and B at single ascending dose levels in healthy adult subjects to evaluate pharmacokinetics and relative bioavailability. Subjects were randomized to receive a single dose of fasting formulation A or a single dose of fasting formulation B. After a 21-day washout period, subjects then crossed over to receive the other formulation. 30 subjects (10 / group) received single oral doses of formulations A and B of 50 mg (group 1), 300 mg (group 2), and 600 mg (group 3). Subsequently, a 1,000 mg dose of formulation A was administered. Blood was drawn before and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, 120, 144, 168, 192, and 336 h after administration.

[0298] Figure 9 Shown are the plasma concentration-time profiles for Formulations A and B over 336 hours.

[0299] Figure 10 The plasma concentration time profiles for Formulations A and B over 24 hours are shown.

[0300] Figure 11 Comparison of formulations A and B max .

[0301] Figure 12 The area under the curve (AUC) of Formulations A and B were compared.

[0302] Figure 13 Comparison of formulations A and B max and geometric means and 90% confidence intervals for the areas under the curves.

[0303] A summary of the pharmacokinetic data is provided in Table 12.

[0304] Table 12: Summary of Single-Dose Steady-State PK Data

[0305] Bezulatinib is slowly absorbed after oral administration, with a median time to maximum concentration of 12 to 16 hours after dosing. Subsequently, plasma concentrations decline in a monophasic manner with an elimination period of t 1 / 2 It ranges from 48.6 to 71.4 hours.

[0306] Across the dose range of 50 mg to 600 mg, higher bezuracinib exposure and faster absorption were observed with Formulation B compared to Formulation A, and the difference in exposure between the two formulations increased with dose. The geometric mean ratios (GMRs) of Formulation B / Formulation A at 50 mg, 300 mg, and 600 mg were 0.1% and 0.2%, respectively, for C and C, respectively. max are 1.23, 1.37, and 1.80, and for AUC 0-∞ They are 1.09, 1.24 and 1.35.

[0307] After a single dose of 600 mg of Formulation B, compared to 1000 mg of Formulation A with GMR (which is max is 1.26 and for AUC 0-∞ 1.10) compared to bezulatinib C max Slightly higher, while AUC 0-∞ quite.

[0308] Both formulations were well tolerated across dose levels, without any clinically significant AEs or SAEs. All AEs were low grade and reversible.

[0309] As shown in this example, Formulation B delivered more drug product (as measured by maximum plasma concentration and AUC), and it did so in a dose-dependent manner. Similar results have been demonstrated in previous examples for SDD formulations with HPMCAS-H, but surprisingly without HPMCAS-L, in rats and non-human primates. These results led to the selection of Formulation B for further study in combination therapy.

[0310] Example 8: Evaluation of Formulation B co-administered with sunitinib malate in humans

[0311] In a randomized, open-label, multicenter clinical study, bezulatinib formulation B was co-administered with sunitinib malate in humans with GIST. Fourteen (14) patients received histologically confirmed gastrointestinal stromal tumor (GIST) with at least one measurable lesion that was locally advanced, unresectable, or metastatic according to mRECIST v1.1, and documented disease progression on imatinib or intolerance to imatinib. Patients received a 600 mg dose of bezulatinib formulation B once daily with a 37.5 mg dose of sunitinib malate until steady state. A summary of the pharmacokinetic data is provided in Table 13.

[0312] Table 13: Summary of Single-Dose Steady-State PK Data

[0313] Surprisingly, the exposure and absorption to steady state of 600 mg bezuratinib Formulation B co-administered with 37.5 mg sunitinib malate were significantly higher than a single 600 mg dose of bezuratinib Formulation B. This synergistic effect has not been previously observed with other formulations of bezuratinib co-administered with sunitinib malate.

[0314] Products

[0315] The article of manufacture comprises a combination of a container for holding tablets suitable for oral administration of Compound (I) and a printed label instruction that provides a discussion about when a particular dosage form should be administered with food and when it should be taken on an empty stomach. The tablets will be contained in any suitable container capable of holding and dispensing.

[0316] The label and instructions will be consistent with the treatment methods described above. The label can be associated with the container by any means that maintains physical proximity of the two, as non-limiting examples, they can both be contained within packaging material (such as a box or plastic shrink wrap), or can be associated with instructions that are adhered to the container, such as with glue or other adhesive or retaining means that does not obscure the label and instructions.

[0317] Although the present invention has been described by discussing its embodiments and non-limiting examples, a person skilled in the art may envision other embodiments and variations that are also within the intended scope of the present invention when reading the specification and claims, and the scope of the present invention should therefore be interpreted and limited only by the scope of the appended claims.

[0318] equivalent

[0319] It should be understood that although the present disclosure has been described in conjunction with the detailed description of the present disclosure, the foregoing description is intended to illustrate rather than limit the scope of the present disclosure, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the appended claims.

Claims

1. A spray-dried solid dispersion comprising: (a) 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (Compound (I)), (b) a pharmaceutically acceptable polymer, and The 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (Compound (I)) is dispersed in a polymer matrix formed by the pharmaceutically acceptable polymer.

2. The spray-dried dispersion of claim 1, wherein the 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (Compound (I)) is in amorphous form.

3. The spray-dried dispersion of claim 1, wherein the 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (Compound (I)) is in the free base form.

4. The spray-dried solid dispersion of claim 1, wherein the pharmaceutically acceptable polymer is hypromellose acetate succinate grade H (HPMCAS-H).

5. The spray-dried solid dispersion of claim 1, wherein the spray-dried solid dispersion comprises at least about 1 wt% to at least about 25 wt% of 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (Compound (I)).

6. The spray-dried solid dispersion of claim 1, wherein the spray-dried solid dispersion comprises at least about 75% by weight to at least about 99% by weight of the pharmaceutically acceptable polymer.

7. The spray-dried solid dispersion of claim 1, wherein the weight ratio of the 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (Compound (I)) to the pharmaceutically acceptable polymer is from about 1:3 to about 1:

99.

8. The spray-dried solid dispersion of claim 1, further comprising a solvent.

9. The spray-dried solid dispersion of claim 1, wherein the solvent is a combination of water and tetrahydrofuran.

10. The spray-dried solid dispersion of claim 9, wherein the volume ratio of water to tetrahydrofuran is from about 1:2 to about 1:

99.

11. A tablet comprising: The spray-dried solid dispersion according to any one of claims 1 to 10, and One or more pharmaceutically acceptable ingredients selected from one or more binders, one or more buffers, one or more diluents, one or more disintegrants, one or more fillers, one or more film coatings, one or more lubricants, one or more glidants and one or more surfactants.

12. The tablet of claim 11, wherein the one or more pharmaceutically acceptable ingredients comprise colloidal silicon dioxide, croscarmellose sodium, sodium stearyl fumarate, mannitol, and microcrystalline cellulose.

13. A tablet comprising: 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (Compound (I)), dispersed in a polymer matrix formed of the pharmaceutically acceptable polymer, and One or more pharmaceutically acceptable ingredients selected from one or more binders, one or more buffers, one or more diluents, one or more disintegrants, one or more fillers, one or more film coatings, one or more lubricants, one or more glidants and one or more surfactants.

14. The tablet according to claim 13, wherein the 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (Compound (I)) dispersed in the polymer matrix formed by the pharmaceutically acceptable polymer is a spray-dried solid dispersion.

15. The tablet according to claim 13, wherein the 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (Compound (I)) is in an amorphous form.

16. The tablet according to claim 13, wherein the 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (Compound (I)) is in the form of a free base.

17. The tablet of claim 13, wherein the pharmaceutically acceptable polymer is hypromellose acetate succinate grade H (HPMCAS-H).

18. The tablet of claim 13, wherein the one or more pharmaceutically acceptable ingredients comprise colloidal silicon dioxide, croscarmellose sodium, sodium stearyl fumarate, mannitol, and microcrystalline cellulose.

19. The tablet of claim 13, wherein the tablet comprises at least about 1% by weight to at least about 20% by weight of 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (Compound (I)).

20. The tablet of claim 13, wherein the tablet comprises at least about 10% by weight to at least about 90% by weight of the pharmaceutically acceptable polymer.

21. The tablet of claim 13, wherein the tablet comprises at least about 3% by weight to at least about 65% by weight of the one or more pharmaceutically acceptable ingredients selected from one or more binders, one or more buffers, one or more diluents, one or more disintegrants, one or more fillers, one or more lubricants, one or more glidants, and one or more surfactants.

22. A tablet comprising: at least about 1 wt% to at least about 20 wt% of 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (Compound (I)), at least about 10 weight percent to at least about 90 weight percent of hypromellose acetate succinate grade H (HPMCAS-H), and at least about 3% by weight to at least about 65% by weight of the one or more pharmaceutically acceptable ingredients selected from one or more binders, one or more buffers, one or more diluents, one or more disintegrants, one or more fillers, one or more lubricants, one or more glidants, and one or more surfactants.

23. A method of treating a subject having a disease or condition selected from the group consisting of acute myeloid leukemia (AML), gastrointestinal stromal tumor (GIST), mast cell leukemia (MCL), and mastocytosis, the method comprising orally administering to the subject a tablet according to any one of claims 11 to 22.

24. The method of claim 23, further comprising administering to the subject a therapeutic agent in combination with the tablet.

25. The method of claim 24, wherein the therapeutic agent is sunitinib malate.

26. The method of claim 23, wherein the disease or condition is acute myeloid leukemia (AML).

27. The method of claim 23, wherein the disease or condition is gastrointestinal stromal tumor (GIST).

28. The method of claim 23, wherein the disease or disorder is mastocytosis.

29. The method of claim 28, wherein the mastocytosis is advanced systemic mastocytosis (AdvSM).

30. The method of claim 28, wherein the mastocytosis is non-advanced systemic mastocytosis (NonAdvSM).

31. The method of claim 28, wherein the mastocytosis is indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM).

32. The method of claim 23, wherein the tablet is taken once daily.

33. The method of claim 23, wherein the tablet is taken twice daily.

34. The method of claim 23, wherein the tablets are taken continuously in 28-day cycles.

35. The method of claim 23, wherein the single-dose target area under the curve (AUC) is 500 to 80,000 (ng.h / mL).

36. The method of claim 23, wherein the single dose maximum plasma concentration (C max ) is 100 to 800 (ng / mL).

37. The method of claim 25, wherein the once daily steady-state target area under the curve (AUC) is 30,000 to 50,000 (ng.h / mL) when a 600 mg dose of bezulatinib is co-administered with 37.5 mg of sunitinib malate.

38. The method of claim 25, wherein when a 600 mg dose of bezulatinib is co-administered with 37.5 mg of sunitinib malate, the maximum plasma concentration (C max ) is 1,500 to 2,500 (ng / mL).

Images