Bezucrastinib formulation

Abstract

The present disclosure relates to formulations of bezucrastinib, methods of making such formulations, and methods of using such formulations in the treatment of conditions, diseases, or disorders that benefit from modulation of c-Kit protein kinase and / or mutant c-kit protein kinase. 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 from the pharmaceutically acceptable polymer.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 476,812, filed December 22, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present disclosure relates to novel dosage forms containing 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 the ability to increase dosage. [Background technology]

[0003] background Receptor protein tyrosine kinases (RPTKs) regulate key signaling cascades that control cell growth and proliferation. The stem cell factor (SCF) receptor C-Kit is a type III transmembrane RPTK containing five extracellular immunoglobulin (IG) domains, a single transmembrane domain, and a split cytoplasmic kinase domain separated by a kinase insert segment. 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 have been implicated in various pathological conditions (Roskoski, 2005, Biochemical and Biophysical Research Comm. 338:1307-1315). For example, evidence for the contribution of c-Kit to neoplastic 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. Furthermore, c-Kit has been implicated in playing a role in the carcinogenesis of female genital tract sarcomas of neuroectodermal origin and Schwann cell neoplasms associated with neurofibromatosis. Mast cells have been found to be involved in modifying 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). Therefore, pharmaceutical formulations containing c-Kit inhibitors would be of high therapeutic value in treating patients suffering from diseases or conditions such as acute myeloid leukemia (AML), gastrointestinal stromal tumor (GIST), mast cell leukemia (MCL), and mastocytosis. Because oral drug delivery is a common route of administration due to its versatility, ease of administration, and patient compliance, oral formulations of c-Kit inhibitors are urgently needed. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Roskoski,2005,Biochemical and Biophysical Research Comm.338:1307-1315 [Non-patent document 2] ang et al.,J Clin Invest.2003,112:1851-1861 [Non-patent document 3] Viskochil, J Clin Invest.2003,112:1791-1793 Summary of the Invention

[0006] A brief overview 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 from the pharmaceutically acceptable polymer.

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

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

[0010] In one embodiment of the present disclosure, Compound (I) is in amorphous form.

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

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

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

[0014] In an embodiment of the present disclosure, the spray-dried solid dispersion comprises at least about 1% to at least about 25% by weight of Compound (I).

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

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

[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 about 1:2 to about 1:99.

[0018] The present disclosure also relates to a tablet comprising one or more pharmaceutically acceptable ingredients selected from the group consisting of a spray-dried solid dispersion comprising Compound (I) and a pharmaceutically acceptable polymer (wherein Compound (I) is dispersed in a polymer matrix formed from the pharmaceutically acceptable polymer), one or more binders, one or more buffering agents, 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 polymeric matrix formed from a pharmaceutically acceptable polymer, and one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more binders, one or more buffering agents, 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 tablets of the present disclosure, Compound (I) dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer is a spray-dried solid dispersion.

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

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

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

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

[0026] In an embodiment of the present disclosure, the tablet comprises at least about 3% to at least about 65% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more binders, one or more buffering agents, 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 embodiment, the tablet of the present disclosure comprises at least about 1% to at least about 20% by weight of Compound (I), at least about 10% to at least about 90% by weight of hydroxypropyl methylcellulose acetate succinate grade H (HPMCAS-H), and at least about 3% to at least about 65% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more binders, one or more buffering agents, 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 suffering from a disease or condition comprising orally administering to the subject a tablet disclosed herein.

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

[0030] In an embodiment 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 tumor (GIST), and mastocytosis.

[0031] In an embodiment of the present disclosure, the mastocytosis treated by oral administration of the tablets disclosed herein are progressive systemic mastocytosis (AdvSM), non-progressive 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 in a 28-day cycle.

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

[0034] In yet another aspect, the methods of the disclosure provide a method for administering a medicament for the treatment of a subject with ... max ) results.

[0035] In embodiments of the disclosed methods, 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 when a 600 mg dose of bezucrastinib is co-administered with 37.5 mg of sunitinib malate.

[0036] In other aspects of the disclosed methods, once-daily maximum steady-state plasma concentration (C max ) is 1,500 to 2,500 (ng / mL) in increments of 500 ng.h / mL when a 600 mg dose of bezucrastinib is coadministered with 37.5 mg of sunitinib malate. BRIEF DESCRIPTION OF THE DRAWINGS [Brief explanation of the drawings]

[0037] [Figure 1] FIG. 1 is a chart showing polymer screening with API using KinetiSol® technology.

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

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

[0040] [Figure 4] FIG. 4 is a plot showing non-sink total drug dissolution test results for 10%, 15%, and 20% drug-loaded SDD samples using gastric transit at 37° C.

[0041] [Figure 5] FIG. 5 is a plot showing non-sink free drug dissolution test results for 10%, 15% and 20% drug loaded SDD samples using gastric transit at 37° C.

[0042] [Figure 6] FIG. 6 is a process flow diagram showing steps towards the preparation of Formulations A and B.

[0043] [Figure 7] FIG. 7 shows the plasma concentration time curves of tablets made with SDD and KSD amorphous dispersions in non-human primates.

[0044] [Figure 8] FIG. 8 shows the area under the curve for tablets made with SDD and KSD amorphous dispersions in non-human primates.

[0045] [Figure 9] FIG. 9 shows the plasma concentration time curves of Formulations A and B at different doses over a 336 hour period.

[0046] [Figure 10] FIG. 10 shows the plasma concentration time curves of Formulations A and B at different doses over a 24-hour period.

[0047] [Figure 11] Figure 11 compares the Cmax of Formulations A and B at different doses.

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

[0049] [Figure 13] Figure 13 compares the geometric means and 90% confidence intervals for Cmax and area under the curve for Formulations A and B at different doses. DETAILED DESCRIPTION OF THE INVENTION

[0050] Detailed Description 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. [ka]

[0051] Compound (I) is also known by its international nonproprietary name, bezucrastinib.

[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 the abnormal activity of c-Kit protein kinase and / or mutant c-Kit protein kinase have previously been disclosed in U.S. Patent No. 9,676,748 and U.S. Patent No. 10,301,280, the entire contents of which are incorporated herein by reference.

[0053] Compound (I) was first disclosed in U.S. Patent Nos. 9,676,748 and 10,301,280. Over the nearly decade since, it has proven difficult to prepare Compound (I) in a tablet form suitable for commercial development. In particular, Compound (I) has a very high melting point (>365°C), is virtually insoluble in aqueous conditions (0.32 μg / mL at pH 7.0), and is virtually insoluble in most organic solvents. Furthermore, no suitable salt or cocrystal of Compound (I) has been found that readily crystallizes upon tablet formation. Finally, existing tablet forms of Compound (I) only allow a relatively small percentage of the API to be packed into the tablet, necessitating repeated administration of many tablets, potentially jeopardizing patient compliance.

[0054] The applicant has surprisingly discovered a process for addressing the low solubility of Compound (I) and formulating tablets containing Compound (I), in which Compound (I) is in amorphous and free base form. The process is elegant, rapid, cost-effective, time-saving, and industrially convenient.

[0055] The problem of low solubility of Compound (I) was overcome by preparing a spray-dried dispersion (SDD). Specifically, an amorphous molecular dispersion of Compound (I) in a polymer matrix (e.g., hydroxypropyl methylcellulose acetate succinate grade H (HPMCAS-H)) was created by dissolving Compound (I) and the polymer in a solvent system (e.g., THF and water) and then spray-drying the solution. Surprisingly, this formulation allowed for a larger amount of Compound (I) to be loaded into tablets than previous formulations, and the formulation also delivered more Compound (I) to the blood of human subjects than previous formulations.

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

[0057] I. Definition For convenience, certain terms used in the specification, examples, and claims are collected 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] When a range of values ​​is provided, each intervening value between the upper and lower limits of that range, and any other stated or intervening value within that stated range, is intended to be encompassed within the disclosure. For example, if a range of 1 mg to 8 mg is stated, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, and 7 mg, as well as ranges of values ​​above 1 mg and below 8 mg, are also intended to be expressly 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 "bezucrastinib." All of these terms may be used interchangeably.

[0060] As used herein, the term "amorphous" refers to a solid form of Compound (I) that is not crystalline. Amorphous solids do not exhibit a distinct X-ray diffraction pattern with sharp maxima. They are thermodynamic non-equilibrium materials that do not exhibit long-range periodicity.

[0061] As used herein, the terms "approximately" and "about" refer to values ​​similar to a stated reference value. In certain embodiments, the term "approximately" or "about" refers to a range of values ​​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 or less) of the stated reference value, unless otherwise specified or clear from the context (except when such number exceeds 100% of possible values).

[0062] "Combination therapy" refers to 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. Two or more therapeutic agents may be delivered simultaneously, for example, in separate pharmaceutical compositions or the same pharmaceutical composition, or at different times. For example, they may be delivered simultaneously or during overlapping periods, and / or one therapeutic agent may be delivered before or after the other therapeutic agent. Treatment with combination therapy includes treatment with either single agent, optionally before or after a period of simultaneous treatment with both agents. However, it is contemplated that effective amounts of two or more therapeutic agents will be present in a patient during a certain period.

[0063] As used herein, the term "Compound (I)" 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 "condition" may be used interchangeably or may differ in that a particular disease or condition may not have a known causative agent (and thus the etiology has not yet been elucidated) and therefore is not yet recognized as a disease, but only as an undesirable condition or syndrome, with a more or less specific set of symptoms identified by clinicians.

[0065] As used herein, the term "excipient" includes any substance used as a vehicle for delivering an active ingredient to a subject, as well as any substance added to an active ingredient, for example, to improve its handling characteristics or to enable the resulting composition to be formed into an orally deliverable unit dose having a desired shape and consistency. Excipients can include, by way of example and not limitation, fillers, binders, surfactants, disintegrants, glidants, lubricants, or combinations thereof, substances added to improve the appearance of the dosage form, and any other substance other than the active ingredient conventionally used in the preparation of oral dosage forms. The term "excipient" includes inactive substances as well as functional excipients that may impart beneficial properties to 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, and the like.

[0066] As used herein, the term "in vitro" refers to events that take place not in a living organism (e.g., an animal, plant, or microorganism), but in an artificial environment, such as in a test tube or reaction vessel, in cell culture, in a Petri dish, etc.

[0067] As used herein, the term "in vivo" refers to events that take place within an organism (e.g., an animal, plant, or microorganism, or cells or tissues thereof).

[0068] As used herein, "mammal" includes both humans and 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 wildlife.

[0069] As used herein, the term "pharmaceutically acceptable" refers to compounds, salts, compositions, dosage forms, etc. that are suitable for use in contact with the tissues of humans and / or other mammals without undue toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio. In some embodiments, "pharmaceutically acceptable" means approved by a federal or state government regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in mammals (e.g., animals), and more particularly in 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, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. 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 together with pharmaceutically acceptable excipients 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 containing a drug and a polymer, wherein the drug is non-crystalline and amorphous. Amorphous dispersions of drugs can be prepared by various manufacturing processes, such as spray drying, co-precipitation, 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 molecularly "dissolved" in the solid matrix. A spray-dried dispersion can be made by dissolving a drug and a polymer in an organic solvent to produce a solution, followed by spray-drying the solution. Techniques for preparing solid dispersions of amorphous drugs in polymers are disclosed, for example, in U.S. Pat. Nos. 9,095,585 and 9,468,604, the contents of each of which are incorporated herein by reference in their entireties. Solid dispersions are also described, for example, in U.S. Pat. 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] As used herein, the term "stable" refers to an amorphous form of Compound (I) that does not convert to any other solid form and contains less than 5% (wt / wt) total of other forms (or, e.g., less than 4% w / w, less than 3% w / w, less than 2% w / w) when stored for at least about 3 months at temperatures up to about 40°C and a relative humidity of about 25% to about 75%.

[0075] As used herein, the terms "therapeutic agent" or "prophylactic agent" refer 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 "actives" or "active agents."

[0076] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of a composition that, when administered to a mammal, preferably a human, is sufficient to effect treatment in the mammal, preferably a human. The amount of a 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 being treated, but can be routinely determined by one of ordinary skill in the art having regard to their own knowledge and this disclosure.

[0077] As used herein, the term "oral formulation" refers to a composition or vehicle used to administer a compound disclosed herein (e.g., Compound (I)) to a subject in need thereof by oral administration. Typically, oral formulations are administered via the mouth, and as used herein, "oral formulation" is intended to encompass any substance that is administered to a subject and absorbed across a membrane, e.g., a mucosa, of the digestive 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 via the mouth 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, the solid dispersions disclosed herein comprise an active ingredient (e.g., Compound (I)) dispersed in at least one other component, such as a polymer (e.g., HPMCAS-H).

[0079] As used herein, the term "treating" or "treatment" encompasses the treatment of a disease or condition of interest in a mammal, preferably a human, having the disease or condition of interest, and includes preventing the disease or condition from occurring in a mammal, inhibiting the disease or condition, i.e., halting its development, alleviating the disease or condition, i.e., causing regression of the disease or condition, or alleviating the symptoms resulting from the disease or condition, i.e., alleviating pain without addressing the underlying disease or condition, particularly when such mammal is predisposed to but has not yet been diagnosed with the condition. The term "treating" also includes any effect that results in the improvement of a condition, disease, disorder, etc., e.g., alleviating, reducing, modulating, or eliminating.

[0080] In general, solid 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 evaluates the thermal properties of SDD. For amorphous SDD, analysis by mDSC yields a single glass transition temperature. Because crystalline phases exhibit unique thermal signatures, mDSC can also detect crystalline phase separation. PXRD, which uses X-rays to identify crystalline forms in solid powders, 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 provide additional technical information to further define each solid form (a so-called "fingerprint") that cannot necessarily be described solely by reference to numerical values ​​or peak positions. In any case, those skilled in the art will understand that such graphical representations of data may be subject to small variations in peak relative intensity and peak position due to certain factors, such as, but not limited to, variations in instrument response and variations in sample concentration and purity, all of which are well known to those 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, X-ray diffractograms of crystalline materials exhibit narrow peaks of high intensity due to the fact that X-rays are scattered only in specific directions (due to the periodic arrangement of atoms). In contrast, X-ray diffractograms of amorphous materials generally exhibit 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 (2-theta).

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

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

[0083] All ranges recited herein (including those reciting a range "between" two values) include the endpoints. The terms "substantially" and "about" should be construed as modifying a term or value in a non-absolute manner. This includes, at least, the expected degree of experimental, technical, and instrumental error for a given technique used to measure a value.

[0084] Less than the full measure of the disclosure may be claimed for any reason, reserving the right to qualify or exclude any individual member of any such group, including any subrange or combination of subranges within a group that may be claimed according to ranges or in any similar manner. Further, less than the full measure of the disclosure may be claimed for any reason, reserving the right to qualify or exclude any individual excipient, polymer, compound, or group thereof, or any member of a claimed group.

[0085] Throughout this disclosure, various patents, patent applications and publications are referenced.The disclosures of these patents, patent applications and publications are incorporated by reference in their entirety into this disclosure in order to more fully describe the state of the art known to those skilled in the art as of the date of this disclosure.This disclosure will control in the event of any inconsistency between the cited patents, patent applications and publications and this disclosure.

[0086] II. Spray-dried dispersion The dispersion of an active agent and a pharmaceutically acceptable polymer described herein is produced 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 that includes a dispersion of at least one active agent and at least one excipient, such as 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 hydroxypropyl methylcellulose acetate succinate grade H (HPMCAS-H).

[0088] In the spray drying process, the active agent and the polymer are dissolved in a common solvent. Here, "common" means that the solvent, which may be a mixture of compounds, dissolves both the active agent and the polymer. After both the active agent and the polymer are dissolved, the solvent is rapidly removed by evaporation in the spray drying apparatus to form a substantially homogeneous solid dispersion. In such a dispersion, the active agent is dispersed as homogeneously as possible throughout the polymer, which can be considered a solid solution of the active agent dispersed in the polymer. In an embodiment of the present disclosure, the active agent and the polymer are dissolved in a solvent that is a combination of water and tetrahydrofuran.

[0089] The solvent is removed by the spray drying process. The term "spray drying" is conventionally used to broadly refer to a process that involves breaking a liquid mixture into small droplets (atomization) and rapidly removing the solvent from the mixture in a spray drying apparatus where there is a strong driving force to evaporate the solvent from the droplets. The spray drying process and spray drying equipment are generally described in Perry's Chemical Engineers' Handbook, pages 20-54 to 20-57 (Sixth Edition 1984). Further details regarding the spray drying process and equipment are reviewed by Marshall, "Atomization and Spray-Drying," 50 Chem. Eng. Prog. Monogr. Series 2 (1954), and Masters, Spray Drying Handbook (Fourth Edition 1985). Furthermore, additional process 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 generally provided by maintaining the partial pressure of the solvent within the spray dryer sufficiently below the vapor pressure of the solvent at the temperature of the droplets being dried. This can be achieved by (1) maintaining a partial vacuum (e.g., 0.01-0.50 atm) within the spray dryer; or (2) mixing the droplets with a warm drying gas; or (3) both (1) and (2). Additionally, some of the heat required for solvent evaporation can be provided by heating the spray solution.

[0090] The drying gas can be virtually any gas, but inert gases such as nitrogen, nitrogen-enriched air, or argon are utilized to minimize the risk of fire or explosion due to ignition of flammable vapors and to minimize undesired oxidation of the drug, concentration-enhancing polymer, or other materials in the dispersion. The temperature of the drying gas at the gas inlet of the apparatus is typically 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 collection cone typically ranges from about 0°C to about 100°C.

[0091] A suitable solvent for the spray-drying process can be any organic compound in which the active agent and polymer are mutually soluble. The solvent should have relatively low toxicity and be removed from the dispersion to a level acceptable according to the International Committee on Harmonization (ICH) guidelines. Removal of 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 process 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-borne feed depends on the desired ratio of drug to polymer in the dispersion and the solubility of the drug and polymer in the solvent. Generally, to reduce the total amount of solvent that must be removed to form the solid amorphous dispersion, it is desirable to use as high a combined drug and polymer concentration in the solvent-borne feed as possible, provided that the drug and polymer are dissolved in the solvent in the temperature range of the process.

[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 formed powder remains in the spray-drying chamber for about 5 to 60 seconds to allow further evaporation of the solvent. The final solvent content of the solid dispersion upon exiting the dryer should be low to reduce the mobility of the drug molecules in the dispersion, thereby improving its stability. Generally, the solvent content of the dispersion upon exiting the spray-drying chamber should be less than about 10% by weight. In some embodiments, the solvent content of the dispersion upon exiting the spray-drying chamber is less than about 9% by weight. In some embodiments, the solvent content of the dispersion upon exiting the spray-drying chamber is less than about 8% by weight. In some embodiments, the solvent content of the dispersion upon exiting the spray-drying chamber is less than about 7% by weight. In some embodiments, the solvent content of the dispersion upon exiting the spray-drying chamber is less than about 6% by weight. In some embodiments, the solvent content of the dispersion upon exiting the spray-drying chamber is less than about 5% by weight. In some embodiments, the solvent content of the dispersion upon exiting the spray-drying chamber is less than about 4% by weight. In some embodiments, the solvent content of the dispersion upon exiting the spray-drying chamber is less than about 3% by weight. In some embodiments, the solvent content of the dispersion upon exiting the spray-drying chamber is less than about 2% by weight. In some embodiments, the solvent content of the dispersion upon exiting the spray-drying chamber is less than about 1% by weight. Subsequent processing steps such as tray drying can be used to remove 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)); and (b) a pharmaceutically acceptable polymer, wherein Compound (I) is dispersed in a polymer matrix formed from the pharmaceutically acceptable polymer.

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

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

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

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

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

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

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

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

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

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

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

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

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

[0108] In an embodiment of the present disclosure, the spray-dried solid dispersion includes hydroxypropyl methylcellulose acetate succinate (HPMCAS) as the pharmaceutically acceptable polymer.

[0109] In an embodiment of the present disclosure, the spray-dried solid dispersion includes hydroxypropyl methylcellulose 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 pharmaceutically acceptable polymer is from about 1:3 to about 1:99.

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

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

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

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

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

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

[0117] Such pharmaceutical compositions may be in 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, and such tablets are suitable for single administration of precise dosages. Such dosage forms should allow the pharmaceutical composition to reach target cells. Other factors are well known in the art, including considerations such as toxicity and dosage forms that delay the pharmaceutical composition from exerting its effect. Techniques and formulations can generally be found in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams and Wilkins, Philadelphia, Pa., 2005 (incorporated herein by reference).

[0118] The methods and pharmaceutical compositions are typically used to treat human subjects, however, they can 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 granulated, the excipients may be added before granulation (and thus may be intragranular) and / or after granulation (and thus may be extragranular).

[0120] Excipients used in pharmaceutical compositions can impart good powder flow and compression properties to the material being compressed. It should be noted that excipients can serve multiple functions. Desirable properties of excipients include high compressibility, allowing for the creation of strong tablets at low compression forces; good powder flow properties, which can improve the powder flow properties of other excipients in the composition; and cohesiveness, for example, to prevent tablet disintegration during processing, shipping, and handling. Such properties are imparted to these excipients by pre-processing steps such as, but not limited to, dry granulation (e.g., by roller compaction, slugging), wet granulation, or spray-dried 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 flavoring agents (e.g., in the case of chewable tablets). Examples of excipients are found, for example, in the Handbook of Pharmaceutical Excipients (5 th edition), edited by Raymond C. Rowe, Paul J. Sheskey, and Sian C. Owen; Publisher: Pharmaceutical Press.

[0121] In some embodiments, pharmaceutical compositions contain pharmaceutically acceptable carriers or excipients, such as fillers, binders, disintegrants, glidants, lubricants, complexing agents, solubilizers, and surfactants, 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, several types of starch, cellulose derivatives, gelatin, lipids, liposomes, nanoparticles, etc. Carriers also include physiologically compatible liquids for solvents or suspensions, including, for example, sterile solutions of water for injection (WFI), saline, dextrose solution, Hank's solution, Ringer's solution, vegetable oils, mineral oils, animal oils, polyethylene glycols, liquid paraffin, etc. Examples of excipients include colloidal silicon dioxide, silica gel, talc, magnesium silicate, calcium silicate, sodium aluminosilicate, magnesium trisilicate, powdered cellulose, macrocrystalline cellulose, carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, 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, and castor seed oil.Mineral oil, polyethylene glycol (e.g., PEG 4000-8000), polyoxyethylene glycol, poloxamer, povidone, crospovidone, croscarmellose sodium, alginic acid, casein, methacrylate divinylbenzene copolymer, docusate sodium, cyclodextrin (e.g., 2-hydroxypropyl-δ-cyclodextrin), polysorbate (e.g., polysorbate 80), cetrimide, TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate), magnesium lauryl sulfate, sodium lauryl sulfate, polyethylene glycol ether, difatty acid ester of polyethylene glycol, or polyoxyalkylene sorbitan fatty acid ester (e.g., polyoxyethylene sorbitan esther). The sugars may include sorbitan fatty acid esters, sorbitan fatty acid esters, such as 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, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, dextran, dextrin, dextrose, cellulose acetate, maltodextrin, simethicone, polydextrose, 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, added, for example, to increase the bulk weight of the blend and provide a practical size for compression. Fillers that can be used include calcium salts, such as dibasic calcium phosphate, and one or more sugars, such as lactose, sucrose, dextrose, microcrystalline cellulose (MCC), mannitol, and maltodextrin. Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to, confectioner's sugar, compressible sugars, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose, and talc. In some embodiments, the filler is microcrystalline cellulose, which can be produced by controlled hydrolysis of alpha-cellulose. Suitable microcrystalline cellulose has an average particle size of about 20 nm to about 200 nm. Suitable microcrystalline celluloses can include, for example, Avicel® PH-101, Avicel® PH-102, Avicel® PH-103, Avicel® PH-105, Avicel® PH-113, and Avicel® PH-200 manufactured by FMC Corporation. In some embodiments, the one or more fillers include Avicel® PH-113 microcrystalline cellulose and Parteck® M100 (mannitol).

[0123] The pharmaceutical composition may also contain one or more lubricants. As used herein, the term "lubricant" is typically added to prevent tableting materials from adhering to punches, minimize friction during tablet compression, and facilitate removal of the compressed tablet from the die. Examples of lubricants include, but are not limited to, colloidal silica, magnesium trisilicate, talc, magnesium carbonate, magnesium oxide, glyceryl behaptate, polyethylene glycol, ethylene oxide polymers (e.g., Carowax), sodium lauryl sulfate, magnesium stearate, aluminum stearate, calcium stearate, sodium stearyl fumarate, stearic acid, magnesium lauryl 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, the one or more lubricants include sodium stearyl fumarate.

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

[0125] One or more disintegrants may be present in the pharmaceutical compositions provided herein in an amount necessary to promote dissolution (e.g., increase the tablet disintegration rate). As used herein, the term "disintegrant" refers to an excipient that can resist the physical forces of particle binding in a tablet or capsule when the oral formulation is placed in an aqueous environment. Disintegrants include starch derivatives and salts of carboxymethylcellulose. 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 polyvinylpyrrolidone (e.g., Polyplasdone™, polyvinylpolypyrrolidone, crospovidone), cross-linked calcium carboxymethylcellulose and cross-linked sodium carboxymethylcellulose (croscarmellose sodium); and soy polysaccharides. In some embodiments, the one or more disintegrants include Ac-Di-Sol® croscarmellose sodium, which aids in the 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 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 from the pharmaceutically acceptable polymer. In some embodiments, the pharmaceutically acceptable polymer is hydroxypropyl methylcellulose acetate succinate grade H (HPMCAS-H).

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

[0128] In one embodiment, described herein is a tablet 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 I) and a pharmaceutically acceptable polymer, such as hydroxypropyl methylcellulose acetate succinate grade H (HPMCAS-H), and one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more binders, one or more buffering agents, 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 tablets 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% 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 embodiments, the tablet comprises at least about 5% to at least about 20% Compound I by weight.

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

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

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

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

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

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

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

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

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

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

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

[0143] The tablets of the present disclosure comprise at least about 3% to at least about 65% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more binders, one or more buffering agents, 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% to at least about 65% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more binders, one or more buffering agents, 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] The tablets of the present disclosure comprise at least about 10% to at least about 65% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more binders, one or more buffering agents, 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] The tablets of the present disclosure comprise at least about 15% to at least about 65% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more binders, one or more buffering agents, 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] The tablets of the present disclosure comprise at least about 20% to at least about 65% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more binders, one or more buffering agents, 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] The tablets of the present disclosure comprise at least about 25% to at least about 65% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more binders, one or more buffering agents, 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] The tablets of the present disclosure comprise at least about 30% to at least about 65% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more binders, one or more buffering agents, 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] The tablets of the present disclosure comprise at least about 35% to at least about 65% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more binders, one or more buffering agents, 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] The tablets of the present disclosure comprise at least about 40% to at least about 65% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more binders, one or more buffering agents, 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] The tablets of the present disclosure comprise at least about 45% to at least about 65% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more binders, one or more buffering agents, 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] The tablets of the present disclosure comprise at least about 50% to at least about 65% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more binders, one or more buffering agents, 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] The tablets of the present disclosure comprise at least about 55% to at least about 65% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more binders, one or more buffering agents, 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] The tablets of the present disclosure comprise at least about 60% to at least about 65% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more binders, one or more buffering agents, 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 tablets comprising at least about 1% 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% to at least about 90% by weight of hydroxypropyl methylcellulose acetate succinate grade H (HPMCAS-H), and at least about 3% to at least about 65% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more binders, one or more buffering agents, 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] Tablets may be provided in unit dosage forms containing a predetermined amount of active ingredient per unit dose. Such units may 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, the route of administration, and the age, weight, and condition of the patient. Preferred unit dosage formulations are those containing a daily dose, weekly dose, monthly dose, sub-dose, or an appropriate fraction thereof, of the active ingredient. Furthermore, such pharmaceutical formulations may be prepared by any method well known in the art of pharmacy.

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

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

[0160] In yet another embodiment, the tablets of the present disclosure are taken consecutively in a 28 day cycle.

[0161] The unit dose administered is determined based on the activity of the API (in vitro, e.g., compound IC 50The dosage can be determined by standard procedures taking into account factors such as: in vivo activity in animal models (e.g., bioavailability or biological half-life), pharmacokinetic results in animal models (e.g., biological half-life or bioavailability), the age, size, and weight of the subject, and any disorders associated with the subject. The importance of these and other factors is well known to those skilled in the art. Generally, the dosage will be within the range of about 0.01 to 50 mg / kg, and also within the range of 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 to treat the same disease.Such combinations include administering the compound and one or more other therapeutic agents at different times, or co-administering the compound and one or more other therapeutic agents.In some embodiments, the dosage of the pharmaceutical compositions of the present disclosure or other therapeutic agents used in combination can be adjusted by methods well known to those skilled in the art, for example, to reduce the dosage compared to the compound or treatment used alone.

[0163] Use in combination includes use with other treatments, drugs, medical procedures, etc., where it is understood that the other treatment or procedure may be administered at a different time from the pharmaceutical compositions described herein (e.g., within a short time, such as within a few hours (e.g., 1, 2, 3, 4 to 24 hours), or within a longer time (e.g., 1 to 2 days, 2 to 4 days, 4 to 7 days, 1 to 4 weeks)), or at the same time as the pharmaceutical compositions described herein. Use in combination also includes use with treatments or medical procedures, such as surgery, administered once or infrequently, with the pharmaceutical compositions described herein administered within a short or longer time before or after the other treatment or procedure. In some embodiments, the present disclosure provides for the delivery of a pharmaceutical composition described herein and one or more other therapeutic agents delivered by different or the same route of administration. Use in combination for any route of administration includes the delivery of a pharmaceutical composition described herein and one or more other therapeutic agents delivered together in any formulation by the same route of administration, including formulations in which the two compounds maintain their therapeutic activity when administered. In one embodiment, other drug therapies can be co-administered with the pharmaceutical compositions described herein. Use in combination by co-administration includes the administration of co-formulations or formulations of chemically linked compounds, or the administration of two or more compounds administered by the same or different routes in separate formulations within a short time of each other (e.g., within 1 hour, 2 hours, 3 hours, up to 24 hours). Co-administration of separate formulations includes co-administration via delivery through a single device, such as the same inhalation device, the same syringe, or administration from separate devices within a short time of each other. Co-formulation of the compounds described herein with one or more additional drug therapies delivered by the same route includes preparing materials together so that they can be administered by a single device, including separate compounds combined in a single formulation, or compounds that are chemically linked but modified to still maintain their biological activity. Such chemically linked compounds can have a bond that is substantially maintained in vivo, or the bond can be broken in vivo to separate the two active components.

[0164] Provided herein are embodiments of a method for treating a subject suffering from 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, there is also provided herein a use of a pharmaceutical composition or tablet described herein for 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.

[0166] Disease indications and regulation of Vc-Kit kinase Exemplary Diseases Associated with Mutant Forms of Ac-Kit or c-Kit The formulations described herein are useful for treating c-Kit-related disorders, such as diseases associated with unregulated kinase signaling, including cell proliferation disorders, fibrotic disorders, and metabolic disorders, among others. As described in more detail below and in Lipson et al., US20040002534 (U.S. Application No. 10 / 600,868, filed June 23, 2003), which is incorporated herein by reference in its entirety, cell proliferation 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 cancer, diseases, and conditions, as described below. Furthermore, the association between c-Kit abnormalities and diseases is not limited to cancer. Thus, c-Kit has been implicated in malignant tumors, including mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors (GISTs), metastatic GISTs, glioblastomas, astrocytomas, neuroblastomas, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinomas, intraepithelial carcinomas, Schwann cell neoplasms associated with neurofibromatosis, acute myeloid leukemia (AML), acute lymphoblastic leukemia, chronic myeloid leukemia, mastocytosis, melanoma (mucosal and cutaneous), thyroid carcinoma, breast cancer, germ cell tumors including mixed germ cell tumors, ovarian germ cell tumors, dysgerminomas, seminomas, large cell neuroendocrine carcinomas, prostate cancer, and canine mast cell tumors, as well as in asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, and inflammation. It has been associated with inflammatory diseases including idiopathic bowel syndrome, transplant rejection, eosinophilia, urticaria pigmentosa (UP), persistent ectatic macular telangiectasia (TMEP), systemic mastocytosis, progressive systemic mastocytosis (AdvSM), systemic mastocytosis with associated hematologic neoplasms (SM-AHN), non-progressive systemic mastocytosis (NonAdvSM), indolent systemic mastocytosis (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 mutant forms of c-Kit has been associated with diseases or conditions such as gastrointestinal stromal tumors (GISTs), mast cell leukemia, germ cell tumors, T-cell lymphoma, mastocytosis, acute lymphoblastic leukemia, and seminoma.

[0168] Exemplary Bc-Kit-Associated Malignancies Aberrant expression and / or activation of c-Kit and / or mutant forms of c-Kit have been implicated in various cancers (Roskoski, 2005, Biochemical and Biophysical Research Comm. 338:1307-1315). Evidence for the contribution of c-Kit to neoplastic 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. Furthermore, c-Kit has been implicated in playing a role in carcinogenesis of the female genital 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 neoplasms associated with neurofibromatosis (Ryan, et al., 1994, J. Neuro. Res. 37:415-432). Mast cells have been found to be involved in modifying 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 in the treatment of neurofibromatosis as well as malignant tumors.

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

[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 contributing to colony formation and hematopoiesis. c-Kit expression is frequently observed in acute myeloid leukemia (AML) and, in some cases, acute lymphoblastic leukemia (ALL) (for reviews, see Sperling, et al., 1997, Haemat 82:617-621; Escribano, et al., 1998, Leuk. Lymph. 30:459-466). Although c-Kit is expressed in the majority of AML cells, its expression does not appear to be prognostic for disease progression (Sperling, et al., 1997, Haemat 82:617-621). However, SCF protected AML cells from apoptosis induced by chemotherapeutic agents (Hassan, et al., 1996, Acta. Hem. 95:257-262). Inhibition of c-Kit according to the present disclosure can enhance the effectiveness of these agents and induce apoptosis in AML cells.

[0171] 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) has been shown to be significantly enhanced by SCF in combination with 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 appears to result primarily from the inhibition of apoptotic death (Jones, Curr. Opin. Onc. 1997, 9:3-7). The Philadelphia chromosome product p210 BCR-ABLp210BCR-ABL and c-Kit have been reported to mediate the inhibition of apoptosis (Bedi, et al., Blood 1995, 86:1148-1158). Because p210BCR-ABL and c-Kit both inhibit apoptosis and p62dok has been suggested as 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 does not mediate the inhibition of p210BCR-ABL. BCR-ABL It has also been reported that c-Kit directly interacts with β-glucan (Hallek, et al., Brit. J Haem. 1996, 94:5-16), suggesting that c-Kit plays a more causative role in CML pathology. Therefore, inhibition of c-Kit may be useful in treating the above disorders.

[0172] Gastrointestinal cancer: Normal colonic mucosa does not express c-Kit (Bellone et al., 1997, J. Cell Physiol. 172:1-11). However, c-Kit is frequently expressed in colon carcinomas (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 carcinoma cell lines (Toyota et al., 1993, Turn Biol. 14:295-302; Lahm et al., 1995, Cell Growth & Different. 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 inhibits 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 carcinoma 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 also appears to be important in gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the digestive system. More than 90% of GISTs express c-Kit, consistent with the presumed origin of these tumor cells from interstitial cells of Cajal (ICCs) (Hirota, et al., 1998, Science 279:577-580). ICCs are thought to regulate gastrointestinal contractions, and patients lacking c-Kit in ICCs presented with myopathic chronic idiopathic intestinal pseudo-obstruction (Isozaki, et al., 1997, Amer. J. of Gast. 9 332-334). c-Kit expressed in GISTs from several different patients was observed to have mutations in the intracellular juxtamembrane domain that result in constitutive activation of c-Kit (Hirota, et al., 1998, Science 279:577-580). Therefore, inhibition of c-Kit kinase may be an effective means for the treatment of these cancers.

[0174] Overexpression or constitutive activation of Kit mutations is implicated in and associated with gastrointestinal stromal tumors (GISTs), with most GISTs containing oncogenic KIT or PDGFRA 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, demonstrated that the D816V KIT mutation is resistant to imatinib, suggesting that additional types of c-Kit inhibitors may be useful. Many GISTs harbor activating mutations in the KIT juxtamembrane domain (Lux et al., 2000, American Journal of Pathology, 156:795). Constitutive activation of the Kit receptor tyrosine kinase is a central pathogenic event in most GISTs and is generally due to oncogenic point mutations (Heinrich, et al. 2002, Human Pathology, 33:484-495). Inhibition of wild-type KIT and / or specific mutant KIT isoforms with small molecule tyrosine kinase inhibitors has become the standard of care for treating patients with metastatic GISTs (Schittenhelm, et al. 2006, Cancer Res., 66:473-481). Therefore, inhibition of c-Kit kinase and / or mutant c-Kit kinase may be an effective means for treating GISTs.

[0175] Testicular cancer: Male germ cell tumors are histologically classified into seminomas, which retain germ cell characteristics, and nonseminomas, which can show features of germ cell differentiation. Both seminomas and nonseminomas are thought to begin with a preinvasive 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 essential for normal gonadal development during embryogenesis (Loveland, et al., 1997, J. Endocrinol 153:337-344). Loss of either the receptor or ligand resulted in animals lacking germ cells. In the postnatal testis, c-Kit has been found to be expressed in Leydig cells and spermatogonia, whereas SCF was 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 frequently arise 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 may contribute to tumorigenesis (Kondoh, et al., 1995, Oncogene 10:341-347) associated with cellular loss of functional p53 and retinoblastoma gene products through association with E6 and E7 (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-defective mutants of SCF (Kondoh, et al., 1995, Oncogene 10:341-347) or c-kit (Li, et al., 1996, Canc. Res. 56:4343-4346) inhibited testicular tumor formation in mice expressing HPV16 E6 and E7.C-kit kinase activation is crucial for tumorigenesis in these animals, and therefore modulation of the c-kit kinase pathway according to the present disclosure will prevent or treat such disorders.

[0176] Expression of c-kit in germ cell tumors indicates that the receptor is expressed by the majority of intraepithelial carcinomas and seminomas, but c-kit is expressed by a small proportion of nonseminomas (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 provides a means for treating these disorders.

[0177] CNS cancer: SCF and c-kit are expressed throughout the developing rodent CNS, and their expression patterns indicate a role in the growth, migration, and differentiation of neuroectodermal cells. Expression of both receptors and ligands has also been reported in the adult brain (Hamel, et al., 1997, J. Neuro-Onc. 35:327-333). c-kit expression has also been observed in normal human brain tissue (Tada, et al., 1994, J. Neuro 80:1063-1073). Glioblastomas and astrocytomas, which define the majority of intracranial tumors, arise from the 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 the c-kit / SCF autocrine loop, and expression of both receptor and ligand was observed in 45% of the tumor samples examined. In two cell lines, anti-c-kit antibodies inhibited cell proliferation, suggesting that the SCF / c-kit autocrine loop contributed to growth (Will Cohen, et al., 1994, Blood 84:3465-3472). Therefore, c-kit kinase inhibitors can be used to treat these cancers.

[0179] Exemplary mast cell diseases involving Cc-Kit Excessive activation of c-kit is also associated with diseases resulting from an excess of mast cells. Mastocytosis is a term used to describe a heterogeneous group of disorders characterized by excessive mast cell proliferation (Metcalfe, 1991, J. Invest. Derm 93:2S-4S; Golkar, et al., 1997, Lancet 349:1379-1385). Elevated c-kit expression has been reported in mast cells from patients with aggressive mastocytosis (Nagata, et al., 1998, Leukemia 12:175-181).

[0180] Furthermore, 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 thus c-kit, directly and indirectly regulates the activation of both mast cells and eosinophils, thereby affecting key cells involved in allergy and asthma through multiple mechanisms. Due to this reciprocal regulation of mast cell and eosinophil function and the role SCF may play in this regulation, c-kit inhibition can be used to treat allergy-related chronic rhinitis, inflammation, and asthma.

[0181] Mastocytosis: SCF (also known as mast cell growth factor) stimulation of c-kit has been reported to be essential 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 a c-kit mutation that attenuates its signaling activity showed significantly fewer mast cells in the skin (Tsujimura, 1996, Pathol Int 46:933-938). Excessive activation of c-kit may be associated with diseases resulting from an excess of mast cells.

[0182] Mastocytosis is limited to the skin in most patients, but can involve other organs in 15-20% of patients (Valent, 1996, Wein / Klin Wochenschr 108:385-397; Golkar, et al., 1997, Lancet 349:1379-1385). Among patients with systemic mastocytosis, the disease can range from 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 in malignant mast cells from canine mast cell tumors (London, et al., 1996, J. Compar. Pathol. 115:399-414), as well as in 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] Mast cell chymase has been reported to cleave membrane-bound SCF into a soluble, 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 pathogenesis of mastocytosis. Transgenic mice overexpressing a form of SCF that cannot be proteolytically released from keratinocytes did not develop mastocytosis, whereas similar animals expressing normal SCF in keratinocytes exhibited a phenotype resembling human cutaneous mastocytosis (Kunisada, et al., 1998, J. Exp. Med. 187:1565-1573). The formation of large amounts of soluble SCF may contribute to the pathology associated with mastocytosis in some patients, and the present disclosure may treat or prevent such disorders by modulating 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). Furthermore, activating mutations of 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 may prove to have a significant therapeutic role in the treatment of these disorders.

[0185] In some patients, c-kit activating mutations may be involved in the pathogenesis of the disease, and these patients can be treated or prevented by regulating the SCF interaction with c-kit kinase.SCF activation of c-kit has been shown to prevent mast cell apoptosis, which may be important 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).Inhibition of mast cell apoptosis can lead to the accumulation of mast cells associated with mastocytosis. Thus, the observation of c-kit activation resulting from receptor overexpression, excessive formation of soluble SCF, or mutations in the c-kit gene that constitutively activate its kinase provides the rationale that inhibition of the kinase activity of c-kit would reduce mast cell numbers and benefit patients with mastocytosis.

[0186] For cells with activating c-kit mutations, c-kit inhibitors have been found to inhibit or even kill the cells (Ma et al., 2000, J Invest Dermatol. 114:392-394), especially 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, inhibitors STI571 (Gleevec) and SU9529 do not inhibit the cells, so that additional types of c-kit inhibitors are useful. Therefore, c-kit inhibitors can be used against both wild-type c-kit and c-kit with mutations, for example, activating mutations in the regulatory region and / or catalytic region.

[0187] Mastocytosis has been shown to be characterized by a pathological increase in mast cells in tissues associated with KIT mutations (Metcalfe, 2008, Blood, 112:946-956; and Ma, et al., 2002). The c-kit D816 mutation 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 oncogenic protein KITD816V by 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 essential for the development, survival, and growth of mast cells (Kitamura, et al., 1995, Int. Arch. Aller. Immunol. 107:54-56; Metcalfe, et al., 1997, Physiol. Rev. 77:1033-1079). Furthermore, SCF cooperates with the eosinophil-specific regulatory factor IL-5 to enhance the development of eosinophil progenitor cells (Metcalf, et al., 1998, Proc. Natl. Acad. Sci., USA 95:6408-6412). SCF has also been reported to induce mast cells to secrete factors that promote eosinophil survival (Kay et al., 1997, Int. Arch. Aller. Immunol. 113:196-199) and 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 mediator release from mast cells and primes these cells for IgE-induced degranulation (Columbo, et al., 1992, J. Immunol. 149:599-602) and sensitizes their responsiveness to eosinophil-derived granule major basic protein (Furuta, et al., 1998, Blood 92:1055-1061). Among the factors released by activated mast cells are 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 promotes mast cell production of the eosinophil chemotactic 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 influences 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 regulates tissue infiltration. Thus, SCF may influence key cells involved in allergy and asthma through multiple mechanisms. Currently, corticosteroids are the most effective treatment for chronic rhinitis and allergy-related inflammation (Naclerio et al., 1997, JAMA 278:1842-1848; Meltzer, 1997, Aller. 52:33-40). These agents act through multiple mechanisms, including reducing circulating and infiltrating mast cells and eosinophils, and decreasing eosinophil survival associated with inhibition of cytokine production (Meltzer, 1997, Aller. 52:33-40). Steroids have also been reported to inhibit SCF expression by fibroblasts and resident connective tissue cells, resulting in decreased 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 SCF may play in this regulation, inhibition of c-kit kinase provides a means for treating allergy-related chronic rhinitis, inflammation, and asthma.

[0191] Inflammatory arthritis (e.g., rheumatoid arthritis): Due to the association of mast cells with 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, such as rheumatoid arthritis.

[0192] Multiple sclerosis: Mast cells have been shown to play a broad role in autoimmune diseases, as demonstrated in a mouse model of multiple sclerosis (MS), experimental allergic encephalomyelitis (EAE). Mast cells have been shown to be necessary 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.

[0193] VI. Methods for treating conditions mediated by c-Kit kinase In another aspect, the present disclosure provides a method for treating a subject suffering from or at risk for a c-kit and / or mutant c-kit protein kinase-mediated disease or condition, 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, Del550-558, Del557-561, N822K, V654A, N822H, Del550-558+V654A, Del557-561+V654A, Ins503AY, V560G, 558NP, Del557-558, 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 comprises administering to a subject an effective amount of a tablet described herein in combination with one or more other treatments for the disease or condition.

[0195] In some embodiments, the present disclosure provides a method of inhibiting unwanted proliferation of tumor cells expressing D816 (e.g., D816F, D816H, D816N, D816Y, or D816V) and / or V560G mutant c-kit protein kinase. The method includes 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 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 of treating a c-kit protein kinase D816 (e.g., D816F, D816H, D816N, D816Y, or D816V) and / or V560G mutation-positive patient. The method comprises administering an effective amount of a tablet described herein to a patient in need thereof. In some embodiments, the patient is D816V mutation-positive. In other embodiments, the patient is V560G mutation-positive. In some embodiments, the patient is D816V and V560G mutation-positive. In certain cases, the patient is afflicted with gastrointestinal stromal tumor (GIST) and / or mastocytosis.

[0197] In some embodiments, diseases or conditions treatable 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; including, but not limited to, melanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma, sarcoma, carcinoma (e.g., gastrointestinal cancer, liver cancer, biliary tract cancer, bile duct cancer (cholangiocarcinoma), colon cancer, lung cancer, gallbladder cancer, breast cancer, pancreatic cancer, thyroid cancer, kidney cancer, ovarian cancer, adrenocortical carcinoma, and prostate cancer), lymphoma (e.g., histiocytic lymphoma), neurofibromatosis, gastrointestinal stromal tumor, acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuroendocrine tumors (e.g., thyroid cancer, thyroid cancer, and thyroid cancer), and other tumors. Neoplastic diseases including medullary carcinoma, carcinoid, small cell lung cancer, Kaposi's sarcoma, and pheochromocytoma; acute pain, chronic pain, cancer-related pain, pain of neuropathic or inflammatory origin including, but not limited to, migraine; cardiovascular diseases including, but not limited to, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis (e.g., thrombotic microangiopathy syndrome), atherosclerosis, and reperfusion injury; psoriasis, eczema, arthritis and autoimmune diseases and conditions, osteoarthritis, endometriosis, scar formation, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease (IBD) D) inflammation and / or proliferation, including, but not limited to; immunodeficiency diseases, including, but not limited to, organ transplant rejection, graft-versus-host disease, and HIV-associated Kaposi's sarcoma; kidney, cystic, or prostate diseases, including, but not limited to, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, benign prostatic hyperplasia, polycystic liver disease, tuberous sclerosis, von Hippel-Lindau disease, medullary cystic kidney disease, nephronophthisis, and cystic fibrosis; metabolic disorders, including, but not limited to, obesity; Helicobacter pylori, hepatitis, and infectious diseases, including but not limited to influenza virus, 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 (a skeletal-facial syndrome), Leopard syndrome, cardiofacial-cutaneous syndrome (CFC), and neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair, and endocrine disorders; and sarcopenia, muscular dystrophy (Duchenne,Myopathies include, but are not limited to, Becker, Emery-Dreifuss, limb-girdle, facioscapulohumeral, myotonic, oculopharyngeal, distal, and congenital muscular dystrophies; motor neuron diseases (including, but not limited to, amyotrophic lateral sclerosis, childhood progressive spinal muscular atrophy, intermediate 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); endocrine myopathies (including, but not limited to, hyperthyroid myopathy and hypothyroid myopathy); peripheral nerve diseases (Charcot-Marie-Thompson syndrome, Diseases related to muscle regeneration or degeneration, including, but not limited to, myotonia congenita, paramyotonia congenita, central core disease, nemaline myopathy, myotubular myopathy, and periodic paralysis; and metabolic disorders of muscle, including, but not limited to, phosphorylase deficiency, acid maltase deficiency, phosphofructokinase deficiency, debranching enzyme deficiency, mitochondrial myopathy, carnitine deficiency, carnitine palmatyltransferase deficiency, phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency, and myoadenylate deaminase deficiency. In one embodiment, the disease or condition is selected from the group consisting of melanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma, sarcoma, liver cancer, biliary tract cancer, cholangiocarcinoma, colon cancer, lung cancer, gallbladder cancer, breast cancer, pancreatic cancer, thyroid cancer, kidney cancer, ovarian cancer, adrenocortical carcinoma, prostate cancer, histiocytic lymphoma, neurofibromatosis, gastrointestinal stromal tumor, acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, medullary thyroid carcinoma, carcinoid, 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 the group consisting of melanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma, colon cancer, thyroid cancer, lung cancer, ovarian cancer, prostate cancer, liver cancer, gallbladder cancer, gastrointestinal stromal tumor, biliary tract cancer,Selected from the group consisting of cholangiocarcinoma, acute pain, chronic pain, and polycystic kidney disease.

[0198] In other embodiments, diseases or conditions treatable 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, senile chorea, Huntington's disease, neoplastic diseases, complications associated with 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 ... tumors, sarcomas of neuroectodermal origin, leiomyosarcoma, lung carcinoma, breast carcinoma, pancreatic carcinoma, colon carcinoma, hepatocellular carcinoma, kidney carcinoma, carcinoma of the female genital tract, squamous cell carcinoma, carcinoma in situ, lymphoma, histiocytic lymphoma, non-Hodgkin's lymphoma, MEN2 syndrome, neurofibromatosis, Schwann cell neoplasm, myelodysplastic syndrome, leukemia, tumor angiogenesis, thyroid cancer, liver cancer, bone cancer, skin cancer, brain cancer, cancer of the central nervous system, 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 Cancer, pain of neuropathic origin, pain of inflammatory origin, acute pain, chronic pain, migraine, cardiovascular disease, heart failure, cardiac hypertrophy, 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, Grave's disease, myasthenia gravis, multiple sclerosis, osteoarthritis Arthritis, endometriosis, skin scarring, tissue scarring, vascular restenosis, fibrotic disorders, eosinophilia, CNS inflammation, pancreatitis, nephritis, atopic dermatitis, hepatitis, immunodeficiency, severe combined immunodeficiency, organ transplant rejection, graft-versus-host disease, kidney disease, prostate disease, diabetic nephropathy, nephrosclerosis, glomerulonephritis, interstitial nephritis, lupus nephritis, benign prostatic hyperplasia, chronic renal failure, tubular necrosis, diabetes-related renal complications, associated nephropathy, type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity, hepatic steatosis, insulin resistance, hyperglycemia, lipolysisObesity, infectious diseases, 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 disorders, Noonan syndrome, Crouzon syndrome, acrocephalic polydactyly type I, Pfeiffer syndrome, Jackson-Weiss syndrome, Costello syndrome, skeletal facial syndrome, Leopard syndrome, cardio-facio-cutaneous syndrome, neural crest syndromes causing cardiovascular, skeletal, gut, skin, hair or endocrine disorders, disorders of bone structure or mineralization, osteoporosis, increased risk of fractures, hypercalcemia, bone metastases, Grave's 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 the group consisting of mast cell tumor, small cell lung cancer, testicular cancer, gastrointestinal stromal tumor (GIST), metastatic GIST, glioblastoma, astrocytoma, neuroblastoma, carcinoma of the female genital tract, sarcoma of neuroectodermal origin, colorectal carcinoma, carcinoma in situ, Schwann cell neoplasm associated with neurofibromatosis, acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, mastocytosis, urticaria pigmentosa (UP), persistent ectatic telangiectasia (TMEP), systemic mastocytosis, indolent systemic, smoldering systemic, aggressive systemic, mast cell leukemia, mast cell sarcoma melanoma, and canine mast cell tumor, as well as inflammatory diseases including asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, inflammatory bowel syndrome, transplant rejection, and eosinophilia. In certain cases, the disease is caused by c-kit and / or c-kit mutants, e.g., D816F, D816H, D816N, D816Y, D816V, K642E, Y823D, Del550-558, Del557-561, N822K, V654A, N822H, Del550-558+V654A, Del557-561+V654A, Ins503AY, V560G, 558NP, Del557-558, Del The disease is a W559-560, F522C, Del579, R634W, K642E, T801I, C809G, D820Y, N822K, N822H, Y823D, Y823C, or T670I mutant-mediated disease. In one embodiment, the disease is a D816 (e.g., D816F, D816H, D816N, D816Y, or D816V) mutant-mediated disease. In another embodiment, the disease is a D816V mutant-mediated disease. In yet another embodiment, the disease is a V560G mutant-mediated disease. In another embodiment, the disease is a D816V and V560G mutant-mediated disease. In one embodiment, the disease is cancer, preferably selected from the group consisting of melanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma, colon cancer, thyroid cancer, lung cancer, ovarian cancer, prostate cancer, liver cancer, gallbladder cancer, gastrointestinal stromal tumor, biliary tract cancer, and cholangiocarcinoma. In one embodiment, the cancer is melanoma, colon cancer, thyroid cancer, or lung cancer.

[0200] In some embodiments, the present disclosure provides a method of treating a disease or condition selected from urticaria pigmentosa (UP), persistent ectasia tegumentosa (TMEP), systemic mastocytosis, indolent systemic, smoldering systemic, aggressive systemic, mast cell leukemia, mast cell sarcoma, GIST, and metastatic GIST, comprising orally administering to a subject in need thereof an effective amount of a tablet 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), comprising administering to the subject an effective amount of any one or more compounds described herein. In certain embodiments, the method comprises orally administering to the subject an effective amount of a tablet described herein in combination with one or more other treatments for the disease or condition.

[0202] In some embodiments, the present disclosure provides any of the c-kit D816F, D816H, D816N, D816Y, D816V, K642E, Y823D, Del550-558, Del557-561, N822K, V654A, N822H, Del550-558+V654A, Del557-561+V654A, Ins503AY, V560G, 558NP, Del557-558, Del Provided are methods for treating a W559-560, F522C, Del579, R634W, K642E, T801I, C809G, D820Y, N822K, N822H, Y823D, Y823C, or T670I mutant protein kinase-mediated disease or condition in an animal subject in need thereof, the method comprising administering to the subject an effective amount of a tablet described herein. In certain embodiments, the method comprises administering to the subject an effective amount of a tablet described herein in combination with one or more other treatments for the disease or condition. In some embodiments, the c-kit mutant protein kinase is a c-kit D816 (e.g., 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, tablets comprising Compound (I) described herein are c-kit and / or mutant c-kit kinase inhibitors having an IC of 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. 50In some embodiments, the compounds described herein have an IC of 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 against c-kit, c-kit D816V mutant, c-kit V560G mutant, or D816V / V560G mutant. 50 In some embodiments, the compounds 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 a c-kit mutant protein kinase, such as a D816V, V560G, or D816V / V560G mutant protein kinase, comprising contacting a tablet containing Compound (I) as described herein with a cell or a c-kit mutant protein kinase, either in vitro or in vivo.

[0205] In certain embodiments, the present disclosure provides for the manufacture of a medicament for treating a disease or condition described herein. In other embodiments, the tablets described herein are for use in treating a disease or condition described herein.

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

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

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

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

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

[0211] In specific embodiments, the diseases or conditions treated by oral administration of the tablets of the present disclosure are indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM). [Example]

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

[0213] Example 1. Properties of bezucrastinib

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

[0215] Table 1: Characteristics of bezucrastinib. [Table 1]

[0216] Example 2. Solubility Studies

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

[0218] 2.1 Solubility in biologically relevant media

[0219] The solubility of bezucrastinib was investigated in biorelevant media at 37°C. The biorelevant media included 0.01 N hydrochloric acid, fasted-state simulated intestinal fluid (FaSSIF) with or without bile salts, simulated intestinal fluid (SIF) with various concentrations of bile salts (0, 0.5%, and 1%), and fasted-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 ultracentrifuging the samples at 470,000 x gravity for 7 minutes. 100 μL aliquots were removed, diluted 5-fold in DMSO and methanol, and tested by the HPLC method described in Table 2. Six (6) replicates were performed in each medium. In all cases, bezucrastinib was virtually insoluble (free drug concentration ≤ 1.2 μg / mL).

[0220] Table 2: HPLC method. [Table 2]

[0221] 2.2 Solubility in organic solvents

[0222] The solubility of bezucrastinib was investigated 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 an ultracentrifuge at 470,000x gravity for 7 minutes. 100 μL aliquots were removed, diluted 5-fold in DMSO and methanol, and tested by HPLC. Three (3) replicates were performed in each solvent. Bezucrastinib was poorly soluble (free drug concentration <5.0 mg / mL) in all solvents except DMSO (free drug concentration <20 mg / mL).

[0223] Table 3: Organic solvents used to assay the solubility of the API. [Table 3-1] [Table 3-2]

[0224] 2.3 Effect of pH on solubility

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

[0226] Example 3. Amorphous solid dispersion formulation studies

[0227] Due to the poor water solubility and lipophilicity of bezucrastinib, amorphous dispersion techniques were investigated to improve bioavailability.

[0228] In ASDs, the solubility of the drug substance is improved by breaking down its crystalline lattice to generate a higher-energy amorphous form. Polymers also play an important role in improving the solubility and bioavailability of amorphous APIs through drug-polymer interactions. As shown below in Example 3, numerous amorphous solid dispersion techniques have been attempted to address the known low solubility of lipophilic bezucrastinib. Applicants surprisingly discovered that certain polymers, and even polymer grades, can produce unexpectedly superior results. Polymers can stabilize ASDs, prevent drug crystallization, and provide improved physical stability under various accelerated stability conditions, such as elevated temperatures and relative humidity. The following studies were conducted using this approach.

[0229] 3.1 KinetiSol®

[0230] KinetiSol® is a fusion-based process for the production of amorphous solid dispersions (“KSD”) (Ellenberger et al., (AAPS PharmSciTech, 2018)) and is incorporated herein by reference. In an effort to generate the best amorphous solid dispersion, the KinetiSol® approach was applied to APIs. An initial polymer screen with the API using KinetiSol® technology was performed as shown in Figure 1. Hypromellose (HPMC) and hypromellose acetate succinate (HPMCAS) polymers proved promising, but several polymers appeared to perform well in vitro.

[0231] Bezucrastinib KSD was prepared using a KinetiSol® small-scale compounder (Formulator II) and a large-scale compounder (Batch Compounder, GMP Gen 1 Continuous / Batch Compounder) designed and manufactured by DisperSol Technologies LLC (Georgetown, TX, USA). Prior to compounding, the API and polymer / oligomer excipients were accurately weighed and blended to prepare a physical mixture (PM). These physical mixtures were then loaded into the KinetiSol® compounder chamber. Within the chamber, a shaft with protruding blades rotated at various incremental speeds without external heat application to impart friction and shear forces to the sample material. The mass temperature was monitored using an infrared probe. Once the molten mass reached the target temperature, the mass was rapidly ejected, collected, and pressed between two stainless steel plates to rapidly quench the sample. The rotation speed ranged from 3,000 to 7,2000 rpm, and the set temperatures ranged from 180°C to 250°C.

[0232] The quenched mass obtained after KinetiSol® processing was milled using a laboratory-scale rotor mill (i.e., IKA Tube Mill 100 (IKA Works GmbH & Co. KG, Staufen, Germany)). For milling, pieces of the quenched mass were loaded into a 20 mL milling chamber and operated for 30–60 seconds at a milling speed between 10,000–20,000 rpm. The milled material was then passed through a #60 mesh screen (≦250 μm). The material retained on the screen (i.e., >250 μm) was circulated through the mill with the same parameters. This process of milling and sieving was repeated until all material had passed through the screen. The resulting material (<250 μm) was labeled KSD.

[0233] Four batches of formulations (polymers (% 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 for 4 weeks at accelerated conditions when packaged in a sealed container. Animal studies conducted in rats and dogs demonstrated that HPMCAS E5- and HPMCAS LMP-based formulations increased bioavailability compared to other formulations, including a spray-dried solid dispersion used as a control. However, low assay and greater than 2% total impurities were formed during processing. Furthermore, the dispersions were dark in appearance, and possible polymer degradation was observed. Therefore, the KinetiSol® approach was discontinued.

[0234] 3.2. Finely Precipitated Bulk Powder ("MBP")

[0235] MBP is a solvent-controlled co-precipitation process in which an API is dissolved in DMSO with a polymer, followed by precipitation in an antisolvent (acidified cold water) to obtain a polymer-stabilized amorphous-solid dispersion. The method for preparing samples for this MBP process can be found in Shah, et al. (Journal of Pharmaceutical Sciences, Vol. 102, No. 3, 2013) and U.S. Patent No. 9,447,089, which are incorporated herein by reference.

[0236] Two grades of HPMCAS polymer were used to prepare MBP samples at 20% and 15% drug loading, as shown in Table 4. 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, followed by chilled purified water, and then dried at 30 °C. The MBP samples were analyzed using X-ray powder diffraction (XRPD) techniques.

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

[0238] Table 4: Formulations for the MBP approach. [Table 4]

[0239] 3.3.Hot Process Spray Drying

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

[0241] API-SDD prototype fabrication involved the following polymer and drug loadings for this study: 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 hot process showed partial crystallinity by XRPD. The chemical stability of the hot process SDD was evaluated by HPLC. Potency was off target for most SDD due to manufacturing issues where the API precipitated and was trapped in an in-line filter. Low levels of impurities were formed during hot process spray drying (<0.16). Hot process spray drying was discontinued due to in-process precipitation manufacturing issues.

[0243] 3.4. Spray drying

[0244] Screening methodologies for developing spray-dried amorphous solid dispersions are reviewed 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) are 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 interactions between manufacturing process, formulation parameters, physical structure, and the performance of solid dispersions with respect to stability and drug release characteristics are 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 sophistication 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 making homogeneous spray-dried solid amorphous dispersions of drugs using a pressure nozzle is disclosed in US Pat. No. 7,780,988, the entire contents of which are incorporated herein by reference.

[0246] Methods and compositions for improving the bioavailability of an active agent and achieving rapid dissolution of a drug from a spray-dried dispersion in a capsule are disclosed in U.S. Patent Application Publication No. 2018 / 0161269, the entire contents of which are incorporated herein by reference.

[0247] A spray drying process featuring continuous preparation and immediate spray drying of a solution comprising an API, excipients, and a solvent is disclosed in WO 2019 / 162688, the entire contents of which are incorporated herein by reference.

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

[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 U.S. Patent Application Publication No. 2005 / 0031692, the entire contents of which are incorporated herein by reference.

[0250] Due to the limited solubility of the API in volatile organic solvents, spray-dried dispersions (SDDs) were prepared using THF and water solvent systems.

[0251] API-SDD prototype fabrication involved the following polymer 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 from 3-40 2θ at a scan rate of 2° / min. All SDDs appeared amorphous by XRPD for the 20% drug-loaded composition.

[0252] 3.4.1. Non-sink dissolution test

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

[0254] Figures 2-5 show assays from non-sink dissolution tests. In general, HPMCAS performed best in non-sink dissolution tests. Grade H retained free drug to a greater extent than the other polymers. Results also show that 10% drug loading outperformed 20% drug loading. With respect to free drug retention, 20% HPMCAS-H SDD performed better than 10% HPMCAS-L SDD. Physical mixing of HPMCAS-H into 20% HPMCAS-L SDD had no effect.

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

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

[0257] The concentrations of total drug (microcentrifuge assay) and free drug (ultracentrifuge assay) are shown in Table 5.

[0258] Table 5: Formulations for microcentrifuge and ultracentrifuge assays. [Table 5]

[0259] All SDDs outperformed the crystalline API for total and free drug. The 10% drug load in HPMCAS-L resulted in higher total and free drug concentrations throughout 60 minutes than the 20%-loaded SDD. However, at 6 hours, 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, and 10% HPMCAS-L produced the highest area under the curve for total drug concentration.

[0260] Figure 4 shows the non-sink total drug dissolution test results for 10%, 15%, and 20% drug-loaded SDD samples using gastric transit at 37°C. Samples were loaded in 0.01 N hydrochloric acid (pH 2) at a concentration of 3 mg API / mL for 30 minutes and then diluted to 1 mg API / mL in simulated intestinal fluid containing 0.224% bile salts at pH 6.5. Total drug concentrations at 60 minutes are shown in Table 6.

[0261] Figure 5 shows the non-sink free drug dissolution test results for 10%, 15% and 20% drug loaded SDD samples using gastric transit at 37°C. The free drug concentrations and total concentrations at 60 minutes are shown in Table 6.

[0262] Table 6: SDD formulations for microcentrifuge and ultracentrifuge assays. [Table 6]

[0263] The results in Table 6 demonstrate that all HPMCAS-H SDDs show significant improvements in free drug and durability compared to the HPMCAS-L SDD. The 15% API-85% HPMCAS-H SDD appears to perform similarly to the 10% API-90% HPMCAS-H SDD, and both are superior to the 20% API-80% HPMCAS-H SDD.

[0264] The 10% API-90% HPMCAS-L SDD formed colloids, and the free drug values ​​suggested precipitation. The 15% and 20% API-HPMCAS-L SDDs barely formed colloids, and the supersaturation was not sustained sufficiently.

[0265] 3.4.2.4-week stability test

[0266] SDD samples were placed for stability at 40°C and 75% relative humidity in open containers and at 40°C under ambient humidity in closed containers to assess physical stability by XRPD and glass transition temperature by differential scanning calorimetry (DSC). Chemical stability of SDD was assessed by HPLC.

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

[0268] After 4 weeks of exposure to these conditions in an open container, samples with 15% and 20% drug loading were found to have crystal formation. Both SDDS with 10% drug loading appeared to be free of crystals. The 20% API 80% HPMCAS-L SDD appeared to have more significant crystallization than the 20% API 80% HPMCAS-H SDD.

[0269] Glass transition temperatures were measured using modulated differential scanning calorimetry (25-375 °C ramp at 3 °C / min modulated at 1 °C / min). mDSC analysis of the SDD from the stability study was performed. All formulations showed a change in glass transition temperature, indicating that physical changes occurred under these conditions. Chemical stability and impurities of the SDD were analyzed by HPLC. Minimal impurity growth was observed in the HPMCAS-H lot after 4 weeks at stable conditions. Compared to the HPMCAS-H lot, more impurity growth was observed in the HPMCAS-L lot, with impurities increasing as drug loading increased.

[0270] Example 4. Evaluation of SDD and KSD amorphous solid dispersions (ASD) in rats

[0271] SDD and KSD amorphous solid dispersions (ASD) were evaluated in a single-dose pharmacokinetic study in male Sprague-Dawley rats, as described below. Six rats were administered the amorphous dispersions by oral gavage in 0.5% methylcellulose (Methocel A4M) in water at a dose of 100 mg / kg. The rats were 8-14 weeks old and weighed between 275-325 grams at the start of dosing. The animals were fasted overnight before oral dosing and then provided with food approximately 4 hours after dosing. Water was available ad libitum, and each animal was allowed to acclimate to the laboratory environment for a minimum of 1 day prior to the study.

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

[0273] Area under the curve (AUC) and C for SDD and KSD formulations max The results are shown in Table 7. 10% HPMCAS-L KSD had the highest AUC and C for all amorphous dispersions. max Among the SDDs, the 10% HPMCAS-H SDD had the highest AUC and C max This resulted in...

[0274] Table 7: Summary of rat TK data - SDD and KSD amorphous solid dispersions. [Table 7-1] [Table 7-2]

[0275] Example 5. Development of tablet formulation

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

[0277] Due to the low drug loading of SDD, quality tables could not be generated for direct compression.Wet granulation is generally not used for amorphous dispersions because it causes recrystallization.

[0278] Tablets were formulated by two different processes. Tablets developed from process A gave rise to formulation A. Tablets developed from process B gave rise to formulation B.

[0279] 5.1. Tablet Formulation: Process 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 then blended 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 composition is provided in Table 8, and a process flow diagram is provided in Figure 6.

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

[0283] As discussed below, Process A and its formulations were discontinued after analysis of human pharmacokinetic data compared to that of formulations obtained by Process B.

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

[0285] After spray drying using HPMCAS-H as the polymer, the 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 blended 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 a process flow diagram is provided in Figure 6.

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

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

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

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

[0291] The animals were fasted for 2 hours before oral dosing and then given food approximately 2 hours after dosing. Water was available ad libitum. Serial blood samples (approximately 0.5 mL each) were obtained from each animal by direct venipuncture via the femoral, saphenous, or other available vein at the following time points: pre-dose and 2, 4, 6, 8, and 24 hours post-dose. The results of the study are shown in Table 11.

[0292] Table 11: Summary of non-human primate TK data - SDD and KSD amorphous dispersions. [Table 11]

[0293] FIG. 7 shows the plasma concentration time curves of tablets made with SDD and KSD amorphous dispersions in non-human primates.

[0294] FIG. 8 shows the area under the curve for tablets made with SDD and KSD amorphous dispersions in non-human primates.

[0295] 10% HPMCAS-L KSD had the highest AUC per dose and C per dose of all amorphous dispersions. max Among the SDDs, the 10% HPMCAS-H SDD had the highest AUC and C maxLower bezucrastinib exposure was observed with 15% and 20% drug-loaded SDDs compared with 10% drug-loaded SDDs.

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

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

[0298] FIG. 9 shows the plasma concentration time curves of Formulations A and B over a 336 hour period.

[0299] FIG. 10 shows the plasma concentration time curves of Formulations A and B over a 24 hour period.

[0300] Figure 11 shows the C of formulations A and B. max Compare.

[0301] FIG. 12 compares the area under the curve (AUC) of Formulations A and B.

[0302] Figure 13 shows the C of formulations A and B. max and compare the geometric means and 90% confidence intervals of the areas under the curve.

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

[0304] Table 12: Summary of single dose steady-state PK data. [Table 12]

[0305] Bezucrastinib is slowly absorbed after oral administration, with the median time to maximum concentration reaching 12 to 16 hours after administration. Plasma concentrations then declined monophasically, with an elimination phase of t 1 / 2 The mean time to recovery was 48.6 to 71.4 hours.

[0306] Higher bezucrastinib exposure and faster absorption were observed with Formulation B compared with Formulation A across the dose range of 50 mg to 600 mg, and the difference in exposure between the two formulations increased with dose. The geometric mean ratio (GMR) of Formulation B / Formulation A was C at doses of 50 mg, 300 mg, and 600 mg, respectively. max 1.23, 1.37, and 1.80 for AUC 0-∞ For the α- and β-actinates, the values ​​were 1.09, 1.24, and 1.35.

[0307] Bezucrastinib C max was slightly higher, but AUC 0-∞ was comparable after a single dose of 600 mg of Formulation B compared to 1000 mg of Formulation A, and C max About 1.26 and AUC 0-∞ The GMR was 1.10.

[0308] Both formulations across dose levels were well tolerated and did not show any clinically significant AEs or SAEs. All AEs were low grade and reversible.

[0309] As shown in this example, Formulation B delivered more drug (as measured by maximum plasma concentration and AUC), and did so in a dose-dependent manner. Similar results in rats and non-human primates for SDD formulations containing HPMCAS-H, but unexpectedly not HPMCAS-L, have already been shown in previous examples. These results led to the selection of Formulation B for further study in combination treatments.

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

[0311] Bezucrastinib Formulation B was coadministered with sunitinib malate in humans with GIST in a randomized, open-label, multicenter clinical study. Fourteen (14) patients were admitted with histologically confirmed gastrointestinal stromal tumor (GIST) with at least one measurable lesion per mRECIST v1.1, which was locally advanced, unresectable, or metastatic, and had documented disease progression or intolerance to imatinib. Patients received a 600 mg dose of bezucrastinib Formulation B and a 37.5 mg dose of sunitinib malate once daily 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. [Table 13]

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

[0314] manufactured goods

[0315] The article of manufacture includes a container holding tablets suitable for oral administration of Compound (I) in combination with printed labeling instructions that provide a discussion of when a particular dosage form should be administered with food and when it should be taken on an empty stomach. The tablets may be housed in any suitable container capable of holding and dispensing the tablets.

[0316] The labeling instructions will be consistent with the methods of treatment described hereinabove. The labeling may be associated with the container by any means that maintains physical proximity of the two; by way of non-limiting example, they may both be contained in packaging material such as a box or plastic shrink wrap, or may be associated with instructions that are attached to the container with an adhesive or the like that does not obscure the labeling instructions or other attaching or retaining means.

[0317] While the present invention has been described by a discussion of embodiments thereof and non-limiting examples thereof, those skilled in the art may, upon reading the specification and claims, envision other embodiments and variations that are also within the intended scope of the invention, and therefore the scope of the present invention is to be interpreted and defined solely by the appended claims.

[0318] equivalent

[0319] While the present disclosure has been described in conjunction with its detailed description, it is to be understood that the foregoing description is intended to be illustrative and not limiting of the scope of the disclosure, which is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. 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; A spray-dried solid dispersion in which 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 from the pharmaceutically acceptable polymer.

2. 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. 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 free base form.

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

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

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

7. 2. 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. 10. The spray-dried solid dispersion of claim 1, further comprising a solvent.

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

10. 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 spray-dried solid dispersion according to any one of claims 1 to 10, one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more binders, one or more buffering agents, 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; tablets, including

12. 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. 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 from a pharmaceutically acceptable polymer; one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more binders, one or more buffering agents, 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; tablets, including

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 a polymer matrix formed from a 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 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 free base form.

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

18. 14. 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 according to 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. 14. The tablet of claim 13, wherein the tablet comprises at least about 10% to at least about 90% by weight of the pharmaceutically acceptable polymer.

21. 14. The tablet of claim 13, wherein the tablet comprises at least about 3% to at least about 65% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more binders, one or more buffering agents, 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. 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% to at least about 90% by weight of hydroxypropyl methylcellulose acetate succinate grade H (HPMCAS-H); at least about 3% to at least about 65% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more binders, one or more buffering agents, 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; tablets, including

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

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

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

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

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

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

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

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

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

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

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

34. 24. The method of claim 23, wherein the tablets are taken consecutively in a 28 day cycle.

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

36. Single dose maximum plasma concentration (C ｍａｘ 24. The method of claim 23, wherein the saturation level of ...

37. 26. 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 bezucrastinib is co-administered with 37.5 mg of sunitinib malate. 【Request Item 38】 The once-daily steady-state maximum plasma concentration (C) of bezucrastinib when co-administered with 37.5 mg of sunitinib malate at a 600 mg dose was ｍａｘ 26. The method of claim 25, wherein the saturation level of ...

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