Solid dispersion of myeloid kinase group inhibitor and pharmaceutical composition comprising said solid dispersion

Abstract

Provided herein are solid dispersions of 5-chloro-N-(3-cyclopropyl-5-{[(3R, 5S)-dimethylpiperazine-1-yl] methyl} phenyl)-4-(6-methyl-1H-indol-3-yl) pyrimidine-2-amine and methods for preparing the solid dispersions. The solid dispersions of 5-chloro-N-(3-cyclopropyl-5-{[(3R, 5S)-dimethylpiperazine-1-yl] methyl} phenyl)-4-(6-methyl-1H-indol-3-yl) pyrimidine-2 Also provided herein is a pharmaceutical composition comprising a solid dispersion of 5-chloro-N-(3-cyclopropyl-5-{[(3R, 5S)-dimethylpiperazin-1-yl] methyl} phenyl)-4-(6-methyl-1H-indol-3-yl) pyrimidine-2-amine, and a use thereof. The invention also provides a pharmaceutical composition comprising a solid dispersion of 5-chloro-N-(3-cyclopropyl-5-{[(3R, 5S)-dimethylpiperazin-1-yl] methyl} phenyl)-4-(6-methyl-1H-indol-3-yl) pyrimidine-2-amine.

Description

Technical Field

[0001] This document provides a solid dispersion of 5-chloro-N-(3-cyclopropyl-5-{[(3R,5S)-dimethylpiperazin-1-yl]methyl}phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidine-2-amine. This document also provides a pharmaceutical composition comprising a solid dispersion of 5-chloro-N-(3-cyclopropyl-5-{[(3R,5S)-dimethylpiperazin-1-yl]methyl}phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidine-2-amine. Background Technology

[0002] FMS-like tyrosine kinase 3 (FLT3) (a receptor tyrosine kinase) is normally expressed in hematopoietic progenitor cells and plays an important role in the expression of normal stem cells and the immune system. Aberrant overexpression and mutations of FLT3 are common in patients with leukemia. In particular, various mutations in FLT3, such as D835V, D835Y, and internal tandem repeats (ITD), have been found in acute myeloid leukemia (AML). AML is a hematopoietic stem cell disorder characterized by the abnormal proliferation and differentiation of blast cells in the bone marrow and peripheral blood. FLT3 has recently been identified as one of the most important targets for AML treatment.

[0003] Similarly, intracellular kinases SYK and JAK1 / 2, as well as c-KIT alternative receptor kinase, mediate oncogenic signaling in AML, which can promote resistance to certain FLT3 inhibitors.

[0004] Spleen tyrosine kinase (SYK) (a non-receptor protein tyrosine kinase) is an important mediator of immune receptor signaling in B cells, mast cells, neutrophils, and macrophages. SYK is expressed in 90% of AML blasts, and its activity is associated with adverse outcomes in AML patients, independent of age, cytogenetics, and white blood cell count. Typically, phosphorylation of spleen tyrosine kinase (SYK), which is frequently overexpressed and constitutively activated in AML, is increased in cells stimulated via chemokine receptors and integrins. Activation of SYK in the bone marrow microenvironment may induce leukemic protection. Furthermore, cytokines released by bone marrow stromal cells can protect leukemia cells from drug cytotoxicity by inducing JAK / STAT signaling (Blood. 2017, 130(6), 789-802; Blood Adv. 2019, 3(7), 1061-1072).

[0005] The Janus-associated kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway plays a crucial role in hematopoietic growth factor signaling. Overactive JAK-STAT signaling is associated with the pathogenesis of myeloid malignancies, including acute myeloid leukemia (AML). Significant advances in understanding the biology of AML have led to a surge in novel therapeutics with mechanistic mechanisms for treating newly diagnosed and relapsed / refractory (R / R) AML. Selective targeting of the JAK-STAT pathway has proven to be an effective therapeutic strategy for myeloproliferative neoplasms and is also being evaluated in related myeloid malignancies, including AML (Blood Reviews, 2020, 40, 100634).

[0006] c-KIT mutations have been reported in almost all systemic mastocytosis, 20% to 40% of core-binding factor (CBF) acute myeloid leukemia (AML), and approximately 20% of high-grade myelodysplastic syndromes (MDS) and MDS-derived AML. c-KIT mutations in AML confer an increased risk of relapse and reduced overall survival (Br J Haematol. 2003, 121(5), 775-777; Leuk Res. 2006, 30(10), 1235-1239; J Clin Oncol. 2006, 24(24), 3904-3911).

[0007] 5-Chloro-N-(3-cyclopropyl-5-{[(3R,5S)-dimethylpiperazin-1-yl]methyl}phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidine-2-amine is a potent inhibitor of the myeloid kinase group (FLT3, SYK, JAK, and mutant c-KIT kinases) and can be used to treat B-lineage tumors, such as acute myeloid leukemia. The compound and its synthesis have been described in PCT application publication WO2020 / 022600 A1, which is incorporated herein by reference in its entirety. There remains interest in developing effective and safe formulations of this compound and other related bioactive molecules. Summary of the Invention Technical issues

[0008] This document provides a solid dispersion of 5-chloro-N-(3-cyclopropyl-5-{[(3R,5S)-dimethylpiperazin-1-yl]methyl}phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidine-2-amine. This document also provides a pharmaceutical composition comprising a solid dispersion of 5-chloro-N-(3-cyclopropyl-5-{[(3R,5S)-dimethylpiperazin-1-yl]methyl}phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidine-2-amine. Solution to the problem

[0009] This article describes pharmaceutical formulations and compositions comprising the compound 5-chloro-N-(3-cyclopropyl-5-{[(3R,5S)-dimethylpiperazin-1-yl]methyl}phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidine-2-amine and its amorphous form, as well as methods of using them.

[0010]

[0011] (Compound A)

[0012] It is given as compound A or its pharmaceutically acceptable salt, solvate, stereoisomer or prodrug.

[0013] This invention includes an amorphous form of compound A, pharmaceutical compositions comprising compound A, and methods of treating cancer by administering compound A or compositions comprising compound A. Related synthesis and methods of using compound A are disclosed in PCT applications WO 2020022600, WO 2020171646, WO 2020171649, WO 2020262974, and WO2021066443, which are incorporated herein by reference in their entirety. Accordingly, in one aspect, the invention provides a solid dispersion comprising compound A or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and a polymer carrier. In a specific embodiment, compound A is in a solid dispersion and is substantially amorphous, and is dispersed in a polymer matrix of a polymer carrier in an amount of about 10 parts by weight to about 55 parts by weight based on 100 parts by weight of compound A.

[0014] In one embodiment, the present invention provides a solid dispersion comprising compound A, wherein the solid dispersion is formed by solvent evaporation methods (such as spray drying and fluidized bed granulation).

[0015] In yet another embodiment, the polymer carrier is a hydrophilic carrier. In a more specific embodiment, the polymer carrier is hydroxypropyl methylcellulose. In yet another more specific embodiment, the polymer carrier is hydroxypropyl methylcellulose acetate succinate.

[0016] In another aspect, the present invention provides a pharmaceutical composition comprising a solid dispersion of compound A and a pharmaceutically acceptable excipient. The pharmaceutical composition comprises a) about 20% to about 50% w / w of the solid dispersion of compound A, b) about 25% to about 70% w / w of a filler / binder, c) about 4.0% to about 20% w / w of a disintegrant, d) about 0.25% to about 5.0% w / w of a flow aid / adsorbent, and e) about 0.5% to about 2.5% w / w of a lubricant, wherein the solid dispersion of compound A comprises substantially amorphous compound A, and based on the combined weight of compound A and a hydrophilic polymer carrier, the substantially amorphous compound A is dispersed in the polymer matrix of the hydrophilic polymer carrier in an amount of about 64.5% w / w to about 91% w / w of compound A.

[0017] In one embodiment, the pharmaceutical composition is a solid oral dosage form selected from tablets, powders, granules, capsules, and pills. In a specific embodiment, the solid oral dosage form is a tablet.

[0018] In another embodiment, the solid dispersion of compound A of the pharmaceutical composition is formed by spray drying.

[0019] In some embodiments, improved pharmacokinetic (PK) characteristics are provided, depending on the formulation or solid oral dosage form of the pharmaceutical composition, compared to a reference formulation containing the same amount of compound A. In one embodiment, PK characteristics include drug exposure (C0.05). max ) and area under the curve (AUC). In a specific embodiment, the pharmaceutical composition is a tablet, wherein the tablet provides approximately 2 to 3 times the drug exposure to compound A (e.g., maximum plasma concentration (C0.05) relative to a reference tablet containing the same amount of compound A but not containing an amorphous solid dispersion of compound A. max The area under the curve (AUC) is increased by about 2 to about 3 times compared to a reference tablet containing the same amount of compound A but not containing an amorphous solid dispersion of compound A. In another specific embodiment, the drug exposure or AUC is measured in beagle dogs.

[0020] In another aspect, the present invention provides a pharmaceutical composition for use in capsules, the pharmaceutical composition comprising a solid dispersion of compound A and a pharmaceutically acceptable excipient. The pharmaceutical composition comprises a) about 50% to about 97.5% w / w of the solid dispersion of compound A, b) about 0% to about 48% w / w of a filler / binder, c) about 0% to about 20% w / w of a disintegrant, d) about 0% to about 4.0% w / w of a flow aid / adsorbent, and e) about 0.2% to about 4.0% w / w of a lubricant, wherein the solid dispersion of compound A comprises substantially amorphous compound A, and based on the combined weight of compound A and a hydrophilic polymer carrier, the substantially amorphous compound A is dispersed in the polymer matrix of the hydrophilic polymer carrier in an amount of about 64.5% w / w to about 91% w / w of compound A.

[0021] In another aspect, the present invention provides a solid oral formulation comprising about 20% to about 50% w / w of a solid dispersion of compound A, wherein the solid dispersion of compound A comprises substantially amorphous compound A, and the substantially amorphous compound A is dispersed in a polymer matrix of hydroxypropyl methylcellulose at an amount of about 64.5% to about 91% w / w of compound A based on the combined weight of compound A and hydroxypropyl methylcellulose, such that the solid oral formulation provides about 2 to 3 times the increase in drug exposure or area under curve (AUC) relative to a reference tablet containing the same amount of compound A but not containing the amorphous solid dispersion of compound A. Beneficial effects of the invention

[0022] In another aspect, the present invention provides a method of treating a disease or condition using the pharmaceutical composition of the present invention. Exemplary diseases or conditions include B-lineage tumors, such as leukemia. In a specific embodiment, the disease or condition is acute myeloid leukemia. Attached Figure Description

[0023] Figures 1A to 1E Examples 1-3 are shown respectively. Figures 1A to 1C ) and Comparative Examples 1-3 (respectively) Figures 1D to 1F Scanning electron micrograph of a solid dispersion of compound A;

[0024] Figure 2 This is a graph showing the saturated solubility of the solid dispersions of compound A in Examples 1-3 and Comparative Example 1;

[0025] Figure 3A and Figure 3B The images show the X-ray powder diffraction (XRPD) pattern and differential scanning calorimetry (DSC) curve of the solid dispersion of compound A in Example 1, respectively. Figure 3C and Figure 3D The XRPD pattern and DSC curve of the formulation in Comparative Example 1 are shown.

[0026] Figures 4A to 4D These are XRPD patterns of compound A solid dispersion tablets under different storage conditions, and Figure 4E This is the XRPD pattern of the crystalline compound A monohydrate of Comparative Example 1;

[0027] Figure 5 is a graph comparing the average plasma concentration-time curves of tablets from Example C and Comparative Example B. Detailed Implementation

[0028] Specific terms

[0029] Certain embodiments will now be described in detail, examples of which are illustrated herein. While the enumerated embodiments will be described, it should be understood that they are not intended to limit the invention to those embodiments. In contrast, the invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the invention as defined by the claims. Those skilled in the art will recognize that many methods and materials similar to or equivalent to those described and materials herein can be used in the practice of the invention. The invention is by no means limited to the methods and materials described. In the event that one or more of the incorporated documents and similar materials differ from or contradict this application, including but not limited to defined terminology, usage of terminology, described techniques, etc., this application shall prevail.

[0030] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. It should be understood that the foregoing general description and the following detailed description are merely exemplary and explanatory and do not limit any of the claimed subject matter. In this application, the use of the singular includes the plural meaning unless expressly stated otherwise. It must be noted that, as used in the specification and appended claims, the singular forms “a” and “the” include plural indicators unless the context clearly specifies otherwise. In this application, the use of “or” means “and / or” unless otherwise stated. Furthermore, the use of the term “including” and other forms such as “include,” “includes,” and “included” is non-limiting.

[0031] The chapter headings used in this document are for organizational purposes only and should not be construed as limiting the subject matter described. All references or portions thereof cited in this publication (including, but not limited to, patents, patent applications, articles, books, manuals, and papers) are expressly incorporated herein by reference in their entirety for any purpose.

[0032] When used before numerical values, the term "about" indicates that the value may vary within a reasonable range, such as within ±10%, ±5%, or ±1% of the stated value. Throughout this specification, numerical ranges are provided for certain quantities. It should be understood that these ranges include all sub-ranges therein. Thus, the range "50 to 80" includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values ​​within a given range can be endpoints of the ranges thus encompassed (e.g., the range 50-80 includes ranges with endpoints such as 55-80, 50-75, etc.).

[0033] As used herein, the term "comprising" is intended to mean that compositions and methods include the listed elements, but do not exclude other elements. When used to define compositions and methods, "consistently comprising" should mean excluding other elements that give any significance to the composition for its intended use, but do not exclude elements that do not materially affect one or more characteristics of the composition or method. "Constitutes" should mean excluding elements not specifically listed. Embodiments defined by each of these transitional terms are within the scope of this invention.

[0034] The term "pharmaceutically acceptable" indicates that, taking into account the disease or condition to be treated and the corresponding route of administration, the indicated material does not possess characteristics that would cause a medical practitioner with reasonable caution to avoid administering the material to a patient. For example, it is often required that such a material be substantially sterile, e.g., for use in injectable formulations.

[0035] In the context of this invention, the terms "therapeuticly effective" or "effective amount" indicate that the amount of material or material is effective in preventing, alleviating, or improving one or more symptoms of a disease or medical condition, and / or prolonging the survival of the treated subject. In some embodiments, a "therapeuticly effective amount" of compound A refers to the dose and / or duration of administration required to inhibit the myeloid kinase groups (FLT3, SYK, JAK, and mutant c-KIT kinases) (such as wild-type or mutant). Furthermore, a therapeutically effective amount can be an amount in which the overall beneficial therapeutic effect outweighs toxicity or undesirable side effects. The therapeutically effective amount of compound A can vary depending on the disease state, age, and weight of the treated subject. Therefore, dosing regimens are typically adjusted according to individual needs in each particular case and are within the scope of the art. In some embodiments, an appropriate daily dose of compound A administered to an adult can be from about 10 mg to about 2500 mg; or from about 50 mg to about 1000 mg, although the upper and lower limits may be exceeded when indicated. The daily dose of compound A can be administered as a single dose, in multiple doses, or, for parenteral administration, as a subcutaneous injection.

[0036] "Bioavailability" refers to the percentage of administered compound A delivered into the systemic circulation of the studied animal or human. It is the total exposure (AUC) of the drug when administered intravenously. (0-∞) Oral bioavailability is typically defined as 100% bioavailability (F%). "Oral bioavailability" refers to the extent to which compound A is absorbed into the systemic circulation when the pharmaceutical composition is taken orally, compared to intravenous injection.

[0037] As used herein, the term “area under the curve” or its acronym “AUC” is a pharmacokinetic term used to refer to a method of measuring the bioavailability or extent of absorption of a drug based on a graph of the plasma concentration pool of an individual (e.g., a human or another test animal) or an individual sampled at frequent intervals. AUC refers to the area under the plasma concentration-time curve of the administered drug (e.g., compound A), calculated as follows over the entire sample collection interval using a trapezoidal rule. AUC is a measure of total bioavailability and is proportional to the total amount of drug remaining unchanged in the plasma of that individual or test animal. AUC is typically given over time intervals from zero to infinity; however, it is obviously impossible to measure the plasma drug concentration of a patient “to infinity,” therefore mathematical equations are used to estimate AUC from a finite number of concentration measurements.

[0038] As used in this article, the term "AUCo" 0-∞ "" refers to the area under the blood drug concentration-time curve extrapolated to infinity.

[0039] As used herein, the term "maximum plasma concentration" or its symbol "C" max "This is the highest plasma concentration of the drug or delivery agent observed within the sampling interval. It is a measure of drug exposure."

[0040] As used in this article, the symbol "T" max "Indicates the time after administration when the maximum plasma concentration of the drug was observed."

[0041] As used herein, the term "crystallization" refers to a solid phase in which the material has a regular, ordered internal structure at the molecular level and exhibits a unique X-ray diffraction pattern with defined peaks. Such materials will also exhibit liquid properties when sufficiently heated, but the change from solid to liquid is characterized by a phase transition, typically a first-order phase transition (melting point). The absence of crystalline drugs in amorphous dispersions can be characterized by modulated differential scanning calorimetry (mDSC), X-ray powder diffraction (XRPD), near-infrared spectroscopy (NIR), or any other standard analytical technique. For example, mDSC assesses the thermal properties of amorphous dispersions. Analysis by mDSC will produce a single glass transition temperature. mDSC can also detect crystalline phase separation, as the crystalline phase will display a unique thermal signal. XRPD uses X-rays to identify crystalline forms in solid powders and can be used, for example, to confirm that a solid dispersion is a single amorphous phase that does not possess measurable crystalline material.

[0042] As used herein, the term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and, depending on temperature, can exhibit physical properties of a solid or liquid. Typically, such materials do not display distinctive X-ray diffraction patterns and, while exhibiting solid properties, are more formally described as liquids. Upon heating, a change in properties from solid to liquid occurs, characterized as a change of state, typically a second-order change (glass transition).

[0043] As used herein, the term "substantially amorphous" is intended to mean that more than 60%; or more than 65%; or more than 70%; or more than 75%; or more than 80%; or more than 85%; or more than 90%; or more than 95%; or more than 99% of the compound present in the composition are in an amorphous form. "Substantially amorphous" can also refer to a material having no more than about 20% crystallinity, or no more than about 10% crystallinity, or no more than about 5% crystallinity, or no more than about 2% crystallinity, or no more than about 1% crystallinity.

[0044] As used herein, the term "solid dispersion" means a solid system comprising at least two components, wherein one component (a drug, such as compound A) is dispersed throughout the other components (a polymer carrier). In a solid dispersion, the components of the polymer carrier form a matrix, and the molecular dispersion of the drug occurs within this polymer matrix. In addition to these two components, the solid dispersion may also contain a small amount of excipients, such as flow aids / adsorbents. The compound (crystalline or amorphous particles, optionally micronized or nanoparticles) is uniformly dispersed within the polymer matrix. In some embodiments, the solid dispersion comprises compound A dispersed in molecular form together with the polymer. Preferably, the solid dispersion exists as a single-phase system.

[0045] As used herein, the term "dispersed in molecular form" refers to the random distribution of a compound (e.g., compound A) within a polymer. In some embodiments, the compound exists in the polymer in a final, finely divided state. See, for example, MGVachon et al., J Microencapsulation 14:281-301 (1997) and Vandelli et al., J Microencapsulation, 10: 55-65 (1993). In some embodiments, the compound (e.g., compound A) may be dispersed in its solid state within a matrix formed of a polymer, such that the compound is fixed in its amorphous form. Whether a compound is dispersed in molecular form within a polymer can be demonstrated in various ways, such as by the resulting solid molecular complex having a single glass transition temperature, a value that is intermediate between the glass transition temperature of the drug and the glass transition temperature of the polymer carrier.

[0046] As used herein, the term "amorphous solid dispersion" refers to a solid dispersion comprising a drug and a polymer carrier, wherein the drug is non-crystalline and substantially amorphous. Amorphous solid dispersions of drugs can be prepared by various manufacturing methods, such as, but not limited to, solvent evaporation (also known as solvent treatment), spray drying, coprecipitation, or hot melt extrusion. Spray-dried dispersions (SDDs) are single-phase amorphous molecular dispersions of drugs in a polymer matrix; they are a type of amorphous solid in which the drug is "dissolved" in molecular form within a solid matrix. Spray-dried dispersions can be manufactured by dissolving the drug and polymer in an organic solvent to produce a solution, and then evaporating the solution (e.g., spray drying). Techniques for preparing amorphous drug solid dispersions in polymers are disclosed, for example, in U.S. Patent No. 9,095,585, the contents of which are incorporated herein by reference in their entirety.

[0047] "Stereoisomers" are compounds composed of identical atoms bonded by the same bonds but having different, non-interchangeable three-dimensional structures. This disclosure considers various stereoisomers and mixtures thereof, and includes "enantiomers," which are two stereoisomers whose molecules are non-overlapping mirror images of each other.

[0048] "Tautomer" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. This disclosure includes tautomers of any of the compounds described.

[0049] "Prodrug" refers to a derivative of the compound described in this disclosure, which will be converted into the compound in vivo.

[0050] As used herein, the term "formulation" or "pharmaceutical formulation" refers to a pharmaceutical composition comprising at least one therapeutically active agent and a pharmaceutically acceptable excipient or carrier. Non-limiting examples of formulations include tablets, capsules, gel capsules, syrups, liquids, gels, suspensions, solid dispersions, or combinations thereof.

[0051] As used herein, the term "dosage form" refers to one or more pharmaceutical compositions that provide a specific amount of a therapeutically active agent, such as a unit dose. In one embodiment, a dosage form may be provided in one or more pharmaceutical compositions. For example, if a subject is given 200 mg of the therapeutically active agent (unit dose) at one time, the dosage form may comprise two tablets, each containing 100 mg of the therapeutically active agent, wherein the two tablets are the same pharmaceutical composition.

[0052] As used herein, the term "filler / binder" generally refers to any pharmaceutically acceptable substance (such as any pharmaceutically acceptable film) that can be used to bind the active and inert components of a carrier together to maintain viscous and discrete portions. Fillers / binders can also be used to stabilize compounds. Examples of fillers / binders can include starch, sugars, disaccharides, sucrose, lactose, lactose monohydrate, polysaccharides, cellulose, cellulose ethers, hydroxypropyl cellulose, sugar alcohols, xylitol, sorbitol, maltitol, microcrystalline cellulose, calcium carbonate or sodium carbonate, dicalcium phosphate, compressible sugars, calcium hydrogen phosphate dihydrate, mannitol, and tricalcium phosphate.

[0053] As used herein, the term "disintegrant" generally refers to a substance that, upon addition to a solid dosage form, promotes the breakage or disintegration of the solid dosage form after administration and allows the active ingredient to be released as efficiently as possible to allow for rapid dissolution of the solid dosage form. Examples of disintegrants may include corn starch, sodium starch glycolate, croscarmellose sodium, crospovidone, microcrystalline cellulose, modified corn starch, sodium carboxymethyl starch, povidone, pregelatinized starch, and alginate.

[0054] As used herein, the term "flow aid / adsorbent" generally refers to a substance used in tablet and capsule formulations to improve the flow properties of the tablets during compression, prevent unwanted adhesion to the mold, and produce an anti-caking effect. Examples of flow aids / adsorbents may include colloidal silica, talc, fumed silica, starch, starch derivatives, and bentonite.

[0055] The term "lubricant" generally refers to a substance added to a powder blend to prevent compacted powder clumps from adhering to equipment during tableting or encapsulation. Lubricants can help eject tablets from the mold and improve powder flow. Examples of lubricants can include magnesium stearate, stearic acid, silica, fats, calcium stearate, polyethylene glycol, sodium stearoyl fumarate, or talc; and solubilizers such as fatty acids, including lauric acid, oleic acid, and C8 / C10 fatty acids.

[0056] As used herein, the symbol “% w / w” refers to the weight content of the component calculated based on the ratio of the target component to the total weight of the composition containing the component.

[0057] The term "treatment" means one or more of the relief, reduction, delay, decrease, improvement, or management of at least one symptom of a subject's condition. The term "treatment" may also mean one or more of the prevention of the onset of a condition, the delay of the onset of a condition (i.e., at a stage prior to the clinical manifestation of the condition), or the reduction of the risk of the development or worsening of the condition.

[0058] As used in this article, "subject" can be a human, a non-human primate, a mammal, a rat, a mouse, a cow, a horse, a pig, a sheep, a goat, a dog, a cat, etc.

[0059] “Mammals” include humans as well as livestock (such as laboratory animals (e.g., mice, rats, monkeys, dogs, etc.) and domestic pets (e.g., cats, dogs, pigs, cattle, sheep, goats, horses, rabbits)) and non-livestock (such as wild animals, etc.).

[0060] solid dispersion of compound A

[0061] One aspect of the present invention is the amorphous form of compound A.

[0062]

[0063] (Compound A)

[0064] Or its pharmaceutically acceptable salt, solvate, or solvate salt. In another specific embodiment, the amorphous form exhibits the same characteristics as... Figure 3A The patterns are substantially similar to X-ray powder diffraction (XRPD) patterns. In another embodiment, the amorphous form of compound A exhibits as shown in... Figure 3A The X-ray powder diffraction (XRPD) pattern in the image. In another embodiment, the amorphous form exhibits a pattern similar to... Figure 3B The differential scanning calorimetry (DSC) curves are substantially similar. In another embodiment, the amorphous form exhibits as... Figure 3B Differential scanning calorimetry (DSC) curves.

[0065] In another embodiment, the amorphous form of compound A originates from different storage conditions. In another embodiment, the amorphous form is provided as a pharmaceutical composition. In yet another embodiment, the composition relates to a solid dispersion.

[0066] In one aspect, the present invention provides a solid dispersion of compound A.

[0067] :

[0068] [Compound A]

[0069] For the purposes of the solid dispersions mentioned above, other forms of Compound A besides those represented by Compound A are considered as starting materials in the manufacture of said solid dispersions. Other forms of Compound A suitable as starting materials for solid dispersions may include any hydrate of Compound A, such as monohydrate, dehydrated form, trihydrate; anhydrous form; any pharmaceutically acceptable salt of Compound A, such as hydrochloride; any solvate, such as ethanolate; and any hydrate of pharmaceutically acceptable salts of Compound A. These other forms can be used as starting materials for the preparation of solid dispersions using solvent evaporation methods (such as spray drying or fluidized bed granulation).

[0070] Therefore, this disclosure relates to pharmaceutical compositions and formulations comprising compound A, wherein said composition is a solid dispersion. In one embodiment, the solid dispersion is formed by solvent evaporation (also known as solvent treatment), hot melt extrusion, or spray drying. In one embodiment, the solid dispersion is a spray-dried dispersion (SDD).

[0071] In one embodiment, the solid dispersion is prepared by solvent evaporation, wherein after both the therapeutic agent and the polymer carrier are dissolved in the same solvent or solvent mixture, the solvent or solvent mixture is rapidly removed by evaporation or by mixing with a non-solvent. Rapid removal of the solvent or solvent mixture can be achieved using spray drying, spray coating (pot coating, fluidized bed coating, etc.), and precipitation by rapidly mixing the polymer and drug solution with CO2, water, or other non-solvents. In one embodiment, the solid dispersion is a supersaturated solid solution, wherein the concentration of the therapeutic agent in the polymer carrier is higher than its equilibrium value.

[0072] In one embodiment, the solid dispersion has a single glass transition temperature. A single glass transition temperature of the solid dispersion indicates a high degree of homogeneity.

[0073] In one embodiment, the solid dispersion comprises one or more water-soluble polymers. In one embodiment, the solid dispersion comprises one or more cellulose derivatives. In one embodiment, the solid dispersion comprises one or more water-soluble cellulose polymers. In one embodiment, the solid dispersion comprises one or more cellulose or non-cellulose polymers. In one embodiment, the solid dispersion comprises one or more polymers that are neutral or ionizable in an aqueous solution. In one embodiment, the solid dispersion comprises one or more polymers that are ionizable and cellulose-based. In one embodiment, the solid dispersion comprises one or more polymers that are ionizable cellulose polymers. In one embodiment, the solid dispersion comprises one or more amphiphilic polymers. In one embodiment, the solid dispersion comprises one or more hydrophilic polymers. In one embodiment, the solid dispersion comprises one or more water-soluble hydrophilic polymers. In one embodiment of the pharmaceutical composition of this disclosure, compound A or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof is present at about 10% to about 90% (inclusive of all values ​​and subranges) of the total composition (which may include one or more additional therapeutically active agents and / or other pharmaceutically acceptable excipients and / or coatings) by weight. In one embodiment of the solid dispersion, compound A or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof is present at about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90% (inclusive of all values) of the total composition by weight.In one embodiment, compound A or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, by weight, comprises approximately 10% to approximately 80%, approximately 10% to approximately 70%, approximately 10% to approximately 60%, approximately 10% to approximately 50%, approximately 10% to approximately 40%, approximately 10% to approximately 30%, approximately 10% to approximately 20%, approximately 15% to approximately 85%, approximately 15% to approximately 75%, approximately 15% to approximately 65%, approximately 15% to approximately 55%, approximately 15% to approximately 45%, approximately 15% to approximately 35%, approximately 15% to approximately 25%, approximately 20% to approximately 80%, approximately 20% to approximately 70%, approximately 2% to approximately 2% of the total composition. The following values ​​are present: 0% to about 60%, about 20% to about 50%, about 20% to about 40%, about 20% to about 30%, about 25% to about 85%, about 25% to about 75%, about 25% to about 65%, about 25% to about 55%, about 25% to about 45%, about 25% to about 35%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, about 30% to about 50%, about 30% to about 40%, about 35% to about 85%, about 35% to about 75%, about 35% to about 65%, about 35% to about 55%, or about 35% to about 45% (inclusive of all values ​​therein).

[0074] In one embodiment of the solid dispersion, the weight ratio of the polymer or polymer carrier to compound A or its pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug is about 90:10, about 85:15, about 80:20, about 75:25, about 70:30, about 65:35, about 60:40, about 55:45, about 50:50, about 45:55, about 40:60, about 35:65, about 30:70, about 25:75, about 20:80, or about 10:90, including all values ​​in between.

[0075] In one embodiment, the solid dispersion contains less than about 10% by weight of any solvent. In one embodiment, the solid dispersion contains less than about 8% by weight of any organic solvent. In one embodiment, the solid dispersion contains less than about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, about 1%, or about 0.5% by weight of any organic solvent (inclusive).

[0076] The solid dispersion may comprise compound A and a polymer carrier, wherein compound A is substantially amorphous and dispersed within a polymer matrix of the polymer carrier. Based on 100 parts by weight of compound A, the solid dispersion comprises about 10 parts by weight to about 55 parts by weight of the polymer carrier. In one embodiment, based on 100 parts by weight of compound A, the solid dispersion comprises about 10 parts by weight to about 50 parts by weight, or about 12 parts by weight to about 50 parts by weight of the polymer carrier. In a specific embodiment, the polymer carrier comprises about 15 parts by weight to about 50 parts by weight. In a more specific embodiment, the polymer carrier comprises about 20 parts by weight to about 50 parts by weight. In still more specific embodiments, the polymer carrier comprises about 25 parts by weight to about 50 parts by weight. In a detailed embodiment, the polymer carrier comprises about 25 parts by weight to about 45 parts by weight.

[0077] The polymer carrier can be selected from any polymer that allows compound A to be sufficiently dispersed, such that a solid dispersion can be formed. The polymer carrier is preferably water-soluble or hydrophilic. The polymer carrier may contain a mixture of two or more polymers. Examples of polymer carriers include, but are not limited to, vinyl polymers and copolymers; vinylpyrrolidine-vinyl acetate copolymers (“PVP-VA”); polyvinyl alcohol; polyvinyl alcohol-polyvinyl acetate copolymers; polyvinyl acetate phthalate (PVAP); polyvinylpyrrolidine (“PVP”); cross-linked polyvinyl chloride; poly(acrylic acid) (such as Carbomer®); acrylate and methacrylate copolymers; methacrylate-methyl methacrylate copolymers (such as Eudragit®); polyethylene glycol (e.g., PEG 4000, PEG 6000, PEG 8000, PEG...). 20000); D-α-tocopherol polyethylene glycol 1000 succinate (TPGS1000); polyethylene-polyvinyl alcohol copolymer (PEG-PVA); polyoxyethylene-polyoxypropylene block copolymer (also known as poloxamer); graft copolymers composed of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate (such as Soluplus®); cellulose polymers, such as hydroxypropyl methylcellulose acetate (“HPMCA”), hydroxypropyl methylcellulose (“HPMC” or hydroxypropyl methylcellulose), hydroxypropyl cellulose (“HPC”), methylcellulose (MC), hydroxyethyl methylcellulose, hydroxyethyl cellulose, The polymer carrier includes hydroxyethyl cellulose acetate and hydroxyethyl ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate (“HPMCAS”), hydroxypropyl methyl cellulose phthalate (“HPMCP”), carboxymethyl ethyl cellulose (“CMEC”), cellulose acetate phthalate (“CAP”), cellulose acetate succinate (“CAS”), hydroxypropyl methyl cellulose acetate phthalate (“HPMCAP”), cellulose trimellitate acetate (“CAT”), hydroxypropyl methyl cellulose trimellitate acetate (“HPMCAT”), and carboxymethyl cellulose butyrate acetate (“CMCAB”); chitosan; phospholipid complexes, etc. The polymer carrier may contain a mixture of two or more of the polymers listed above. In another embodiment, the polymer carrier is hydrophilic.

[0078] In yet another embodiment, the polymer carrier is hydroxypropyl methylcellulose (HPMC). In yet another embodiment, the hydroxypropyl methylcellulose has a methoxy substitution rate of 19%-30% and a hydroxypropyl substitution rate of 4%-12%. In a specific embodiment, the hydroxypropyl methylcellulose is HPMC 2208 or HPMC 2910. In a more specific embodiment, HPMC 2208 has a viscosity of about 100-300,000 mPa·s. In yet another more specific embodiment, HPMC 2910 has a viscosity of about 3,000-10,000 mPa·s.

[0079] In another embodiment, the polymer carrier is hydroxypropyl methylcellulose acetate succinate (HPMCAS). In a specific embodiment, the viscosity of HPMCAS is about 2 to about 4 mPa·s.

[0080] In one embodiment, compound A is dispersed in a polymer matrix in molecular form. In another embodiment, the solid dispersion forms a single phase.

[0081] In another embodiment, in addition to compound A and the polymer carrier, the solid dispersion further comprises up to 5% by weight of a flow aid / adsorbent. In yet another embodiment, the flow aid / adsorbent is colloidal silica.

[0082] In another embodiment, the solid dispersion of compound A does not contain a surfactant.

[0083] Method for manufacturing solid dispersion of compound A

[0084] Solid dispersions are typically prepared using a solvent-based evaporation method. The solvent evaporation method works by dissolving the drug substance and polymer carrier in a suitable solvent (a co-solvent or separate solvents for each of the two components) to form a feed solution, which can then be subjected to a solvent removal process (e.g., spray drying) to form a solid dispersion. Common methods for preparing solid dispersions include:

[0085] (a) Dissolving compound A and at least one polymer support in a suitable co-solvent or two or more separate solvents, and

[0086] (b) Evaporate the co-solvent or separate solvent to form a solid dispersion.

[0087] In step (b), the solvent evaporation is performed by spray drying, melt extrusion, freeze drying, rotary evaporation, drum drying, fluidized bed granulation, or other solvent removal methods. Methods known in the art can be used to prepare solid dispersions of compound A, and these methods are familiar to those skilled in the art. In one embodiment, the solid dispersion is prepared by conventional spray drying technology. In another embodiment, the solvent evaporation method used for preparation is vacuum evaporation. In yet another embodiment, the solid evaporation used is fluidized bed granulation. In other embodiments, other techniques known in the art can be used to prepare solid dispersions, such as hot melt extrusion, kneading, co-milling, simple melting, microwave-induced melting, KinettiSol® dispersion, simple solvent evaporation, freeze drying, electrospinning, fluidized bed coating, solvent melting, supercritical carbon dioxide, and coprecipitation methods.

[0088] Exemplary methods for producing solid dispersions of compound A by spray drying and by hot melt extrusion, as well as solvent evaporation methods, are briefly described below.

[0089] 1. Solid dispersion obtained by spray drying

[0090] When available, a suitable co-solvent or co-solvent system for both compound A and the polymer support can be used. In the case of a co-solvent, a pre-weighed amount of compound A is slowly added to the spray solution while mixing, followed by the slow addition of the polymer support (e.g., HPMC) to produce a feed solution. Alternatively, separate solvents for compound A and the polymer support can be used and combined to obtain the feed solution.

[0091] The resulting feed solution is spray-dried using a standard pharmaceutical-grade spray dryer (such as the MS-150). After spray drying, the spray-dried dispersion (SDD) can be dried in an oven until residual acetone is below 5000 ppm according to ICH guidelines. The dried SDD is then transferred to a suitable container with a desiccant to prevent moisture absorption. The SDD can be further formulated, for example, by dry granulation and blending, as described below.

[0092] Suitable solvents for spray drying are solvents or mixtures of solvents in which both compound A and the polymer carrier have sufficient solubility (greater than 1 mg / mL). If each component of the solid dispersion requires a different solvent to achieve the desired solubility, separate solvents may be used. The solvent may be volatile, with a boiling point of 150ºC or lower. Furthermore, the solvent should have relatively low toxicity, and the solvent should be removed from the dispersion to a level acceptable according to the International Committee on Harmonization (ICH) guidelines. Removing the solvent to this level may require subsequent processing steps, such as tray drying. Examples of suitable solvents include, but are not limited to, alcohols such as methanol, ethanol, n-propanol, isopropanol (“IPA”), and butanol; ketones such as acetone, methyl ethyl ketone (“MEK”), and methyl isobutyl ketone; esters such as ethyl acetate (“EA”) and propyl acetate; and various other solvents such as tetrahydrofuran (“THF”), acetonitrile (“ACN”), dichloromethane, toluene, and 1,1,1-trichloroethane; and any combinations thereof. Low-volatility solvents, such as dimethyl acetate or dimethyl sulfoxide (“DMSO”), can be used. Mixtures of solvent and water can also be used, provided the polymer carrier is sufficiently soluble to make the spray drying method feasible. Typically, due to the hydrophobic nature of the low-solubility drug, non-aqueous solvents can be used, meaning the solvent contains less than about 10% by weight of water.

[0093] In some embodiments, the polymer carrier is HPMC, and the suitable solvent for spray drying is a separate solvent system made of ethanol and water, wherein ethanol is used for compound A and water is used for HPMC. In a more specific embodiment, water is used in an excess of 100-140 times the weight of HPMC and ethanol in an excess of 5-12 times the weight of compound A.

[0094] Suitable spray drying parameters are known in the art, and the selection of appropriate parameters for spray drying is within the knowledge of a skilled craftsman. For example, the target feed concentration is typically from about 1% to about 50%, and the viscosity is from about 1 cP to about 300 cP, or from about 1 cP to about 80 cP, or from about 4 cP to 60 cP. The inlet temperature of the spray drying instrument is typically from about 50ºC to 190ºC, while the outlet temperature is from about 30ºC to 90ºC. Two-fluid nozzles and / or hydraulic nozzles can be used to spray dry compound A. In some cases, the particle size (D) of the material being spray dried is... 90 Typically, particle sizes are less than approximately 500 μm, 200 μm, 150 μm, 100 μm, 50 μm, or 25 μm. In other cases, if further particle size reduction is required, a milling step can be used.

[0095] 2. Solid dispersions obtained by hot melt extrusion

[0096] Solid dispersions of amorphous compound A (referred to herein as formulations, HMIE solid dispersion formulations, or HME formulations) can be formulated using a hot melt extrusion method, which includes hot melt extrusion, milling, blending, and optionally tableting. Multiple hot melt extrusion and milling batches can be combined for blending and tableting to produce larger batch sizes.

[0097] The amount of material used to prepare the solid dispersion is within the weight percentage or ratio range of any embodiment described in this disclosure.

[0098] [Hot melt extrusion and milling]

[0099] A suitable amount of compound A and one or more solubilizers (such as copovidone as a non-limiting example) are added to the blender and blended for about 5 minutes. Non-limiting examples of blending / mixing equipment that can be used include diffusion mixers (e.g., V-type blenders or box blenders) or convection mixers (e.g., vertical high-intensity mixers). In another embodiment, a V-type blender is used for blending / mixing. The contents are then sieved, transferred back to the blender, and blended for about 10 minutes.

[0100] Weigh an appropriate amount of one or more solubilizers (such as polyethylene glycol 400 (PEG400)) into a suitable container. Set up the extruder using an additional approximately 20 g of PEG 400, which is not part of the solid dispersion. Set up the extruder using an appropriate setpoint and adjust the flow rate using approximately 20 g of PEG 400.

[0101] Add the blend to the feed hopper and begin the extrusion process. Adjust and monitor the extrusion parameters as needed. Collect the resulting pellet extrudate, which can be weighed and placed in a suitable container.

[0102] Pharmaceutical compositions, solid dosage forms

[0103] In another aspect, the present invention provides a pharmaceutical composition comprising a solid dispersion of compound A as described above and a pharmaceutically acceptable excipient.

[0104] The pharmaceutical composition comprises

[0105] a) A solid dispersion of compound A, comprising approximately 20% to approximately 50% w / w.

[0106] b) Approximately 25% to approximately 70% w / w of fillers / adhesives,

[0107] c) Approximately 4.0% to approximately 20% w / w of disintegrant.

[0108] d) Approximately 0.25% to approximately 5.0% w / w of flow aid / adsorbent, and

[0109] e) Lubricant of approximately 0.5% to approximately 2.5% w / w;

[0110] The compound A solid dispersion is as described above. The compound A solid dispersion is an amorphous solid dispersion. More specifically, the compound A solid dispersion comprises compound A, which is substantially amorphously dispersed in a polymer matrix of a hydrophilic polymer carrier at an amount of about 64.5% to about 91% w / w, the weight percentage being based on the total weight of compound A and the hydrophilic polymer carrier.

[0111] The filler / binder in the pharmaceutical composition may be selected from starch, sugars, disaccharides, sucrose, lactose, lactose monohydrate, polysaccharides, cellulose, cellulose ethers, hydroxypropyl cellulose, sugar alcohols, xylitol, sorbitol, maltitol, microcrystalline cellulose, calcium carbonate or sodium carbonate, dicalcium phosphate, compressible sugars, calcium hydrogen phosphate dihydrate, mannitol, tricalcium phosphate, and any combination thereof.

[0112] The disintegrant in the pharmaceutical composition may be selected from starch, sodium starch glycolate, croscarmellose sodium cellulose, cross-linked polyvinyl cellulose, microcrystalline cellulose, modified corn starch, sodium carboxymethyl starch, polyvinyl cellulose, pregelatinized starch, alginate, and any combination thereof.

[0113] In one embodiment, the pharmaceutical composition comprises c) about 4.5% to about 15% w / w of a disintegrant. In another embodiment, the pharmaceutical composition comprises c) about 4.9% to about 12% w / w of a disintegrant. In yet another embodiment, the pharmaceutical composition comprises c) about 4.9% to about 10% w / w of a disintegrant.

[0114] The gliding agent / adsorbent in the pharmaceutical composition may be selected from colloidal silica, talc, fumed silica, starch, starch derivatives, bentonite, and any combination thereof.

[0115] The lubricant in the pharmaceutical composition may be selected from magnesium stearate, stearic acid, silicon dioxide, fat, calcium stearate, polyethylene glycol, sodium stearoyl fumarate or talc, lauric acid, oleic acid, C8 / C10 fatty acids and any combination thereof.

[0116] Examples of polymer carriers include, but are not limited to, polyvinylpyrrolidone-vinyl acetate copolymer (“PVP-VA”); polyvinyl alcohol; polyvinyl alcohol-polyvinyl acetate copolymer; polyvinyl acetate phthalate (PVAP); polyvinylpyrrolidone (“PVP”); polyethylene glycol (e.g., PEG 4000, PEG 6000, PEG 8000, PEG 20000); D-α-tocopherol polyethylene glycol 1000 succinate (TPGS). 1000); polyethylene glycol polyvinyl alcohol copolymer (PEG-PVA); cellulose polymers, such as hydroxypropyl methylcellulose acetate (“HPMCA”), hydroxypropyl methylcellulose (“HPMC” or hydroxypropyl methylcellulose), hydroxypropyl cellulose (“HPC”), methylcellulose (MC), hydroxyethyl methylcellulose, hydroxyethyl cellulose, hydroxyethyl cellulose acetate and hydroxyethyl ethyl cellulose, hydroxypropyl methylcellulose acetate succinate (“HPMCAS”), hydroxypropyl methylcellulose phthalate (“HPMCP”), carboxymethyl ethyl cellulose (“CMEC”), cellulose phthalate acetate (“CAP”), cellulose succinate acetate (“CAS”), hydroxypropyl methylcellulose acetate phthalate (“HPMCAP”), cellulose trimellitate acetate (“CAT”), hydroxypropyl methylcellulose trimellitate. Mixtures of two or more polymers listed above can be used as hydrophilic polymer carriers. In a specific embodiment, the hydrophilic polymer carrier is hydroxypropyl methylcellulose (HPMC). In another specific embodiment, hydroxypropyl methylcellulose has a methoxy substitution rate of 19%-30% and a hydroxypropyl substitution rate of 4%-12%. In a specific embodiment, hydroxypropyl methylcellulose is HPMC 2208 or HPMC 2910. In a more specific embodiment, HPMC 2208 has a viscosity of about 2,500-10,000 mPa·s. In yet another more specific embodiment, HPMC 2910 has a viscosity of about 100-300,000 mPa·s. In yet still more specific embodiments, the polymer carrier is hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0117] In another embodiment, the compound A solid dispersion is formed by spray drying. In yet another specific embodiment, the spray-dried compound A solid dispersion comprises hydroxypropyl methylcellulose as a hydrophilic polymer carrier.

[0118] In yet another embodiment, the pharmaceutical composition is a solid oral dosage form in the form of tablets, pills, capsules, granules, modulated release formulations, controlled release formulations, sustained-release formulations, immediate-release formulations, or powders.

[0119] In another embodiment, the pharmaceutical composition or spray-dried formulation described herein provides improved pharmacokinetic (PK) characteristics compared to a reference tablet formulation of compound A, wherein the reference tablet formulation is in crystalline form rather than in the form of an amorphous solid dispersion. In a specific embodiment, the pharmaceutical composition is a tablet or capsule that provides 2-3 times the drug exposure (i.e., Cp) in humans or test animals compared to a reference tablet formulation containing the same amount of compound A but not an amorphous solid dispersion of compound A. max The amount increases. For pharmaceutical compositions or formulations containing compound A in its non-free base form, "equivalent amount" means the equivalent amount of the free base in its anhydrous form used for comparison. In another embodiment, the drug exposure (C) is... max The comparison was based on beagles, meaning the test animals were beagles.

[0120] In another specific embodiment, the pharmaceutical composition or spray-dried formulation described herein, wherein the pharmaceutical composition is a tablet or capsule, provides a 2-3 fold increase in area under the curve (AUC) in humans or test animals compared to a reference tablet formulation containing the same amount of compound A but not containing an amorphous solid dispersion of compound A (i.e., the reference tablet has crystalline compound A). For pharmaceutical compositions or formulations containing compound A in its non-free base form, "the same amount" means an equivalent amount in its anhydrous free base form used for comparison. In another embodiment, the area under the curve comparison is based on beagle dogs, i.e., the test animals are beagle dogs.

[0121] In yet another embodiment, the pharmaceutical composition or spray-dried formulation described herein provides immediate release of compound A, wherein the immediate-release pharmaceutical composition is a tablet or capsule. In still another embodiment, the immediate-release pharmaceutical composition comprises c) about 4.5% to about 15% w / w of a disintegrant. In still another embodiment, the pharmaceutical composition comprises c) about 4.9% to about 12% w / w of a disintegrant. In even still another embodiment, the pharmaceutical composition comprises c) about 4.9% to about 10% w / w of a disintegrant.

[0122] In another aspect, the present invention provides a solid oral formulation comprising a solid dispersion of compound A, which provides improved pharmacokinetic (PK) characteristics compared to a reference tablet formulation comprising the same amount of compound A in its free base form but not in an amorphous solid dispersion form. For a solid oral formulation of compound A comprising a non-free base form, "the same amount" means an equivalent amount in the anhydrous form of the free base used for comparison. The solid dispersion of compound A in the solid oral formulation comprises substantially amorphous compound A, which is dispersed in a polymer matrix of hydroxypropyl methylcellulose at an amount of about 64.5% to about 91% w / w, based on the combined weight of compound A and hydroxypropyl methylcellulose. In a particular embodiment, the solid oral formulation is a tablet.

[0123] In the implementation scheme, the solid oral formulation is a pharmaceutical composition that provides 2-3 times the drug exposure (i.e., C) in humans or test animals compared to a reference tablet formulation containing the same amount of compound A but not containing an amorphous solid dispersion of compound A. max The drug exposure (C) increases. In specific implementation plans, drug exposure (C) is... max The comparison is based on beagle dogs, meaning the test animals are beagle dogs. In another specific implementation, the solid oral formulation is a tablet or capsule.

[0124] In another embodiment, the solid oral formulation is a pharmaceutical composition that provides a 2-3 fold increase in area under the curve (AUC) in humans or test animals compared to a reference tablet formulation containing the same amount of compound A but not containing an amorphous solid dispersion of compound A. In a specific embodiment, the AUC comparison is based on beagle dogs, i.e., the test animals are beagle dogs. In yet another specific embodiment, the solid oral formulation is a tablet or capsule. In still another embodiment, the solid oral formulation is a tablet containing c) about 4.9% to about 10% w / w of a disintegrant.

[0125] In yet another embodiment, the solid dispersion of compound A in the solid oral formulation is formed by solvent evaporation methods (such as spray drying and fluidized bed granulation).

[0126] In some embodiments, the compositions described herein (including, for example, the pharmaceutical compositions described herein) are formulated into tablets comprising a solid dispersion. Such tablets may be referred to herein as "solid dispersion tablets". In some embodiments, the compositions described herein (including, for example, the pharmaceutical compositions described herein) are formulated into tablets comprising a spray-dried solid dispersion. Such tablets may be referred to herein as "spray-dried solid dispersion tablets".

[0127] In some embodiments, solid dosage forms (e.g., tablets, effervescent tablets, and capsules) are prepared by mixing compound A with one or more pharmaceutical excipients to form a bulk blend composition. When these bulk blend compositions are referred to as homogeneous, it means that particles of compound A are uniformly dispersed throughout the composition, such that the composition can be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. Individual unit doses may also include film coatings that disintegrate upon oral ingestion or contact with a diluent. These formulations can be manufactured using conventional pharmacological techniques. Conventional pharmacological techniques include, for example, one or a combination of the following methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry granulation or non-aqueous granulation, (5) wet granulation, or (6) melt processing.

[0128] Dry granulation and blending of spray-dried solid dispersions with in-particle and out-of-particle excipients

[0129] The technique of dry granulation and blending a solid dispersion of compound A with a pharmaceutical composition containing said solid dispersion to manufacture tablets is familiar to those skilled in the art. The procedure is briefly outlined below.

[0130] Compressed tablets are solid dosage forms prepared by compacting the bulk blend of the formulation described above. In various embodiments, compressed tablets designed to dissolve in the mouth will include one or more flavoring agents. In other embodiments, compressed tablets will include a film encapsulating the final compressed tablet. In some embodiments, film coating may provide a delayed release of compound A from the formulation. In other embodiments, film coating may contribute to patient compliance (e.g., Opadry® coating or sugar coating). Film coatings (including Opadry®) typically range from about 1% to about 3% of the tablet weight. In other embodiments, compressed tablets include one or more additional excipients.

[0131] The spray-dried solid dispersion and the intragranular excipient can be dispensed into suitable containers. The intragranular excipient used is one or more lubricants (such as sodium stearoyl fumarate as a non-limiting example); one or more flow aids / adsorbents (such as colloidal silica as a non-limiting example); one or more disintegrants (such as croscarmellose sodium as a non-limiting example); and one or more fillers / binders (such as mannitol and microcrystalline cellulose as non-limiting examples). The spray-dried solid dispersion and the intragranular excipient are added to a blender of appropriate size and blended. The blend is passed through a sieve (such as a comul) to improve blend homogeneity and remove large particles. The blend is further blended and then discharged into a suitable container.

[0132] The blend is then dry-granulated to produce strips using a suitable roller press (such as a TFC-220 roller press or others) and by using selected process parameters (roller type, RPM, and roller pressure). The resulting strips are then milled (this can be done, for example, using a comul) to produce free-flowing granules.

[0133] Then, an appropriate amount of excipient is added. The excipient includes one or more lubricants (such as sodium stearoyl fumarate as a non-limiting example); one or more flow aids / adsorbents (such as colloidal silica and croscarmellose sodium as non-limiting examples); granulation and blending are then performed to obtain a blend for tablet compression.

[0134] The granulated spray-dried solid dispersion can then be tableted and packaged as described below.

[0135] Tableting

[0136] A rotary tableting machine can be used to compress granulated, spray-dried solid dispersions. The rotary tableting machine can be configured to produce target tablet weight, hardness, and friability. Weight and hardness can be monitored during initial startup and at approximately 15-minute intervals. Metal checks and weight sorting of tablets are possible.

[0137] Pharmaceutical compositions for use in capsules

[0138] In another aspect, the present invention provides a pharmaceutical composition for use in capsules, the pharmaceutical composition comprising the solid dispersion of compound A described above and a pharmaceutically acceptable excipient.

[0139] The pharmaceutical composition comprises:

[0140] a) A solid dispersion of compound A, approximately 50% to approximately 97.5% w / w;

[0141] b) Fillers / adhesives of approximately 0% to approximately 48% w / w;

[0142] c) Disintegrants of approximately 0% to approximately 20% w / w;

[0143] d) Approximately 0% to approximately 4.0% w / w of flow aid / adsorbent; and

[0144] e) Lubricant of about 0.2% to about 4.0% w / w.

[0145] Manufacturing capsules

[0146] Applying pharmaceutical technology to a solid dispersion of compound A and a pharmaceutical composition containing said solid dispersion to form capsules is a process familiar to those skilled in the art. The procedure is briefly outlined below.

[0147] In some embodiments, the preparation is made by placing the bulk blend of the solid formulation inside a capsule. In some embodiments, the solid formulation is placed in a soft gelatin capsule. In some embodiments, the formulation is placed in a hard gelatin capsule. In some embodiments, the solid formulation is placed in a standard gelatin capsule or a non-gelatin capsule (such as a capsule containing HPMC). In some embodiments, the solid formulation is placed in a sprinkle capsule, which can be swallowed whole or opened and its contents sprinkled onto food before consumption. In some embodiments, the therapeutic dose is divided into multiple (e.g., two, three, or four) capsules. In some embodiments, the entire dose of the formulation is delivered in capsule form.

[0148] Capsules can be of any shape or size. The shape and size of capsules can vary depending on the method of preparation and intended use. Hard-shell capsule sizes are conventionally named (000), (00), (0), (1), (2), (3), (4), and (5), where the larger number corresponds to the smaller size. For example, one teaspoon can fill approximately seven size "0" capsules and approximately five size "00" capsules. Size "00" capsules are typically the largest size intended for human consumption. Soft gel capsule sizes range from 1 to 120, depending on the desired shape and other characteristics of the product. Typically, shapes include, but are not limited to, round, oval, rectangular, tubular, and special shapes (such as animal-shaped, star-shaped, heart-shaped, or square). For example, capsules can be oval and be sizes 2, 3, 4, 5, 6, 7, 7.5, 8.5, 10, 12, 16, 20, 30, 40, 60, 65, 80, or larger. The capsules may be, for example, rectangular and have dimensions of 3, 4, 5, 6, 8, 9.5, 11, 12, 14, 16, 20, 22, 24 or larger. Other exemplary capsules include round capsules, such as those with dimensions of 1, 2, 3, 4, 5, 6, 7, 9, 15, 20, 28, 40, 90 or larger, and tubular capsules, such as those with dimensions of 5, 6, 8, 17.5, 30, 45, 55 or 120. The capsules may be of any color and have any amount of transparency; for example, the capsules may be, but are not limited to, opaque capsules, translucent capsules, or pearlescent capsules. In some embodiments, a solid formulation is filled into a hard gelatin capsule. In some embodiments, the capsule is a two-piece hard gelatin capsule. In some embodiments, the capsule is sealed. In some embodiments, the capsule is unsealed.

[0149] Therapeutic uses and dosage

[0150] In another aspect, this document provides a method for treating a patient by administering the pharmaceutical composition described above. In some embodiments, this document provides a method for inhibiting the activity of one or more tyrosine kinases (such as FLT3, SYK, JAK, and mutant c-KIT (D815H, D816V)) in a mammal or for treating a disease, disorder, or condition that would benefit from inhibition of one or more tyrosine kinases (such as FLT3, SYK, JAK, and mutant c-KIT (D815H, D816V)), said method comprising administering to said mammal a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof, its hydrate, or a hydrate of a pharmaceutically acceptable salt thereof.

[0151] In some implementations, the pharmaceutical composition is administered to a human.

[0152] In some implementations, the pharmaceutical composition is administered orally.

[0153] In other embodiments, a pharmaceutical composition is used to formulate a drug for inhibiting tyrosine kinase activity.

[0154] In yet another aspect, this document provides a method for treating cancer in mammals, the method comprising administering to the mammal a pharmaceutical composition or formulation comprising an amorphous solid dispersion of compound A as described herein. In some embodiments, the cancer is a B-cell malignancy. In some embodiments, the cancer is leukemia. In yet another embodiment, the leukemia is acute myeloid leukemia.

[0155] In one embodiment, the pharmaceutical composition is a solid dosage form containing a therapeutically effective amount of compound A. In some embodiments, the solid dosage form can be administered via multiple routes, depending on the desired treatment and the area to be treated. In another embodiment, the treatment is for cancer. In yet another embodiment, the cancer is leukemia. In yet another embodiment, the leukemia is acute myeloid leukemia. In some embodiments, administration is oral. Oral administration may include formulations for once-daily or twice-daily (BID) administration.

[0156] Pharmaceutical compositions comprising a solid dispersion of compound A can be formulated into unit dosage forms, each dose containing about 1 mg to about 1,000 mg (1 g), more typically about 5 mg to about 100 mg of compound A (the active ingredient). The term "unit dosage form" refers to a physically discrete unit suitable as a single dose for human subjects and other patients, each unit containing a predetermined amount of the active ingredient (i.e., compound A or its pharmaceutically acceptable salts, amorphous forms, hydrates, etc.) calculated to produce the desired therapeutic effect when combined with suitable pharmaceutical excipients.

[0157] In some embodiments, the pharmaceutical composition is formulated as a dosage form of 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, or 250 mg. In some embodiments, the solid preparation is formulated as a dosage form of 10 mg, 20 mg, or 80 mg.

[0158] In some embodiments, the compositions provided herein contain about 1 mg to about 50 mg of active ingredient compound A. Those skilled in the art will understand that this includes compounds or compositions containing about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of active ingredient. In some embodiments, the compositions provided herein contain about 10 mg of active ingredient.

[0159] In some embodiments, the compositions provided herein contain about 50 mg to about 500 mg of active ingredient. Those skilled in the art will understand that this includes compounds or compositions containing about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about 450 mg to about 500 mg of active ingredient.

[0160] In some embodiments, the compositions provided herein contain about 500 mg to about 1,000 mg of active ingredient. Those skilled in the art will understand that this includes compounds or compositions containing about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of active ingredient.

[0161] The daily dose of compound A or its hydrate, a pharmaceutically acceptable salt of compound A, or a hydrate of its salt may vary within a wide range or any range thereof, from 1.0 mg to 10,000 mg / adult / day or higher. In some embodiments, for oral administration, the pharmaceutical composition may be provided in tablet form containing about 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, and 500 mg of the active ingredient for symptomatic dose adjustment in the patient to be treated. An effective amount of the drug is typically supplied at dose levels of about 0.1 mg / kg to about 1000 mg / kg body weight / day or any range thereof. In some embodiments, the range is about 0.5 to about 500 mg / kg body weight / day or any range thereof. In some embodiments, it is about 1.0 to about 250 mg / kg body weight / day or any range thereof. In some embodiments, the dosage is about 0.1 to about 100 mg / kg body weight / day or any range thereof. In some embodiments, the range is about 0.1 to about 50.0 mg / kg body weight / day or any amount or range thereof. In some embodiments, the range is about 0.1 to about 15.0 mg / kg body weight / day or any range thereof. In some embodiments, the range is about 0.5 to about 7.5 mg / kg body weight / day or any amount or range thereof. A pharmaceutical composition containing compound A, its hydrate, its pharmaceutically acceptable salt, or a hydrate of a pharmaceutically acceptable salt thereof may be administered in a regimen of 1 to 4 times daily or as a single daily dose.

[0162] This disclosure also relates to a method for treating cancer, the method comprising administering to a subject in need any of the pharmaceutical compositions disclosed herein. This disclosure also relates to a method for treating cancer, the method comprising administering to a subject in need any of the amorphous forms of compound A disclosed herein.

[0163] In a specific embodiment, the cancer is leukemia, such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute promyelocytic leukemia (APL), hairy cell leukemia, or chronic neutrophilic leukemia (CNL). In a specific embodiment, the leukemia is AML. In another specific embodiment, the leukemia includes leukemia cancer with a mutation in the FLT3 gene. In another specific embodiment, the FLT3 gene has an internal tandem repeat (ITD) mutation. In yet another specific embodiment, the FLT3 gene has at least one FLT3 mutation selected from F691L, D835Y, D835F, D835I, D835H, D835V, and D835A.

[0164] List of implementation plans

[0165] 1. A solid dispersion comprising: compound A; and

[0166] The polymer carrier is based on about 10 parts by weight to about 55 parts by weight of 100 parts by weight of compound A.

[0167] The compound A thereon is substantially amorphous and dispersed in the polymer matrix of the polymer carrier within the solid dispersion.

[0168] 2. The solid dispersion according to embodiment 1, wherein, based on 100 parts by weight of compound A, the amount of the polymer carrier is about 10 parts by weight to about 50 parts by weight, particularly about 12 parts by weight to 50 parts by weight, more particularly about 15 parts by weight to 50 parts by weight, and still more particularly about 20 parts by weight to about 50 parts by weight.

[0169] 3. The solid dispersion according to embodiment 1, wherein the polymer carrier is selected from polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA); polyvinyl alcohol; polyvinyl alcohol-polyvinyl acetate copolymer; polyvinyl acetate phthalate (PVAP); polyvinylpyrrolidone (PVP); polyethylene glycol (e.g., PEG 4000, PEG 6000, PEG 8000, PEG 20000); D-α-tocopherol polyethylene glycol 1000 succinate (TPGS). 1000); polyethylene glycol-polyvinyl alcohol copolymer (PEG-PVA); cellulose polymers such as hydroxypropyl methylcellulose acetate (“HPMCA”), hydroxypropyl methylcellulose (“HPMC” or hydroxypropyl methylcellulose), hydroxypropyl cellulose (“HPC”), methylcellulose (MC), hydroxyethyl methylcellulose, hydroxyethyl cellulose, hydroxyethyl cellulose acetate and hydroxyethyl ethyl cellulose, hydroxypropyl methylcellulose acetate succinate (“HPMCAS”), hydroxypropyl methylcellulose phthalate (“HPMCP”), carboxymethyl ethyl cellulose (“CMEC”), cellulose acetate phthalate (“CAP”), cellulose acetate succinate (“CAS”), hydroxypropyl methylcellulose acetate phthalate (“HPMCAP”); D-α-tocopherol polyethylene glycol succinate (TPGS); chitosan; phospholipid complexes; and any mixtures thereof.

[0170] 4. The solid dispersion according to embodiment 3, wherein the polymer carrier is a hydrophilic carrier.

[0171] 5. The solid dispersion according to embodiment 2, wherein the polymer carrier is one or more cellulose derivatives selected from the following: hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, cellulose acetate, and cellulose acetate phthalate.

[0172] 6. The solid dispersion according to embodiment 1, wherein the solid dispersion is formed by solvent evaporation.

[0173] 7. The solid dispersion according to embodiment 1, wherein the solvent evaporation method is spray drying or fluidized bed granulation.

[0174] 8. The solid dispersion according to embodiment 1, wherein the solid dispersion further comprises a flow aid / adsorbent.

[0175] 9. A pharmaceutical composition comprising...

[0176] a) A solid dispersion of compound A, approximately 20% to approximately 50% w / w;

[0177] b) Approximately 25% to approximately 70% w / w of fillers / adhesives;

[0178] c) Approximately 4.0% to approximately 20% w / w of disintegrant;

[0179] d) Approximately 0.25% to approximately 5.0% w / w of flow aid / adsorbent; and

[0180] e) Lubricant of approximately 0.5% to approximately 2.5% w / w;

[0181] Wherein, compound A is a compound of compound A or a pharmaceutically acceptable salt thereof:

[0182] [Compound A]

[0183] ,and

[0184] The solid dispersion of compound A comprises substantially amorphous compound A, which is dispersed in the polymer matrix of the hydrophilic polymer carrier at an amount of about 64.5% to about 91% w / w, based on the combined weight of compound A and the hydrophilic polymer carrier.

[0185] 10. The pharmaceutical composition according to embodiment 9, wherein the pharmaceutical composition is selected from the following solid oral dosage forms: tablets, powders, granules, capsules, and pills.

[0186] 11. The pharmaceutical composition according to embodiment 10, wherein the solid oral dosage form is a tablet.

[0187] 12. The pharmaceutical composition according to embodiment 9, wherein the hydrophilic polymer carrier is hydroxypropyl methylcellulose.

[0188] 13. The pharmaceutical composition according to embodiment 9, wherein the filler / binder is selected from starch, sugars, disaccharides, sucrose, lactose, lactose monohydrate, polysaccharides, cellulose, cellulose ethers, hydroxypropyl cellulose, sugar alcohols, xylitol, sorbitol, maltitol, microcrystalline cellulose, calcium carbonate or sodium carbonate, dicalcium phosphate, compressible sugars, calcium hydrogen phosphate dihydrate, mannitol, tricalcium phosphate, and any combination thereof.

[0189] 14. The pharmaceutical composition according to embodiment 9, wherein the disintegrant is selected from starch, sodium starch glycolate, croscarmellose sodium, cross-linked polyvinyl cellulose, microcrystalline cellulose, modified corn starch, sodium carboxymethyl starch, polyvinyl cellulose, pregelatinized starch, alginate, and any combination thereof.

[0190] 15. The pharmaceutical composition according to embodiment 9, wherein the gliding agent / adsorbent is selected from colloidal silica, talc, fumed silica, starch, starch derivatives, bentonite, and any combination thereof.

[0191] 16. The pharmaceutical composition according to embodiment 9, wherein the lubricant is selected from magnesium stearate, stearic acid, silica, fat, calcium stearate, polyethylene glycol, sodium stearoyl fumarate or talc, lauric acid, oleic acid, C8 / C10 fatty acids and any combination thereof.

[0192] 17. The pharmaceutical composition according to embodiment 9, wherein the solid dispersion of compound A is formed by spray drying.

[0193] 18. The pharmaceutical composition according to embodiment 9, wherein the pharmaceutical composition comprises c) about 4.5% to about 15% w / w of a disintegrant, more specifically c) about 4.9% to about 12% w / w of a disintegrant, still more specifically c) about 4.9% to about 10% w / w of a disintegrant.

[0194] 19. The pharmaceutical composition according to embodiment 11, wherein the tablet provides about 2 to about 3 times the increase in drug exposure relative to a reference tablet containing the same amount of compound A but not containing an amorphous solid dispersion of compound A.

[0195] 20. The pharmaceutical composition according to embodiment 20, wherein the comparison of drug exposure is based on beagle dogs.

[0196] 21. The pharmaceutical composition according to embodiment 11, wherein the tablet provides about 2 to about 3 times the area under the curve (AUC) increase relative to a reference tablet containing the same amount of compound A but not containing an amorphous solid dispersion of compound A.

[0197] 22. The pharmaceutical composition according to embodiment 21, wherein the area under the curve comparison is based on beagle dogs.

[0198] 23. A pharmaceutical composition for use in capsules, said pharmaceutical composition comprising...

[0199] a) A solid dispersion of compound A, approximately 50% to approximately 97.5% w / w;

[0200] b) Fillers / adhesives of approximately 0% to approximately 48% w / w;

[0201] c) Disintegrants of approximately 0% to approximately 20% w / w;

[0202] d) Approximately 0% to approximately 4.0% w / w of flow aid / adsorbent; and

[0203] e) Lubricant of approximately 0.2% to approximately 4.0% w / w;

[0204] Wherein compound A is the following compound A or a pharmaceutically acceptable salt thereof:

[0205] [Compound A]

[0206] ,and

[0207] The solid dispersion of compound A comprises substantially amorphous compound A, which is dispersed in the polymer matrix of the hydrophilic polymer carrier at an amount of about 64.5% to about 91% w / w, based on the combined weight of compound A and the hydrophilic polymer carrier.

[0208] 24. The pharmaceutical composition according to embodiment 9, wherein the pharmaceutical composition comprises about 4.9% to about 12% w / w of a disintegrant.

[0209] 25. A solid oral formulation comprising about 20% to about 50% w / w of a solid dispersion of compound A.

[0210] The oral formulation described herein provides approximately 2 to 3 times the increase in drug exposure compared to a reference tablet containing the same amount of compound A but excluding compound A amorphous solid dispersion.

[0211] The solid dispersion of compound A comprises substantially amorphous compound A, which is dispersed in a polymer matrix of hydroxypropyl methylcellulose at an amount of about 64.5% to about 91% w / w, based on the combined weight of compound A and hydroxypropyl methylcellulose.

[0212] 26. A solid oral formulation comprising about 20% to about 50% w / w of a solid dispersion of compound A.

[0213] The oral formulation described herein provided an area under the curve that was approximately 2 to 3 times greater than that of a reference tablet containing the same amount of compound A but not containing an amorphous solid dispersion of compound A.

[0214] The solid dispersion of compound A comprises substantially amorphous compound A, which is dispersed in a polymer matrix of hydroxypropyl methylcellulose at an amount of about 64.5% to about 91% w / w, based on the combined weight of compound A and hydroxypropyl methylcellulose.

[0215] 27. The solid oral form according to embodiment 25 or claim 26, wherein the solid dispersion of compound A is formed by spray drying.

[0216] 28. A solid oral formulation comprising about 20% to about 50% w / w of a solid dispersion of compound A, and

[0217] The solid dispersion of compound A comprises substantially amorphous compound A, which is dispersed in a polymer matrix of hydroxypropyl methylcellulose at an amount of about 64.5% to about 91% w / w, based on the combined weight of compound A and hydroxypropyl methylcellulose.

[0218] 29. The solid oral formulation according to embodiment 26 or 28, wherein the solid oral formulation further comprises about 4.9% to about 12% w / w of a disintegrant.

[0219] 30. The solid oral formulation according to embodiment 29, wherein the solid oral formulation further comprises microcrystalline cellulose and mannitol.

[0220] 31. A method of treating cancer in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the pharmaceutical composition or formulation described herein, the pharmaceutical composition or formulation comprising an amorphous solid dispersion of compound A.

[0221] 32. The method according to embodiment 31, wherein the cancer is leukemia.

[0222] 33. The method according to embodiment 32, wherein the leukemia is acute myeloid leukemia.

[0223] 34. The method according to embodiment 31, wherein the pharmaceutical composition is a capsule.

[0224] 35. The method according to embodiment 31, wherein the pharmaceutical composition or formulation is administered in combination with another therapeutic agent.

[0225] Example

[0226] For illustrative purposes, the following examples are included. However, it should be understood that these examples are not intended to limit the invention, but merely to suggest methods for carrying out the invention. Those skilled in the art will recognize that the described chemical reactions can be readily adapted to prepare the compounds described herein, and alternative methods for preparing said compounds are considered to be within the scope of the invention. For example, the compounds described herein can be successfully synthesized by modifications obvious to those skilled in the art, such as by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art besides those described, and / or by conventionally altering the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be considered suitable for preparing the compounds described herein. Those skilled in the art will also recognize that the described solid dispersions and compositions can be readily adapted to prepare other dispersions and compositions, and alternative methods and alternative compositions for preparing said dispersions and compositions are considered to be within the scope of the invention.

[0227] Experimental Example 1: Analysis of the amorphous solid dispersion of compound A

[0228] In this embodiment, spray drying was used to prepare an amorphous solid dispersion of compound A. As shown in Table 1 below, the crystalline compound A monohydrate in its free base form was dissolved in ethanol, and the polymer carrier HPMC 2910 (AnycoatC, Lotte Fine Chemical, Korea; 4.5 mPa·s, methoxy content 28%-30%, hydroxypropoxy content 7%-12%) was dissolved in water, as shown in Table 1 below. The resulting aqueous and ethanol solutions were then combined at a ratio of 3200:800 to prepare the spray-drying feed solution. The feed solution was sprayed using a small spray dryer B-290 (Buchi, Switzerland). Briefly, the spray dryer was preheated, with the inlet and outlet temperatures set to 80ºC and 37ºC, respectively. At the end of preheating, the spraying of the feed was started, with the product temperature set to 35ºC and the pump set to 8-10 rpm, accompanied by magnetic stirring at 150 rpm to prevent precipitation. The spray-dried material was then collected and dried in a chamber at 60ºC for 2 hours.

[0229] For comparison, in Comparative Example 1, the crystalline compound A monohydrate was used as an undispersed crystalline solid formulation of compound A without processing; in Comparative Example 2, a spray-dried formulation of compound A without a polymer carrier was prepared; and in Comparative Example 3, a spray-dried dispersion with an excess of polymer carrier was prepared. The compositions of the obtained spray-dried examples and the formulations of the comparative examples are given in Table 1 below.

[0230] Composition of the preparation

[0231] The physical appearance (scanning electron microscopy), solubility, and crystallinity (X-ray diffraction and differential scanning calorimetry) of the formulations of the examples and the formulations of the comparative examples were evaluated to determine their amorphous characteristics and improvements in solubility.

[0232] 1. Physical appearance

[0233] For the embodiments and comparative embodiments described above, at a ratio of 4000 ( Figures 1A to 1C , Figure 1F ) or 2500 times ( Figure 1D and Figure 1E The needle-like crystals of compound A monohydrate were observed using scanning electron microscopy (TM3000 SEM, Hitachi, Japan) at a magnification of 1000x. (Comparative Example 1) Figure 1D It is very prominent in (crystallization control) and in comparative example 2 ( Figure 1E It can also be observed in the spherical aggregates in Examples 1-3. Figures 1A to 1C The solid dispersion of the product (characterized by the presence of smooth, round aggregates) does not contain such crystalline needle-like structures. Comparative Example 3 (excess polymer carrier control, although lacking crystalline needle-like structures) is characterized by non-uniform particle size of the coarse aggregates.

[0234] 2. Saturated solubility

[0235] The saturated solubility of the formulations from Examples 1-3 and Comparative Example 1 was evaluated. Briefly, the spray-dried material was measured and pretreated using a multi-tube vortex mixer in 0.01 N HCl (pH 2.0) with stirring at 1,000 rpm, at an amount set to a theoretical concentration of 50,000 μg / mL for compound A. Stirring was maintained until solubility was measured after 30 minutes or 24 hours by allowing the test solution to stand for one hour. The test solution was then centrifuged at 3,000 rpm for 10 minutes, and the supernatant was filtered through a 0.45 μm PVDF filter for pretreatment before subsequent HPLC determination. Figure 2 As shown, the amorphous solid dispersions of Examples 1-3 all exhibited superior solubility compared to the crystalline control of Comparative Example 1. Solubility was related to the polymer carrier content.

[0236] 3. Crystallinity

[0237] The crystallinity of compound A in the formulations of Example 1 and Comparative Example 1 was evaluated. X-ray diffraction was performed using a Bruker D8 Advance diffractometer with CuKα radiation (40 kV, 40 mA) at a scan rate of 3° / min in the 2θ range of 4.0–45°. Differential scanning calorimetry (DSC) was performed using a Scinco (Korea) N-650 calorimeter with nitrogen at a heating rate of 10° / min in the temperature range of 25°C–250°C.

[0238] Compound A in the spray-dried solid dispersion of Example 1 is amorphous, as evidenced by the lack of characteristic peaks in the diffraction pattern. Figure 3A There are no thermal peaks in the DSC curve. Figure 3B This is evidenced by [example 1]. In contrast, compound A of Comparative Example 1 exhibits sharp XRD peaks ([example 2]). Figure 3C ) and a distinct endothermic peak near 160ºC ( Figure 3D This indicates high crystallinity.

[0239] Experimental Example 2: Analysis of tablets prepared from the amorphous solid dispersion of compound A

[0240] In this embodiment, tablets of compound A were prepared based on the amorphous solid dispersion of the present invention, and their amorphous stability was evaluated.

[0241] Table 2 summarizes the formulation of tablets containing 100 mg of compound A monohydrate. A spray-dried amorphous solid dispersion of compound A was prepared as described in Experimental Example 1 above, except that the dispersion further contained a flow aid / adsorbent at a level of 1.03% by weight. This dispersion was then first mixed with the intragranular excipient using a Turbular® mixer (WAB, Switzerland) for 300 rotations. It was then compacted using a hydraulic press at a roller speed of 4 MPa and 4.0 rpm, and fed into a screw feeder at 15 rpm. It was then granulated using a vibrator at 100 rpm and sieved through a 1.0 mm sieve. These granules were finally mixed with an extragranular lubricant using a Turbular® mixer for 60 rotations. The granules were then compressed using an Autotab® 200 tablet press (Ichihashi Seiki Co., Japan) to a target hardness of 12-14 kp, and coated using an SFC-30F (Sejong Pharmatech, Korea) coating machine with Opadry (Colorcon, USA) coating agents at an inlet temperature of 65ºC, an outlet temperature of 45ºC, and a washing speed of 4 rpm. The coating pump rate was 2 rpm, and the product temperature was 40ºC-50ºC.

[0242] Table 2. Composition of Tablets

[0243] The stability of the solid amorphous form under three different storage conditions was evaluated using a representative tablet of the present invention (on day 20). The tablet of Example C described above was selected for testing. The three different storage conditions are summarized in Table 3.

[0244] Storage stability test conditions

[0245] Figure 4A The image shows the X-ray diffraction pattern of the tablet in Example C at the initial time point (note the peaks produced by other components such as excipients). Figure 4E The diffraction pattern is a comparison of Example 1 (i.e., crystalline compound A hydrate without spray drying) at the initial time point. Figure 4A peaks and Figure 4E The peaks in the image clearly lack matching, which is consistent with the mismatch between the polymorphic states (i.e., amorphous and crystalline states) of compound A in these two cases. For example... Figure 4B (high temperature), Figure 4C (Acceleration) and Figure 4D As shown in the (high humidity) test, a similar absence of the peak at the 2θ position corresponding to the crystallization peak was observed in the stored test samples. Therefore, the tablets of the present invention did not undergo polymorphic changes under the tested storage conditions.

[0246] Experimental Example 3: Saturated solubility of different solid formulations of compound A

[0247] In this embodiment, the saturated solubility of different solid formulations containing the amorphous solid dispersion of compound A of the present invention was determined. The solubility determined for solid dosage formulations of compound A solid dispersion with a flow aid / adsorbent (Example 1) and tablets (Example C) and capsules (Example D) incorporating the solid dispersion was compared with the dispersion-free control of Comparative Example 1. The capsules of Example D were prepared by filling capsule No. 2 with the solid dispersion of Example 1, except that a lubricant was mixed into the dispersion before filling the capsule. The composition of the prepared solid formulations is summarized in Table 4.

[0248] Composition of the preparation

[0249] The pretreatment for saturated solubility measurement was performed as follows. A test solution was prepared at a concentration of 2,000 µg / mL for target compound A by placing the formulation prepared according to Table 4 in an acetate buffer (pH 5.5, prepared according to USP) at ambient temperature and stirring for 30 minutes. The buffer solution was then centrifuged, and the supernatant was collected and analyzed by high-performance liquid chromatography (HPLC).

[0250] Solubility of the formulation.

[0251] The results show that solid oral dosage forms using the solid dispersion of compound A of the present invention can achieve high solubility; for example, capsule formulations can achieve the solubility level of the solid dispersion itself.

[0252] Experimental Example 4: Pharmacokinetic analysis of solid formulations prepared from the amorphous solid dispersion of compound A Analysis

[0253] In this embodiment, in vivo experiments were conducted to evaluate the benefits of the solid dispersion formulation compared to conventional formulations. Pharmacokinetic properties were determined and compared between tablets prepared with and without the amorphous solid dispersion of the present invention.

[0254] Tablets (Example C) or capsules (Example D) were formulated from 100 mg of compound A monohydrate (as summarized in Table 6) under spray drying conditions. For the undispersed tablets of Comparative Example B, the excipients were simply mixed with the crystalline compound A monohydrate without spray drying, followed by the addition of a lubricant and direct compaction and coating.

[0255] Composition of the preparation

[0256] Each of the resulting formulations was administered in parallel to fasted male beagle dogs in the test group (n = 4) via a single oral dose of 100 mg of compound A, and pharmacokinetic parameters were determined by collecting blood samples at fixed time points. The results are summarized in Table 7.

[0257] PK parameters of tablets.

[0258] Figures 5A to 5C The mean plasma concentration-time curves for the solid formulation are shown. According to Example C of the invention, the tablets achieve higher solubility when used in a solid dispersion, resulting in a significant improvement in drug exposure and absorption. In beagle dogs, the Example C tablets reached the maximum plasma concentration (C0.05) of compound A within an interval of 3 to 10 hours. max ), reaching Cmax The time occurred 3 hours later. Compared to the tablet of Comparative Example B, the tablet of Example C showed approximately 3 times the drug exposure (C... max The solubility, drug exposure, and absorption of the tablets according to Example D of the present invention are also increased, along with an area under the curve (AUC) of approximately 2.6 times. Higher solubility, drug exposure, and absorption can also be achieved when using a solid dispersion. Compared to the tablets of Comparative Example B, the capsules of Example D exhibit approximately 2.8 times the drug exposure (C). max This increases the area under the curve (AUC) by approximately 2.9 times.

[0259] Formulation Example 1: Spray-dried amorphous solid dispersion of compound A

[0260] Hydroxypropyl methylcellulose acetate succinate (HPMCAS) can be used as a polymer carrier to prepare a spray-dried dispersion of compound A. Table 8 provides exemplary compositions of this HPMCAS-based spray-dried dispersion. The same procedure described in Experimental Example 1 can be used for preparation, except that HPMCAS (preferably having a suitably low pH solubility threshold, e.g., AQOAT) is used. ® LF hydroxypropyl methylcellulose acetate succinate (Shin-Etsu, Japan) was used to replace HPMC, and the amounts of water and ethanol used were adjusted as shown in Table 8 to account for changes in solubility.

[0261] Composition of HPMCAS formulations

[0262] Formulation Example 2: Non-spray dried solid dispersion example

[0263] 1. An amorphous solid dispersion of compound A obtained by vacuum drying.

[0264] A working suspension of compound A was prepared by mixing an ethanol solution of compound A with an aqueous solution of HPMC in which silica was suspended. This working suspension was dried under reduced pressure in a vacuum dryer for 24 hours. The dried mixture was then milled in a mixer and passed through a 30-mesh round sieve to produce an amorphous solid dispersion of compound A.

[0265] 2. Preparation of amorphous solid dispersion of compound A tablets by fluidized bed granulation

[0266] Table 9 provides exemplary compositions of amorphous solid dispersion tablets of compound A based on HPMC, prepared by fluidized bed granulation.

[0267] Compositions for fluidized bed granulation

[0268] In summary, formulations containing amorphous solid dispersions of compound A in spray-dried form have proven advantageous compared to conventional tablets of the same dosage that do not rely on this solid dispersion technology.

[0269] It should be understood that the enumerated embodiments are not intended to limit the invention to those embodiments. In contrast, the invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the invention as defined by the claims. Therefore, the foregoing description is considered merely illustrative of the principles of the invention.

[0270] The terms “comprise,” “comprising,” “include,” “including,” and “includes” are used in this specification and the following claims to indicate the presence of the stated features, wholes, components, or steps, but do not exclude the presence or addition of one or more other features, wholes, components, steps, or groups thereof.

Claims

1. A solid dispersion comprising Compound A: [Compound A], or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

2. The solid dispersion of claim 1, wherein the solid dispersion comprises a polymeric carrier.

3. The solid dispersion of claim 2, wherein the amount of the polymeric carrier is about 10 parts by weight to about 55 parts by weight based on 100 parts by weight of Compound A; and wherein Compound A is substantially amorphous and is present in a polymeric matrix of the polymeric carrier.

4. The solid dispersion of claim 1 or claim 2, wherein the amount of the polymeric carrier is about 10 parts by weight to about 50 parts by weight based on 100 parts by weight of Compound A.

5. The solid dispersion of any one of claims 2-4, wherein the polymeric carrier is one or more selected from the group consisting of methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, cellulose acetate, cellulose acetate phthalate, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), crospovidone, polyethylene glycol (PEG), methylcellulose (MC), methacrylic acid-methyl methacrylate copolymer, poly(acrylic acid), cellulose acetate phthalate (CAP), chitosan, polyethylene glycol-vinyl acetate copolymer (PEG-PVA), graft copolymer of ethylene glycol-vinyl caprolactam-vinyl acetate, polyvinyl acetate phthalate (PVAP), polyoxyethylene-polyoxypropylene block copolymer, and D-alpha-tocopheryl polyethylene glycol succinate (TPGS).

6. The solid dispersion of claim 2, wherein the polymeric carrier is a hydrophilic carrier.

7. The solid dispersion of any one of claims 2-6, wherein the polymeric carrier is one or more cellulose derivatives selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, cellulose acetate, and cellulose acetate phthalate.

8. The solid dispersion of claim 1, wherein the solid dispersion is formed by solvent evaporation, hot melt extrusion, or spray drying of a dispersion.

9. The solid dispersion of claim 8, wherein the solvent evaporation is spray drying or fluid bed granulation.

10. The solid dispersion of claim 1, wherein the solid dispersion further comprises a glidant / adsorbent.

11. A pharmaceutical composition comprising a therapeutically effective amount of Compound A having the structure: ​ or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein the composition is a solid dispersion.

12. The pharmaceutical composition of claim 11, wherein the solid dispersion comprises a polymeric carrier.

13. The pharmaceutical composition of claim 11 or 12, comprising a) about 20% w / w to about 50% w / w of a Compound A solid dispersion; b) about 25% w / w to about 70% w / w of a filler / binder; c) about 4.0% w / w to about 20% w / w of a disintegrant; d) about 0.25% w / w to about 5.0% w / w of a glidant / desintegrant; and e) about 0.5% w / w to about 2.5% w / w of a lubricant; wherein the Compound A solid dispersion comprises substantially amorphous Compound A dispersed in a polymeric matrix of a hydrophilic polymeric carrier in an amount of about 64.5% w / w to about 91% w / w Compound A, based on the combined weight of the Compound A and the hydrophilic polymeric carrier.

14. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition is a solid oral dosage form selected from a tablet, a powder, a granule, a caplet, and a pill.

15. The pharmaceutical composition of claim 14, wherein the solid oral dosage form is a tablet.

16. The pharmaceutical composition of any one of claims 11-15, wherein the hydrophilic polymeric carrier is hydroxypropyl methylcellulose.

17. The pharmaceutical composition of any one of claims 13-16, wherein the filler / binder is one or more selected from the group consisting of starch, a saccharide, a disaccharide, sucrose, lactose, lactose monohydrate, a polysaccharide, cellulose, a cellulose ether, hydroxypropyl cellulose, a sugar alcohol, xylitol, sorbitol, maltitol, microcrystalline cellulose, calcium or sodium carbonate, dicalcium phosphate, compressible sugar, dicalcium phosphate dihydrate, mannitol, tricalcium phosphate, and any combination thereof.

18. The pharmaceutical composition of any one of claims 13-17, wherein the disintegrant is one or more selected from the group consisting of starch, sodium starch glycolate, croscarmellose sodium, crospovidone, microcrystalline cellulose, modified corn starch, sodium carboxymethyl starch, povidone, pregelatinized starch, alginic acid, and any combination thereof.

19. The pharmaceutical composition of any one of claims 13-18, wherein the glidant / desintegrant is one or more selected from the group consisting of colloidal silicon dioxide, talc, fumed silicon dioxide, starch, starch derivatives, bentonite, and any combination thereof.

20. The pharmaceutical composition of any one of claims 13-19, wherein the lubricant is one or more selected from the group consisting of magnesium stearate, stearic acid, silicon dioxide, a fat, calcium stearate, polyethylene glycol, sodium stearyl fumarate, or talc, lauric acid, oleic acid, C8 / C10 fatty acids, and any combination thereof.

21. The pharmaceutical composition of any one of claims 11-20, wherein the Compound A solid dispersion is formed by spray drying.

22. The pharmaceutical composition of any one of claims 11-21, wherein the tablet provides about 2-fold to about 3-fold increase in drug exposure relative to a reference tablet comprising the same amount of Compound A but not comprising an amorphous solid dispersion of Compound A.

23. The pharmaceutical composition of claim 22, wherein the drug exposure comparison is based on beagle dogs.

24. The pharmaceutical composition of claim 15, wherein the tablet provides about 2-fold to about 3-fold increase in area under the curve (AUC) relative to a reference tablet comprising the same amount of Compound A but not comprising an amorphous solid dispersion of Compound A.

25. The pharmaceutical composition of claim 24, wherein the area under the curve comparison is based on beagle dogs.

26. A pharmaceutical composition for a capsule, the pharmaceutical composition comprising a) about 50% w / w to about 97.5% w / w of a Compound A solid dispersion; b) about 0% w / w to about 48% w / w of a filler / binder; c) about 0% w / w to about 20% w / w of a disintegrant; d) about 0% w / w to about 4.0% w / w of a glidant / superdisintegrant; and e) about 0.2% w / w to about 4.0% w / w of a lubricant; wherein Compound A is [Compound A], or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and wherein the Compound A solid dispersion comprises substantially amorphous Compound A dispersed in a polymeric matrix of a hydrophilic polymer carrier in an amount of about 64.5% w / w to about 91% w / w Compound A, based on the combined weight of the Compound A and the hydrophilic polymer carrier.

27. A solid oral formulation comprising about 20% to about 50% w / w of a Compound A solid dispersion, wherein the oral formulation provides about 2-fold to about 3-fold increase in drug exposure relative to a reference tablet comprising the same amount of Compound A but not comprising an amorphous solid dispersion of Compound A, wherein the Compound A solid dispersion comprises substantially amorphous Compound A dispersed in a polymeric matrix of hydroxypropyl methylcellulose in an amount of about 64.5% w / w to about 91% w / w Compound A, based on the combined weight of the Compound A and the hydroxypropyl methylcellulose.

28. A solid oral formulation comprising about 20% w / w to about 50% w / w of a Compound A solid dispersion, wherein the oral formulation provides about 2-fold to about 3-fold increase in area under the curve relative to a reference tablet comprising the same amount of Compound A but not comprising an amorphous solid dispersion of Compound A, and wherein the Compound A solid dispersion comprises substantially amorphous Compound A dispersed in a polymer matrix of hydroxypropyl methylcellulose in an amount of about 64.5% w / w to about 91% w / w Compound A, based on the combined weight of the Compound A and hydroxypropyl methylcellulose.

29. The solid oral formulation of claim 27 or claim 28, wherein the Compound A solid dispersion is formed by spray drying.

30. A method for treating cancer, comprising administering to a subject in need thereof the solid dispersion, pharmaceutical composition, or solid oral formulation of any one of claims 1-29.

31. The method of claim 30, wherein the cancer is a leukemia, such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute promyelocytic leukemia (APL), hairy cell leukemia, or chronic neutrophilic leukemia (CNL).

32. The method of claim 31, wherein the leukemia is AML.

33. The method of any one of claims 30-32, wherein the cancer or leukemia comprises cancer cells having a mutation in the FLT3 gene.

34. The method of claim 33, wherein the FLT3 gene has an internal tandem duplication (ITD) mutation.

35. The method of claim 33 or claim 34, wherein the FLT3 gene has at least one FLT3 mutation selected from F691L, D835Y, D835F, D835I, D835H, D835V, and D835A.

36. An amorphous form of Compound A: ###0001### (Compound A) or an amorphous form of a pharmaceutically acceptable salt, solvate, or solvate salt thereof; wherein the amorphous form exhibits an X-ray powder diffraction (XRPD) pattern substantially similar to the pattern in FIG. 3A.

37. An amorphous form of Compound A: ###0002### (Compound A) or an amorphous form of a pharmaceutically acceptable salt, solvate, or solvate salt thereof; wherein the amorphous form exhibits an X-ray powder diffraction (XRPD) pattern as in FIG. 3A.

38. An amorphous form of Compound A or an amorphous form of a pharmaceutically acceptable salt, solvate, or solvate salt thereof; the amorphous form exhibits a differential scanning calorimetry (DSC) curve substantially similar to FIG. 3B.

39. The amorphous form of any one of claims 36-38, having a purity in the range of about 80% to about 99%.

40. The amorphous form of any one of claims 36-38, having a purity of about 95% or greater.

41. The amorphous form of any one of claims 36-38, having a purity of about 99% or greater. ​ ​ ​ ​ 42. The amorphous form of any one of claims 36-41, comprising less than 10% of a crystalline form of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

43. The amorphous form of any one of claims 36-41, comprising less than 5% of a crystalline form of Compound A or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

44. A substance for inhibiting a myeloid kinase group, wherein the myeloid kinase group means FMS-like tyrosine kinase 3 (FLT3), Spleen tyrosine kinase (SYK), Janus kinase (JAK), and / or mutant c-KIT.

45. A substance for binding or inhibiting FMS-like tyrosine kinase 3 (FLT3).

46. The substance of claim 44 or 45, wherein the substance is in amorphous form.

47. The substance of any one of claims 44-46, wherein the substance is in free base form.

48. The substance of any one of claims 44-47, wherein the substance is in monohydrate form.

Images