Compound forms with enhanced bioavailability and formulations thereof

Abstract

The present invention generally relates to amorphous forms of compounds with enhanced water solubility and dissolution rate, amorphous solid dispersions thereof, and oral pharmaceutical preparations, and methods for preparing the same. The present invention specifically relates to amorphous forms of 5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazole-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine, amorphous solid dispersions thereof, and oral pharmaceutical preparations, and methods for preparing the same.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of Provisional Patent Application No. 62 / 816,402, filed on March 11, 2019, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention generally relates to amorphous forms of compounds having low water solubility and dissolution rate in crystalline form (BCS class II substances), amorphous solid dispersions thereof, oral pharmaceutical preparations thereof, and methods for preparing amorphous dispersions and preparations. The present invention specifically relates to amorphous forms and amorphous solid dispersions of 5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine and oral pharmaceutical preparations thereof, as well as methods for preparing them. Background Art

[0004] The bioavailability of an orally administered therapeutic agent is the extent to which the agent is absorbed by the body and becomes available to the target in vivo (e.g., for interaction or complexation, etc.) at the target site (e.g., within or on a cell, etc.). To be bioavailable, a therapeutic agent generally needs to have a certain water solubility relative to the dose administered.

[0005] The Biopharmaceutics Classification System (BCS) is a system developed by the U.S. Food and Drug Administration (FDA) to classify the forms of active pharmaceutical ingredients (APIs) based on their solubility and intestinal permeability as follows: Class I: high solubility, high permeability; Class II: low solubility, high permeability; Class III: high solubility, low permeability; Class IV: low solubility, low permeability. Formulating compositions of BCS Class II APIs to improve solubility and therefore bioavailability can be a challenge.

[0006] One way to make certain compounds more soluble is to prepare an amorphous form of the compound. However, preparing an amorphous form of some compounds can be difficult, and preparing an amorphous form that is stable enough to be used in a pharmaceutical formulation is particularly difficult. In some cases, amorphous solid dispersions (ASDs) can be used to increase the solubility and bioavailability of certain substances. However, identifying an ASD formulation that is stable and does not interfere with the bioavailability of the active pharmaceutical ingredient (API) is difficult.

[0007] Therefore, there is a continuing need in the art and a continuing demand in the market for pharmaceutical compositions with improved solubility and bioavailability, thereby providing convenience of administration and increasing API loading. Summary of the invention

[0008] In one aspect described herein, an amorphous form of 5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine has the formula of Compound A:

[0009]

[0010] In another aspect described herein, the amorphous form of Compound A is at least 90% amorphous.

[0011] In another aspect described herein, the amorphous form of Compound A is a substantially pure amorphous form.

[0012] In one aspect described herein, an amorphous solid dispersion (ASD) comprises an amorphous form of Compound A and a stabilizing polymer.

[0013] In another aspect described herein, the stabilizing polymer is selected from polyvinylpyrrolidone or hydroxypropylmethylcellulose acetate succinate.

[0014] In another aspect described herein, the stabilizing polymer is hydroxypropylmethylcellulose acetate succinate.

[0015] In another aspect described herein, the ratio of the weight of Compound A to the weight of the stabilizing polymer is from about 5:95 to about 60:40.

[0016] In another aspect described herein, the ratio of the weight of Compound A to the weight of the stabilizing polymer is from about 10:90 to about 40:60.

[0017] In one aspect described herein, the ASD is obtained by solvent casting a solution comprising Compound A and a stabilizing polymer.

[0018] In one aspect described herein, the ASD is obtained by spray drying a solution comprising Compound A and a stabilizing polymer.

[0019] In one aspect described herein, a method for preparing an ASD comprises: (a) dissolving Compound A and one or more stabilizing polymers in a solvent to form a solution; and (b) drying the solution to form an ASD, wherein Compound A is in an amorphous form.

[0020] In another aspect described herein, the solvent is selected from acetone, methyl ethyl ketone, dichloromethane or methanol.

[0021] In another aspect described herein, the solution is dried to form an ASD of Compound A by solvent casting.

[0022] In another aspect described herein, the solution is dried to form an ASD of Compound A by spray drying.

[0023] In one aspect described herein, a pharmaceutical composition comprises a mixture of an ASD of Compound A and one or more pharmaceutically acceptable excipients.

[0024] In another aspect described herein, the one or more pharmaceutically acceptable excipients are selected from a diluent, a disintegrant, a lubricant or a surfactant.

[0025] In another aspect described herein, the surfactant is selected from sodium lauryl sulfate or Poloxamer 407.

[0026] In one aspect described herein, a method for preparing a pharmaceutical composition comprises: (a) grinding an ASD of compound A to form a solid dispersion powder; (b) mixing the powder with one or more pharmaceutically acceptable excipients to form a mixture; (c) granulating the mixture to form granules; and (d) compressing or encapsulating the granules to form tablets or capsules, respectively. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 A flow chart of a method for preparing a tablet described herein from a spray dried dispersion (SDD) of Compound A and a stabilizing polymer is shown;

[0028] Figure 2 shows the powder X-ray diffraction pattern of the original compound A (Form I);

[0029] Figure 3 An overlay of powder X-ray diffraction patterns of Form I and crystalline polymorphs Forms A and B of Compound A is shown;

[0030] Figure 4 An overlay of differential scanning calorimetry (DSC) curves of Form I, Form A, and Form B of Compound A is shown;

[0031] Figure 5 DSC thermograms of HPMC-AS L and HPMC-AS L milled with Compound A having Form A are shown;

[0032] Figure 6 DSC thermograms of PVP CL and PVP CL milled with Compound A having Form A are shown;

[0033] Figure 7 DSC thermograms of PVP VA and PVP VA milled with Compound A having Form A are shown;

[0034] Figure 8 DSC thermograms of PVP K30 and PVP K30 milled with Compound A having Form A are shown;

[0035] Fig. 9DSC thermograms of HPMC phthalate and HPMC phthalate milled with Compound A having Form A are shown;

[0036] Fig.10 shows X-ray powder diffraction patterns of Compound A having Form A, a physical mixture of Compound A having Form A and a polymer, and an HPMCAS-LG-based ASD of Compound A without a surfactant;

[0037] Fig.11 shows X-ray powder diffraction patterns of Compound A having Form A, a physical mixture of Compound A having Form A and a polymer, and an HPMCAS-LG based ASD of Compound A containing Poloxamer 407;

[0038] Fig.12 shows X-ray powder diffraction patterns of Compound A having Form A, a physical mixture of Compound A having Form A and a polymer, and an ASD of Compound A based on HPMCAS-LG containing sodium dodecyl sulfate (SLS);

[0039] Fig.13A shows the DSC thermogram of a physical mixture of Compound A and a polymer without surfactant having Form A;

[0040] Fig. 13B DSC thermogram showing the ASD of Compound A without surfactant;

[0041] Fig.14A shows the DSC thermogram of a physical mixture of Compound A, polymer and Poloxamer 407;

[0042] Fig. 14B shows the DSC thermogram of ASD of Compound A containing Poloxamer 407;

[0043] Fig.15A shows the DSC thermogram of the physical mixture of compound A, polymer and SLS;

[0044] Fig. 15B shows the DSC thermogram of ASD of Compound A containing SLS;

[0045] Fig.16 DSC thermograms of ASD containing different amounts of Compound A are shown;

[0046] Fig.17 shows the X-ray powder diffraction patterns of ASD containing different amounts of Compound A;

[0047] Fig.18X-ray powder diffraction patterns of compound A and two different SDDs, one containing PVP-VA-64 and the other containing HPMC-AS-L, are shown;

[0048] Fig.19 The SDD dissolution profiles of Compound A with HPMC-AS-LG and with PVP-VA-64 are shown;

[0049] Fig. 20 shows X-ray powder diffraction patterns of Compound A having Form A, SDD of Compound A and HPMC-AS, a mixture of Compound A and HPMC-AS for an active tablet formulation, and HPMC-AS for a placebo formulation;

[0050] Fig.21 Shown is the disintegration of active formulation tablets with different concentrations of Poloxamer 407 at 1 minute after storage under open conditions at 40°C / 75% RH for 6 months. DETAILED DESCRIPTION

[0051] In one aspect described herein, an amorphous form of 5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine has the formula of Compound A:

[0052]

[0053] In another aspect described herein, the amorphous form of Compound A is at least 90% amorphous.

[0054] In another aspect described herein, the amorphous form of Compound A is a substantially pure amorphous form.

[0055] In one aspect described herein, an amorphous solid dispersion (ASD) comprises an amorphous form of Compound A and a stabilizing polymer.

[0056] In another aspect described herein, the stabilizing polymer is selected from polyvinylpyrrolidone or hydroxypropylmethylcellulose acetate succinate.

[0057] In another aspect described herein, the stabilizing polymer is hydroxypropylmethylcellulose acetate succinate.

[0058] In another aspect described herein, the ratio of the weight of Compound A to the weight of the stabilizing polymer is from about 5:95 to about 60:40.

[0059] In another aspect described herein, the ratio of the weight of Compound A to the weight of the stabilizing polymer is from about 10:90 to about 40:60.

[0060] In one aspect described herein, the ASD is obtained by solvent casting a solution comprising Compound A and a stabilizing polymer.

[0061] In another aspect described herein, the ASD is obtained by spray drying a solution comprising Compound A and a stabilizing polymer.

[0062] In one aspect described herein, a method for preparing an ASD comprises: (a) dissolving Compound A and one or more stabilizing polymers in a solvent to form a solution; and (b) drying the solution to form an ASD, wherein Compound A is in an amorphous form.

[0063] In another aspect described herein, the solvent is selected from acetone, methyl ethyl ketone, dichloromethane or methanol.

[0064] In another aspect described herein, the solution is dried to form an ASD of Compound A by solvent casting.

[0065] In another aspect described herein, the solution is dried to form an ASD of Compound A by spray drying.

[0066] In one aspect described herein, a pharmaceutical composition comprises a mixture of an ASD of Compound A and one or more pharmaceutically acceptable excipients.

[0067] In another aspect described herein, the one or more pharmaceutically acceptable excipients are selected from a diluent, a disintegrant, a lubricant or a surfactant.

[0068] In another aspect described herein, the surfactant is selected from sodium lauryl sulfate or poloxamer 407.

[0069] In one aspect described herein, a method for preparing a pharmaceutical composition comprises: (a) grinding an ASD of compound A to form a solid dispersion powder; (b) mixing the powder with one or more pharmaceutically acceptable excipients to form a mixture; (c) granulating the mixture to form granules; and (d) compressing or encapsulating the granules to form tablets or capsules, respectively.

[0070] definition

[0071] The term "amorphous" as used herein refers to a form of a solid compound that lacks a regular crystal structure. Without being bound by theory, it is believed that amorphous Compound A requires less dissolution energy than crystalline Compound A, and this reduced dissolution energy requirement contributes at least in part to increasing the dissolution rate and / or potentially reducing the therapeutic onset time exhibited by the amorphous form of Compound A and compositions thereof.

[0072] The term "Form I" refers to the form of Compound A as described in International Publication No. WO2014 / 081906. Compound A and a method for preparing a crystalline (non-amorphous) form thereof are disclosed. When synthesized according to the method described in WO2014 / 081906, Compound A is obtained as a crystalline powder with a melting point of 240 to 242°C. The compounds disclosed therein can be used to treat cancer, including solid tumors and blood cancers, such as but not limited to diffuse intrinsic pontine glioma (DIPG), ovarian cancer, pancreatic cancer, sarcoma and blood cancers, etc.

[0073] The terms "Form A" and "Form B" refer to forms of Compound A that are purified anhydrous crystalline polymorphic forms. Further studies of Compound A described in Example 1 below indicate that Form A is the most stable anhydrous crystalline form of the compound, and Form B converts to Form A. In the stable Form A crystalline form, Compound A is a BCS II material.

[0074] Although oral dosage forms of Compound A in the Form A crystalline form can be prepared, a variety of methods have been used to increase the solubility and / or dissolution rate of the compound in such formulations, including micronizing Compound A prior to formulation, and adding pharmaceutical excipients such as disintegrants and surfactants. Examples of such oral dosage forms are provided in Example 2 below.

[0075] Soluble capsule oral dosage forms can be prepared from a crystalline form of compound A. Such capsules can be prepared by dissolving compound A having form A in a water-soluble organic solvent, such as polyethylene glycol 300 or 400, ethanol, propylene glycol, glycerol, N-methyl-2-pyrrolidone, dimethylacetamide and / or dimethyl sulfoxide and a nonionic surfactant, such as polysorbate 20, polysorbate 80, Solutol HS 15, sorbitan monooleate, poloxamer 407, lauric acid macrogol glyceride (Gelucire 44 / 14) or other suitable surfactants. Examples of such capsule formulations are provided in Examples 3 and 4 below. Due to the addition of excipients in dissolved form, the capsule size limits the loading amount of API in a standard capsule. For example, the capsules used in Example 4 below contain 10 or 50 mg of compound A. In order to administer higher doses of compound A to human subjects, as done in the clinical trials discussed in Example 11, more capsules must be taken to provide the desired dose.

[0076] Amorphous form of Compound A

[0077] The amorphous form of Compound A disclosed herein is significantly more soluble than the crystalline form of the above-mentioned compound. When formulated as an amorphous solid dispersion (ASD) with a polymer, the amorphous form of Compound A is stable. As described below, the resulting compound-polymer matrix results in greater solubility of the amorphous form of Compound A in ASD and higher loading capacity of API in ASD. Therefore, the amount of API that can be loaded in a tablet or capsule is significantly increased, thereby minimizing the need to administer a large number of tablets or capsules for a single therapeutically effective dose.

[0078] In one aspect, the amorphous form of Compound A in the ASD disclosed herein is at least 90% amorphous, more preferably at least 95% amorphous, even more preferably at least 99% amorphous. In another aspect, the amorphous form of Compound A is a substantially pure amorphous form. In another aspect, the substantially pure amorphous form of Compound A does not contain a detectable amount of a crystalline form of Compound A.

[0079] Solid dispersion

[0080] When combined with a stabilizing polymer in an ASD, an amorphous form of Compound A can be prepared in a stable form. The term "solid dispersion" as used herein refers to an amorphous solid dispersion (ASD) in which the API is present in a substantially amorphous form in a stabilizing polymer matrix. In order to be effective, the stabilizing polymer is preferably compatible with the compound and is capable of releasing the compound from the stabilizing polymer matrix formed therewith when administered to a subject.

[0081] Several techniques have been developed to prepare solid dispersions, including hot melt extrusion, coprecipitation, spray drying, hot melt congealing or solvent casting. Therefore, based on the matrix formed by the dispersed polymer, solid dispersions prepared by these different methods may differ in properties such as porosity, surface area, density, stability, hygroscopicity, solubility and therefore bioavailability.

[0082] In one aspect described herein, the ASD of Compound A is prepared by solvent casting. In another aspect described herein, the ASD is prepared by spray drying, in which case the ASD is in the form of a spray dried dispersion (SDD).

[0083] The terms "stabilizing polymer" and "stabilizing polymer matrix" refer to polymers described herein for use in preparing ASDs that, when mixed with an amorphous form of Compound A, form a matrix that effectively stabilizes the amorphous form of Compound A, thereby reducing the conversion of amorphous Compound A to crystalline Compound A when contained therein. In one aspect, the stabilizing polymer is selected from hydroxypropylmethylcellulose ("hydroxymethylcellulose" or HPMC), acetic acid succinate (HPMCAS), polyvinylpyrrolidone ("povidone" or PVP), or vinylpyrrolidone-vinyl acetate copolymer ("copovidone" or PVP VA 64). The stabilizing polymer is preferably one that is readily bioavailable to a subject when orally administered to a subject. In another aspect, the stabilizing polymer is selected from HPMCAS, L-type HPMCAS, or M-type HPMCAS. L-type refers to a polymer that has a high ratio of succinyl to acetyl substitution, while M-type has a medium ratio, and each type dissolves at different pH levels. In another aspect, the stabilizing polymer is L-type HPMCAS.

[0084] In one aspect described herein, the ASD optionally includes a surfactant to further enhance the solubility of Compound A in the ASD. In another aspect, the surfactant is selected from sodium lauryl sulfate and poloxamer 407. In another aspect, the surfactant is poloxamer 407.

[0085] In one aspect described herein, the ratio of Compound A to the stabilizing polymer in the ASD stabilizes the amorphous form of Compound A in the matrix. In another aspect described herein, the ratio of Compound: polymer is selected from the range of about 5:95 to about 60:40 by weight, or from the range of about 10:90 to about 40:60 by weight. In another aspect described herein, the ratio of Compound: polymer is about 40:60 by weight. In one aspect described herein, in the absence of excipients in the ASD, the amount of Compound A loaded is selected from the range of about 30% to about 50% by weight, or from the range of about 30% to about 50% by weight. In another aspect described herein, the loading amount of Compound A is about 40% by weight.

[0086] In one aspect described herein, a method for preparing an ASD of Compound A comprises dissolving Compound A in one or more stabilizing polymers in a solvent liquid to form a solution, and then drying the solution to form a solid dispersion, wherein Compound A is present in a non-crystalline form in a compound-polymer matrix. In another aspect described herein, the drying step is performed by solvent casting. In another aspect described herein, the drying step is performed by spray drying. In another aspect described herein, the solvent used is selected based on the solubility of Compound A in the solvent.

[0087] In another aspect described herein, the selected solvent meets the green chemistry requirements and standards specified in the residual solvent impurity guide formulated by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH Guidelines). In another aspect described herein, mechanical means such as heating and stirring can also be used to promote the dissolution of Compound A in a solvent liquid. The solvent liquid may also include a non-organic part, such as water. Non-limiting examples of suitable solvents that can be used include, for example, water-alcohol mixtures, methanol, ethanol, isopropanol, acetone and methyl ethyl ketone. On the one hand, the solvent used is acetone, ethanol, isopropanol or methyl ethyl ketone. On the other hand, the solvent is acetone.

[0088] In one aspect described herein, spray drying can be used to prepare the ASD of compound A. Typically, spray drying is a process in which a solution containing a dissolved substance and a stabilizing polymer is quickly sprayed on a warm air stream to form a dry powder. In another aspect described herein, the ASD can be optionally ground or pulverized to provide a fine powder or micronized powder form of the ASD. The resulting ASD or its powder can be directly loaded into a capsule for oral administration. In another aspect described herein, a pharmaceutical composition may contain an ASD or its powder mixed with one or more additional excipients. In one aspect provided herein, the amount of ASD contained in the pharmaceutical composition is selected from a range of about 5% to about 90% by weight, a range of about 20% to about 80% by weight, a range of about 30% to about 70% by weight, or a range of about 40% to about 60% by weight. In another aspect provided herein, the amount of ASD contained in the pharmaceutical composition is selected from a range of 40% to about 60% by weight.

[0089] In one aspect provided herein, the ASD or a pharmaceutical composition thereof comprises an aqueous suspension for oral administration. In another aspect, the aqueous suspension can be prepared by dissolving the ASD or a pharmaceutical composition thereof (e.g., one or more tablets or capsules) in water. In another aspect, a therapeutically effective dose of the aqueous suspension can be administered to a patient, such as a child, who has difficulty swallowing tablets or capsules.

[0090] Pharmaceutical composition

[0091] As used herein, the term "excipient" refers to any substance, which is not itself a therapeutic agent, used as a carrier or vehicle to deliver a therapeutic agent to a subject, or added to a pharmaceutical composition to improve its handling or storage characteristics or to allow or facilitate the formation of dosage units of the composition into discrete articles, such as capsules or tablets suitable for oral administration. Excipients include, but are not limited to, diluents, disintegrants, binders, adhesives, surfactants, lubricants, glidants, surface modifiers, substances added to mask or counteract unpleasant tastes or odors, flavorings, dyes, fragrances, and substances added to improve the appearance of the composition.

[0092] In one aspect described herein, a pharmaceutical composition containing an ASD of Compound A mixed with one or more pharmaceutically acceptable excipients and a stabilizing polymer may contain the desired amount of Compound A per dosage unit, and if intended for oral administration, the dosage unit form of the pharmaceutical composition may be selected from tablets, caplets, pills, hard or soft capsules, lozenges, cachets, powders, granules or suspensions. In one aspect described herein, the pharmaceutical composition is in the form of discrete dosage units, such as tablets or capsules, containing a predetermined amount of Compound A. In a preferred aspect, the discrete dosage unit is a tablet.

[0093] Excipients

[0094] In another aspect described herein, the pharmaceutical composition described herein optionally comprises one or more pharmaceutically acceptable diluents as excipients. Suitable diluents are selected from lactose, including anhydrous lactose or lactose monohydrate, starch, including directly compressible and hydrolyzed starch, mannitol, sorbitol, xylitol, glucose and glucose monohydrate, sucrose-based diluents, including fructose, calcium-based diluents, including calcium hydrogen sulfate monohydrate, calcium hydrogen phosphate dihydrate, calcium sulfate dihydrate or granular calcium lactate trihydrate, dextran, inositol, hydrolyzed cereal solids, amylose, cellulose, including amorphous cellulose and powdered cellulose of food grade origin, microcrystalline cellulose, modified or co-processed microcrystalline cellulose, extragranular microcrystalline cellulose or silicified microcrystalline cellulose, calcium carbonate, glycine, bentonite, polyvinylpyrrolidone, and the like. In another aspect described herein, such diluents may be included as part of the total weight of the composition, ranging from about 5% to about 90%, about 10% to about 60%, or about 30% to about 50%. The diluent selected preferably exhibits suitable flow properties and, where tableting is desired, enhances compressibility.

[0095] In another aspect described herein, pharmaceutically acceptable diluents are optionally selected from microcrystalline cellulose, modified or co-processed microcrystalline cellulose, extragranular microcrystalline cellulose or silicified microcrystalline cellulose, or lactose monohydrate, alone or in combination. In another aspect described herein, such diluents may be present as part of the total weight of the composition in a range of about 30% to about 50%. In another aspect described herein, such diluents may be present at about 40% of the total weight of the composition.

[0096] On the one hand, lactose and microcrystalline cellulose, either alone or in combination, have been found to be chemically compatible with Compound A after comparison with other diluents. On the other hand, extragranular microcrystalline cellulose, i.e., microcrystalline cellulose added to the composition after the granulation step, can be used to increase hardness (for tablets). On the other hand, lactose monohydrate provides a pharmaceutical composition with suitable Compound A release rate, stability, and pre-compression flowability.

[0097] In another aspect, the pharmaceutical compositions described herein optionally include one or more pharmaceutically acceptable disintegrants as adjuvants, particularly for tablet formulations. Suitable disintegrants include starches, including sodium starch glycolate and pregelatinized corn starch, clays, celluloses (e.g., purified cellulose), microcrystalline cellulose, methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, alginates, crospovidones, and gums, such as agar, guar, locust bean, karaya, pectin, and tragacanth, alone or in combination. Cross-linked sodium carboxymethylcellulose is a preferred disintegrant for tablet or capsule disintegration. Cross-linked sodium carboxymethylcellulose imparts excellent intragranular disintegration capabilities to the granular compositions described herein.

[0098] Disintegrants may be added at any suitable step during the preparation of the composition, in particular prior to granulation or during the lubrication step prior to compression. If present, such disintegrants comprise a total of about 0.2% to about 30%, preferably about 0.2% to about 10%, more preferably about 1% to about 6% of the total weight of the composition.

[0099] Compositions described herein optionally include one or more pharmaceutically acceptable adhesives or adhesives as adjuvants, particularly for tablet formulations. Such adhesives and adhesives preferably impart sufficient cohesive force to the powder being tableted, to allow normal processing operations, such as sizing, lubrication, compression and packaging, but still allow tablets to disintegrate when ingested and the composition to be absorbed. Suitable adhesives and adhesives alone or in combination include acacia, astragalus, sucrose, gelatin, glucose, starch, such as but not limited to pregelatinized starch, cellulose, such as but not limited to methylcellulose and sodium carboxymethylcellulose, alginic acid and alginates, magnesium aluminum silicate, polyethylene glycol, guar gum, polysaccharide acid, bentonite, povidone, such as povidone K-15, K-30 and K-29 / 32, polymethacrylate, HPMC, hydroxypropyl cellulose, hydroxypropyl cellulose acetate succinate (HPMC-AS) and ethyl cellulose. If present, such binders and / or adhesives collectively comprise from about 0.5% to about 60%, preferably from about 0.75% to about 40%, more preferably from about 1% to about 30% of the total weight of the composition.

[0100] In one aspect described herein, the composition optionally comprises one or more pharmaceutically acceptable surfactants as excipients to enhance the bioavailability of Compound A. Non-limiting examples of surfactants that can be used include quaternary ammonium compounds such as sodium dioctyl sulfosuccinate, polyoxyethylene alkylphenyl ethers such as nonoxynol 9, nonoxynol 10, and octoxynol 9, poloxamers (polyoxyethylene and polypropylene block copolymers such as poloxamer 407), polyoxyethylene fatty acid glycerides and oils such as polyoxyethylene (8), caprylic / capric monoglyceride and diglyceride, polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil, polyethylene alkyl ethers such as polyoxyethylene (20) cetearyl alcohol. Ethers, polyoxyethylene fatty acid esters, such as polyoxyethylene (40) stearate, polyoxyethylene sorbitan esters, such as polysorbate 20 and polysorbate 80 (e.g., Tween 80), propylene glycol fatty acid esters, such as propylene glycol laurate, sodium lauryl sulfate, fatty acids and salts thereof, such as oleic acid, sodium oleate and triethanolamine oleate, glycerol fatty acid esters, such as sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate, tyloxapol and mixtures thereof. In another aspect described herein, anionic surfactants such as poloxamer 407 are particularly preferred. If present, such surfactants constitute in total about 0.25% to about 20%, preferably about 0.4% to about 10%, more preferably about 0.5% to about 5% of the total weight of the composition.

[0101] In one aspect described herein, the composition optionally comprises one or more pharmaceutically acceptable lubricants (including anti-adhesives and / or glidants) as excipients. Suitable lubricants include diglycerides, stearic acid and salts thereof (including magnesium stearate, calcium stearate and sodium stearate), hydrogenated vegetable oils, colloidal silicon dioxide, talc, waxes, boric acid, sodium benzoate, sodium acetate, sodium fumarate, sodium chloride, DL-leucine, polyethylene glycol, sodium oleate, sodium lauryl sulfate and magnesium lauryl sulfate, alone or in combination. In another aspect described herein, magnesium stearate is a preferred lubricant for reducing friction between equipment and granular mixtures, for example, during tableting. If present, such lubricants account for about 0.1% to about 10% of the total weight of the composition, preferably about 0.25% to about 5%, more preferably about 0.5% to about 3%.

[0102] Suitable anti-adherents include talc, corn starch, DL-leucine, sodium lauryl sulfate, and metal stearates. Talc is a preferred anti-adherent or glidant, used, for example, to reduce the adhesion of the formulation to the surface of the equipment and to reduce static electricity when the composition is mixed. If present, talc accounts for about 0.1% to about 10% of the total weight of the composition, more preferably about 0.25% to about 5%, and even more preferably about 0.5% to about 2%.

[0103] Glidants can be used to promote powder flow in solid formulations. Suitable glidants include colloidal silicon dioxide, starch, talc, tricalcium phosphate, powdered cellulose and magnesium trisilicate. Colloidal silicon dioxide is particularly preferred. If present, such glidants comprise from about 0.1% to about 5%, more preferably from about 0.25% to about 5%, and more preferably from about 0.5% to about 3% of the total weight of the composition.

[0104] Other excipients such as colorants, flavorings and sweeteners are known in the pharmaceutical art and can be used in the compositions described herein. Tablets can be coated, for example, with an enteric coating, a non-functional cosmetic coating, a dry powder compression coating or no coating. The compositions described herein may also include, for example, a buffer.

[0105] In one aspect described herein, the pharmaceutical composition comprises an ASD, preferably an SDD, of about 40% to about 60% by weight of Compound A and HPMC-AS, wherein the ratio of Compound A to HPMC-AS is from about 10:90 to about 40:60. In another aspect, the pharmaceutical composition further comprises about 30% to about 50% microcrystalline cellulose and lactose monohydrate, about 1% to about 6% by weight cross-linked carboxymethylcellulose sodium, about 0.5% to about 5% by weight poloxamer 407, and about 0.5% to about 3% by weight magnesium stearate. In another aspect, the pharmaceutical composition further comprises about 0.5% to about 2% colloidal silicon dioxide.

[0106] In one aspect described herein, a method for preparing a pharmaceutical composition comprises mixing an ASD of a Compound A mixture with one or more excipients to form a mixture, and then compressing or encapsulating the mixture to form a tablet or capsule, respectively.

[0107] In another aspect described herein, Figure 1 As shown, the method for preparing a pharmaceutical composition comprises: (a) mixing the ASD of compound A with one or more excipients to form a mixture, (b) granulating the mixture to form granules, and (c) compressing or encapsulating the granules to form capsule tablets, respectively. The granules can be initially prepared as dry granules. Dry granulation can be accomplished by compaction, such as by rolling and milling, followed by a process such as crushing in a sieve or shearing in a blender or mill to form a granular material. Preferably, a lubricant is added before tableting. The preparation of the granules can be carried out independently under low shear or high shear. The granules formed by the preferred process have acceptable content uniformity, are easy to disintegrate, flow well, so that weight changes can be reliably controlled during capsule filling or tableting, and are dense enough in bulk so that a batch can be processed in the selected equipment to show acceptable dosage form characteristics.

[0108] In a standard disintegration test, preferred excipients for the tablet compositions described herein provide a disintegration time of less than about 30 minutes, preferably about 20 minutes or less, more preferably about 10 minutes or less, and even more preferably about 5 minutes or less.

[0109] Therapeutic dose of compound A

[0110] In one aspect described herein, a pharmaceutical composition includes a unit dosage form of an ASD of Compound A administered as a dosage unit. The term "dosage unit" herein refers to a portion of a pharmaceutical composition that contains an amount of a therapeutic or prophylactic agent, in this case Compound A, suitable for a single oral administration to provide a therapeutic effect. Typically, one dosage unit is required per administration to provide a dose containing a sufficient amount of the agent to produce the desired effect. Such doses can be administered repeatedly as needed.

[0111] The terms "effective amount", "prophylactically effective amount" or "therapeutically effective amount" as used herein refer to an amount of Compound A in the form of ASD that is effective in producing the desired preventive, therapeutic, ameliorative, inhibitory or prophylactic effect in cancer in a patient in need thereof.

[0112] In the context of administering a pharmaceutical composition comprising Compound A in the form of an ASD to a patient, the term "effective amount" as used herein refers to an amount of Compound A in the form of an ASD that is sufficient to achieve at least one or more of the following effects in the patient or patient's cells, as applicable: (i) inhibition of tumor proliferation; (ii) reduction in tumor size or number; (iii) alleviation or amelioration of the severity of cancer or symptoms associated therewith; (iv) prevention of progression of cancer or symptoms associated therewith; (v) regression of cancer or symptoms associated therewith; (vi) prevention of development or onset of cancer or symptoms associated therewith; (vii) prevention of recurrence of cancer or symptoms associated therewith; (viii) reduction in the duration of symptoms associated with cancer; (ix) reduction or elimination of cancer stem cells or tumor stem cell populations; (x) reduction or elimination of tumor or neoplasm growth; (xi) reduction or elimination of proliferation of cancer cells or tumor cells; (xii) (xiii) eradicating or controlling primary, regional and / or metastatic cancer; (xiv) reducing patient mortality; (xv) delaying the increase in the number of patients; (xvi) prolonging the remission time of patients; (xvii) maintaining or controlling the size of a tumor or neoplasm so that its size does not increase or increases less than the size of the tumor after administration of standard therapy as measured by conventional methods available to those skilled in the art, such as MRI, X-ray and CAT scans; (xviii) delaying the progression of the disease; (xix) improving patient survival; (xx) reducing the rate of patient hospitalization; (xxi) shortening the length of patient hospitalization; (xxii) enhancing or improving the preventive or therapeutic effect of another therapy; (xxiii) reducing the number of symptoms associated with cancer; (xxiv) improving the cancer-free survival rate of patients; and / or (xxv) increasing the symptom-free survival rate of cancer patients.

[0113] In general, the term "effective amount" also includes the amount of Compound A given to a patient in the form of ASD, ranging from about 0.001 mg / Kg / day to about 500 mg / Kg / day, or about 0.01 mg / Kg / day to about 500 mg / Kg / day, or about 0.1 mg to about 500 mg / Kg / day, or about 1.0 mg / day to about 500 mg / Kg / day, given in single, divided or continuous doses to patients or subjects with a body weight in the range of about 40 to about 200 Kg (for patients or subjects above or below this range, especially children below 40 Kg, the dosage can be adjusted). It is expected that ordinary adult subjects have an intermediate body weight in the range of about 60 to about 100 Kg. The effective amount of the object will also depend on various factors, including the weight, size and health of the object. The effective amount of a given patient can be determined according to the skill and judgment of the clinician.

[0114] On the other hand, when the daily dose is adjusted based on the weight of the subject or patient, the ASD form of compound A can be formulated for delivery at about 2, 5, 10, 20, 50, 80, 100, 150, 200, 250, 300 or 500 mg / Kg / day. The daily dose adjusted according to the weight of the subject or patient can be administered as a single, divided or continuous dose. On the other hand, when the dose of compound A in the form of ASD is administered more than once a day, the dose can be administered once, twice, three times or more a day. On the other hand, the subject is administered with an effective amount of one or more ASD forms of compound A, wherein the effective amount of each dose may be different. Another aspect described herein includes an effective amount of ASD form of compound A in the range of about 0.001 mg / Kg / day to about 500 mg / Kg / day.

[0115] Within the scope described herein, an "effective amount" of ASD form of Compound A for use in the manufacture of a medicament or in a method of treating cancer in a subject in need thereof is intended to include dosage ranges from about 0.1 ng to about 3500 mg per day, from about 0.1 μg to about 3500 mg per day, from about 0.1 mg to about 3500 mg per day, from about 1 mg to about 3500 mg per day, from about 1 mg to about 3000 mg per day, from about 0.05 mg to about 1500 mg per day, from about 0.5 mg to about 1500 mg per day, from about 1 mg to about 1500 mg per day, from about 5 mg to about 1500 mg per day, from about 10 mg to about 600 mg per day, from about 0.5 mg to about 2000 mg per day, or from about 5.0 mg to about 1500 mg per day.

[0116] Another aspect described herein includes an effective amount of Compound A in ASD Form ranging from about 0.1 ng to about 3500 mg.

[0117] In one aspect described herein, the pharmaceutical composition is a tablet or capsule administered at a therapeutically effective dose ranging from about 10 mg to about 1000 mg, or from about 50 mg to about 400 mg, or from about 50 mg to about 200 mg. In another aspect described herein, a typical dosage unit comprises about 10, 20, 25, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350 or 400 mg of Compound A in ASD. On the one hand, for adults, the therapeutically effective amount of ASD form Compound A per dosage unit in the composition described herein is generally about 50 mg to about 400 mg. On the other hand, the therapeutically effective amount of ASD form Compound A per dosage unit in the composition described herein is about 100 mg to about 200 mg, for example, about 100 mg or about 200 mg. On the other hand, the therapeutically effective amount of ASD form Compound A per dosage unit as described herein is about 50 mg or about 200 mg. Dosage units containing a therapeutically effective amount of ASD Form of Compound A may optionally be adapted to the desired frequency of administration for achieving the desired daily dose.

[0118] In one or more aspects described herein, the effective amount of the ASD form of the compound A composition administered to any type of cancer can be initially estimated by in vitro or in vivo results, the in vitro results are from cell culture assays using patient cells or cell lines known to those skilled in the art, and the in vivo results are from relevant animal models, such as mouse, chimpanzee, marmoset or silk monkey animal models. Relevant animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes of administration for humans. Therapeutic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, such as ED 50 (the dose that is therapeutically effective in 50% of the population) and LD 50 (the dose that is lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is called the therapeutic index and can be expressed as a ratio, LD 50 / ED 50 In some aspects, the effective amount is such that a large therapeutic index is achieved. In further aspects, the dose is within the range of ED with little or no toxicity. 50 The dosage may vary within this range depending on the dosage form employed, sensitivity of the patient, and route of administration.

[0119] In one aspect described herein, the concentration-biological effect (pharmacodynamic) relationship observed for Compound A in ASD form indicates that the target plasma concentration range is about 0.001 μg / mL to about 50 μg / mL, about 0.01 μg / mL to about 20 μg / mL, about 0.05 μg / mL to about 10 μg / mL, or about 0.1 μg / mL to about 5 μg / mL. In another aspect described herein, the target plasma concentration can be in the range of about 3hr·μg / mL to about 70hr·μg / mL, about 3hr·μg / mL to about 60hr·μg / mL, about 3hr·μg / mL to about 50hr·μg / mL, about 3hr·μg / mL to about 40hr·μg / mL, about 3hr·μg / mL to about 30hr·μg / mL, about 3hr·μg / mL to about 20hr·μg / mL, about 3hr·μg / mL to about 10hr·μg / mL, etc., or any range between the two.

[0120] To achieve such plasma concentrations, Compound A in ASD form may be administered in doses ranging from 0.001 μg to 100,000 mg, depending on the route of administration in single, divided or continuous doses for patients weighing about 40 to about 100 kg (the dose may be adjusted for patients above or below this weight range, particularly children under 40 kg).

[0121] The exact dosage will be determined by the practitioner based on factors relevant to the subject. Dosage and administration may be adjusted to provide adequate levels of active agent or to maintain the desired effect. Administration factors that may be considered include the severity of the disease state, the subject's general health, the subject's race, age, weight and sex, diet, dosing time and frequency, drug combination, reaction sensitivity, tolerance to toxicity associated with drug metabolites, experience with other cancer therapies and regimens, and tolerance / response to such therapies and regimens. Depending on the half-life and clearance rate of a particular formulation, a long-acting pharmaceutical composition may be administered every 2, 3 or 4 days, once a week, or once every two weeks.

[0122] Compound A in the ASD form can be administered to a subject by oral, ocular, rectal, buccal, topical, nasal, ocular, subcutaneous, intramuscular, intravenous (bolus and infusion), intracerebral, transdermal, and pulmonary routes.

[0123] The term "oral administration" herein includes any form of delivery of a therapeutic agent or composition thereof to a subject, wherein the agent or composition is placed in the subject's mouth, whether or not the agent or composition is immediately swallowed. Absorption of the agent may occur in any part or parts of the gastrointestinal tract, including the oral cavity, esophagus, stomach, duodenum, ileum, and colon. The term "orally deliverable" herein means suitable for oral administration.

[0124] Use of ASD Composition

[0125] Pharmaceutical compositions of Compound A in the form of an amorphous solid dispersion (ASD), including any dosage form disclosed herein, can be used to treat various types of cancer, including solid tumors and hematological cancers, by administering a therapeutically effective amount of an oral dosage form of the composition to a subject in need thereof. The dosage form administered preferably comprises a solid dispersion of Compound A as disclosed herein.

[0126] One aspect described herein includes non-limiting examples of cancer types that can be treated with the pharmaceutical compositions of Compound A in the form of amorphous solid dispersions disclosed herein, such as: leukemias, such as but not limited to acute leukemias, acute lymphocytic leukemias, acute granulocytic leukemias, such as myeloblastic leukemias, promyelocytic leukemias, myelomonocytic leukemias, monocytic leukemias and erythroleukemic leukemias, and myelodysplastic syndromes; chronic leukemias, such as but not limited to chronic myeloid (granulocytic) leukemias, chronic lymphocytic leukemias, hairy cell leukemias; polycythemia vera; lymphomas, such as but not limited to Hodgkin's lymphomas, non-Hodgkin's lymphomas; multiple myeloma, such as but not limited to smoldering multiple myeloma, non-secretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary leukocytoma, and extramedullary leukocytoma; Waldenstrom's macroglobulinemia; monoclonal gammopathy of undetermined significance; benign monoclonal gammopathy; heavy chain disease; bone and connective tissue sarcomas such as, but not limited to, bone sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft tissue sarcoma, angiosarcoma (angiosarcoma), fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, neurothecoma, rhabdomyosarcoma, synovial sarcoma; glial brain tumors (i.e., gliomas) such as, but not limited to, astrocytomas, ependymomas, oligodendrogliomas, brain stem gliomas, optic nerve gliomas, diffuse intrinsic pontine gliomas, mixed gliomas (i.e., oligoastrocytomas), glioblastomas cystoma, glioblastoma multiforme, non-glioma, acoustic neuroma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma, pineoblastoma, primary brain lymphoma; breast cancer, including but not limited to ductal carcinoma, adenocarcinoma, lobular (cancer cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, Paget's disease and inflammatory breast cancer; adrenal cancer, such as but not limited to pheochromocytoma and adrenocortical carcinoma; thyroid cancer, such as but not limited to papillary or follicular thyroid cancer, medullary thyroid cancer and anaplastic thyroid cancer; pancreatic cancer, such as but not limited to insulinoma, gastrinoma, glucagonoma, sclerostinoma VIPoma, somatostatin-secreting tumors, and carcinoid or islet cell tumors; pituitary cancers, such as but not limited to Cushing's disease, prolactin-secreting tumors, acromegaly, and diabetes insipidus; eye cancers, such as but not limited to ocular melanomas, such as iris melanoma, choroidal melanoma, and ciliary body melanoma, and retinoblastoma; vaginal cancers, such as squamous cell carcinoma, adenocarcinoma, and melanoma; vulvar cancers, such as squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget's disease; cervical cancers, such as but not limited to squamous cell carcinoma and adenocarcinoma; uterine cancers, such as but not limited to endometrial carcinoma and uterine sarcoma; ovarian cancers, such as but not limited to ovarian Epithelial cancers, borderline tumors; germ cell tumors and stromal tumors; esophageal cancers such as but not limited to squamous carcinoma, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, breast cancer, verrucous carcinoma and oat cell (cancer cell) carcinoma; gastric cancers such as but not limited to adenocarcinoma, fungal (polypoid), ulcerative, superficial spreading, diffuse spreading, malignant lymphoma, liposarcoma, fibrosarcoma and carcinosarcoma; colon cancer; rectal cancer; liver cancers such as but not limited to hepatocellular carcinoma and hepatoblastoma; gallbladder cancer such as adenocarcinoma; bile duct cancers such as but not limited to papillary, nodular and diffuse; lung cancers such as non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large cell carcinoma, small cell lung cancer;Testicular cancers, such as, but not limited to, germ cell tumors, seminoma, anaplastic, classical (typical), spermatocyte non-seminoma, embryonal carcinoma, teratoma carcinoma, choriocarcinoma (yolk sac tumor); prostate cancers, such as, but not limited to, prostatic intraepithelial neoplasia, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; kidney cancer (penal cancer); oral cancers, such as, but not limited to, squamous cell carcinoma; basal carcinoma (basal salivary gland cancer, such as but not limited to adenocarcinoma, mucoepidermoid carcinoma and adenoid cystic carcinoma; pharyngeal cancer, such as but not limited to squamous cell carcinoma and verrucous carcinoma; skin cancer, such as but not limited to basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, melanoma malignant melanoma, acral melanoma; kidney cancer, such as but not limited to renal cell carcinoma, adenocarcinoma, renal hypertrophy, fibrosarcoma, transitional cell carcinoma (renal pelvis and / or ureter); Wilms' tumor, bladder cancer, such as but not limited to transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, carcinosarcoma. In addition, cancer includes myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangioendothelioma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchial carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma and papillary adenocarcinoma (for a review of such diseases, see Fishman et al., 1985, Medicine, 2d Ed., JB Lippincott Co., Philadelphia and Murphy et al., 1997, Informed Decisions: The Complete Book of Cancer Diagnosis, Treatment, and Recovery, Viking Penguin, Penguin Books USA, Inc., USA). ;

[0127] Another aspect described herein includes other examples of cancer types that can be treated with the pharmaceutical compositions of Compound A in the ASD form disclosed herein, such as: carcinomas, including bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, and skin cancer; including squamous cell carcinoma; lymphoid hematopoietic tumors, including leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma; myeloid hematopoietic tumors, including These include acute and chronic myeloid leukemias and promyelocytic leukemias; mesenchymal tumors, including fibrosarcoma and rhabdomyosarcoma; other tumors, including melanoma, seminoma, teratoma, neuroblastoma; central and peripheral nervous system tumors, including astrocytoma, neuroblastoma, glioma, and schwannoma; mesenchymal tumors, including fibrosarcoma, rhabdomyosarcoma, and osteosarcoma; and other tumors, including melanoma, xeroderma pigmentosum, keratoacanthoma, seminoma, follicular thyroid carcinoma, and teratoma.

[0128] Another aspect described herein includes other examples of cancer types that can be treated with the pharmaceutical compositions of Compound A in the ASD form disclosed herein, such as: cancers associated with abnormal apoptosis, including but not limited to follicular lymphoma, cancers with p53 mutations, hormone-dependent tumors of the breast, prostate and ovary, and precancerous lesions, such as familial adenomatous polyposis and myelodysplastic syndrome. Another aspect described herein includes other examples of cancer types that can be treated with the pharmaceutical compositions of Compound A in the ASD form disclosed herein, such as: malignant tumors or abnormal changes in proliferation (such as metaplasia and abnormal proliferation), or hyperproliferative diseases in any part of the skin, lung, liver, bone, brain, stomach, colon, breast, prostate, bladder, kidney, pancreas, ovary and / or uterus according to the methods described herein. Another aspect described herein includes other examples of cancer types that can be treated with the pharmaceutical compositions of Compound A in the ASD form disclosed herein, such as: sarcoma or melanoma.

[0129] In a specific aspect, the cancer treated as described herein is a leukemia, lymphoma or myeloma (e.g., multiple myeloma). Non-limiting examples of leukemias and other blood-borne cancers that can be treated with the methods described herein include acute lymphocytic leukemia (ALL), acute lymphocytic B-cell leukemia, acute lymphocytic T-cell leukemia, acute myeloblastic leukemia (AML), acute promyelocytic leukemia (APL), acute monocytic leukemia, acute erythroleukemia, acute megakaryocytic leukemia, acute myelomonocytic leukemia, acute non-lymphocytic leukemia, acute undifferentiated leukemia, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), and hairy cell leukemia.

[0130] Non-limiting examples of lymphomas that can be treated according to the methods described herein include Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, and polycythemia vera.

[0131] In another aspect, the cancer treated as described herein is a solid tumor. Examples of solid tumors that can be treated according to the methods described herein include, but are not limited to, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, gastric cancer, oral cancer, nasal cancer, pharyngeal cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, ulcerative colitis ... carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatocellular carcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, small cell lung cancer, bladder cancer, lung cancer, epithelial cancer, glioma, glioblastoma multiforme, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, skin cancer, melanoma, neuroblastoma, and retinoblastoma.

[0132] In another aspect, cancers treated as described herein include, but are not limited to, brain cancer, gastric cancer, hematological cancer, lung cancer, non-small cell lung cancer, pancreatic cancer, prostate cancer, salivary gland cancer, colorectal cancer, hepatocellular carcinoma, liver cancer, breast cancer or sarcoma, esophageal cancer or sarcoma, gastric cancer or sarcoma, fibrosarcoma, glioblastoma, diffuse intrinsic pontine glioma, medulloblastoma, neuroblastoma, diffuse large B-cell lymphoma, B-cell non-Hodgkin lymphoma, Hodgkin lymphoma, or chronic or acute myeloid leukemia.

[0133] On the other hand, cancers treated as described herein include, but are not limited to, tumors that recur despite treatment with improved surgical and radiation techniques. There are many reasons for tumor recurrence, one of which is the presence of cancer stem cells (CSC) or tumor stem cells (tumor-initiating cells) in the tumor population. CSC is defined as a stem cell population associated with any type of blood cancer, solid tumor cancer, or metastatic cancer. Tumor stem cells are those cells that are specifically found in tumors. Both have characteristics similar to normal stem cells. Like normal stem cells, CSC and tumor stem cells have the potential for self-renewal. However, unlike normal stem cells, CSC and tumor stem cells are unable to undergo terminal differentiation and proliferation in an uncontrolled manner. Their enhanced DNA repair ability also enables them to develop resistance to cytotoxic chemotherapeutic drugs designed to kill cancer cells and tumor cells. Therefore, targeting CSC and tumor stem cells may be an effective cancer treatment method. Another approach is to target various transcription factors responsible for maintaining the self-renewal ability of CSC and tumor stem cells.

[0134] As used herein, the terms "treat," "treatment," or "treating" refer to: (i) preventing a disease, disorder, and / or condition from occurring in a subject who may be susceptible to the disease, disorder, and / or condition but has not yet been diagnosed as having the disease, disorder, and / or condition; (ii) inhibiting a disease, disorder, and / or condition, i.e., arresting its development; and / or (iii) ameliorating a disease, disorder, and / or condition, i.e., causing regression of the disease, disorder, and / or condition.

[0135] As used herein, the term "subject" refers to members of the human, horse, pig, cow, mouse, rat, dog, and cat species. In some aspects, the subject is a mammal or a warm-blooded vertebrate. In other aspects, the subject is a human. As used herein, the term "patient" can be used interchangeably with "subject" and "human".

[0136] In some aspects, the subject is a human being between 0 and 6 months old, between 6 and 12 months old, between 6 and 18 months old, between 18 and 36 months old, between 1 and 5 years old, between 5 and 10 years old, between 10 and 15 years old, between 15 and 20 years old, between 20 and 25 years old, between 25 and 30 years old, between 30 and 35 years old, between 35 and 40 years old, between 40 and 45 years old, between 45 and 50 years old, between 50 and 55 years old, between 55 and 60 years old, between 60 and 65 years old, between 65 and 70 years old, between 70 and 75 years old, between 75 and 80 years old, between 80 and 85 years old, between 85 and 90 years old, between 90 and 95 years old, or between 95 and 100 years old. In some aspects, the subject is a human infant. In other aspects, the subject is a human toddler. In other aspects, the subject is a human child. In other aspects, the subject is an adult. In other aspects, the subject is an elderly person.

[0137] As used herein, the term "elderly" refers to a person who is 65 years of age or older; the term "adult" refers to a person who is 18 years of age or older; the term "human child" refers to a human being between 1 and 18 years of age; the term "human infant" refers to a human being between newborn and one year old; and, the term "human toddler" refers to a human being between 1 and 3 years of age.

[0138] In some aspects, the subject is in an immunocompromised or immunosuppressed state or is at risk of becoming immunocompromised or immunosuppressed. In some aspects, the subject is receiving or recovering from immunosuppressive therapy. In some aspects, the subject suffers from or is at risk of cancer, AIDS, or a bacterial infection. In some aspects, the subject is, will, or has undergone surgery, chemotherapy, and / or radiotherapy. In some aspects, the subject suffers from cystic fibrosis, pulmonary fibrosis, or other conditions that affect the lungs. In some aspects, the subject has, will, or has undergone a tissue transplant.

[0139] In some aspects, cancer may become difficult to treat by conventional "standard of care" therapy, so that the patient has stopped conventional therapy. On the one hand, without being limited by theory, the term "refractory" refers to at least some significant parts of cancer cells, tumor cells, cancer stem cells or tumor stem cells that continue to proliferate despite treatment. It can be determined in vivo or in vitro by any method known in the art for analyzing the effects of therapy on cancer cells, tumor cells, cancer stem cells or tumor stem cells whether cancer is refractory to a particular therapy, in which case the art-recognized meaning of "refractory" is used. In some aspects, patients with refractory cancer are patients whose cancer is unresponsive or resistant to conventional or "standard of care" therapy. In some aspects, patients with refractory cancer suffer from worsening cancer. When a tumor or neoplasm is not significantly eradicated and / or symptoms are not significantly alleviated, it is proved that the disease is worsening, i.e., lack of clinical response to treatment. It can be determined in vivo or in vitro by any method known in the art for determining the effectiveness of a therapy for treating cancer to determine whether a patient suffers from refractory cancer, in which case the art-recognized meaning of "refractory" is used.

[0140] In certain aspects, the patient to be treated according to the methods described herein is a patient who has been treated with antibiotics, antivirals, antifungals or other biological therapies, immunotherapies or anticancer therapies. These patients include patients with refractory cancers or patients who are too young for conventional therapies. In some aspects, the patient to be treated is naive and has not received any previous treatment. In any of the foregoing aspects, the patient to be treated can receive small molecule therapy.

[0141] In some aspects, the ASD form of Compound A can be administered to a patient prophylactically to prevent the development of cancer in patients at risk of cancer. In some aspects, the ASD form of Compound A can be administered therapeutically to patients who are sensitive to adverse reactions to conventional therapies. In some aspects, the subject administered the ASD form of Compound A has not received prior treatment. In other aspects, the ASD form of Compound A is administered to a subject who has received prior treatment. In some aspects, the subject administered the ASD form of Compound A has stopped prior treatment due to lack of benefit from treatment, side effects of treatment, or unacceptable levels of toxicity.

[0142] In some aspects, the subject to whom the ASD form of Compound A is administered will undergo or has undergone surgery, chemotherapy, antibody therapy, hormone therapy, and / or radiation therapy. In certain aspects, the patient has undergone surgery to remove a tumor or neoplasm. In certain aspects, the subject will undergo or has undergone or is undergoing a tissue or organ transplant.

[0143] For any composition of Compound A, the effective amount to be administered for any type of cancer can be initially estimated from in vitro or in vivo results, the in vitro results are from cell culture assays using patient cells or cell lines known to those skilled in the art, and the in vivo results are from relevant animal models, such as mouse, chimpanzee, marmoset or tamarin animal models. Relevant animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes of administration for humans. Therapeutic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, such as ED 50 (the dose that is therapeutically effective in 50% of the population) and LD 50 (the dose that is lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is called the therapeutic index and can be expressed as a ratio, LD 50 / ED 50 In some aspects, the effective amount is such that a large therapeutic index is achieved. In further aspects, the dose is within the range of ED with little or no toxicity. 50 The dosage may vary within this range depending on the dosage form employed, sensitivity of the patient, and route of administration.

[0144] More specifically, the concentration-biological effect (pharmacodynamic) relationship observed for Compound A indicates that the target plasma concentration range is about 3hr·μg / mL to about 70hr·μg / mL, about 3hr·μg / mL to about 60hr·μg / mL, about 3hr·μg / mL to about 50hr·μg / mL, about 3hr·μg / mL to about 40hr·μg / mL, about 3hr·μg / mL to about 30hr·μg / mL, about 3hr·μg / mL to about 20hr·μg / mL, about 3hr·μg / mL to about 10hr·μg / mL, etc., or any range therebetween. In order to achieve such a plasma concentration, Compound A or a form thereof described herein can be administered in doses ranging from 0.001 μg to 100,000 mg, depending on the route of administration in single, divided or continuous doses for patients weighing about 40 to about 100 kg (the dosage can be adjusted for patients above or below this weight range, especially children under 40 kg).

[0145] The exact dosage will be determined by the practitioner based on factors relevant to the subject. Dosage and administration may be adjusted to provide adequate levels of the active agent or to maintain the desired effect. Administration factors that may be considered include the severity of the disease state, the subject's general health, the subject's race, age, weight and sex, diet, time and frequency of administration, drug combinations, reaction sensitivities, tolerance to toxicity associated with drug metabolites, experience with other cancer therapies and regimens, and tolerance / response to such therapies and regimens.

[0146] Combination therapy

[0147] The method of treating cancer by administering the ASD form of Compound A disclosed above, or a pharmaceutical composition thereof, in combination with one or more additional agents may further comprise administering to a subject in need thereof an effective amount of the ASD form of Compound A, or a pharmaceutical composition thereof, selected from anticancer agents, antiproliferative agents, chemotherapeutic agents, immunomodulators, antiangiogenic agents, anti-inflammatory agents, alkylating agents, steroidal and non-steroidal anti-inflammatory agents, analgesics, leukotriene antagonists, b2-agonists, anticholinergic agents, hormonal agents, biological agents, microtubule binding agents, glucocorticoids, corticosteroids, antibacterial agents, antihistamines, antimalarials, antiviral agents, antibiotics, etc., and, optionally, radiation therapy.

[0148] According to the methods described herein, combination products may include a combination of active ingredients that may be: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered sequentially or in parallel as separate formulations; (3) by any other combination regimen known in the art. When delivered as separate formulations in alternation therapy, the methods described herein may include, for example, but not limited to, administration or delivery as separate solutions, emulsions, suspensions, tablets, pills, or capsules or by separate injections in separate syringes. Typically, when administered in alternation, an effective dose of each active ingredient is administered consecutively, one dose following the other. In contrast, when administered in parallel or simultaneously, effective doses of two or more active ingredients are administered together. Various alternative combinations of intermittent sequential or parallel combined administration may also be used.

[0149] Specific examples of such agents include, but are not limited to, immunomodulators (e.g., interferon, penicillamine, etc.), anti-angiogenic agents, anti-inflammatory agents (e.g., adrenocortical hormones, corticosteroids (e.g., beclomethasone, budesonide), flunisolide, fluticasone, triamcinolone, methylprednisolone, prednisolone, prednisone, hydrocortisone), glucocorticoids, steroidal and nonsteroidal anti-inflammatory drugs (e.g., aspirin, ibuprofen, diclofenac, and COX-2 inhibitors)), analgesics, leukotriene antagonists (e.g., montelukast, methylxanthines, zafirlukast, and zileuton), β2-agonists (e.g., salbutamol, biterol, non The drugs include, but are not limited to, chlorpromazine, isoetharine, metaproterenol, pirbuterol, albuterol, terbutaline, formoterol, salmeterol and albuterol terbutaline), anticholinergics (e.g., ipratropium and oxitropium), antibacterials (e.g., sulfasalazine, dapsone, etc.), antihistamines, antimalarials (e.g., hydroxychloroquine), antivirals (e.g., nucleoside analogs (e.g., zidovudine, acyclovir, ganciclovir, vidarabine, idoxuridine, trifluridine, ribavirin, foscarnet, amantadine, rimantadine, saquinavir, indinavir, ritonavir and AZT), and antibiotics (e.g., dactinomycin (formerly known as actinomycin), bleomycin, erythromycin, penicillin, mithramycin and anthramycin (AMC)).

[0150] Specific examples of additional agents that can be used in combination with the ASD form of Compound A include, but are not limited to, acivicin, aclarubicin, acodazole hydrochloride, aclonine, adozelesin, aldesleukin, hexamethylmelamine, aminomycin, ametantrone acetate, aminoglutethimide, amsacrine, anastrozole, anthracycline, anthramycin, asparaginase, asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene hydrochloride, bisnafidedimesylate, bisphosphonates (e.g., pamidronate), Sodium clondronate Zoledronic acid Alendronate etidronate, ibandornate, cimadronate, risedromate, and tiludromate), bizelesin, bleomycin sulfate, brequinar sodium, bropirimine, busulfan, cactinomycin, calusterone, caracemide, carbetimer, carboplatin, carmustine, carrubicin hydrochloride, carzelesin, cedefingol, chlorambucil, cirolemycin, cisplatin, cladribine, cristalin mesylate mesylate), cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunomycin hydrochloride, decitabine, demethylating agents, dexormaplatin, dezaguanine, dezaguanine mesylate, diaziquone, docetaxel, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, dromostanolone propionate propionate), duazomycin, edatrexa, eflornithine hydrochloride, EphA2 inhibitors, esamitrucin, enloplatin, enprobamate, epipropidine, epirubicin hydrochloride, erbulozole, esorubicin hydrochloride, estramustine, estramustine sodium phosphate, etanidazole, etoposide, etoposide phosphate, etoprine, fadrozole hydrochloride, fazarabine, fenretinide, floxuridine, fludarabine phosphate, 5-fluorouracil, flucitabine, fosquatone, fostriecin sodium, gemcitabine, gemcitabine hydrochloride, histone deacetylase inhibitors, hydroxyurea, idarubicin hydrochloride, ifosfamide, imofosine, imatinib mesylate, interleukin II (including recombinant interleukin II or rIL2),Interferon α2a, interferon α2b, interferon αn1, interferon αn3, interferon βIa, interferon γIb, iproplatin, irinotecan hydrochloride, lanreotide acetate, lenalidomide, letrozole, leuprolide acetate, liarozole hydrochloride hydrochloride), lometrexol sodium, lomustine, loxantrone hydrochloride, masoprocol, maytansine, dichloromethyl diethylamine hydrochloride, anti-CD2 antibody, megestrol acetate, melengestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate, methotrexate sodium, metoprine, metodepa, mitindomide, mitocarcin, mitocromin, mitogillin, mitomalcin, mitomycin, mitosper, mitocin tan, mitoxantrone hydrochloride, mycophenolic acid, nocodazole, nogamycin, ormaplatin, oxisuran, paclitaxel, pegaspargase, peliomycin, pentamustine, peplomycin sulfate, perphosphamide, pipobroman, piposufan, pyrroloanthrone hydrochloride, plicamycin, promestane, porfimer sodium, porphyrin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofuranoside, riboprine, roglulimine, safengo, safengo hydrochloride, semustine, sparfosate sodium), sparse mycin, spirogermanium hydrochloride, spiromustine, spiroplatin, streptomycin, streptozotocin, sulfachlorpyrifos, talithromycin, tecogalansodium, tegafur, tiloxantrone hydrochloride, temoporfin, teniposide, troxitone, testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin, tirapazamine, toremifene citrate, triptolan acetate, Triciribine phosphate, trimetrexate, trimetrexate glucuronide, triptorelin, tobradazole hydrochloride, uracil mustard, uredepa, vapreotide, verteporfin, vinblastine sulfate, vincristine sulfate, vindesine, vindesine sulfate, vinposide sulfate, vincristine sulfate, vingrosin sulfate, vinorelbine tartrate, vinprodine sulfate, vinorelbine sulfate, volitinib, vorozole, zeniplatin, zinostatin, zorubicin hydrochloride, etc.

[0151] Other examples of cancers mediated by treatment according to the present method include treatment with an anticancer agent or an antiproliferative agent, wherein the anticancer agent or antiproliferative agent is selected from, but not limited to, 20-Epi-1,25-dihydroxyvitamin D3 (MC 1288, MC 1301, KH 1060), 5-ethynyluracil, abiraterone, aclarubicin, acylfulvene, adecypenol, adolesin, aldesleukin, ALL-TK antagonists, hexamethylmelamine, ambamustine, amidox, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, andrographolide, angiogenesis inhibitors, antagonist D, antagonist G, antarelix, antidorsalizing morphogenetic protein-1, protein-1), antiandrogens, antiestrogens, antineoplastons, antisense oligonucleotides, aphidicolin glycinate, apoptosis gene regulators, apoptosis regulators, apurinic acid, ara-CDP-DL-PTBA (0-palmitoyl-1-thioglycerol), arginine deaminase, asulacrine, atamestane, amustine, axinastatin 1, axinastatin 2, axinastatin 3, azasetron, azatoxin, azatyrosine, baccatin III derivatives, balanol, batimastat, BCR / ABL antagonists, benzochlorins, benzoylstaurosporine, β-lactam derivatives, β-alethine, β-clarithromycin B B), betulinic acid, bFGF inhibitors, bicalutamide, bisantrene, bisaziridinylspermine, binafad, bistratene A, bizolexin, breflate, bropirimine, budotitane, buthionine sulfoximine, calcipotriol, calciphosphotin C, camptothecin derivatives, canarypox IL-2, capecitabine, carboxamide-amino-triazole (CaRestM3), CARN700, cartilage-derived inhibitors, cardzelesin, casein kinase inhibitor (ICOS), castanospermine, cecropin B (cecropinB), cetrorelix, chlorinns, chloroquinoxaline sulfonamide, cicaprost, cis-porphyrin, cladribine, clomifene analogues, clotrimazole, collismycin A, collismycin B, combretastatin A4, combretastatin analogues, conagenin, crambescidin 816, crisnatol, candida albicans 8, candida albicans A derivatives, curacin A, cyclopentanthraquinone, cycloplatam, cypemycin, cytarabine ocfosfate (YNK01 or ), cytolytic factor, cytostatin, dacliximab, decitabine, dehydrodidemnin B, deslorelin, dexamethasone, dexifosfamide, dexrazoxane, dexverapamil, diaziquone, ecteinascin B, didox, diethylnorspermine, dihydro-5-azacytidine, dihydropaclitaxel, dioxamycin, diphenylspiromustine, docetaxel, docosanol, dolasetron, doxifluridine, droloxifene, dronabinol, duocarmycin SA SA), ebselen, ethomustine, edilfosine, edrecolomab, eflornithine, elemene, ethidium bromide, epirubicin, epristeride, estramustine analogs, estrogen agonists, estrogen antagonists, etanidazole, etoposide phosphate, exemestane, fadrozole, fazarabine, fenretinide, filgrastim, finasteride, flavopiridol, flezlastine, fluasterone, fludarabine, fluorodaunorunicin hydrochloride, fofomek, fostramestane, fostramestine, fostramustine, gadolinium texaphyrin, gallium nitrate, galocitabine, ganirelix, gelatinase inhibitors, gemcitabine, glutathione inhibitors, HMG CoA reductase inhibitors (e.g., atorvastatin, cerivastatin, fluvastatin, fluvastatin, lupitor, lovastatin, rosuvastatin, and simvastatin), sulfonamides (hepsulfam), regulatory proteins, hexamethylenebisacetamide, hyperforin, ibandronic acid, idarubicin, idoxifene, idemenone, imofosine, ilomastat, imidazoacridone, imiquimod, immunostimulatory peptides, insulin-like growth factor-1 receptor inhibitors, interferon agonists, interferons, interleukins, iodobenzylguanidine, iodoxorubicin, ipomeanol, 4-iropra, irsogladine, isobengazole, isohomohalicondrin B, itasetron, jasplakinolide, kahalalide F F), lamellarin N triacetatetriacetate), lanreotide, leinamycin, lenograstim, lentinan sulfate, leptolstatin, letrozole, leukemia inhibitory factor, interferon alpha, leuprolide / estrogen / progesterone combination, leuprolide, levamisole, LFA-3TIP), lirazole, linear polyamine analogs, lipophilic disaccharide peptides, lipophilic platinum compounds, lissoclinamide 7, lobaplatin, lombricine, lometrexol, lonidamine, loxantrone, lovastatin, loxoribine, lutetium texaphyrin, lysofylline, lytic peptide, maytansine, mannostatin A), Marimastat, Masoprofen, Maspin, Matrixlysin inhibitor, Matrix metalloproteinase inhibitor, Menolil, Merbarone, Meterelin, Methioninase, Metoclopramide, MIF tautomerase inhibitor, Mifepristone, Miltefosine, Milistostim, Mismatched double-stranded RNA, Mitoguanidine, Dibromodulanol, Mitomycin analogs, Mitonastat, Mitotoxin Fibroblast Growth Factor-Saporin, Mitoxantrone, Mofaradine, Molgramostim, Monoclonal antibody, Human chorionic gonadotropin, Monophosphoryl lipid A / Mycobacterial cell wall skeleton (CWS / MPL), Mopiridol, Multidrug resistance gene inhibitor, Multiple tumor suppressor gene 1-based therapy, Mustard anticancer agent, Indian Ocean sponge B (mycaperoxideB), mycobacterial cell wall extract, myriaporone, N-acetyldinaline, N-substituted benzamides, nafarelin, nagrestip, naloxone / pentazocine combination, napavin, naphterpin, nartograstim, nedaplatin, nemorubicin, neridronic acid, neutral endopeptidase, nilutamide, nisamycin, nitric oxide regulators, nitrogen oxide antioxidants, nitramines, 06- benzylguanine, octreotide, okicenone, oligonucleotides, onapristone, oracin, oral cytokine inducers, oramaplatin, oxalitone, oxaliplatin, oxaunomycin, paclitaxel, paclitaxel analogs, paclitaxel derivatives, palaumine, palmitoylrhizoxin, pamidronate, panaxatriol, panomifen, parabactin, pazelliptine, pegaspargase, peldesine (BCX 340), pentosan polysulfate sodium, pentostatin, pentrozole, perfluoroammonium bromide, perphosphamide, perillyl alcohol dehydrogenase, phenazinomycin, phenyl acetate, phosphatase inhibitors, picibanil, pilocarpine hydrochloride, pirarubicin, piroxine, placetin A, placetin B, plasminogen activator inhibitor, platinum complex, platinum compound, platinum-triamine complex, porfimer sodium, porphyrin firomycin), prednisone, propyl diacridone, prostaglandin J2, proteasome inhibitors, protein A-based immunomodulators, protein kinase C inhibitors, microalgal, protein tyrosine phosphatase inhibitors, purine nucleoside phosphorylase inhibitors, purpurin, pyrazoloacridine, pyridinium oxyhemoglobin polyoxyethylene conjugates, raf antagonists, raltitrexed, ramosetron, ras farnesyl protein transferase inhibitors, ras inhibitors, ras-GAP inhibitors, demethylated retiritin, rhenium Re 186 etidronate, rhizoxin, ribozyme, RII retinamide, roglulimide, roxitomine, romotide, roquine, rubiginone B1, ruboxyl, safingol, saintopin, SarCNU, myophylline A, sargramostim, Sdi1 mimetic, semustine, senescence-derived inhibitor 1, sense oligonucleotide, signal transduction inhibitor, signal transduction regulator, single-chain antigen binding protein, sizoran, sobuzoxane, sodium borocaptate, sodium phenylacetate, solverol, somatomedin binding protein, sonermin, sparlfosic acid, spicamycin D, spiromustine, splenopentin, spongistatin 1, squalamine, stem cell inhibitor, stem cell division inhibitor, stipiamide, stromelysin inhibitor, sulfinic acid, superactive vasoactive intestinal peptide antagonist, suradista, suramin, swainsonine, synthetic glycosaminoglycan, tamustine, 5-fluorouracil, folinic acid, tamoxifen methyl iodide, tauromustine, tazarotene, teicogalan sodium, tegafur , tellurapyrylium, telomerase inhibitors, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, tetrazolamine, thaliblastine, thiocoraline, thrombopoietin, thrombopoietin mimetics, thymofasin, thymopoietin receptor agonists, thymotrinan, thyroid stimulating hormone, tinethylpurpurin ethyl etiopurpurin), tirapazamine, titaniumocene bichloride, topsentin, toremifene, totipotent stem cell factor, translation inhibitor, retinoic acid, triacetyluridine, triciribine, trimetrexate, triptorelin, tropisetron, torosterolamide, tyrosine kinase inhibitors, tyrphostins, UBC inhibitors, ubenimex, urogenital sinus-derived growth inhibitory factor, urokinase receptor antagonist, vapreotide, variolin B, vector system, erythrocyte gene therapy, thalidomide, velaresol, veramine, verdins, verteporfin, vinorelbine, vinblastine, volitinib, vorizole, zanoteron, zeniplatin, zilascorb, zinostatin stimalamer, etc.

[0152] In some aspects, the additional agent is one or more immunomodulators used in combination with the ASD form of Compound A. Non-limiting examples of immunomodulators include proteinaceous agents such as cytokines, peptide mimetics and antibodies (e.g., human, humanized, chimeric, monoclonal, polyclonal, Fvs, ScFvs, Fab or F(ab)2 fragments or epitope binding fragments), nucleic acid molecules (e.g., antisense nucleic acid molecules and triple helices), cancer molecules, organic compounds, and inorganic compounds.

[0153] In particular, one or more immunomodulators that can be used in combination with the ASD form of Compound A include, but are not limited to, methotrexate, leflunomide, cyclophosphamide, cytoxan, cyclosporine A, minocycline, azathioprine, Antibiotics (e.g., FK506 (tacrolimus)), methylprednisolone (MP), corticosteroids, steroids, mycophenolate mofetil, rapamycin (sirolimus), mizoribine, deoxyspergualin, brequinar, malononitriloamindes (e.g., leflunamide), T cell receptor modulators, cytokine receptor modulators, and mast cell modulators.

[0154] In one aspect, the immunomodulator is a chemotherapeutic agent. In another aspect, the immunomodulator is an immunomodulator other than a chemotherapeutic agent. In some aspects, the additional agent used as described herein is not an immunomodulator.

[0155] In some aspects, the additional agent is one or more anti-angiogenic agents that can be used in combination with the ASD form of Compound A. Non-limiting examples of anti-angiogenic agents include proteins, polypeptides, peptides, fusion proteins, antibodies (e.g., human, humanized, chimeric, monoclonal, polyclonal, Fvs, ScFvs, Fab fragments, F(ab)2 fragments, and antigen-binding fragments thereof), such as antibodies that immunospecifically bind to TNF-α, nucleic acid molecules (e.g., antisense molecules or triple helices), organic molecules, inorganic molecules, and cancer molecules that reduce or inhibit angiogenesis. In other aspects, the additional agent described herein is not an anti-angiogenic agent.

[0156] In some aspects, the additional agent that can be used in combination with the ASD form of Compound A is one or more anti-inflammatory agents. Non-limiting examples of anti-inflammatory agents include any anti-inflammatory agent that can be used to treat inflammatory diseases. Non-limiting examples of anti-inflammatory agents include nonsteroidal anti-inflammatory drugs (NSAIDs), steroidal anti-inflammatory drugs, anticholinergics (e.g., atropine sulfate, atropine nitrate, and ipratropium bromide). 2-agonists (e.g., salbutamol ( and ), Bitotero Levosalbutamol Metaproterenol Piributerol Terbutaline and ), salbutamol( and ), FORADIL )、Salmeterol( and SEREVENT )), methylxanthines (e.g. theophylline ( and )) etc. Examples of NSAIDs include, but are not limited to, aspirin, ibuprofen, celecoxib Diclofenac Etodolac Fenoprofen Indomethacin Ketorolac Oxaprozin Nabumentone Sulindac Tolmentin Rofecoxib Naproxen Ketoprofen Nabumetone Such NSAIDs work by inhibiting cyclooxygenases (e.g., COX-1 and / or COX-2). Examples of steroidal anti-inflammatory drugs include, but are not limited to, glucocorticoids, dexamethasone, Corticosteroids (eg, methylprednisolone ), cortisone, hydrocortisone, prednisone ( and ), prednisolone ( and ), triamcinolone, sulfapyridine, eicosanoid inhibitors (such as prostaglandins, thromboxanes and leukotrienes), etc.

[0157] In certain aspects, additional agents that can be used in combination with the ASD form of Compound A are alkylating agents, nitrosoureas, antimetabolites, anthracyclines, topoisomerase II inhibitors, mitotic inhibitors, and the like. Alkylating agents include, but are not limited to, busulfan, cisplatin, carboplatin, chlorambucil, cyclophosphamide, ifosfamide, decarboxazid, mechlorethamine, triamterene, thiazolinamide, and the like. Nitrosoureas include, but are not limited to, carmustine Lomustine Etc. Antimetabolites include but are not limited to 5-fluorouracil, capecitabine, methotrexate, gemcitabine, cytarabine, fludarabine, etc. Anthracyclines include but are not limited to daunomycin, doxorubicin, epirubicin, idarubicin, mitoxantrone, etc. Topoisomerase II inhibitors include but are not limited to topotecan, irinotecan, etoposide (VP-16), teniposide, etc. Mitotic inhibitors include but are not limited to taxanes (paclitaxel, docetaxel) and vinca alkaloids (vinblastine, vincristine and vinorelbine), etc.

[0158] In more specific aspects, additional anticancer, antiproliferative, or chemotherapeutic agents that can be used in combination with the ASD form of Compound A include, but are not limited to, aflibercept, amsacrine, bleomycin, busulfan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clofarabine, crisantaspase, cyclophosphamide, cytarabine, dacarbazine, actinomycin, daunomycin (IV and liposomal), docetaxel, doxorubicin (IV and liposomal), enzastaurin, epirubicin, acinar, etoposide, fludarabine, 5-fluorouracil (5-FU), gemcitabine, carmustine implant, hydroxyurea, idarubicin, ifosfamide, imatinib mesylate, irinotecan, lanreotide, lenalidomide, folinic acid, cyclohexyl lomustine, melphalan, mercaptopurine, mesna, methotrexate, mitomycin, mitoxantrone, octreotide, oxaliplatin, paclitaxel, pemetrexed, pentostatin, procarbazine, raltitrexed, satraplatin, sorafenib, streptozotocin, sunitinib, tegafur uracil), temozolomide, teniposide, thalidomide, thiotepa, thioguanine, topotecan, treosulfan, vatalanib, vinblastine, vincristine, vindesine, vinorelbine, savolitinib, ZD6474, monoclonal antibodies (e.g., bevacizumab, cetuximab, IMC-A12, IMC-1121B, medi-522, rituximab, etc.), hormone drugs (e.g., anastrozole, bicalutamide, buserelin, cyproterone acetate, diethylstilbestrol, exemestane, flutamide, goserelin (breast and prostate), letrozole, leuprolide, medroxyprogesterone, megestrol acetate, tamoxifen, toremide fen, triptorelin, etc.), biologics (e.g., interferon, interleukin-12, etc.), angiogenic receptor tyrosine kinase (RTK) inhibitors (e.g., AE-941, angiostatin, carboxyamidotriazole, cilengitide, endostatin, halofuginone hydrobromide, 2-methoxyestradiol, squalamine lactate, SU6668, etc.), tubulin binding agents (e.g., combretastatin A4 phosphate, etc.), matrix metalloproteinase inhibitors (e.g., BMS-275291, etc.), and / or serine / threonine / tyrosine kinase inhibitors and optionally non-steroidal or COX-2 anti-inflammatory agents (e.g., celecoxib, etc.) or corticosteroids (e.g., prednisone, etc.).

[0159] In more specific aspects, the one or more additional anticancer, antiproliferative, or chemotherapeutic agents that can be used in combination with the ASD form of Compound A are selected from bevacizumab, carboplatin, cisplatin, docetaxel, doxorubicin, exemestane, gemcitabine, 5-fluorouracil, imatinib, irinotecan, sorafenib, sunitinib, temozolomide, savolitinib, or a combination thereof.

[0160] In some aspects, the ASD form of Compound A is used in combination with one or more additional anticancer agents, antiproliferative agents, or chemotherapeutic agents and radiation therapy, which includes the use of X-rays, gamma rays, and other radiation sources to destroy cancer cells or tumor cells. In specific aspects, the radiation therapy is administered as external beam radiation or teletherapy, where the radiation comes from a remote source. In other aspects, the radiation therapy is administered as internal therapy or brachytherapy, where the radiation source is placed close to the cancer cells, tumor cells, and / or tumor mass.

[0161] Currently available anticancer, antiproliferative or chemotherapeutic agents, their dosing regimens, routes of administration and recommended uses alone or in combination are known in the art and have been described in literature such as the Physician's Desk Reference.

[0162] Any anticancer, antiproliferative or chemotherapeutic agent or anticancer therapy known to be useful, or that has been or is currently used to treat cancer, can be used in combination with a pharmaceutical composition comprising an ASD form of Compound A administered as described herein. See, e.g., Gilman et al., Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 10th ed., McGraw-Hill, New York, 2001; The Merck Manual of Diagnosis and Therapy, Berkow, MD et al. (eds.), 17th Ed., Merck Sharp & Dohme Research Laboratories, Rahway, NJ, 1999; Cecil Textbook of Medicine, 20th Ed., Bennett and Plum (eds.), WB Saunders, Philadelphia, 1996, and the Physician's Desk Reference for information on cancer therapies (e.g., the use of preventive or therapeutic agents) that have been or are being used to prevent, treat and / or manage various types of cancer.

[0163] Example

[0164] The following examples illustrate aspects of the ASD forms of Compound A described herein, as well as illustrate comparative forms of Compound A and compositions thereof. These examples should not be construed as limiting.

[0165] Example 1

[0166] Compound A prepared according to the method described in WO2014 / 081906, hereinafter referred to as "Type I" or "original" form, was found to be a crystalline white to off-white solid. According to the results of dynamic vapor sorption (DVS), the original form was found to be somewhat hygroscopic, with a water absorption rate of about 1.3% at 95% RH, and was almost insoluble in phosphate buffer at pH 6.5, with a solubility of <1 μg / mL, and in fasting state intestinal fluid (FaSSIF) at pH 6.5, the solubility was about 18 μg / mL. The cLogP of Type I of Compound A is 5.2, indicating that the compound is highly lipophilic and has a weakly basic aromatic amino group (pKa<3).

[0167] X-ray diffraction analysis of compound A showed that Form I was crystalline in nature, as shown in Figure 2 As shown. Polymorph screening studies have shown that compound A has two solvated forms, referred to herein as Form A and Form B. Form A is prepared by dissolving Form I of compound A in ethanol, shaking at 25°C for 72 hours, centrifuging the resulting mixture to separate the solid material from the supernatant, and then vacuum drying the sample at 50°C overnight. The resulting sample is characterized herein by XRPD, DSC, and TGA.

[0168] Form B was obtained by dissolving Form I in isopropanol to form a saturated solution and then adding water as an anti-solvent while stirring until a precipitate formed. The solid material was separated from the supernatant by centrifugation, dried under vacuum at 50°C overnight, and characterized by XRPD, DSC and TGA.

[0169] The superposition of the XRPD spectra of Form I, Form A and Form B is shown in Figure 3 The overlay of DSC scans of Form I, Form A, and Form B of Compound A is shown in Figure 4 The polymorph stability study of the two crystalline polymorphs showed that form A is more stable than form B.

[0170] Example 2

[0171] It has been found that the presence of a surfactant increases the water solubility of the Type A form of Compound A. Therefore, two solid dosage forms of Compound A, Type A Tablet 1 and Type A Tablet 2, were prepared as shown in Table 1 below.

[0172] Table 1 - Composition of two solid dosage forms

[0173]

[0174] Two tablet dosage forms were prepared as follows. Form A of Compound A, sodium lauryl sulfate and microcrystalline cellulose were premixed, and then mannitol, crospovidone and silicon dioxide were added and mixed. The mixture was granulated using a dry granulation process and then tablets were obtained using a tablet press. The tablets were crushed and sieved through 12 and 18 meshes to obtain granules. Depending on the dosage, the granules were loaded into No. 0 or No. 00 white opaque gelatin capsules.

[0175] The two prototype tablet formulations were also evaluated in cynomolgus monkeys as described in Example 11 below. The absolute oral bioavailability of Form A Tablets 1 and 2 was 9% and 34%, respectively, and the AUC 0-无穷大 (AUC 0-inf ) exposures were 1.77 and 6.98 hr·μg / mL, respectively. Neither formulation reached the target exposure (AUC 0-无穷大 ).

[0176] Example 3

[0177] Two capsule dosage forms of Compound A dissolved Form A were developed using polyethylene glycol 4000, Tween 80 and two different solvents, laurate macrogol glyceride and Solutol HS15, as shown in Table 2 below.

[0178] Table 2 - Composition of two capsule formulations

[0179]

[0180] The in vitro dissolution behavior of the two capsule dosage forms in 0.01N HCl and FaSSIF, pH 6.5 was evaluated. Both showed complete dissolution within 45 minutes in 0.01N HCl and FaSSIF, pH 6.5. The two prototype dosage forms were further evaluated in a monkey PK study, described in Example 11 below.

[0181] Example 4

[0182] Two additional capsule dosage forms were also developed, containing 10 mg and 50 mg doses of Form A of Compound A, respectively, dissolved in a mixture of polyethylene glycol 4000 and lauric acid macrogol glyceride for human testing. The compositions of these two dosage forms are provided in Table 3 below:

[0183] Table 3 - Composition of dissolved capsule formulations

[0184]

[0185] Although the formulation performed well in clinical trials, the loading of active pharmaceutical ingredient (API) and the amount of capsule administered were not optimal for treating cancer patients.

[0186] Example 5

[0187] The ASD form of Compound A was tested as a possible approach to improve dissolution rate, solubility, and thus oral bioavailability. To explore this approach for Compound A, the following polymers were evaluated for preparing amorphous SDDs: polyvinylpyrrolidone K30 (PVP K30), polyvinylpyrrolidone vinyl acetate 64 (PVP-VA-64), polyvinylpyrrolidone standard fine CL (PVP CL), hypromellose acetate succinate (HPMCAS-L), and hypromellose phthalate. The individual polymers were ground with Compound A at a 1:1 ratio and analyzed by DSC to examine the thermal behavior of the Compound A-polymer matrix before selecting the polymer for preparing the amorphous spray-dried dispersion (SDD).

[0188] In order to confirm the solid state of the amorphous form of compound A in the polymer under molten conditions, thermal characterization was performed using DSC. In order to confirm the presence or absence of crystalline form A of compound A in the polymer under molten conditions, thermal characterization was performed using DSC. The resulting thermogram is provided in Figure 5-9 middle, Figure 5 This is the thermal spectrum of HPMCAS-AS-L. Figure 6 is the thermal spectrum of CL containing PVP, Figure 7 This is the thermal spectrum of PVP-VA. Figure 8 This is the thermal spectrum of PVP K30. Fig. 9 Thermograms containing HPMC phthalate. In each figure, thermograms containing and not containing Compound A polymers are provided. Based on the DSC thermograms, two polymers, specifically HPMC-AS-L and PVP-VA-64, were screened for further study in which the endothermic peak of Compound A Form A was absent.

[0189] Example 6

[0190] The amorphous physical state of different polymers and Compound A-polymer ratios was evaluated using computational and experimental techniques. The polymers evaluated were PVP VA 64, PVP K30, HPMC-AS, Acrylic Resin L100-55, HPMC E3, and HPMCE15. Screening and formulation development combined the use of certain evaluation tools. The miscibility assay is a computer simulation used to evaluate the phase separation tendency of different stabilizing carriers. The amount of Compound A prepared with various process solvents was evaluated at various loadings. The results of solvent casting experiments using different stabilizing carriers and Compound A loadings were used to further narrow down the formulation variables and supersaturation studies. The precipitation inhibition of different stabilizing carriers was also evaluated using the solvent transfer method. Based on the miscibility, physicochemical properties and water solubility measurements of the polymers, three prototype spray drying intermediates, [Compound A: HPMC-AS L] and [Compound A: HPMC-AS M] and [Compound A: PVP VA 64] were further evaluated at the selected ratio [40:60% w / w]. However, the PVP VA 64-based SDI was found to be more hygroscopic compared to the HPMCAS L-based and HPMCAS M-based formulations.

[0191] Example 7

[0192] The ASD of compound A was obtained using a solvent casting technique. Compound A and a polymer were dissolved in methyl ethyl ketone (MEK) and a surfactant (sodium dodecyl sulfate (SLS0 or poloxamer 407) and water. The surfactant solution was slowly added to the solution of compound A and a polymer (hydroxypropyl methylcellulose acetate succinate (HPMC-AS-L)) to obtain a uniform solution. The solvent was evaporated at about 80-85° C. for three days to obtain the ASD of compound A, as shown in Table 4:

[0193] Table 4: ASD formulation composition

[0194]

[0195] The XRPD analysis results of ASD-1, ASD-2 and ASD-3 are shown in Fig.10 , 11 and 12. The DSC results obtained from the mixtures of ASD-1, ASD-2 and ASD-3 before solvent casting are shown in Fig.13A , 14A and 15A, while the ASDs prepared from the same three mixtures were shown in Fig. 13B , 14B and 15B. Both XRPD and DSC results confirmed that all three mixtures were crystalline prior to solvent casting, and the resulting dispersions thus prepared were found to be amorphous in each case.

[0196] Stability studies were performed on each of the three solid dispersions prepared as described above. After two weeks at 40°C and 75% relative humidity (RH), samples of each solid dispersion were tested by DSC and XRPD. Both the ASD-1 dispersion (no surfactant) and the ASD-3 dispersion (containing poloxamer 407) remained amorphous, while some peaks appeared in the XRPD of ASD-2 (containing SLS), indicating that there was a detectable amount of crystalline compound A in ASD-2. The results indicate that solid dispersions of compound A can be stable in the absence of SLS as a surfactant in the dispersion.

[0197] The solubility of Compound A in solid amorphous dispersions with two different grades of HPMC-AS (L and M grades) was evaluated. Compound A was found to be more soluble in amorphous dispersions made with HPMC-AS L than those using HPMC-AS M grade polymer.

[0198] Example 8

[0199] To optimize the loading of API, amorphous dispersions of Compound A were prepared by solvent casting different percentages (10, 50, 70 and 90) of API in solid dispersion. 10% and 90% were positive controls for evaluation purposes only. The DSC and XRPD scans of the four dispersions are shown in Fig.16 and 17 As shown therein, due to Fig.16 The DSC showed a melting endotherm, and 50% loading of the API in the solid dispersion was not feasible. Therefore, the loading of the API in the solid dispersion was kept at 40%.

[0200] Example 9

[0201] Spray dried dispersions (SDDs) were prepared with each of the two stable polymers HPMC-AS-LG and PVP-VA-64 identified for further study in Example 5 above by completely dissolving each polymer and Compound A in acetone and then spray drying. Powder X-ray diffraction results obtained from each SDD and from Compound A alone are shown in Fig.18 The XRPD results showed that Compound A in both dispersions was amorphous.

[0202] Example 10

[0203] SDD formulations of Compound A and HPMC-AS-L (SDD1) or PVP-VA-64 (SDD2) were prepared according to Table 5 below:

[0204] Table 5 - Spray dried dispersion formulations

[0205]

[0206] Two SDDs were prepared in the same manner as described in Example 8 above. Compound A, SDD, SLS and microcrystalline cellulose were premixed in a low shear mixer. Mannitol, crospovidone and silicon dioxide were added and mixed in a low shear mixer. The dry blend was granulated by a dry granulation process to prepare granules on a tablet press. The granules were crushed and sieved through 12 and 18 meshes successively to obtain granules, and the granules with a final API loading of 17% w / w were filled into No. 0 white opaque gelatin capsules (50 mg strength).

[0207] The dissolution behavior of two formulations, SDD1 and SDD2, in a biorelevant medium, fasted state simulated intestinal fluid (FaSSIF), pH 6.5, was evaluated using the dissolution parameters shown in Table 6 below.

[0208] Table 6 - Dissolution parameters

[0209] Dissolution Apparatus USP Device II (Paddles) temperature 37℃±0.5℃ Rotation speed 50rpm <![CDATA[Dissolution buffer / volume 1 > 600mL; FaSSIF, pH 6.5 Capsule No. One size 0 gelatin capsule strength 50mg <![CDATA[Sampling volume 2 > 5mL <![CDATA[Sampling time point (T min )]]> <![CDATA[(T0,T5,T 15 ,T 30 ,T 45 ,T 60 ,T 120 )]]>

[0210] The dissolution profiles obtained for the two SDD preparations are shown in Fig.19 The dissolution profile of SDD made from HPMC-AS-L showed complete dissolution within 45 min.

[0211] Embodiment 11

[0212] A pharmacokinetic monkey study was conducted comparing two tablets of crystalline Compound A prepared in Example 2, a capsule dosage form prepared in Example 3, and SDD2 capsules prepared in Example 8 and a prototype formulation of a spray dried intermediate (SDI) having the composition shown in Table 7 below.

[0213] Table 7 - SDI tablet compositions used in monkey PK studies

[0214]

[0215] The results of the study are summarized in Table 8 below.

[0216] Table 8 - Monkey PK study results

[0217]

[0218] As can be seen from Table 8, at a dose of about 50 mg / animal (about 10 mg / kg), when administered in the dissolved formulation of Capsule 2 (7% API load), the mean systemic exposure (AUC 0-无穷大 ) provided the highest relative bioavailability and exposure. The amorphous SDD1 formulation showed relatively good exposure (AUC: 14433 ng·hr / mL) and an absolute bioavailability of approximately 70%.

[0219] A formulation with compound A and HPMC-AS LG SDD with 40% loading was developed. Excipient compatibility studies determined that certain excipients were stable with the ASD form of compound A. Excipients selected from microcrystalline cellulose, lactose monohydrate, cross-linked sodium carboxymethyl cellulose, poloxamer 407, colloidal silicon dioxide, and the SDD intermediate (SDI) form of compound A were premixed and sieved. Magnesium stearate was then added to the premix as a lubricant. A dry granulation process was used to increase the density of the premix. Lubricant magnesium stearate and extragranular excipients microcrystalline cellulose, lactose monohydrate, and cross-linked sodium carboxymethyl cellulose were then added to the granular mixture. The mixture having the composition shown in Table 9 below was pressed into tablets of varying strengths.

[0220] Table 9 - Mixture Composition

[0221] Ingredient name %w / w g / batch Compound A / HPMC-AS (40%) SDD 50 2000 Microcrystalline Cellulose 22.6 903 Lactose Monohydrate 15.9 635 Croscarmellose Sodium 4.7 188 Poloxamer 407 5.0 200 Colloidal Silica 0.90 36 Magnesium Stearate 0.95 38 total: 100.0 4000

[0222] For comparative purposes, placebo tablets were prepared with the same excipients as the mixture, but without SDD.

[0223] The mixtures of Form A with Compound A, Compound A / HPMC-AS (40%) SDD and placebo were each analyzed by X-ray powder diffraction. The resulting XRPD showed Fig. 20 The results indicate that SDD and the SDD blend are amorphous. As can be seen from the comparison with the placebo XRPD, the only peaks in the XRPD of the blend are from the excipients.

[0224] Example 12

[0225] Tablets in SDD form with 50 mg and 200 mg of Compound A were prepared from a single granulation batch using different amounts of granules for each of the two dosage strengths. The granulation composition of each of the two tablet doses is shown in Table 10 below:

[0226] Table 10 - Composition of 50 mg and 200 mg strength Compound A SDD tablets

[0227]

[0228] Granules were obtained by dry granulation, grinding and mixing processes. Dry granules were obtained by sieving a mixture of microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, poloxamer 407, colloidal silicon dioxide and SDD together, and then magnesium stearate was added and mixed to obtain a first mixture. The density of the first mixture was increased by dry granulation to provide a first portion of granules. The second portion of magnesium stearate was sieved through a 30-mesh screen, then mixed with the first portion of granules and mixed in a V-blender for 2 minutes to obtain a second mixture. A roller press was then used and ground to obtain a second portion of granules. The milled granules were added to a V-blender and mixed with microcrystalline cellulose, lactose monohydrate and croscarmellose sodium of the extragranular excipients. The extragranular excipients were sieved through a 30-mesh screen, then added to a V-blender and mixed with the granules for 2 minutes to provide a third mixture. The third mixture was compressed into different tablet strengths using a mold that provided a tablet size that met the tablet size. In a 12-month stability study, both tablet dosage forms were found to be stable at 25°C and 60% relative humidity.

[0229] The 50 mg and 200 mg tablets prepared as described in this example have improved dissolution and bioavailability, while providing convenience for reducing the dosage form dosage and increasing the API loading. Wherein twice daily administration of 200 mg tablets or four daily administration of 50 mg tablets will provide a therapeutically effective amount for treating human patients with various cancers, including diffuse intrinsic pontine glioblastoma (DIPG), ovarian cancer, pancreatic cancer, sarcomas such as leiomyosarcoma, and blood cancers such as acute myeloid leukemia.

[0230] Embodiment 13

[0231] 50 mg and 200 mg tablets prepared as described in Example 12 above were suspended in water or apple juice, and the stability of each resulting suspension was tested at room temperature for 24 hours. Each tablet disintegrated in less than 3 minutes. XRPD and HPLC showed that Compound A remained amorphous in each suspension, and no impurities were detected.

[0232] Having fully described the claimed subject matter, one of ordinary skill in the art will appreciate that the same can be implemented within a broad range of equivalents without affecting the scope of the subject matter or aspects described herein.

[0233] Embodiment 14

[0234] The stability of the active formulation tablets having the composition described in Table 10 was tested under different storage conditions. At 25°C / 60% relative humidity (RH), both 50 mg and 200 mg Compound A tablets showed acceptable stability over 24 months. However, at 40°C / 75% relative humidity (RH), both 50 mg and 200 mg tablets failed to disintegrate at 6 months. This incomplete dissolution was independent of pH, and X-ray powder diffraction (XRPD) and mDSC analysis confirmed that Compound A was chemically and physically stable in tablet form, remaining amorphous even after one year at 40°C / 75% relative humidity (RH).

[0235] To determine whether reducing the concentration of poloxamer 407 (5% w / w) in the active tablet formulation could alleviate the observed slow dissolution, tablets of 25 mg strength were prepared with different concentrations of poloxamer 407 (1% w / w, 2% w / w, or 5% w / w; Table 11) and placed under closed conditions at 5°C (control), 25°C / 60% RH, or 40°C / 75% RH in both open and closed conditions. The hardness of all tablets tested remained at an average of 4.3 kP.

[0236] Table 11: Composition of active tablet formulations with different concentrations of Poloxamer 407

[0237]

[0238] Abbreviations: Hydroxypropyl methylcellulose + acetate succinate: HPMCAS; Spray dried dispersion: SDD; USP / NF refer to United States Pharmacopoeia (USP) and National Formulary (NF), respectively.

[0239] In the dissolution medium (500 mL of 0.1 N HCl + 0.2% w / v CTAB, 37°C, paddle speed: 75 rpm; see Tables 12 and Fig.21 ), the disintegration and dissolution profiles of active tablet formulations stored for 2 weeks at 40°C / 75%RH under open conditions were evaluated. The active tablet formulation containing 5% w / w poloxamer 407 showed tablet swelling but no disintegration. Consistent with this finding, only minimal API release (-6% release) was measured even after 60 minutes in the dissolution test. The active tablets containing 2% w / w poloxamer 407 disintegrated into larger pieces, which was better than the tablets containing 5% w / w poloxamer 407, but the dissolution profile did not reach complete release (-89%) after 60 minutes. However, in the dissolution test, the active tablet formulation containing 1% w / w poloxamer 407 easily disintegrated into small particles, and the dissolution profile was similar to that of the active tablet formulation containing 0% w / w poloxamer 407 (-100% release).

[0240] Table 12: Dissolution release profiles of active formulations with different concentrations of Poloxamer 407 at 40°C / 75%RH, open conditions for 2 weeks

[0241]

[0242] Initial: refers to the % dissolved after 10-60 minutes of a given active tablet formulation (unstored)

[0243] Disintegration and dissolution profiles of these tablet formulations stored under closed conditions at 40°C / 75%RH for 6 months were then determined in dissolution medium (500 mL of 0.1 N HCl + 0.2% w / v CTAB, 37°C, paddle speed: 75 rpm; see Table 13).

[0244] The active tablet formulation containing 5% w / w Poloxamer 407 swelled but did not disintegrate and had minimal release of API at 60 minutes (-6% release) compared to the active tablet formulation containing 0% w / w Poloxamer 407 (-100% release).

[0245] The active tablet formulation containing 2% w / w Poloxamer 407 disintegrated into larger pieces at 60 minutes with almost complete release of API compared to the active tablet formulation containing 0% w / w Poloxamer 407. However, at the 30 minute time point, there was a -10% difference in API release compared to the active tablet formulation containing 0% w / w Poloxamer 407.

[0246] The active tablet formulation containing 1% w / w Poloxamer 407 disintegrated into smaller particles compared to the active tablet formulation with 0% w / w Poloxamer 407, and the dissolution profile showed complete release at 60 minutes.

[0247] Table 13: Dissolution release profiles of active formulations with different concentrations of Poloxamer 407 at 40°C / 75%RH under occluded conditions for 6 months

[0248]

[0249] When tested in monkeys, varying the concentration of poloxamer 407 in the active tablet formulation had no major effect on the kinetic solubility of Compound A or its PK profile and PK parameters.

Claims

1. An amorphous solid dispersion comprising an amorphous form of 5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine and a stable polymer, wherein the 5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine has the molecular formula of compound A: The stabilizing polymer is selected from polyvinyl pyrrolidone or hydroxypropyl methylcellulose acetate succinate; The loading amount of compound A is 30% to 40% by weight.

2. An amorphous solid dispersion comprising an amorphous form of 5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine and a stabilizing polymer, wherein the 5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine has the molecular formula of compound A: The stabilizing polymer is selected from polyvinyl pyrrolidone or hydroxypropyl methylcellulose acetate succinate; The loading amount of compound A was 40% by weight.

3. An amorphous solid dispersion comprising an amorphous form of 5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine and a stabilizing polymer, wherein the 5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine has the molecular formula of compound A: The stabilizing polymer is selected from polyvinyl pyrrolidone or hydroxypropyl methylcellulose acetate succinate; The loading amount of compound A was 25% by weight.

4. An amorphous solid dispersion comprising an amorphous form of 5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine and a stable polymer, wherein the 5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine has the molecular formula of compound A: The stabilizing polymer is selected from polyvinyl pyrrolidone or hydroxypropyl methylcellulose acetate succinate; The loading amount of compound A was 17% by weight.

5. The dispersion according to any one of claims 1 to 4, wherein the amorphous form of compound A is at least 90% amorphous.

6. The dispersion according to claim 5, wherein the amorphous form of Compound A is a pure amorphous form.

7. The dispersion according to any one of claims 1 to 4, wherein the ratio of the weight of compound A to the weight of the stabilizing polymer is from 5:95 to 60:

40.

8. The dispersion according to claim 7, wherein the ratio of the weight of compound A to the weight of the stabilizing polymer is from 10:90 to 40:

60.

9. The dispersion according to any one of claims 1 to 4, wherein the dispersion is obtained by solvent casting a solution comprising compound A and a stabilizing polymer.

10. The dispersion according to any one of claims 1 to 4, wherein the dispersion is obtained by spray drying a solution comprising compound A and a stabilizing polymer.

11. A method for preparing the dispersion according to any one of claims 1 to 4, comprising: (a) dissolving compound A and one or more stabilizing polymers in a solvent to form a solution; and (b) drying the solution to form a dispersion according to any one of claims 1 to 4.

12. The method according to claim 11, wherein the solvent is selected from acetone, methyl ethyl ketone, dichloromethane or methanol.

13. The method of claim 11, wherein the solution is dried by solvent casting to form the dispersion of any one of claims 1 to 4.

14. The method of claim 11, wherein the solution is dried by spray drying to form the dispersion of any one of claims 1 to 4.

15. A pharmaceutical composition comprising a mixture of the dispersion according to any one of claims 1 to 4 and one or more pharmaceutically acceptable excipients.

16. The pharmaceutical composition according to claim 15, wherein the one or more pharmaceutically acceptable excipients are selected from diluents, disintegrants, lubricants or surfactants.

17. The pharmaceutical composition according to claim 16, wherein the surfactant is selected from sodium lauryl sulfate or poloxamer 407.

18. A method for preparing the pharmaceutical composition of claim 15, comprising: (a) grinding the dispersion according to any one of claims 1 to 4 to form a solid dispersion powder; (b) mixing the powder with one or more pharmaceutically acceptable excipients to form a mixture; (c) granulating the mixture to form granules; and (d) compressing or encapsulating the granules into tablets or capsules, respectively.

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