Oral liquid suspension of pan RAF kinase inhibitor

Abstract

Disclosed herein are solid formulations of (R)-2-(1-(6-amino-5-chloropyrimidin-4-carboxamido) ethyl)-N-(5-chloro-4-(trifluoromethyl) pyridin-2-yl) thiazole-5-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof for the preparation of a liquid suspension. In another aspect, the present application provides methods of preparing kits comprising liquid suspensions and solid formulations of Compound A. In another aspect, the present application provides methods of treating cancer with formulations of Compound A. In addition, the present disclosure provides methods of treating pediatric cancer patients by administering formulations of Compound A.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 342,533, filed on May 16, 2022, the entire contents of which are incorporated herein by reference. Background Art

[0003] In 2018, there were 18.1 million new cases and 9.5 million cancer-related deaths worldwide. By 2040, the number of new cancer cases is expected to increase to 29.5 million per year, and the number of cancer-related deaths is expected to increase to 16.4 million. In 2020, there were an estimated 1.8 million newly diagnosed cancer cases and 606,520 cancer deaths in the United States. Cancer remains the second most common cause of death in the United States, accounting for nearly 1 in every 24 deaths.

[0004] Each year, approximately 15,500 children under the age of 18 in the United States and approximately 300,000 worldwide are diagnosed with cancer. In addition, cancer remains the most common cause of disease-related death among children in the United States, resulting in more than 1,700 deaths each year. Despite the need for safer and more effective therapies for childhood cancer, new drugs for pediatric patients are scarce. (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide ("Compound A") (also known as tovorafenib, DAY101, DOT101, TAK-580, BIIB024, or MLN 2480) is a Class II pan-Raf kinase inhibitor that can be used to treat Raf-mediated diseases such as cancer. Compound A is currently administered in the form of an oral tablet. Therefore, there is an unmet need to develop new and useful formulations of Compound A as an effective treatment for pediatric cancer patients. Summary of the invention

[0005] In certain aspects, the present invention provides a pharmaceutical powder comprising:

[0006] (a) an amorphous solid dispersion comprising (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof; and

[0007] (b) one or more pharmaceutically acceptable excipients, wherein the excipients comprise a flow aid and a surfactant.

[0008] In some embodiments, one or more pharmaceutically acceptable excipients stabilize Compound A in an amorphous state and / or aid in its dissolution.

[0009] In some embodiments, the drug powder is reconstituted into an oral liquid suspension. In some embodiments, the amorphous solid dispersion comprises one or more polymers. In some embodiments, the one or more polymers include polyvinyl pyrrolidone, vinyl pyrrolidone-vinyl acetate copolymer (PVP-VA), cross-linked polyvinyl N-pyrrolidone, polyvinyl alcohol (PVA), polysaccharides, hydroxypropyl methylcellulose (HPMC or hydroxypropyl methylcellulose), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), polyethylene oxide, hydroxypropyl-β-cyclodextrin (HP-β-CD), sulfobutyl ether-β-cyclodextrin (Captisol), γ-cyclodextrin, hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyethylene glycol (PEG), polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVAc-PVCap-PEG), polysaccharides, poly (methacrylic acid-co-methyl methacrylate) (Eudragit), poloxamer, silica gel, aluminosilicate or a combination thereof. In some embodiments, the one or more polymers include PVP-VA or HPMCAS.

[0010] In some embodiments, the amorphous solid dispersion comprises about 10wt% to about 90wt% of one or more polymers. In some embodiments, the amorphous solid dispersion comprises about 10wt% to about 90wt% of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the weight ratio of compound A or a pharmaceutically acceptable salt thereof to one or more polymers is 2:1 to 1:2. In some embodiments, the amorphous solid dispersion comprises compound A. In some embodiments, the amorphous solid dispersion is a hot melt extrudate (HME). In some embodiments, the amorphous solid dispersion is prepared by dissolving compound A or a pharmaceutically acceptable salt thereof in a solvent, and then removing at least a portion of the solvent. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is amorphous. In some embodiments, the amorphous solid dispersion has a D50 value of about 10μm to about 500μm. In some embodiments, the drug powder comprises about 10wt% to about 80wt% of an amorphous solid dispersion. In some embodiments, the drug powder comprises about 20wt% to about 60wt% of an amorphous solid dispersion. In some embodiments, one or more pharmaceutically acceptable excipients are mixed with the amorphous solid dispersion in the drug powder. In some embodiments, the drug powder contains about 5wt% to about 80wt% of one or more pharmaceutically acceptable excipients. In some embodiments, one or more pharmaceutically acceptable excipients include defoamers, fillers, colorants, preservatives, flavorings, sweeteners, or a combination thereof. In some embodiments, the defoamer includes simethicone. In some embodiments, the defoamer is present in the drug powder at about 0.1wt% to about 10wt%. In some embodiments, the filler includes polysaccharides, sugars, or derivatives thereof, or both. In some embodiments, the filler includes cellulose, starch, synthetic soluble fiber, sugar alcohol, or a combination thereof. In some embodiments, the filler includes mannitol. In some embodiments, the filler includes microcrystalline cellulose, polydextrose, sodium carboxymethylcellulose (CMC sodium), or a combination thereof. In some embodiments, the drug powder contains about 5wt% to about 80wt% of filler. In some embodiments, the flow aid is selected from silicon dioxide, magnesium stearate, talc, starch, magnesium silicate, hydrated sodium sulfoaluminate and combinations thereof. In some embodiments, silicon dioxide includes fumed silica, colloidal silicon dioxide (CSD) or both. In some embodiments, the pharmaceutical powder comprises about 0.25wt% to about 10wt% of a flow aid. In some embodiments, the surfactant comprises a cationic surfactant, an anionic surfactant, a nonionic surfactant or a combination thereof. In some embodiments, the surfactant comprises sodium lauryl sulfate (SLS). In some embodiments, the surfactant comprises poloxamer. In some embodiments, the pharmaceutical powder comprises about 0.01wt% to about 10wt% of a surfactant.In some embodiments, the pharmaceutical powder comprises:.

[0011] a) about 10 wt % to about 60 wt % of an amorphous solid dispersion comprising (i) about 40 wt % to about 60 wt % of Compound A and (ii) about 40 wt % to about 60 wt % of PVP-VA, wherein the amorphous solid dispersion is a hot melt extrudate;

[0012] b) about 30 wt % to about 70 wt % of a filler, wherein the filler comprises microcrystalline cellulose and mannitol;

[0013] c) about 0.1 wt% to 5 wt% of a surfactant, wherein the surfactant is SLS;

[0014] d) about 0.25 wt% to 6 wt% of a flow aid, wherein the flow aid is CSD; and

[0015] e) about 0.5 wt % to 5 wt % of an anti-foaming agent, wherein the anti-foaming agent is simethicone or dimethicone.

[0016] In certain aspects, the present disclosure provides a kind of oral liquid suspension, the oral liquid suspension comprises a solid preparation (for example, a powder preparation as described herein) and an aqueous solution in a kit as disclosed herein. In some embodiments, a kind of oral liquid suspension, it is produced by contacting a solid preparation (for example, a powder preparation as described herein) in a kit as disclosed herein with an aqueous solution. In some embodiments, the oral liquid suspension comprises a drug powder (for example, a powder preparation as described herein) and an aqueous solution. In some embodiments, a kind of oral liquid suspension, it is produced by contacting a drug powder (for example, a powder preparation as described herein) with an aqueous solution as disclosed herein. In some embodiments, the powder will be reconstituted with water, and the resulting suspension will be administered orally, or administered enterally via a nasal or gastric feeding tube with a dosing syringe. In certain aspects, the present disclosure provides an oral liquid suspension comprising: (a) (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof; (b) one or more pharmaceutically acceptable excipients; and (c) water. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is in the form of an amorphous solid dispersion. In some embodiments, the amorphous solid dispersion comprises one or more polymers. In some embodiments, the one or more polymers include polyvinyl pyrrolidone, vinyl pyrrolidone-vinyl acetate copolymer (PVP-VA), cross-linked polyvinyl N-pyrrolidone, polyvinyl alcohol (PVA), polysaccharides, hydroxypropyl methylcellulose (HPMC or hydroxypropyl methylcellulose), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), polyethylene oxide, hydroxypropyl-β-cyclodextrin (HP-β-CD), sulfobutyl ether-β-cyclodextrin (Captisol), cyclodextrin (e.g., γ-cyclodextrin), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyethylene glycol (PEG), polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVAc-PVCap-PEG), polysaccharides, poly(methacrylic acid-co-methyl methacrylate) (Eudragit), poloxamer, silica gel, aluminosilicate, or a combination thereof. In some embodiments, one or more pharmaceutically acceptable excipients are selected from defoamers, flow aids, surfactants, fillers, colorants, preservatives, flavoring agents, sweeteners and combinations thereof. In some embodiments, an oral liquid suspension is prepared by adding water to a powder formulation of Compound A. In some embodiments, the concentration of Compound A or a pharmaceutically acceptable salt thereof in the oral liquid suspension is about 10 mg / mL to about 125 mg / mL. In some embodiments, the concentration of Compound A or a pharmaceutically acceptable salt thereof in the oral liquid suspension is about 10 to about 50 mg / mL.In some embodiments, the concentration of compound A or its pharmaceutically acceptable salt in the oral liquid suspension is about 25 to about 50 mg / mL. In some embodiments, the aqueous solution is water. In some embodiments, the pH value of the liquid suspension is about 2 to 7. In some embodiments, the suspension is administered via an oral syringe for at least 30 minutes. In some embodiments, after the powder formulation is contacted with the aqueous solution, the suspension remains injectable for at least 15 minutes. In some embodiments, after the powder formulation is contacted with the aqueous solution, the suspension remains injectable for at least 30 minutes. The term injectable refers to the ability to inhale the oral suspension into the barrel of the syringe for administration (e.g., oral administration) to an object (e.g., a child or infant). In some embodiments, the concentration of one or more polymers in the suspension is about 10 mg / mL to about 200 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is about 30 mg / mL to about 50 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is about 60 mg / mL to about 80 mg / mL. In some embodiments, the concentration of filler in the suspension is about 30 mg / mL to about 500 mg / mL. In some embodiments, the concentration of filler in the suspension is about 50 mg / mL to about 300 mg / mL. In some embodiments, the concentration of filler in the suspension is about 125 mg / mL to about 200 mg / mL. In some embodiments, the concentration of surfactant in the suspension is about 0.5 mg / mL to about 10 mg / mL. In some embodiments, the concentration of surfactant in the suspension is about 1 mg / mL to about 2.5 mg / mL. In some embodiments, the concentration of flow aid in the suspension is about 3 mg / mL to about 30 mg / mL. In some embodiments, the concentration of flow aid in the suspension is about 5 mg / mL to about 15 mg / mL. In some embodiments, the concentration of flow aid in the suspension is about 10 mg / mL to about 15 mg / mL. In some embodiments, the concentration of defoamer in the suspension is about 1 mg / mL to about 30 mg / mL. In some embodiments, the concentration of the defoaming agent in the suspension is about 1 mg / mL to about 10 mg / mL. In some embodiments, the concentration of the defoaming agent in the suspension is about 3 mg / mL to about 8 mg / mL. In some embodiments, the suspension comprises, based on the weight of the solids:.

[0017] (a) about 10 wt % to about 50 wt % of an amorphous solid dispersion comprising (i) about 40 wt % to about 60 wt % of Compound A and (ii) about 40 wt % to about 60 wt % of PVP-VA, wherein the amorphous solid dispersion is a hot melt extrudate;

[0018] (b) about 40 wt % to about 70 wt % of a filler, wherein the filler comprises microcrystalline cellulose and mannitol;

[0019] (c) from about 0.25 wt % to about 1 wt % of a surfactant, wherein the surfactant is SLS;

[0020] (d) from about 1 wt % to about 6 wt % of a flow aid, wherein the flow aid is colloidal silicon dioxide (CSD);

[0021] (e) from about 1 wt % to about 5 wt % of an anti-foaming agent, wherein the anti-foaming agent is simethicone; and

[0022] (f) optionally preservatives, flavoring agents, sweeteners or combinations thereof.

[0023] In some embodiments, the suspension comprises, based on weight of solids:

[0024] (a) about 10 wt % of an amorphous solid dispersion comprising (i) about 40 wt % of Compound A and (ii) about 60 wt % of copovidone, wherein the amorphous solid dispersion is a hot melt extrudate;

[0025] (b) about 30 wt % to 32 wt % mannitol;

[0026] (c) about 30 wt % to 32 wt % microcrystalline cellulose;

[0027] (d) about 0.5 wt % to 1 wt % SLS;

[0028] (e) about 4 wt % to 5 wt % CSD;

[0029] (f) about 2 wt% to 3 wt% simethicone; and

[0030] (g) optionally preservatives, flavoring agents, sweeteners or combinations thereof.

[0031] In some embodiments, the oral liquid suspension is bioequivalent to a tablet formulation of Compound A, wherein the tablet composition comprises an amorphous solid dispersion comprising (i) about 40 wt% of Compound A and (ii) about 60 wt% of copovidone, wherein the amorphous solid dispersion is a hot melt extrudate; and one or more pharmaceutically acceptable excipients. In some embodiments, the oral liquid suspension is sufficient to achieve a maximum observed plasma concentration (Cmax) of at least about 100 ng / mL of Compound A in a subject when administered to a human subject in an amount equivalent to about 100 mg of Compound A. In some embodiments, the oral liquid suspension is sufficient to achieve a maximum observed plasma concentration (Cmax) of at least about 100 ng / mL of Compound A in a subject when administered to a human subject in an amount equivalent to about 100 mg of Compound A.

[0032] In certain aspects, the present disclosure provides a method of treating cancer, the method comprising administering to a subject an oral liquid suspension comprising (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve a maximum observed plasma concentration (Cmax) of Compound A of at least 2000 ng / mL in the subject. In some aspects, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a pharmaceutical powder as disclosed herein or a reconstituted oral liquid formulation as disclosed herein. In some aspects, the present disclosure provides a method of treating cancer in a subject, the method comprising reconstructing a solid formulation in a kit as disclosed herein, and administering the reconstituted formulation to the subject. In some embodiments, the subject is 18 years of age or younger. In some embodiments, the cancer is a low-grade glioma. In some aspects, the present disclosure provides a method of treating a subject with pediatric low-grade glioma (pLGG), the method comprising reconstituting an amorphous solid dispersion of Compound A or a salt thereof in an aqueous solution, and administering to a subject in need thereof a pharmaceutically acceptable dose of the reconstituted Compound A or a salt thereof. In some embodiments, the method is administered with food, before consuming food, or after consuming food.

[0033] In certain aspects, the present disclosure provides a kit comprising: (a) a solid formulation of an amorphous solid dispersion of (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof, wherein the solid formulation comprises one or more pharmaceutically acceptable excipients; and (b) instructions for aqueous reconstitution of the solid formulation. In some embodiments, the solid formulation is in the form of a powder, granules, or pellets. In some embodiments, the solid formulation is in the form of a powder. In some embodiments, the amorphous solid dispersion comprises one or more polymers. In some embodiments, the one or more polymers include polyvinyl pyrrolidone, vinyl pyrrolidone-vinyl acetate copolymer (PVP-VA), cross-linked polyvinyl N-pyrrolidone, polyvinyl alcohol (PVA), polysaccharides, hydroxypropyl methylcellulose (HPMC or hydroxypropyl methylcellulose), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), polyethylene oxide, hydroxypropyl-β-cyclodextrin (HP-β-CD), sulfobutyl ether-β-cyclodextrin (Captisol), cyclodextrin (e.g., γ-cyclodextrin), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyethylene glycol (PEG), polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVAc-PVCap-PEG), polysaccharides, poly (methacrylic acid-co-methyl methacrylate) (Eudragit), poloxamer, silica gel, aluminosilicate, or a combination thereof. In some embodiments, the one or more polymers include PVP-VA or HPMCAS. In some embodiments, the one or more polymers include HPMCAS. In some embodiments, one or more polymers include PVP-VA. In some embodiments, one or more polymers include copolyvidone. In some embodiments, the amorphous solid dispersion comprises about 10wt% to about 90wt% of one or more polymers. In some embodiments, the amorphous solid dispersion comprises about 40wt% to about 80wt% of one or more polymers. In some embodiments, the amorphous solid dispersion comprises about 55wt% to about 65wt% of one or more polymers. In some embodiments, the amorphous solid dispersion comprises about 10wt% to about 90wt% of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the amorphous solid dispersion comprises about 20wt% to about 60wt% of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the amorphous solid dispersion comprises about 35wt% to about 45wt% of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the weight ratio of compound A or its pharmaceutically acceptable salt to one or more polymers is 2:1 to 1:2.In some embodiments, the weight ratio of compound A or its pharmaceutically acceptable salt to one or more polymers is about 1: 1 to 1: 2. In some embodiments, the amorphous solid dispersion comprises compound A. In some embodiments, the amorphous solid dispersion is a hot melt extrudate (HME). In some embodiments, the amorphous solid dispersion is prepared by dissolving compound A or its pharmaceutically acceptable salt in a solvent, and then removing at least a portion of the solvent. In some embodiments, the amorphous solid dispersion is prepared by dissolving compound A or its pharmaceutically acceptable salt in a solvent, and then removing at least a portion of the solvent. In some embodiments, the particles in the amorphous solid dispersion have a D50 value of about 10 μm to about 500 μm. In some embodiments, the particles in the amorphous solid dispersion have a D50 value of about 100 μm to about 400 μm. In some embodiments, the solid formulation comprises an amorphous solid dispersion of about 10wt% to about 80wt%. In some embodiments, the solid formulation comprises an amorphous solid dispersion of about 40wt% to about 60wt%. In some embodiments, the solid formulation comprises about 15wt% to about 35wt% of an amorphous solid dispersion. In some embodiments, one or more pharmaceutically acceptable excipients are mixed with the amorphous solid dispersion in the solid formulation. In some embodiments, the amorphous solid dispersion comprises one or more pharmaceutically acceptable excipients. In some embodiments, the solid formulation comprises about 5wt% to about 80wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the solid formulation comprises about 40wt% to about 60wt% of one or more pharmaceutically acceptable excipients. In some embodiments, one or more pharmaceutically acceptable excipients are selected from defoamers, flow aids, surfactants, fillers, colorants, preservatives, flavorings, sweeteners, and combinations thereof. In some embodiments, one or more pharmaceutically acceptable excipients are selected from defoamers, flow aids, surfactants, fillers, and combinations thereof. In some embodiments, the defoamer comprises simethicone. In some embodiments, the solid formulation comprises about 0.1wt% to about 15wt% of a defoamer. In some embodiments, the solid formulation comprises about 1wt% to about 8wt% of a defoamer. In some embodiments, the solid formulation comprises about 3wt% to about 8wt% of a defoamer. In some embodiments, the solid formulation comprises about 0.5wt% to about 3wt% of simethicone. In some embodiments, a flow aid is selected from silicon dioxide, magnesium stearate, talc, starch, magnesium silicate, hydrated sodium sulfoaluminate, and combinations thereof. In some embodiments, silicon dioxide comprises fumed silica, colloidal silicon dioxide (CSD), or both. In some embodiments, the solid formulation comprises about 0.25wt% to about 10wt% of a flow aid. In some embodiments, the solid formulation comprises about 1wt% to about 5wt% of a flow aid.In some embodiments, the surfactant includes a cationic surfactant, an anionic surfactant, a nonionic surfactant, or a combination thereof. In some embodiments, the surfactant includes sodium lauryl sulfate (SLS). In some embodiments, the solid formulation includes about 0.01wt% to about 10wt% of a surfactant. In some embodiments, the solid formulation includes about 0.1wt% to about 2wt% of a surfactant. In some embodiments, the filler includes a polysaccharide, a sugar, or a derivative thereof, or both. In some embodiments, the filler includes cellulose, starch, synthetic soluble fiber, sugar alcohol, or a combination thereof. In some embodiments, the filler includes mannitol. In some embodiments, the filler includes microcrystalline cellulose, polydextrose, sodium carboxymethyl cellulose (CMC sodium), or a combination thereof. In some embodiments, the solid formulation includes about 5wt% to about 80wt% of a filler. In some embodiments, the solid formulation includes about 30wt% to about 75wt% of a filler. In some embodiments, the instructions for aqueous reconstruction are in the form of a reference to the instructions.

[0034] In some embodiments, the solid dosage form in the kit comprises:

[0035] (a) about 10 wt % to about 60 wt % of an amorphous solid dispersion comprising (i) about 40 wt % to about 60 wt % of Compound A and (ii) about 40 wt % to about 60 wt % of PVP-VA, wherein the amorphous solid dispersion is a hot melt extrudate;

[0036] (b) about 30 wt % to 70 wt % of a filler, wherein the filler comprises microcrystalline cellulose and mannitol;

[0037] (c) about 0.1 wt % to 5 wt % of a surfactant, wherein the surfactant is SLS;

[0038] (d) about 0.25 wt% to 6 wt% of a flow aid, wherein the flow aid is CSD; and

[0039] (e) about 0.5 wt % to 5 wt % of an anti-foaming agent, wherein the anti-foaming agent is simethicone.

[0040] In some embodiments, the kit comprises one or more doses of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the kit comprises 1 to 5 unit doses of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the kit comprises a single unit dose of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is a pediatric dose. In some embodiments, each dose comprises about 50 mg to about 800 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, each dose comprises about 300 mg or about 600 mg of Compound A. In some embodiments, the kit further comprises one or more containers, which optionally include a mark indicating a measured value of a volume. In certain aspects, the present disclosure provides a kit comprising a drug powder for reconstitution as disclosed herein.

[0041] In certain aspects, the present disclosure provides a unit dose composition for a powder formulation of compound A, wherein the powder formulation comprises: compound A, and optionally one or more of the following: one or more polymers, one or more fillers, surfactants, defoamers, flow aids, sweeteners and natural flavors. In certain embodiments, the present disclosure provides a unit dose composition for a powder formulation of compound A, wherein the powder formulation comprises: compound A, one or more polymers, one or more fillers, surfactants, defoamers, flow aids, sweeteners and natural flavors. In some embodiments, one or more polymers may be polymers as described herein. In some embodiments, one or more polymers are copolyvidone. In some embodiments, one or more fillers may be fillers as described herein. In some embodiments, one or more fillers are microcrystalline cellulose, mannitol, maltodextrin or a combination thereof. In some embodiments, the surfactant may be a surfactant as described herein. In some embodiments, the surfactant is sodium lauryl sulfate. In some embodiments, the defoamer may be a defoamer as described herein. In some embodiments, the defoamer is simethicone. In some embodiments, the flow aid may be a flow aid as described herein. In some embodiments, the flow aid is colloidal silicon dioxide. In some embodiments, the sweetener can be a sweetener as described herein. In some embodiments, the sweetener is sucralose powder. In some embodiments, the natural flavor can be a natural flavor as described herein. In some embodiments, the natural flavor is artificial strawberry powder.

[0042] In some embodiments, the powder formulation of formula A comprises: about 5% to about 15% w / w of compound A, and optionally one or more of the following: one or more polymers, one or more fillers, surfactants, defoamers, flow aids, sweeteners and natural flavors. In certain embodiments, the powder formulation of formula A comprises about 5% to about 20% w / w of one or more polymers, about 50% to about 70% w / w of one or more fillers, about 0.1% to about 1% w / w of surfactants, about 0.5% to about 2.5% w / w of defoamers, about 1% to about 5% w / w of flow aids, about 0.1% to about 1% w / w of sweeteners and about 0.5% to 1.5% w / w of natural flavors. In some embodiments, a powder formulation of Formula A comprises: about 9% to about 15% w / w of Compound A, about 10% to about 20% w / w of one or more polymers, about 60% to about 70% w / w of one or more fillers, about 0.5% to about 1% w / w of a surfactant, about 1.5% to about 2.5% w / w of an antifoaming agent, about 4% to about 5% w / w of a flow aid, about 0.5% to about 1% w / w of a sweetener, and about 1.0% to 1.5% w / w of a natural flavor. In some embodiments, a powder formulation of Formula A comprises: about 14% to about 15% w / w Compound A, about 14% to about 15% w / w one or more polymers, about 66% to about 67% w / w one or more fillers, about 0.7% to about 0.8% w / w surfactant, about 2.2% to about 2.3% w / w antifoaming agent, about 4.4% to about 4.5% w / w flow aid, about 0.5% to about 0.6% w / w sweetener, and about 1.5% to 1.6% w / w natural flavor.

[0043] In some embodiments, a powder formulation of Formula A comprises: about 5% to about 15% w / w Compound A, about 5% to about 20% w / w copovidone, about 50% to about 70% w / w fillers (including microcrystalline cellulose, mannitol and maltodextrin), about 0.1% to about 1% w / w sodium lauryl sulfate, about 0.5% to about 2.5% w / w simethicone, about 1% to about 5% w / w colloidal silicon dioxide, about 0.1% to about 1% w / w sucralose powder, and about 0.5% to 1.5% w / w artificial strawberry flavor. In some embodiments, a powder formulation of Formula A comprises: about 9% to about 15% w / w Compound A, about 10% to about 20% w / w copovidone, about 60% to about 70% w / w microcrystalline cellulose, mannitol and maltodextrin, about 0.5% to about 1% w / w sodium lauryl sulfate, about 1.5% to about 2.5% w / w simethicone, about 4% to about 5% w / w colloidal silicon dioxide, about 0.5% to about 1% w / w sucralose powder, and about 1.0% to 1.5% w / w artificial strawberry flavor. In some embodiments, a powder formulation of Formula A comprises: about 14% to about 15% w / w Compound A, about 14% to about 15% w / w copovidone, about 66% to about 67% w / w microcrystalline cellulose, mannitol and maltodextrin, about 0.7% to about 0.8% w / w sodium lauryl sulfate, about 2.2% to about 2.3% w / w simethicone, about 4.4% to about 4.5% w / w colloidal silicon dioxide, about 0.5% to about 0.6% w / w sucralose powder, and about 1.5% to 1.6% w / w artificial flavor, such as strawberry flavor.

[0044] In some embodiments, a powder formulation of Formula A comprises: about 5% to about 15% w / w Compound A, about 5% to about 20% w / w copovidone, about 25% to about 35% w / w microcrystalline cellulose, about 25% to about 35% w / w mannitol, and about 2% to about 8% w / w maltodextrin, about 0.1% to about 1% w / w sodium lauryl sulfate, about 0.5% to about 2.5% w / w simethicone, about 1% to about 5% w / w colloidal silicon dioxide, about 0.1% to about 1% w / w sucralose powder, and about 0.5% to 1.5% w / w artificial strawberry flavor. In some embodiments, a powder formulation of Formula A comprises: about 9% to about 15% w / w Compound A, about 10% to about 20% w / w copovidone, about 30% to about 35% w / w microcrystalline cellulose, about 30% to about 35% w / w mannitol and about 4% to about 6% w / w maltodextrin, about 0.5% to about 1% w / w sodium lauryl sulfate, about 1.5% to about 2.5% w / w simethicone, about 4% to about 5% w / w colloidal silicon dioxide, about 0.5% to about 1% w / w sucralose powder, and about 1.0% to 1.5% w / w artificial flavor, such as strawberry flavor. In some embodiments, a powder formulation of Formula A comprises: about 14% to about 15% w / w Compound A, about 14% to about 15% w / w copovidone, about 30% to about 31% w / w microcrystalline cellulose, about 30% to about 31% w / w mannitol and about 5% to about 6% w / w maltodextrin, about 0.7% to about 0.8% w / w sodium lauryl sulfate, about 2.2% to about 2.3% w / w simethicone, about 4.4% to about 4.5% w / w colloidal silicon dioxide, about 0.5% to about 0.6% w / w sucralose powder, and about 1.5% to 1.6% w / w artificial flavor, such as strawberry flavor.

[0045] In some embodiments, the powder formulation of formula A comprises: about 350 mg to about 450 mg of compound A, about 600 mg to about 700 mg of one or more polymers, about 2500 mg to about 3500 mg of one or more fillers, about 25 mg to about 50 mg of surfactants, about 75 mg to about 150 mg of defoamers, about 150 mg to about 250 mg of flow aids, about 10 mg to about 75 mg of sweeteners, and about 50 mg to 100 mg of natural flavors. In some embodiments, the powder formulation of formula A comprises: about 400 mg to about 450 mg of compound A, about 600 mg to about 650 mg of one or more polymers, about 2500 mg to about 3000 mg of one or more fillers, about 30 mg to about 40 mg of surfactants, about 75 mg to about 100 mg of defoamers, about 150 mg to about 200 mg of flow aids, about 10 mg to about 30 mg of sweeteners, and about 50 mg to about 75 mg of natural flavors. In some embodiments, the powder formulation of Formula A comprises: about 420 mg to about 430 mg of Compound A, about 640 mg to about 650 mg of one or more polymers, about 2850 mg to about 3000 mg of one or more fillers, about 30 mg to about 35 mg of surfactants, about 90 mg to about 100 mg of antifoaming agents, about 190 mg to about 200 mg of flow aids, about 20 mg to about 30 mg of sweeteners, and about 60 mg to 70 mg of natural or artificial flavors.

[0046] In some embodiments, the powder formulation of Formula A comprises: about 350 mg to about 450 mg of Compound A, about 600 mg to about 700 mg of copovidone, about 2500 mg to about 3500 mg of microcrystalline cellulose, mannitol and maltodextrin, about 25 mg to about 50 mg of sodium lauryl sulfate, about 75 mg to about 150 mg of simethicone, about 150 mg to about 250 mg of colloidal silicon dioxide, about 10 mg to about 75 mg of sucralose powder, and about 50 mg to 100 mg of artificial strawberry flavor. In some embodiments, the powder formulation of Formula A comprises: about 400 mg to about 450 mg of Compound A, about 600 mg to about 650 mg of copovidone, about 2500 mg to about 3000 mg of microcrystalline cellulose, mannitol and maltodextrin, about 30 mg to about 40 mg of sodium lauryl sulfate, about 75 mg to about 100 mg of simethicone, about 150 mg to about 200 mg of colloidal silicon dioxide, about 10 mg to about 30 mg of sucralose powder, and about 50 mg to 75 mg of artificial strawberry flavor. In some embodiments, the powder formulation of Formula A comprises: about 420 mg to about 430 mg of Compound A, about 640 mg to about 650 mg of copovidone, about 2850 mg to about 3000 mg of microcrystalline cellulose, mannitol and maltodextrin, about 30 mg to about 35 mg of sodium lauryl sulfate, about 90 mg to about 100 mg of simethicone, about 190 mg to about 200 mg of colloidal silicon dioxide, about 20 mg to about 30 mg of sucralose powder, and about 60 mg to 70 mg of artificial flavor, such as strawberry flavor.

[0047] In some embodiments, the powder formulation of Formula A comprises: about 350 mg to about 450 mg of Compound A, about 600 mg to about 700 mg of copovidone, about 1000 mg to about 1500 mg of microcrystalline cellulose, about 1000 mg to about 1500 mg of mannitol, about 175 mg to about 250 mg of maltodextrin, about 25 mg to about 50 mg of sodium lauryl sulfate, about 75 mg to about 150 mg of simethicone, about 150 mg to about 250 mg of colloidal silicon dioxide, about 10 mg to about 75 mg of sucralose powder, and about 50 mg to 100 mg of artificial strawberry flavor. In some embodiments, the powder formulation of Formula A comprises: about 400 mg to about 450 mg of Compound A, about 600 mg to about 650 mg of copovidone, about 1200 mg to about 1500 mg of microcrystalline cellulose, about 1200 mg to about 1500 mg of mannitol, about 200 mg to about 250 mg of maltodextrin, about 30 mg to about 40 mg of sodium lauryl sulfate, about 75 mg to about 100 mg of simethicone, about 150 mg to about 200 mg of colloidal silicon dioxide, about 10 mg to about 30 mg of sucralose powder, and about 50 mg to 75 mg of artificial strawberry flavor. In some embodiments, the powder formulation of Formula A comprises: about 420 mg to about 430 mg of Compound A, about 640 mg to about 650 mg of copovidone, about 1300 mg to about 1400 mg of microcrystalline cellulose, about 1300 mg to about 1400 mg of mannitol, about 200 mg to about 240 mg of maltodextrin, about 30 mg to about 35 mg of sodium lauryl sulfate, about 90 mg to about 100 mg of simethicone, about 190 mg to about 200 mg of colloidal silicon dioxide, about 20 mg to about 30 mg of sucralose powder, and about 60 mg to 70 mg of artificial flavor, such as strawberry flavor.

[0048] In certain aspects, the present disclosure provides a method for preparing an aqueous formulation, the method comprising: (a) providing a solid formulation of an amorphous solid dispersion, wherein the amorphous solid dispersion comprises: (i) (R) -2- (1- (6-amino-5-chloropyrimidine-4-carboxamido) ethyl) -N- (5-chloro-4- (trifluoromethyl) pyridin-2-yl) thiazole-5-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof, and (ii) one or more polymers; and (b) contacting the solid formulation with an aqueous solution. In some embodiments, contacting comprises mixing the solid formulation with an aqueous solution. In some embodiments, mixing comprises shaking the solid formulation and the aqueous solution. In certain aspects, the present disclosure provides a method for preparing an oral liquid suspension of Compound A or a salt thereof, the method comprising reconstructing a solid formulation in a kit as disclosed herein in an aqueous solution. In certain aspects, the present disclosure provides a method for preparing an oral liquid suspension of Compound A or a salt thereof, the method comprising reconstructing a pharmaceutical powder as disclosed herein in an aqueous solution. In some embodiments, the kit comprises a pharmaceutical powder for reconstitution as disclosed herein.

[0049] Incorporation by reference

[0050] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the invention will be obtained by reference to the following detailed description of illustrative embodiments in which the principles of the invention are utilized and the accompanying drawings, in which:

[0052] Figure 1 An exemplary mixing instruction (steps 1 to 12) is illustrated.

[0053] Figure 2 The graph shows the mean plasma concentration (C max ) (ng / mL) versus time (h).

[0054] Figure 3A-3D The diagram shows the difference between Scheme G1 and Scheme H1 ( Figure 3A-3B ) and 300 mg of DAY101 in regimens G2 and H2 ( Figure 3C-Figure 3D Relative bioavailability of HME tablets and PfR (powder for reconstitution) by suspension geometric mean plasma concentration (ng / mL) versus nominal time (h) after administration of 100 mg of DAY101 in .

[0055] Figure 4A-4D The diagram shows the difference between Scheme G1 and Scheme I1 ( Figure 4A-4B ) and 300 mg of DAY101 in regimens G2 and I2 ( Figure 4C-4D ) after administration of 100 mg of DAY101 in the fed and fasted states by comparing the geometric mean plasma concentration (ng / mL) versus the nominal time (h) after dosing.

[0056] Figure 5 The overall taste / palatability assessment on a stacked bar graph is illustrated: Taste / palatability analysis set (Part 1). (Subjects tasted 5 mL of Day 101 HME PfR oral suspension, 6 different formulations (Regimen AF = Formulations 1-6); Rating: 1 = Extremely dislike, 2 = Very dislike, 3 = Moderately dislike, 4 = Mildly dislike, 5 = Neither like nor dislike, 6 = Mildly like, 7 = Moderately like, 8 = Very like, 9 = Extremely like; Results: Dislike (Rating 1-3), Neutral (Rating 4-6), Like (Rating 7-9)).

[0057] Figure 6 The geometric mean (× / ÷geometric SD) plasma concentrations (ng / mL) of DAY101 following a single oral dose of 300 mg DAY101 administered as tablet and suspension formulations to healthy male and female subjects in the fasting state are shown: Regimen H1 and Regimen G1 (Log 10 / linear).

[0058] Figure 7 Graphed are the geometric mean (× / ÷geometric SD) plasma concentrations (ng / mL) of DAY101 following a single oral dose of 100 mg DAY101 administered as tablet and suspension formulations to healthy male and female subjects in the fasting state: Protocol H2 and Protocol G2 (Log10 / Linear).

[0059] Figure 8 Graphed are the geometric mean (× / ÷geometric SD) plasma concentrations (ng / mL) of DAY101 following a single oral dose of 300 mg DAY101 administered as a tablet formulation to healthy male and female subjects in the fed and fasted states: Protocol I1 and Protocol G1 (Log10 / Linear).

[0060] Fig. 9 The geometric mean (× / ÷geometric SD) plasma concentrations (ng / mL) of DAY101 following a single oral dose of 100 mg DAY101 administered as a tablet formulation to healthy male and female subjects in the fed and fasted states are shown: Regimen I2 and Regimen G2 (Log 10 / linear).

[0061] Fig.10 Exemplary mixing instructions are illustrated (Part A: Steps 1 to 17).

[0062] Fig.11 Illustrative instructions for administering a dose of a disclosed liquid suspension via a feeding tube are illustrated (Part B: Steps 19-23). Specific implementation plan

[0063] Although preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided only by way of example. Without departing from the present invention, those skilled in the art will now appreciate many variations, changes and substitutions. It should be understood that in practicing the present invention, various alternatives to the embodiments of the present invention described herein may be adopted. The appended claims are intended to define the scope of the present invention, and thus encompass methods and structures within the scope of these claims and their equivalents.

[0064] definition

[0065] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned herein are incorporated by reference.

[0066] As used in the specification and claims, the singular form "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0067] As used herein, the term "solid dispersion" or "solid formulation" refers to an amorphous dispersion comprising Compound A or a pharmaceutically acceptable salt thereof in a solid state, which is optionally prepared by hot melt extrusion.

[0068] The term "amorphous" as used herein refers to a solid dispersion or solid formulation comprising a solid form of Compound A or a salt thereof that lacks the long-range order characteristic of a crystal, ie, the solid is non-crystalline.

[0069] As used herein, the term "micron" or "μm" refers to a micrometer, which is 1x10 -6 rice.

[0070] The term "in vivo" is used to describe events that occur within the body of a subject.

[0071] The term "ex vivo" is used to describe an event that occurs outside the body of a subject. An ex vivo assay is not performed on a subject. Instead, an ex vivo assay is performed on a sample that is separate from the subject. An example of an ex vivo assay performed on a sample is an "in vitro" assay.

[0072] The term "in vitro" is used to describe an event that occurs in a container used to hold a laboratory reagent so that it is separated from the biological source from which the material is obtained. In vitro assays can encompass cell-based assays in which living or dead cells are employed. In vitro assays can also encompass cell-free assays in which intact cells are not employed.

[0073] The terms "subject," "individual," and "patient" are used interchangeably and refer to humans as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, etc.). In various embodiments, a subject may be a person (e.g., an adult male, an adult female, an adolescent male, an adolescent female, a male child, a female child) under the care of a physician or other health worker in a hospital, outpatient clinic, or other clinical setting. In certain embodiments, a subject may not be under the care or prescription of a physician or other health worker.

[0074] As used herein, the phrase "a subject in need thereof" refers to a subject, as described below, who has, or is at risk of, a pathology to be treated prophylactically or therapeutically with a compound or salt described herein.

[0075] The terms "determine," "measure," "evaluate," "assess," "measure," and "analyze" are generally used interchangeably herein to refer to forms of measurement. The terms include determining whether an element is present (e.g., detecting). These terms may include quantitative determination, qualitative determination, or both quantitative and qualitative determination. Assessments may be relative or absolute. "Detecting the presence of" may include determining the amount of something present in addition to determining whether something is present or not, depending on the context.

[0076] The terms "administer," "administered," "administers," and "administering" are defined as providing a composition to a subject via routes known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, enteral, nasal, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal administration routes. In certain embodiments, the composition may be administered using an oral route. The terms "administer," "administered," "administers," and "administering" a compound should be understood to mean providing a compound of the disclosure or a prodrug of a compound of the disclosure to an individual in need thereof.

[0077] The term "effective amount" or "therapeutically effective amount" refers to an amount of a solid dispersion, liquid formulation, or solid formulation comprising Compound A or a salt thereof that is sufficient to treat one or more symptoms of cancer or cause regression of cancer. For example, in one embodiment, a therapeutically effective amount will refer to an amount of Compound A that reduces the rate of tumor growth, reduces tumor mass, reduces the number of metastases, increases tumor progression time, or increases survival time by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100%.

[0078] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with human tissues without excessive toxicity, irritation, allergic response, etc. and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. See Berge et al., J. Pharmaceutical Sciences, 1977, 66, 1-19.

[0079] As used herein, the term "pharmaceutically acceptable excipient" or "excipient" refers to any ingredient in the composition of the present disclosure other than the solid dispersion of Compound A or its salt. An excipient is generally an inert substance added to a composition to facilitate processing, handling, administration, etc. of the composition. Useful excipients include, but are not limited to, adjuvants, antiadherents, binders, carriers, disintegrants, fillers, flavors, pigments, diluents, lubricants, glidants, preservatives, adsorbents, solvents, surfactants, and sweeteners.

[0080] Conventional pharmaceutical excipients are well known to those skilled in the art. Specifically, those skilled in the art will recognize that a variety of pharmaceutically acceptable excipients can be used in combination with the solid dispersion of Compound 1 and vinylpyrrolidone-vinyl acetate copolymer, including those listed in Handbook of Pharmaceutical Excipients, Pharmaceutical Press, 4th edition (2003) and Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st edition (2005).

[0081] As used herein, "treatment" or "treating" refers to a method for obtaining a beneficial or desired result (including but not limited to a therapeutic benefit) regarding a disease, disorder, or medical condition. In certain embodiments, treatment or treating involves administering a compound or composition disclosed herein to a subject. The therapeutic benefit may include the eradication or alleviation of the underlying disorder being treated. In addition, a therapeutic benefit may be achieved by eradicating or alleviating one or more physiological symptoms associated with the underlying disorder, such as observing an improvement in the subject, although the subject may still suffer from the underlying disorder. Treatment may include, for example, reducing, delaying, or alleviating the severity of one or more symptoms of a disease or condition, or it may include reducing the frequency with which a patient experiences symptoms of a disease, defect, disorder, or adverse condition, etc. Treatment may be used herein to refer to a method that results in a certain level of treatment or alleviation of a disease or condition, and a range of results for this purpose may be expected.

[0082] In certain embodiments, the term "prevent" or "preventing" as it relates to a disease or condition may refer to a compound that reduces the occurrence of a disease or condition in a treated sample relative to an untreated control sample, or delays the onset of or reduces the severity of one or more symptoms of a disease or condition relative to an untreated control sample in a statistical sample. In certain embodiments, "prevent" or "preventing" includes administering a compound or composition to a subject at risk of developing a particular disease, or to a subject reporting one or more physiological symptoms of a disease, even though a diagnosis of the disease may not have yet been made.

[0083] As used herein, the term "vinyl pyrrolidone-vinyl acetate copolymer" refers to a polymer comprising vinyl pyrrolidone and vinyl acetate. Names and abbreviations of vinyl pyrrolidone-vinyl acetate copolymers include, but are not limited to, copovidone, copovidonum, copolyvidone, copovidon, and PVP-VAc copolymers. Copovidone is a vinyl pyrrolidone-vinyl acetate copolymer composed of 6 parts of vinyl pyrrolidone and 4 parts of vinyl acetate, such as CAS 25086-89-9. Examples of copovidone commercial products are VA 64 and 64Fine. Another example is "Plasdone S-630", a 60:40 random copolymer of N-vinyl pyrrolidone and vinyl acetate.

[0084] "HPMCAS" refers to Hydroxypropyl methylcellulose acetate succinate, a polymer containing acetyl and succinyl groups. There are different types and grades of HPMCAS (e.g., HPMCAS-LG, HPMCAS-MG, HPMCAS-HG), which dissolve at different pHs due to different compositions and ratios of their functional groups (e.g., acetyl, succinyl). HPMCAS is classified into L, M, and H grades based on the wt% content of acetyl and succinyl groups. The particle sizes of HPMCAS are fine (F) and granular (G).

[0085] "HPMCP" refers to hydroxypropylmethylcellulose phthalate polymer. There are different types and grades of HPMCP (e.g., HP-55s, HP-50, HP-55) that dissolve at different pHs due to different compositions and ratios of their functional groups (e.g., phthaloyl).

[0086] "HPC" refers to hydroxypropyl cellulose. There are different types and grades of HPC (eg, HPC-SSL, HPC-SL, HOC-SLT).

[0087] The term "w / w" means by weight. For example, 50% w / w means that the mass of the substance is 50% of the total mass of the solution or mixture.

[0088] As used herein, the term "mass median diameter" or "D 50 " describes a diameter in which 50 mass % of the particles in a powder dispersion have a larger equivalent diameter and the other 50 mass % have a smaller equivalent diameter as determined by laser diffraction or other suitable technique in a Malvern Master Sizer Microplus apparatus or its equivalent. For example, if the D of a powder dispersion is 50 is 105 μm, then 50% of the particles are larger than 105 μm and 50% of the particles are smaller than 105 μm. 90 " describes a diameter in which 90% by mass of the particles in a powder dispersion have a smaller equivalent diameter and the other 10% by mass have a larger equivalent diameter. The term "D 10 ” describes a diameter in which 10% by mass of the particles in a powder dispersion have a smaller equivalent diameter, and the other 90% by mass have a larger equivalent diameter.

[0089] Each maximum numerical limitation given throughout this specification is intended to include each lower numerical limitation, just as if such lower numerical limitations were expressly written herein. Each minimum numerical limitation given throughout this specification will include each higher numerical limitation, just as if such higher numerical limitations were expressly written herein. Each numerical range given throughout this specification will include each narrower numerical range falling within such wider numerical range, just as if such narrower numerical ranges were expressly written herein.

[0090] Although various embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Without departing from the present invention, those skilled in the art may conceive of many variations, changes and substitutions. It should be understood that various alternatives to the embodiments of the present invention described herein may be employed.

[0091] Whenever the term "at least", "greater than", or "greater than or equal to" precedes the first value in a series of two or more values, the term "at least", "greater than", or "greater than or equal to" applies to each value in the series. For example, greater than or equal to 1, 2, or 3 is equivalent to greater than or equal to 1, greater than or equal to 2, or greater than or equal to 3.

[0092] Whenever the term "not greater than," "at most," "less than," or "less than or equal to" precedes the first value in a series of two or more values, the term "not greater than," "at most," "less than," or "less than or equal to" applies to every value in the series. For example, less than or equal to 3, 2, or 1 is equivalent to less than or equal to 3, less than or equal to 2, or less than or equal to 1.

[0093] As used herein, the term "about" includes the recited value ± 10%. Thus, "about 10" means 9 to 11. The term "about" may also refer to a value within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, such as limitations of the measurement system. In an example, according to practice for a given value, "about" may mean within 1 standard deviation.

[0094] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0095] Any aspect or embodiment described herein may be combined with any other aspect or embodiment as disclosed herein.

[0096] Pharmaceutical powders and other solid pharmaceutical compositions, liquid preparations

[0097] In certain aspects, the present disclosure provides a solid form pharmaceutical composition comprising (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A). In some embodiments, the solid form pharmaceutical composition is in the form of a powder, granules, flakes, or pellets. In some embodiments, the solid form pharmaceutical composition is in the form of a tablet or capsule.

[0098] In certain aspects, the present disclosure provides a pharmaceutical powder. In some embodiments, the pharmaceutical powder comprises an amorphous solid dispersion of (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof, wherein the solid formulation comprises one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical powder comprises (a) an amorphous solid dispersion comprising (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof; and (b) one or more pharmaceutically acceptable excipients, wherein the excipient comprises a flow aid and a surfactant. In some embodiments, the pharmaceutical powder is configured to be reconstituted into an oral liquid suspension. In some embodiments, the powder for oral suspension comprises 25 mg / mL of tovorafenib after reconstitution with water and the following inactive ingredients: microcrystalline cellulose, copovidone, colloidal silicon dioxide, mannitol, sodium lauryl sulfate, simethicone, maltodextrin, sucralose, and strawberry flavor.

[0099] In some embodiments, each tablet of Compound A contains 100 mg of tovorafenib and the following inactive ingredients: microcrystalline cellulose, copovidone, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, and orange.

[0100] In certain aspects, the present disclosure provides an oral liquid suspension. In some embodiments, the oral liquid suspension comprises a drug powder or other solid preparation as disclosed herein, and an aqueous solution. In some embodiments, an oral liquid suspension is produced by contacting a drug powder as disclosed herein with an aqueous solution. In some embodiments, the aqueous solution is water. In some embodiments, the oral liquid suspension is reconstituted. In some embodiments, the oral liquid suspension comprises a solid preparation and an aqueous solution in a kit as disclosed herein. In some embodiments, an oral liquid suspension is produced by contacting a solid preparation in a kit as disclosed herein with an aqueous solution. In some embodiments, tablets and powders for oral suspensions can be used interchangeably.

[0101] In some embodiments, the solid formulations described herein, such as pharmaceutical powders, contain about 10 wt% to about 80 wt% of an amorphous solid dispersion, which contains compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the solid formulations described herein, such as pharmaceutical powders, contain about 15 wt% to about 80 wt% of an amorphous solid dispersion. In some embodiments, the solid formulation contains about 20 wt% to about 80 wt% of an amorphous solid dispersion. In some embodiments, the solid formulation contains about 25 wt% to about 80 wt% of an amorphous solid dispersion. In some embodiments, the solid formulation contains about 30 wt% to about 80 wt% of an amorphous solid dispersion. In some embodiments, the solid formulation contains about 35 wt% to about 80 wt% of an amorphous solid dispersion. In some embodiments, the solid formulation contains about 40 wt% to about 80 wt% of an amorphous solid dispersion. In some embodiments, the solid formulation contains about 45 wt% to about 80 wt% of an amorphous solid dispersion. In some embodiments, the solid formulation comprises about 50wt% to about 80wt% of an amorphous solid dispersion. In some embodiments, the solid formulation comprises about 55wt% to about 80wt% of an amorphous solid dispersion. In some embodiments, the solid formulation comprises about 60wt% to about 80wt% of an amorphous solid dispersion. In some embodiments, the solid formulation comprises about 65wt% to about 80wt% of an amorphous solid dispersion. In some embodiments, the solid formulation comprises about 70wt% to about 80wt% of an amorphous solid dispersion. In some embodiments, the solid formulation comprises about 75wt% to about 80wt% of an amorphous solid dispersion. In some embodiments, the solid formulation comprises about 20wt% to about 75wt% of an amorphous solid dispersion. In some embodiments, the solid formulation comprises about 20wt% to about 70wt% of an amorphous solid dispersion. In some embodiments, the solid formulation comprises about 20wt% to about 65wt% of an amorphous solid dispersion. In some embodiments, the solid formulation comprises about 20wt% to about 60wt% of an amorphous solid dispersion. In some embodiments, the solid formulation comprises about 20wt% to about 55wt% of an amorphous solid dispersion. In some embodiments, the solid formulation comprises about 20wt% to about 50wt% of an amorphous solid dispersion. In some embodiments, the solid formulation comprises about 20wt% to about 45wt% of an amorphous solid dispersion. In some embodiments, the solid formulation comprises about 20wt% to about 40wt% of an amorphous solid dispersion. In some embodiments, the solid formulation comprises about 20wt% to about 35wt% of an amorphous solid dispersion. In some embodiments, the solid formulation comprises about 20wt% to about 30wt% of an amorphous solid dispersion. In some embodiments, the solid formulation comprises about 20wt% to about 25wt% of an amorphous solid dispersion.In some embodiments, the solid formulation comprises about 10wt% to about 75wt% of an amorphous solid dispersion. In some embodiments, the solid formulation comprises about 10wt% to about 70wt% of an amorphous solid dispersion. In some embodiments, the solid formulation comprises about 10wt% to about 65wt% of an amorphous solid dispersion. In some embodiments, the solid formulation comprises about 10wt% to about 60wt% of an amorphous solid dispersion. In some embodiments, the solid formulation comprises about 10wt% to about 55wt% of an amorphous solid dispersion. In some embodiments, the solid formulation comprises about 10wt% to about 50wt% of an amorphous solid dispersion. In some embodiments, the solid formulation comprises about 10wt% to about 45wt% of an amorphous solid dispersion. In some embodiments, the solid formulation comprises about 10wt% to about 40wt% of an amorphous solid dispersion. In some embodiments, the solid formulation comprises about 10wt% to about 35wt% of an amorphous solid dispersion. In some embodiments, the solid formulation comprises about 10 wt % to about 30 wt % of an amorphous solid dispersion. In some embodiments, the solid formulation comprises about 10 wt % to about 25 wt % of an amorphous solid dispersion. In some embodiments, the solid formulation is a powder. In some embodiments, the solid formulation is in the form of granules or pellets.

[0102] In some embodiments, the solid formulations described herein, such as pharmaceutical powders, contain about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, about 90 wt%, or about 95 wt% of an amorphous solid dispersion. In some embodiments, the solid formulation comprises at least 5 wt%, at least 10 wt%, at least 15 wt%, at least 20 wt%, at least 25 wt%, at least 30 wt%, at least 35 wt%, at least 40 wt%, at least 45 wt%, at least 50 wt%, at least 55 wt%, at least 60 wt%, at least 65 wt%, at least 70 wt%, at least 75 wt%, at least 80 wt%, at least 85 wt%, at least 90 wt%, or at least 95 wt% of an amorphous solid dispersion. In some embodiments, solid preparation comprises at most 5wt%, at most 10wt%, at most 15wt%, at most 20wt%, at most 25wt%, at most 30wt%, at most 35wt%, at most 40wt%, at most 45wt%, at most 50wt%, at most 55wt%, at most 60wt%, at most 65wt%, at most 70wt%, at most 75wt%, at most 80wt%, at most 85wt%, at most 90wt% or at most 95wt% amorphous solid dispersion. In some embodiments, solid preparation is powder. In some embodiments, solid preparation is in the form of granules or pellets.

[0103] Amorphous solid dispersion

[0104] In one aspect, an amorphous solid dispersion is described herein, comprising compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the amorphous solid dispersion has a D50 value of about 10 μm to about 500 μm. In some embodiments, the amorphous solid dispersion has a D50 value of about 50 μm to about 500 μm. In some embodiments, the amorphous solid dispersion has a D50 value of about 100 μm to about 500 μm. In some embodiments, the amorphous solid dispersion has a D50 value of about 150 μm to about 500 μm. In some embodiments, the amorphous solid dispersion has a D50 value of about 200 μm to about 500 μm. In some embodiments, the amorphous solid dispersion has a D50 value of about 250 μm to about 500 μm. In some embodiments, the amorphous solid dispersion has a D50 value of about 300 μm to about 500 μm. In some embodiments, the amorphous solid dispersion has a D50 value of about 350 μm to about 500 μm. In some embodiments, the amorphous solid dispersion has a D50 value of about 400 μm to about 500 μm. In some embodiments, the amorphous solid dispersion has a D50 value of about 450 μm to about 500 μm. In some embodiments, in some embodiments, the amorphous solid dispersion has a D50 value of about 50 μm to about 450 μm. In some embodiments, in some embodiments, the amorphous solid dispersion has a D50 value of about 50 μm to about 400 μm. In some embodiments, in some embodiments, the amorphous solid dispersion has a D50 value of about 50 μm to about 350 μm. In some embodiments, in some embodiments, the amorphous solid dispersion has a D50 value of about 50 μm to about 300 μm. In some embodiments, in some embodiments, the amorphous solid dispersion has a D50 value of about 50 μm to about 250 μm. In some embodiments, in some embodiments, the amorphous solid dispersion has a D50 value of about 50 μm to about 200 μm. In some embodiments, in some embodiments, the amorphous solid dispersion has a D50 value of about 50 μm to about 150 μm. In some embodiments, the amorphous solid dispersion has a D50 value of about 50 μm to about 100 μm. In some embodiments, the amorphous solid dispersion has a D50 value of about 50 μm to about 100 μm. In some embodiments, in some embodiments, the amorphous solid dispersion has a D50 value of about 10 μm to about 450 μm. In some embodiments, in some embodiments, the amorphous solid dispersion has a D50 value of about 10 μm to about 400 μm. In some embodiments, in some embodiments, the amorphous solid dispersion has a D50 value of about 10 μm to about 350 μm.In some embodiments, in some embodiments, the amorphous solid dispersion has a D50 value of about 10 μm to about 300 μm. In some embodiments, in some embodiments, the amorphous solid dispersion has a D50 value of about 10 μm to about 250 μm. In some embodiments, in some embodiments, the amorphous solid dispersion has a D50 value of about 10 μm to about 200 μm. In some embodiments, in some embodiments, the amorphous solid dispersion has a D50 value of about 10 μm to about 150 μm. In some embodiments, the amorphous solid dispersion has a D50 value of about 10 μm to about 100 μm. In some embodiments, in some embodiments, the amorphous solid dispersion has a D50 value of about 10 μm to about 100 μm.

[0105] In some embodiments, the amorphous solid dispersion has a diameter of about 10 μm, about 15 μm, about 20 μm, about 25 μm, about 30 μm, about 35 μm, about 40 μm, about 45 μm, about 50 μm, about 55 μm, about 60 μm, about 65 μm, about 70 μm, about 75 μm, about 80 μm, about 85 μm, about 90 μm, about 95 μm, about 100 μm, about 105 μm, about 110 μm, about 115 μm, about 120 μm, about 125 μm, about 130 μm, about 135 μm, about 140 μm, about 145 μm, about 150 μm, about 155 μm, about 160 μm, about 165 μm, about 170 μm, about 175 μm, about 180 μm, about 185 μm m, about 190 μm, about 195 μm, about 200 μm, about 205 μm, about 210 μm, about 220 μm, about 220 μm, about 230 μm, about 240 μm, about 250 μm, about 260 μm, about 270 μm, about 280 μm, about 290 μm, about 300 μm, about 310 μm, about 320 μm, about 330 μm The D50 value of the present invention is about 340 μm, about 350 μm, about 360 μm, about 370 μm, about 380 μm, about 390 μm, about 400 μm, about 410 μm, about 420 μm, about 430 μm, about 440 μm, about 450 μm, about 460 μm, about 470 μm, about 480 μm, about 490 μm or about 500 μm. In some embodiments, the solid dispersion has a diameter of at least 10 μm, at least 15 μm, at least 20 μm, at least 25 μm, at least 30 μm, at least 35 μm, at least 40 μm, at least 45 μm, at least 50 μm, at least 75 μm, at least 80 μm, at least 85 μm, at least 90 μm, at least 95 μm, at least 100 μm, at least 110 μm, at least 120 μm, at least 125 μm, at least 150 μm, at least 175 μm, at least 180 μm, at least 190 μm, at least 200 μm, at least 210 μm, at least 220 μm, at least 230 μm, at least 240 μm, at least 250 μm, at least 260 μm, at least 270 μm, at least 280 μm, at least 290 μm, at least 300 μm, at least 310 μm, at least 320 μm, at least 330 μm, at least 350 μm, at least 360 μm, at least 370 μm, at least 380 μm, at least 390 μm, at least 400 μm 100 μm, at least 100 μm, at least 100 μm, at least 100 μm, at least 100 μm, at least 100 μm, at least 100 μm, at least 100 μm, at least 100 μm, at least 100 μm, at least 100 μm, at least 100 μm, at least 100 μm, at least 100 μm, at least 100 μm, at least 100 μm, at least 100 μm, at least 100 μm, at least 100 μm, at least 100 μm, at least 100 μm, at least 100 μm, at least 100 μmIn some embodiments, the solid dispersion has a diameter of at most 10 μm, at most 15 μm, at most 20 μm, at most 25 μm, at most 30 μm, at most 35 μm, at most 40 μm, at most 45 μm, at most 50 μm, at most 75 μm, at most 80 μm, at most 85 μm, at most 90 μm, at most 95 μm, at most 100 μm, at most 110 μm, at most 120 μm, at most 125 μm, at most 150 μm, at most 175 μm, at most In some embodiments, the D50 is determined by sieve particle size analysis.

[0106] Amorphous solid dispersions can be produced by any suitable method known in the art. In some embodiments, the amorphous solid dispersions of the present disclosure are produced by hot melt extrusion. In some embodiments, the amorphous solid dispersions of the present disclosure are produced by spray drying. In some embodiments, the amorphous solid dispersions of the present disclosure are prepared by dissolving compound A or its salt and polymer in a solution and then removing the solvent.

[0107] Amorphous solid dispersion-polymer

[0108] In one aspect, described herein is an amorphous solid dispersion comprising Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the amorphous solid dispersion comprises one or more polymers. In some embodiments, the one or more polymers include polyvinyl pyrrolidone, vinyl pyrrolidone-vinyl acetate copolymer (PVP-VA), cross-linked polyvinyl N-pyrrolidone, polyvinyl alcohol (PVA), polysaccharides, hydroxypropyl methylcellulose (HPMC or hydroxypropyl methylcellulose), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), polyethylene oxide, hydroxypropyl-β-cyclodextrin (HP-β-CD), sulfobutyl ether-β-cyclodextrin (Captisol), cyclodextrin (e.g., γ-cyclodextrin), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyethylene glycol (PEG), polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVAc-PVCap-PEG), polysaccharides, poly (methacrylic acid-co-methyl methacrylate) (Eudragit), poloxamer, silica gel, aluminosilicate, or a combination thereof. In some embodiments, the one or more polymers include vinyl pyrrolidone-vinyl acetate copolymer (PVP-VA) or HPMCAS. In some embodiments, the one or more polymers include HPMCAS. In some embodiments, the one or more polymers include vinyl pyrrolidone-vinyl acetate copolymer (PVP-VA).

[0109] In some embodiments, the amorphous solid dispersion comprises about 10wt% to about 90wt% of one or more polymers. In some embodiments, the amorphous solid dispersion comprises about 10wt% to about 80wt% of one or more polymers. In some embodiments, the amorphous solid dispersion comprises about 10wt% to about 70wt% of one or more polymers. In some embodiments, the amorphous solid dispersion comprises about 10wt% to about 60wt% of one or more polymers. In some embodiments, the amorphous solid dispersion comprises about 10wt% to about 50wt% of one or more polymers. In some embodiments, the amorphous solid dispersion comprises about 10wt% to about 40wt% of one or more polymers. In some embodiments, the amorphous solid dispersion comprises about 10wt% to about 30wt% of one or more polymers. In some embodiments, the amorphous solid dispersion comprises about 10wt% to about 20wt% of one or more polymers. In some embodiments, the amorphous solid dispersion comprises about 20wt% to about 90wt% of one or more polymers. In some embodiments, the amorphous solid dispersion comprises about 20wt% to about 80wt% of one or more polymers. In some embodiments, the amorphous solid dispersion comprises about 20wt% to about 70wt% of one or more polymers. In some embodiments, the amorphous solid dispersion comprises about 20wt% to about 60wt% of one or more polymers. In some embodiments, the amorphous solid dispersion comprises about 20wt% to about 50wt% of one or more polymers. In some embodiments, the amorphous solid dispersion comprises about 20wt% to about 40wt% of one or more polymers. In some embodiments, the amorphous solid dispersion comprises about 20wt% to about 30wt% of one or more polymers. In some embodiments, the amorphous solid dispersion comprises about 30wt% to about 90wt% of one or more polymers. In some embodiments, the amorphous solid dispersion comprises about 40wt% to about 80wt% of one or more polymers. In some embodiments, the amorphous solid dispersion comprises about 50wt% to about 70wt% of one or more polymers. In some embodiments, the amorphous solid dispersion comprises from about 40 wt% to about 70 wt% of one or more polymers. In some embodiments, the amorphous solid dispersion comprises from about 40 wt% to about 60 wt% of one or more polymers. In some embodiments, the amorphous solid dispersion comprises from about 20 wt% to about 90 wt% of one or more polymers.

[0110] In some embodiments, the amorphous solid dispersion comprises about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, about 90 wt%, or about 95 wt% of one or more polymers. In some embodiments, the amorphous solid dispersion comprises at least 5 wt%, at least 10 wt%, at least 15 wt%, at least 20 wt%, at least 25 wt%, at least 30 wt%, at least 35 wt%, at least 40 wt%, at least 45 wt%, at least 50 wt%, at least 55 wt%, at least 60 wt%, at least 65 wt%, at least 70 wt%, at least 75 wt%, at least 80 wt%, at least 85 wt%, at least 90 wt%, or at least 95 wt% of one or more polymers. Up to 5wt%, up to 10wt%, up to 15wt%, up to 20wt%, up to 25wt%, up to 30wt%, up to 35wt%, up to 40wt%, up to 45wt%, up to 50wt%, up to 55wt%, up to 60wt%, up to 65wt%, up to 70wt%, up to 75wt%, up to 80wt%, up to 85wt%, up to 90wt% or up to 95wt% of one or more polymers.

[0111] In some embodiments, the suspension described herein comprises one or more polymers as disclosed herein. In some embodiments, the concentration of one or more polymers in the suspension is from about 10 mg / mL to about 200 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 10 mg / mL to about 150 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 10 mg / mL to about 125 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 10 mg / mL to about 100 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 10 mg / mL to about 75 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 10 mg / mL to about 50 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 10 mg / mL to about 25 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 20 mg / mL to about 200 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 20 mg / mL to about 150 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 20 mg / mL to about 125 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 20 mg / mL to about 100 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 20 mg / mL to about 75 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 20 mg / mL to about 50 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 20 mg / mL to about 25 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 30 mg / mL to about 125 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 40 mg / mL to about 125 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 40 mg / mL to about 125 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 50 mg / mL to about 125 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 60 mg / mL to about 125 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 70 mg / mL to about 125 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 80 mg / mL to about 125 mg / mL.In some embodiments, the concentration of one or more polymers in the suspension is about 90 mg / mL to about 125 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is about 100 mg / mL to about 125 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is about 30 mg / mL to about 50 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is about 30 mg / mL to about 60 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is about 30 mg / mL to about 70 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is about 30 mg / mL to about 80 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is about 30 mg / mL to about 90 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is about 30 mg / mL to about 100 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is about 30 mg / mL to about 110 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 30 mg / mL to about 120 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 30 mg / mL to about 125 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 50 mg / mL to about 60 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 50 mg / mL to about 70 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 50 mg / mL to about 80 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 50 mg / mL to about 90 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 50 mg / mL to about 100 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 50 mg / mL to about 110 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is from about 50 mg / mL to about 120 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is about 50 mg / mL to about 125 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is about 60 mg / mL to about 70 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is about 60 mg / mL to about 80 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is about 60 mg / mL to about 90 mg / mL.In some embodiments, the concentration of one or more polymers in the suspension is about 60 mg / mL to about 100 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is about 60 mg / mL to about 110 mg / mL. In some embodiments, the concentration of one or more polymers in the suspension is about 60 mg / mL to about 125 mg / mL.

[0112] In some embodiments, the concentration of the one or more polymers in the suspension is about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL, about 105 mg / mL, about 100 mg / mL, about 115 mg / mL, about 120 mg / mL, or about 125 mg / mL. In some embodiments, the concentration of the one or more polymers in the suspension is at least 10 mg / mL, at least 15 mg / mL, at least 20 mg / mL, at least 25 mg / mL, at least 25 mg / mL, at least 30 mg / mL, at least 35 mg / mL, at least 40 mg / mL, at least 45 mg / mL, at least 50 mg / mL, at least 55 mg / mL, at least 60 mg / mL, at least 65 mg / mL, at least 70 mg / mL, at least 75 mg / mL, at least 80 mg / mL, at least 85 mg / mL, at least 90 mg / mL, at least 95 mg / mL, at least 100 mg / mL, at least 105 mg / mL, at least 100 mg / mL, at least 115 mg / mL, at least 120 mg / mL, or at least 125 mg / mL. In some embodiments, the concentration of the one or more polymers in the suspension is at most 10 mg / mL, at most 15 mg / mL, at most 20 mg / mL, at most 25 mg / mL, at most 25 mg / mL, at most 30 mg / mL, at most 35 mg / mL, at most 40 mg / mL, at most 45 mg / mL, at most 50 mg / mL, at most 55 mg / mL, at most 60 mg / mL, at most 65 mg / mL, at most 70 mg / mL, at most 75 mg / mL, at most 80 mg / mL, at most 85 mg / mL, at most 90 mg / mL, at most 95 mg / mL, at most 100 mg / mL, at most 105 mg / mL, at most 100 mg / mL, at most 115 mg / mL, at most 120 mg / mL, or at most 125 mg / mL.

[0113] Amorphous solid dispersion-Compound A

[0114] In some embodiments, the amorphous solid dispersion disclosed herein comprises Compound A. In some embodiments, the amorphous solid dispersion comprises (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide. In some embodiments, the amorphous solid dispersion comprises In some embodiments, the amorphous solid dispersion is a hot melt extrudate (HME). In some embodiments, the amorphous solid dispersion is prepared by dissolving Compound A or a pharmaceutically acceptable salt thereof in a solvent, and then removing at least a portion of the solvent. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is amorphous.

[0115] In some embodiments, the amorphous solid dispersion comprises about 10wt% to about 90wt% of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the amorphous solid dispersion comprises about 10wt% to about 80wt% of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the amorphous solid dispersion comprises about 10wt% to about 70wt% of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the amorphous solid dispersion comprises about 10wt% to about 60wt% of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the amorphous solid dispersion comprises about 10wt% to about 50wt% of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the amorphous solid dispersion comprises about 10wt% to about 40wt% of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the amorphous solid dispersion comprises about 10wt% to about 30wt% of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the amorphous solid dispersion comprises about 10wt% to about 20wt% of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the amorphous solid dispersion comprises about 20wt% to about 90wt% of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the amorphous solid dispersion comprises about 20wt% to about 80wt% of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the amorphous solid dispersion comprises about 20wt% to about 70wt% of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the amorphous solid dispersion comprises about 20wt% to about 60wt% of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the amorphous solid dispersion comprises about 20wt% to about 50wt% of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the amorphous solid dispersion comprises about 20wt% to about 40wt% of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the amorphous solid dispersion comprises about 20wt% to about 30wt% of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the amorphous solid dispersion comprises about 35wt% to about 45wt% of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the amorphous solid dispersion comprises about 30wt% to about 90wt% of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the amorphous solid dispersion comprises about 40wt% to about 80wt% of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the amorphous solid dispersion comprises about 50wt% to about 70wt% of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the amorphous solid dispersion comprises about 40wt% to about 70wt% of Compound A or a pharmaceutically acceptable salt thereof.In some embodiments, the amorphous solid dispersion comprises about 40 wt% to about 60 wt% of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the amorphous solid dispersion comprises about 20 wt% to about 90 wt% of Compound A or a pharmaceutically acceptable salt thereof.

[0116] In some embodiments, the amorphous solid dispersion comprises about 10 wt%, about 20 wt%, about 30 wt%, about 40 wt%, about 50 wt%, about 60 wt%, about 70 wt%, about 80 wt%, about 90 wt%, or about 95 wt% of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the amorphous solid dispersion comprises at least 10 wt%, at least 20 wt%, at least 30 wt%, at least 40 wt%, at least 50 wt%, at least 60 wt%, at least 70 wt%, at least 80 wt%, at least 90 wt%, at least 95 wt% of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the amorphous solid dispersion contains at most 10 wt%, at most 20 wt%, at most 30 wt%, at most 40 wt%, at most 50 wt%, at most 60 wt%, at most 70 wt%, at most 80 wt%, at most 90 wt%, or at most 95 wt% of Compound A or a pharmaceutically acceptable salt thereof.

[0117] In some embodiments, the weight ratio of Compound A or its pharmaceutically acceptable salt to one or more polymers is 10:1 to 1:10 or 5:1 to 1:5. In some embodiments, the weight ratio of Compound A or its pharmaceutically acceptable salt to one or more polymers is 2:1 to 1:2. In some embodiments, the weight ratio of Compound A or its pharmaceutically acceptable salt to one or more polymers is about 1:1 to 1:2. In some embodiments, the weight ratio of Compound A or its pharmaceutically acceptable salt to one or more polymers is 2 to 0.5. In some embodiments, the weight ratio of Compound A or its pharmaceutically acceptable salt to one or more polymers is 2 to 0.5. In some embodiments, the weight ratio of Compound A or its pharmaceutically acceptable salt to one or more polymers is 2 to 0.75. In some embodiments, the weight ratio of Compound A or its pharmaceutically acceptable salt to one or more polymers is 2 to 1. In some embodiments, the weight ratio of Compound A or its pharmaceutically acceptable salt to one or more polymers is 2 to 1.25. In some embodiments, the weight ratio of Compound A or its pharmaceutically acceptable salt to one or more polymers is 2 to 1.5. In some embodiments, the weight ratio of Compound A or its pharmaceutically acceptable salt to one or more polymers is 2 to 1.75. In some embodiments, the weight ratio of Compound A or its pharmaceutically acceptable salt to one or more polymers is 1.75 to 0.5. In some embodiments, the weight ratio of Compound A or its pharmaceutically acceptable salt to one or more polymers is 1.50 to 0.5. In some embodiments, the weight ratio of Compound A or its pharmaceutically acceptable salt to one or more polymers is 1.25 to 0.5. In some embodiments, the weight ratio of Compound A or its pharmaceutically acceptable salt to one or more polymers is 1 to 0.5. In some embodiments, the weight ratio of Compound A or its pharmaceutically acceptable salt to one or more polymers is 0.75 to 0.5. In some embodiments, the weight ratio of Compound A or its pharmaceutically acceptable salt to one or more polymers is 1 to 1.

[0118] In some embodiments, the weight ratio of Compound A or a pharmaceutically acceptable salt thereof to one or more polymers is about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0. In some embodiments, the weight ratio of Compound A or a pharmaceutically acceptable salt thereof to one or more polymers is at least 0.5, at least 0.6, at least 0.7, at least 0.8, at least 0.9, at least 1.0, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, or at least 2.0. In some embodiments, the weight ratio of Compound A or a pharmaceutically acceptable salt thereof to one or more polymers is at most 0.5, at most 0.6, at most 0.7, at most 0.8, at most 0.9, at most 1.0, at most 1.1, at most 1.2, at most 1.3, at most 1.4, at most 1.5, at most 1.6, at most 1.7, at most 1.8, at most 1.9 or at most 2.0.

[0119] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is in the form of an amorphous solid dispersion. In some embodiments, the concentration of Compound A or a pharmaceutically acceptable salt thereof in the oral liquid suspension described herein is from about 10 mg / mL to about 125 mg / mL. In some embodiments, the concentration of Compound A or a pharmaceutically acceptable salt thereof in the oral liquid suspension is from about 10 mg / mL to about 100 mg / mL. In some embodiments, the concentration of Compound A or a pharmaceutically acceptable salt thereof in the oral liquid suspension is from about 10 mg / mL to about 75 mg / mL. In some embodiments, the concentration of Compound A or a pharmaceutically acceptable salt thereof in the oral liquid suspension is from about 10 to about 50 mg / mL. In some embodiments, the concentration of Compound A or a pharmaceutically acceptable salt thereof in the oral liquid suspension is from about 10 to about 30 mg / mL. In some embodiments, the concentration of Compound A or a pharmaceutically acceptable salt thereof in the oral liquid suspension is from about 10 to about 35 mg / mL. In some embodiments, the concentration of Compound A or its pharmaceutically acceptable salt in the oral liquid suspension is about 10 to about 40 mg / mL. In some embodiments, the concentration of Compound A or its pharmaceutically acceptable salt in the oral liquid suspension is about 10 to about 45 mg / mL. In some embodiments, the concentration of Compound A or its pharmaceutically acceptable salt in the oral liquid suspension is about 25 mg / mL to about 100 mg / mL. In some embodiments, the concentration of Compound A or its pharmaceutically acceptable salt in the oral liquid suspension is about 25 mg / mL to about 75 mg / mL. In some embodiments, the concentration of Compound A or its pharmaceutically acceptable salt in the oral liquid suspension is about 25 to about 50 mg / mL. In some embodiments, the concentration of Compound A or its pharmaceutically acceptable salt in the oral liquid suspension is about 25 to about 30 mg / mL. In some embodiments, the concentration of Compound A or its pharmaceutically acceptable salt in the oral liquid suspension is about 25 to about 35 mg / mL. In some embodiments, the concentration of Compound A or its pharmaceutically acceptable salt in the oral liquid suspension is about 25 to about 40 mg / mL. In some embodiments, the concentration of Compound A or its pharmaceutically acceptable salt in the oral liquid suspension is about 25 to about 45 mg / mL. In some embodiments, the concentration of Compound A or its pharmaceutically acceptable salt in the oral liquid suspension is about 50 to about 125 mg / mL. In some embodiments, the concentration of Compound A or its pharmaceutically acceptable salt in the oral liquid suspension is about 50 to about 100 mg / mL. In some embodiments, the concentration of Compound A or its pharmaceutically acceptable salt in the oral liquid suspension is about 50 to about 75 mg / mL.

[0120] In some embodiments, the concentration of Compound A or its pharmaceutically acceptable salt in the oral liquid suspension is about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL, about 105 mg / mL, about 110 mg / mL, about 115 mg / mL, about 120 mg / mL or about 125 mg / mL. In some embodiments, the concentration of Compound A or its pharmaceutically acceptable salt in the oral liquid suspension is about 10 mg / mL. In some embodiments, the concentration of Compound A or its pharmaceutically acceptable salt in the oral liquid suspension is about 25 mg / mL. In some embodiments, the concentration of Compound A or its pharmaceutically acceptable salt in the oral liquid suspension is about 50 mg / mL. In some embodiments, the concentration of Compound A or its pharmaceutically acceptable salt in the oral liquid suspension is at least 10 mg / mL, at least 15 mg / mL, at least 20 mg / mL, at least 25 mg / mL, at least 30 mg / mL, at least 35 mg / mL, at least 40 mg / mL, at least 45 mg / mL, at least 50 mg / mL, at least 55 mg / mL, at least 65 mg / mL, at least 70 mg / mL, at least 75 mg / mL, at least 80 mg / mL, at least 85 mg / mL, at least 90 mg / mL, at least 95 mg / mL, at least 100 mg / mL, at least 105 mg / mL, at least 110 mg / mL, at least 115 mg / mL, at least 120 mg / mL or at least 125 mg / mL. In some embodiments, the concentration of Compound A, or a pharmaceutically acceptable salt thereof, in the oral liquid suspension is at most 10 mg / mL, at most 15 mg / mL, at most 20 mg / mL, at most 25 mg / mL, at most 30 mg / mL, at most 35 mg / mL, at most 40 mg / mL, at most 45 mg / mL, at most 50 mg / mL, at most 55 mg / mL, at most 65 mg / mL, at most 70 mg / mL, at most 75 mg / mL, at most 80 mg / mL, at most 85 mg / mL, at most 90 mg / mL, at most 95 mg / mL, at most 100 mg / mL, at most 105 mg / mL, at most 110 mg / mL, at most 115 mg / mL, at most 120 mg / mL, or at most 125 mg / mL.

[0121] Pharmaceutically acceptable excipients

[0122] The pharmaceutical compositions described herein, such as pharmaceutical compositions in solid form (such as pharmaceutical powders) and suspensions, may include one or more pharmaceutically acceptable excipients. In some embodiments, one or more pharmaceutically acceptable excipients are mixed with an amorphous solid dispersion in a pharmaceutical powder. In some embodiments, the pharmaceutical powder comprises about 5wt% to about 90wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical powder comprises about 5wt% to about 80wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical powder comprises about 5wt% to about 70wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical powder comprises about 5wt% to about 60wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical powder comprises about 5wt% to about 50wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical powder comprises about 5wt% to about 40wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical powder comprises about 5wt% to about 30wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical powder comprises about 5wt% to about 20wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical powder comprises about 10wt% to about 90wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical powder comprises about 10wt% to about 80wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical powder comprises about 10wt% to about 70wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical powder comprises about 10wt% to about 60wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical powder comprises about 10wt% to about 50wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical powder comprises about 10wt% to about 40wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical powder comprises about 10wt% to about 30wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical powder comprises about 40wt% to about 80wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical powder comprises about 50wt% to about 70wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical powder comprises about 40wt% to about 70wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical powder comprises about 40wt% to about 60wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical powder comprises about 20wt% to about 90wt% of one or more pharmaceutically acceptable excipients.In some embodiments, the pharmaceutical powder comprises about 5wt% to about 25wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical powder comprises about 5wt% to about 20wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical powder comprises about 5wt% to about 15wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical powder comprises about 5wt% to about 10wt% of one or more pharmaceutically acceptable excipients.

[0123] In some embodiments, the pharmaceutical powder comprises about 5wt%, about 10wt%, about 15wt%, about 20wt%, about 25wt%, about 30wt%, about 35wt%, about 40wt%, about 45wt%, about 50wt%, about 55wt%, about 60wt%, about 65wt%, about 70wt%, about 75wt%, about 80wt%, about 85wt%, about 90wt% or about 95wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical powder comprises at least 10wt%, at least 20wt%, at least 30wt%, at least 40wt%, at least 50wt%, at least 60wt%, at least 70wt%, at least 80wt%, at least 90wt%, at least 95wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical powder comprises at most 5 wt%, at most 10 wt%, at most 15 wt%, at most 20 wt%, at most 25 wt%, at most 30 wt%, at most 35 wt%, at most 40 wt%, at most 45 wt%, at most 50 wt%, at most 55 wt%, at most 60 wt%, at most 65 wt%, at most 70 wt%, at most 75 wt%, at most 80 wt%, at most 85 wt%, at most 90 wt%, or at most 95 wt% of one or more pharmaceutically acceptable excipients.

[0124] In some embodiments, the solid formulations described herein include one or more pharmaceutically acceptable excipients and amorphous solid dispersions. In some embodiments, the solid formulation includes about 5wt% to about 90wt% of one or more pharmaceutically acceptable excipients (i.e., one or more pharmaceutically acceptable excipients are present in the solid formulation at about 5wt% to about 90wt%). In some embodiments, the solid formulation includes about 5wt% to about 80wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the solid formulation includes about 5wt% to about 70wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the solid formulation includes about 5wt% to about 60wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the solid formulation includes about 5wt% to about 50wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the solid formulation includes about 5wt% to about 40wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the solid formulation includes about 5wt% to about 30wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the solid formulation comprises about 5wt% to about 20wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the solid formulation comprises about 10wt% to about 90wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the solid formulation comprises about 10wt% to about 80wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the solid formulation comprises about 10wt% to about 70wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the solid formulation comprises about 10wt% to about 60wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the solid formulation comprises about 10wt% to about 50wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the solid formulation comprises about 10wt% to about 40wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the solid formulation comprises about 10wt% to about 30wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the solid formulation comprises about 40wt% to about 80wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the solid formulation comprises about 50wt% to about 70wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the solid formulation comprises about 40wt% to about 70wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the solid formulation comprises about 40wt% to about 60wt% of one or more pharmaceutically acceptable excipients. In some embodiments, the solid formulation comprises about 20wt% to about 90wt% of one or more pharmaceutically acceptable excipients.In some embodiments, the solid formulation comprises one or more pharmaceutically acceptable excipients of about 5wt% to about 25wt%. In some embodiments, the solid formulation comprises one or more pharmaceutically acceptable excipients of about 5wt% to about 20wt%. In some embodiments, the solid formulation comprises one or more pharmaceutically acceptable excipients of about 5wt% to about 15wt%. In some embodiments, the solid formulation comprises one or more pharmaceutically acceptable excipients of about 5wt% to about 10wt%. In some embodiments, the solid formulation comprises one or more pharmaceutically acceptable excipients of about 5wt%, about 10wt%, about 15wt%, about 20wt%, about 25wt%, about 30wt%, about 35wt%, about 40wt%, about 45wt%, about 50wt%, about 55wt%, about 60wt%, about 65wt%, about 70wt%, about 75wt%, about 80wt%, about 85wt%, about 90wt% or about 95wt% of one or more pharmaceutically acceptable excipients. In some embodiments, solid preparation comprises at least 10wt%, at least 20wt%, at least 30wt%, at least 40wt%, at least 50wt%, at least 60wt%, at least 70wt%, at least 80wt%, at least 90wt%, at least 95wt% of one or more pharmaceutically acceptable excipients. In some embodiments, solid preparation comprises at most 5wt%, at most 10wt%, at most 15wt%, at most 20wt%, at most 25wt%, at most 30wt%, at most 35wt%, at most 40wt%, at most 45wt%, at most 50wt%, at most 55wt%, at most 60wt%, at most 65wt%, at most 70wt%, at most 75wt%, at most 80wt%, at most 85wt%, at most 90wt% or at most 95wt% of one or more pharmaceutically acceptable excipients. In some embodiments, solid preparation is powder. In some embodiments, the solid formulation is in the form of granules or pellets.

[0125] In some embodiments, one or more pharmaceutically acceptable excipients include defoamers, fillers, colorants, preservatives, flavorings, sweeteners, or combinations thereof. In some embodiments, one or more pharmaceutically acceptable excipients include colorants, preservatives, flavorings, sweeteners, or combinations thereof. In some embodiments, one or more pharmaceutically acceptable excipients include colorants. In some embodiments, one or more pharmaceutically acceptable excipients include preservatives. In some embodiments, one or more pharmaceutically acceptable excipients include flavorings. In some embodiments, one or more pharmaceutically acceptable excipients include sweeteners.

[0126] Some pharmaceutically acceptable excipients are well known in the pharmaceutical field and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th edition, 2006 and Remington: The Science and Practice of Pharmacy (Gennaro, 21st edition, Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, etc. may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used. Generally, the type of excipient is selected based on the mode of administration and the chemical composition of the active ingredient. Alternatively, the compositions described herein may be formulated as lyophilizates. The compositions described herein may be lyophilized or otherwise formulated as lyophilized products that use one or more suitable excipient solutions for dissolving and / or diluting the medicament of the composition when administered. In other embodiments, the medicament may be encapsulated in liposomes using techniques known and practiced in the art. In certain specific embodiments, the agent is not formulated within a liposome for application in a stent for treating a highly (although not completely) occluded artery.The pharmaceutical composition may be formulated for any suitable mode of administration as described herein and in the art.

[0127] Defoaming agent

[0128] In some embodiments, one or more pharmaceutically acceptable excipients described herein include a defoamer. In some embodiments, the defoamer includes simethicone or dimethicone. In some embodiments, the defoamer includes simethicone. The defoamer can be in the form of a powder on a solid carrier (e.g., a defoamer and maltodextrin, such as 30% simethicone / 70% maltodextrin). In some embodiments, the defoamer is carried by a solid carrier. In some embodiments, the solid carrier is maltodextrin, microcrystalline cellulose or calcium carbonate. In some embodiments, the defoamer is in liquid form. In some embodiments, the defoamer is a suspension.

[0129] In some embodiments, solid formulations such as pharmaceutical powders contain about 0.1wt% to about 15wt% of defoamers. In some embodiments, solid formulations contain about 0.1wt% to about 14wt% of defoamers. In some embodiments, solid formulations contain about 0.1wt% to about 13wt% of defoamers. In some embodiments, solid formulations contain about 0.1wt% to about 12wt% of defoamers. In some embodiments, solid formulations contain about 0.1wt% to about 11wt% of defoamers. In some embodiments, solid formulations contain about 0.1wt% to about 10wt% of defoamers. In some embodiments, solid formulations contain about 0.1wt% to about 9wt% of defoamers. In some embodiments, solid formulations contain about 0.1wt% to about 8wt% of defoamers. In some embodiments, solid formulations contain about 5wt% to about 8wt% of defoamers. In some embodiments, solid formulations contain about 0.1wt% to about 7wt% of defoamers. In some embodiments, the solid formulation comprises about 0.1wt% to about 6wt% of a defoamer. In some embodiments, the solid formulation comprises about 0.1wt% to about 5wt% of a defoamer. In some embodiments, the solid formulation comprises about 0.1wt% to about 4wt% of a defoamer. In some embodiments, the solid formulation comprises about 0.1wt% to about 3wt% of a defoamer. In some embodiments, the solid formulation comprises about 0.1wt% to about 2wt% of a defoamer. In some embodiments, the solid formulation comprises about 0.1wt% to about 1wt% of a defoamer. In some embodiments, the solid formulation comprises about 0.1wt% to about 0.9wt% of a defoamer. In some embodiments, the solid formulation comprises about 0.1wt% to about 0.8wt% of a defoamer. In some embodiments, the solid formulation comprises about 0.1wt% to about 0.7wt% of a defoamer. In some embodiments, the solid formulation comprises about 0.1wt% to about 0.6wt% of a defoamer. In some embodiments, the solid preparation comprises about 0.1wt% to about 0.5wt% of a defoamer. In some embodiments, the solid preparation comprises about 0.1wt% to about 0.4wt% of a defoamer. In some embodiments, the solid preparation comprises about 0.1wt% to about 0.3wt% of a defoamer. In some embodiments, the solid preparation comprises about 0.1wt% to about 0.25wt% of a defoamer. In some embodiments, the solid preparation is a powder. In some embodiments, the solid preparation is in the form of flakes, granules or pellets. In some embodiments, the defoamer comprises simethicone and a carrier such as maltodextrin. In some embodiments, the carrier is starch. In some embodiments, the defoamer comprises simethicone and maltodextrin. In some embodiments, the defoamer comprises simethicone (about 30wt%) and maltodextrin (about 70wt%).In some embodiments, the anti-foaming agent comprises simethicone (30 wt%) and maltodextrin (70 wt%). In some embodiments, the anti-foaming agent comprises simethicone (20-40 wt%) and maltodextrin (60-80 wt%).

[0130] In some embodiments, solid formulations such as pharmaceutical powders contain about 0.1wt% to about 0.2wt% of defoamers. In some embodiments, solid formulations contain about 0.1wt% to about 0.15wt% of defoamers. In some embodiments, solid formulations contain about 0.15wt% to about 15wt% of defoamers. In some embodiments, solid formulations contain about 0.2wt% to about 15wt% of defoamers. In some embodiments, solid formulations contain about 0.25wt% to about 15wt% of defoamers. In some embodiments, solid formulations contain about 0.3wt% to about 15wt% of defoamers. In some embodiments, solid formulations contain about 0.4wt% to about 15wt% of defoamers. In some embodiments, solid formulations contain about 0.5wt% to about 15wt% of defoamers. In some embodiments, solid formulations contain about 0.6wt% to about 15wt% of defoamers. In some embodiments, solid formulations contain about 0.7wt% to about 15wt% of defoamers. In some embodiments, the solid formulation comprises about 0.8wt% to about 15wt% of a defoamer. In some embodiments, the solid formulation comprises about 0.9wt% to about 15wt% of a defoamer. In some embodiments, the solid formulation comprises about 1wt% to about 15wt% of a defoamer. In some embodiments, the solid formulation comprises about 2wt% to about 15wt% of a defoamer. In some embodiments, the solid formulation comprises about 3wt% to about 15wt% of a defoamer. In some embodiments, the solid formulation comprises about 4wt% to about 15wt% of a defoamer. In some embodiments, the solid formulation comprises about 5wt% to about 15wt% of a defoamer. In some embodiments, the solid formulation comprises about 6wt% to about 15wt% of a defoamer. In some embodiments, the solid formulation comprises about 7wt% to about 15wt% of a defoamer. In some embodiments, the solid formulation comprises about 8wt% to about 15wt% of a defoamer. In some embodiments, the solid formulation comprises about 9wt% to about 15wt% of a defoamer. In some embodiments, the solid formulation comprises about 10wt% to about 15wt% of a defoamer. In some embodiments, the solid formulation comprises about 11wt% to about 15wt% of a defoamer. In some embodiments, the solid formulation comprises about 12wt% to about 15wt% of a defoamer. In some embodiments, the solid formulation comprises about 13wt% to about 15wt% of a defoamer. In some embodiments, the solid formulation comprises about 14wt% to about 15wt% of a defoamer. In some embodiments, the solid formulation comprises about 2wt% to about 10wt% of a defoamer. In some embodiments, the solid formulation comprises about 3wt% to about 10wt% of a defoamer. In some embodiments, the solid formulation comprises about 3wt% to about 9wt% of a defoamer. In some embodiments, the solid formulation comprises about 3wt% to about 8wt% of a defoamer.In some embodiments, the solid formulation comprises about 0.1wt% to about 15wt% simethicone. In some embodiments, the solid formulation comprises about 3wt% to about 8wt% simethicone. In some embodiments, the solid formulation comprises about 0.5wt% to about 3wt% simethicone. In some embodiments, the solid formulation is a powder. In some embodiments, the solid formulation is in the form of flakes, granules or pellets.

[0131] In some embodiments, a solid formulation such as a pharmaceutical powder comprises about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, about 1.5 wt%, about 2 wt%, about 2.5 wt%, about 3 wt%, about 3.5 wt%, about 4 wt%, about 4.5 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, or about 15 wt% of a defoaming agent. In some embodiments, the solid formulation comprises at least 0.1 wt%, at least 0.2 wt%, at least 0.3 wt%, at least 0.4 wt%, at least 0.5 wt%, at least 0.6 wt%, at least 0.7 wt%, at least 0.8 wt%, at least 0.9 wt%, at least 1 wt%, at least 1.1 wt%, at least 1.2 wt%, at least 1.3 wt%, at least 1.4 wt%, at least 1.5 wt%, at least 2 wt%, at least 2.5 wt%, at least 3 wt%, at least 3.5 wt%, at least 4 wt%, at least 4.5 wt%, at least 5 wt%, at least 6 wt%, at least 7 wt%, at least 8 wt%, at least 9 wt%, at least 10 wt%, at least 11 wt%, at least 12 wt%, at least 13 wt%, at least 14 wt%, or at least 15 wt% of a defoaming agent. In some embodiments, the solid formulation comprises at most 0.1 wt%, at most 0.2 wt%, at most 0.3 wt%, at most 0.4 wt%, at most 0.5 wt%, at most 0.6 wt%, at most 0.7 wt%, at most 0.8 wt%, at most 0.9 wt%, at most 1 wt%, at most 1.1 wt%, at most 1.2 wt%, at most 1.3 wt%, at most 1.4 wt%, at most 1.5 wt%, at most 2 wt%, at most 2.5 wt%, at most 3 wt%, at most 3.5 wt%, at most 4 wt%, at most 4.5 wt%, at most 5 wt%, at most 6 wt%, at most 7 wt%, at most 8 wt%, at most 9 wt%, at most 10 wt%, at most 11 wt%, at most 12 wt%, at most 13 wt%, at most 14 wt%, or at most 15 wt% of a defoaming agent. In some embodiments, the solid formulation is a powder. In some embodiments, the solid formulation is in the form of flakes, granules, or pellets.

[0132] In some embodiments, the suspension described herein comprises one or more pharmaceutically acceptable excipients as disclosed herein. In some embodiments, one or more pharmaceutically acceptable excipients comprise a defoamer. In some embodiments, the concentration of the defoamer in the suspension is from about 1 mg / mL to about 30 mg / mL. In some embodiments, the concentration of the defoamer in the suspension is from about 1 mg / mL to about 25 mg / mL. In some embodiments, the concentration of the defoamer in the suspension is from about 1 mg / mL to about 20 mg / mL. In some embodiments, the concentration of the defoamer in the suspension is from about 1 mg / mL to about 15 mg / mL. In some embodiments, the concentration of the defoamer in the suspension is from about 1 mg / mL to about 10 mg / mL. In some embodiments, the concentration of the defoamer in the suspension is from about 1 mg / mL to about 9 mg / mL. In some embodiments, the concentration of the defoamer in the suspension is from about 1 mg / mL to about 8 mg / mL. In some embodiments, the concentration of the defoamer in the suspension is from about 1 mg / mL to about 7 mg / mL. In some embodiments, the concentration of the defoamer in the suspension is about 1 mg / mL to about 6 mg / mL. In some embodiments, the concentration of the defoamer in the suspension is about 1 mg / mL to about 5 mg / mL. In some embodiments, the concentration of the defoamer in the suspension is about 1 mg / mL to about 4 mg / mL. In some embodiments, the concentration of the defoamer in the suspension is about 1 mg / mL to about 3 mg / mL. In some embodiments, the concentration of the defoamer in the suspension is about 1 mg / mL to about 2 mg / mL. In some embodiments, the concentration of the defoamer in the suspension is about 5 mg / mL to about 30 mg / mL. In some embodiments, the concentration of the defoamer in the suspension is about 10 mg / mL to about 30 mg / mL. In some embodiments, the concentration of the defoamer in the suspension is about 15 mg / mL to about 30 mg / mL. In some embodiments, the concentration of the defoamer in the suspension is about 20 mg / mL to about 30 mg / mL. In some embodiments, the concentration of the defoamer in the suspension is about 25 mg / mL to about 30 mg / mL. In some embodiments, the concentration of the defoamer in the suspension is about 1 mg / mL to about 10 mg / mL. In some embodiments, the concentration of the defoamer in the suspension is about 3 mg / mL to about 8 mg / mL. In some embodiments, the concentration of the defoamer in the suspension is about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, or about 30 mg / mL.In some embodiments, the concentration of the antifoaming agent in the suspension is at least 1 mg / mL, at least 2 mg / mL, at least 3 mg / mL, at least 4 mg / mL, at least 5 mg / mL, at least 10 mg / mL, at least 15 mg / mL, at least 20 mg / mL, at least 25 mg / mL, or at least 30 mg / mL. In some embodiments, the concentration of the antifoaming agent in the suspension is at most 1 mg / mL, at most 2 mg / mL, at most 3 mg / mL, at most 4 mg / mL, at most 5 mg / mL, at most 10 mg / mL, at most 15 mg / mL, at most 20 mg / mL, at most 25 mg / mL, or at most 30 mg / mL.

[0133] Fillers

[0134] In some embodiments, one or more pharmaceutically acceptable excipients described herein include fillers. In some embodiments, fillers include polysaccharides, sugars or their derivatives, or both. In some embodiments, fillers include polysaccharides. In some embodiments, fillers are sugars. In some embodiments, fillers include cellulose, starch, synthetic soluble fiber, sugar alcohols or a combination thereof. In some embodiments, fillers include cellulose. In some embodiments, fillers include starch. In some embodiments, fillers include maltodextrin. In some embodiments, fillers include HPMC. In some embodiments, fillers include calcium hydrogen phosphate dihydrate (DCP). In some embodiments, fillers include synthetic soluble fiber. In some embodiments, fillers include sugar alcohols. In some embodiments, fillers include mannitol. In some embodiments, fillers include microcrystalline cellulose, polydextrose, sodium carboxymethylcellulose (sodium CMC) or a combination thereof. In some embodiments, fillers include microcrystalline cellulose. In some embodiments, fillers include polydextrose. In some embodiments, fillers include sodium carboxymethylcellulose.

[0135] In some embodiments, the solid formulations described herein, such as pharmaceutical powders, contain about 5wt% to about 90wt% of fillers (i.e., fillers are present in the solid formulation at about 5wt% to about 90wt%). In some embodiments, the solid formulation contains about 5wt% to about 80wt% of fillers. In some embodiments, the solid formulation contains about 5wt% to about 70wt% of fillers. In some embodiments, the solid formulation contains about 5wt% to about 60wt% of fillers. In some embodiments, the solid formulation contains about 5wt% to about 50wt% of fillers. In some embodiments, the solid formulation contains about 5wt% to about 40wt% of fillers. In some embodiments, the solid formulation contains about 5wt% to about 30wt% of fillers. In some embodiments, the solid formulation contains about 5wt% to about 20wt% of fillers. In some embodiments, the solid formulation contains about 10wt% to about 90wt% of fillers. In some embodiments, the solid formulation contains about 10wt% to about 80wt% of fillers. In some embodiments, the solid formulation comprises about 10wt% to about 70wt% of filler. In some embodiments, the solid formulation comprises about 10wt% to about 60wt% of filler. In some embodiments, the solid formulation comprises about 10wt% to about 50wt% of filler. In some embodiments, the solid formulation comprises about 10wt% to about 40wt% of filler. In some embodiments, the solid formulation comprises about 10wt% to about 30wt% of filler. In some embodiments, the solid formulation comprises about 40wt% to about 80wt% of filler. In some embodiments, the solid formulation comprises about 50wt% to about 70wt% of filler. In some embodiments, the solid formulation comprises about 40wt% to about 70wt% of filler. In some embodiments, the solid formulation comprises about 40wt% to about 60wt% of filler. In some embodiments, the solid formulation comprises about 20wt% to about 90wt% of filler. In some embodiments, the solid formulation comprises about 5wt% to about 25wt% of filler. In some embodiments, the solid formulation comprises about 5wt% to about 20wt% of a filler. In some embodiments, the solid formulation comprises about 5wt% to about 15wt% of a filler. In some embodiments, the solid formulation comprises about 5wt% to about 10wt% of a filler. In some embodiments, the solid formulation is a powder. In some embodiments, the solid formulation is in the form of flakes, granules, or pellets.

[0136] In some embodiments, a solid formulation such as a pharmaceutical powder comprises about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, about 90 wt%, or about 95 wt% of a filler. In some embodiments, the solid formulation comprises at least 5 wt%, at least 10 wt%, at least 15 wt%, at least 20 wt%, at least 25 wt%, at least 30 wt%, at least 35 wt%, at least 40 wt%, at least 45 wt%, at least 50 wt%, at least 55 wt%, at least 60 wt%, at least 65 wt%, at least 70 wt%, at least 75 wt%, at least 80 wt%, at least 85 wt%, at least 90 wt%, or at least 95 wt% of filler. In some embodiments, solid preparation comprises at most 5wt%, at most 10wt%, at most 15wt%, at most 20wt%, at most 25wt%, at most 30wt%, at most 35wt%, at most 40wt%, at most 45wt%, at most 50wt%, at most 55wt%, at most 60wt%, at most 65wt%, at most 70wt%, at most 75wt%, at most 80wt%, at most 85wt%, at most 90wt% or at most 95wt% filler. In some embodiments, solid preparation is powder. In some embodiments, solid preparation is in the form of flakes, granules or pellets.

[0137] In some embodiments, the suspension comprises one or more pharmaceutically acceptable excipients as disclosed herein.

[0138] In some embodiments, the concentration of the filler in the suspension is about 30 mg / mL to about 500 mg / mL. In some embodiments, the concentration of the filler in the suspension is about 40 mg / mL to about 500 mg / mL. In some embodiments, the concentration of the filler in the suspension is about 50 mg / mL to about 500 mg / mL. In some embodiments, the concentration of the filler in the suspension is about 60 mg / mL to about 500 mg / mL. In some embodiments, the concentration of the filler in the suspension is about 70 mg / mL to about 500 mg / mL. In some embodiments, the concentration of the filler in the suspension is about 80 mg / mL to about 500 mg / mL. In some embodiments, the concentration of the filler in the suspension is about 90 mg / mL to about 500 mg / mL. In some embodiments, the concentration of the filler in the suspension is about 100 mg / mL to about 500 mg / mL. In some embodiments, the concentration of the filler in the suspension is about 125 mg / mL to about 500 mg / mL. In some embodiments, the concentration of the filler in the suspension is about 150 mg / mL to about 500 mg / mL. In some embodiments, the concentration of the filler in the suspension is about 175 mg / mL to about 500 mg / mL. In some embodiments, the concentration of the filler in the suspension is about 200 mg / mL to about 500 mg / mL. In some embodiments, the concentration of the filler in the suspension is about 250 mg / mL to about 500 mg / mL. In some embodiments, the concentration of the filler in the suspension is about 300 mg / mL to about 500 mg / mL. In some embodiments, the concentration of the filler in the suspension is about 350 mg / mL to about 500 mg / mL. In some embodiments, the concentration of the filler in the suspension is about 400 mg / mL to about 500 mg / mL. In some embodiments, the concentration of the filler in the suspension is about 450 mg / mL to about 500 mg / mL. In some embodiments, the concentration of the filler in the suspension is about 50 mg / mL to about 450 mg / mL. In some embodiments, the concentration of the filler in the suspension is about 50 mg / mL to about 400 mg / mL. In some embodiments, the concentration of the filler in the suspension is about 50 mg / mL to about 350 mg / mL. In some embodiments, the concentration of the filler in the suspension is about 50 mg / mL to about 300 mg / mL. In some embodiments, the concentration of the filler in the suspension is about 50 mg / mL to about 250 mg / mL. In some embodiments, the concentration of the filler in the suspension is about 50 mg / mL to about 200 mg / mL. In some embodiments, the concentration of the filler in the suspension is about 50 mg / mL to about 150 mg / mL.In some embodiments, the concentration of the filler in the suspension is about 50 mg / mL to about 100 mg / mL. In some embodiments, the concentration of the filler in the suspension is about 100 mg / mL to about 250 mg / mL. In some embodiments, the concentration of the filler in the suspension is about 125 mg / mL to about 200 mg / mL. In some embodiments, the concentration of the filler in the suspension is about 50 mg / mL to about 150 mg / mL. In some embodiments, the concentration of the filler in the suspension is about 50 mg / mL, about 75 mg / mL, about 100 mg / mL, about 125 mg / mL, about 150 mg / mL, about 175 mg / mL, about 200 mg / mL, about 250 mg / mL, about 300 mg / mL, about 350 mg / mL, about 400 mg / mL, about 450 mg / mL or about 500 mg / mL. In some embodiments, the concentration of the filler in the suspension is at least 50 mg / mL, at least 75 mg / mL, at least 100 mg / mL, at least 125 mg / mL, at least 150 mg / mL, at least 175 mg / mL, at least 200 mg / mL, at least 250 mg / mL, at least 300 mg / mL, at least 350 mg / mL, at least 400 mg / mL, at least 450 mg / mL, or at least 500 mg / mL. In some embodiments, the concentration of the filler in the suspension is at most 50 mg / mL, at most 75 mg / mL, at most 100 mg / mL, at most 125 mg / mL, at most 150 mg / mL, at most 175 mg / mL, at most 200 mg / mL, at most 250 mg / mL, at most 300 mg / mL, at most 350 mg / mL, at most 400 mg / mL, at most 450 mg / mL, or at most 500 mg / mL.

[0139] Flow aid

[0140] In some embodiments, one or more pharmaceutically acceptable excipients described herein include a flow aid. In some embodiments, the flow aid is a glidant. In some embodiments, the flow aid is selected from silicon dioxide, magnesium stearate, talc, starch, magnesium silicate, hydrated sodium sulfoaluminate, and combinations thereof. In some embodiments, the flow aid is selected from magnesium stearate, talc, starch, magnesium silicate, hydrated sodium sulfoaluminate, and combinations thereof. In some embodiments, the flow aid is silicon dioxide. In some embodiments, silicon dioxide includes fumed silica, colloidal silicon dioxide (CSD), or both. In some embodiments, the flow aid is porous silicon dioxide. In some embodiments, the flow aid is non-porous silicon dioxide.

[0141] In some embodiments, the solid formulations described herein, such as pharmaceutical powders, contain about 0.25 wt % to about 10 wt % of a flow aid (i.e., the flow aid is present in the solid formulation at about 0.25 wt % to about 10 wt %). In some embodiments, the solid formulation contains about 0.5 wt % to about 10 wt % of a flow aid. In some embodiments, the solid formulation contains about 1 wt % to about 10 wt % of a flow aid. In some embodiments, the solid formulation contains about 1.5 wt % to about 10 wt % of a flow aid. In some embodiments, the solid formulation contains about 2 wt % to about 10 wt % of a flow aid. In some embodiments, the solid formulation contains about 2.5 wt % to about 10 wt % of a flow aid. In some embodiments, the solid formulation contains about 3 wt % to about 10 wt % of a flow aid. In some embodiments, the solid formulation contains about 3.5 wt % to about 10 wt % of a flow aid. In some embodiments, the solid formulation contains about 4 wt % to about 10 wt % of a flow aid. In some embodiments, the solid formulation comprises about 4.5wt% to about 10wt% of a flow aid. In some embodiments, the solid formulation comprises about 5wt% to about 10wt% of a flow aid. In some embodiments, the solid formulation comprises about 6wt% to about 10wt% of a flow aid. In some embodiments, the solid formulation comprises about 7wt% to about 10wt% of a flow aid. In some embodiments, the solid formulation comprises about 8wt% to about 10wt% of a flow aid. In some embodiments, the solid formulation comprises about 9wt% to about 10wt% of a flow aid. In some embodiments, the solid formulation comprises about 0.5wt% to about 9wt% of a flow aid. In some embodiments, the solid formulation comprises about 0.5wt% to about 8wt% of a flow aid. In some embodiments, the solid formulation comprises about 0.5wt% to about 7wt% of a flow aid. In some embodiments, the solid formulation comprises about 0.5wt% to about 6wt% of a flow aid. In some embodiments, the solid formulation comprises about 0.5wt% to about 5wt% of a flow aid. In some embodiments, the solid formulation comprises about 0.5wt% to about 4.5wt% of a flow aid. In some embodiments, the solid formulation comprises about 0.5wt% to about 4wt% of a flow aid. In some embodiments, the solid formulation comprises about 0.5wt% to about 3.5wt% of a flow aid. In some embodiments, the solid formulation comprises about 0.5wt% to about 3wt% of a flow aid. In some embodiments, the solid formulation comprises about 0.5wt% to about 2.5wt% of a flow aid. In some embodiments, the solid formulation comprises about 0.5wt% to about 2wt% of a flow aid. In some embodiments, the solid formulation comprises about 0.5wt% to about 1.5wt% of a flow aid. In some embodiments, the solid formulation comprises about 0.5wt% to about 1wt% of a flow aid.In some embodiments, the solid formulation is a powder. In some embodiments, the solid formulation is in the form of flakes, granules, or pellets.

[0142] In some embodiments, the solid formulations described herein, such as pharmaceutical powders, contain about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, about 1.5 wt%, about 2 wt%, about 2.5 wt%, about 3 wt%, about 3.5 wt%, about 4 wt%, about 4.5 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, or about 10 wt% of a flow aid. In some embodiments, the solid formulation comprises %, at least 0.5 wt%, at least 0.6 wt%, at least 0.7 wt%, at least 0.8 wt%, at least 0.9 wt%, at least 1 wt%, at least 1.1 wt%, at least 1.2 wt%, at least 1.3 wt%, at least 1.4 wt%, at least 1.5 wt%, at least 2 wt%, at least 2.5 wt%, at least 3 wt%, at least 3.5 wt%, at least 4 wt%, at least 4.5 wt%, at least 5 wt%, at least 6 wt%, at least 7 wt%, at least 8 wt%, at least 9 wt%, or at least 10 wt% of a flow aid. In some embodiments, the pharmaceutical composition comprises at most 0.5 wt%, at most 0.6 wt%, at most 0.7 wt%, at most 0.8 wt%, at most 0.9 wt%, at most 1 wt%, at most 1.1 wt%, at most 1.2 wt%, at most 1.3 wt%, at most 1.4 wt%, at most 1.5 wt%, at most 2 wt%, at most 2.5 wt%, at most 3 wt%, at most 3.5 wt%, at most 4 wt%, at most 4.5 wt%, at most 5 wt%, at most 6 wt%, at most 7 wt%, at most 8 wt%, at most 9 wt% or at most 10 wt% of a flow aid.

[0143] In some embodiments, the suspension described herein comprises one or more pharmaceutically acceptable excipients as disclosed herein. In some embodiments, one or more pharmaceutically acceptable excipients comprise a flow aid. In some embodiments, the concentration of the flow aid in the suspension is from about 3 mg / mL to about 30 mg / mL. In some embodiments, the concentration of the flow aid in the suspension is from about 3 mg / mL to about 25 mg / mL. In some embodiments, the concentration of the flow aid in the suspension is from about 3 mg / mL to about 20 mg / mL. In some embodiments, the concentration of the flow aid in the suspension is from about 3 mg / mL to about 15 mg / mL. In some embodiments, the concentration of the flow aid in the suspension is from about 3 mg / mL to about 10 mg / mL. In some embodiments, the concentration of the flow aid in the suspension is from about 3 mg / mL to about 5 mg / mL. In some embodiments, the concentration of the flow aid in the suspension is from about 5 mg / mL to about 30 mg / mL. In some embodiments, the concentration of the flow aid in the suspension is about 10 mg / mL to about 30 mg / mL. In some embodiments, the concentration of the flow aid in the suspension is about 15 mg / mL to about 30 mg / mL. In some embodiments, the concentration of the flow aid in the suspension is about 20 mg / mL to about 30 mg / mL. In some embodiments, the concentration of the flow aid in the suspension is about 25 mg / mL to about 30 mg / mL. In some embodiments, the concentration of the flow aid in the suspension is about 5 mg / mL to about 15 mg / mL. In some embodiments, the concentration of the flow aid in the suspension is about 10 mg / mL to about 15 mg / mL. In some embodiments, the concentration of the flow aid in the suspension is about 3 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, or about 30 mg / mL. In some embodiments, the concentration of the flow aid in the suspension is at least 3 mg / mL, at least 5 mg / mL, at least 10 mg / mL, at least 15 mg / mL, at least 20 mg / mL, at least 25 mg / mL, or at least 30 mg / mL. In some embodiments, the concentration of the flow aid in the suspension is at most 3 mg / mL, at most 5 mg / mL, at most 10 mg / mL, at most 15 mg / mL, at most 20 mg / mL, at most 25 mg / mL, or at most 30 mg / mL.

[0144] Surfactants

[0145] Solid formulations and / or liquid formulations described herein may include one or more surfactants. In some embodiments, one or more pharmaceutically acceptable excipients described herein include surfactants. In some embodiments, surfactants include cationic surfactants, anionic surfactants, nonionic surfactants, or a combination thereof. In some embodiments, surfactants are cationic surfactants. In some embodiments, surfactants are anionic surfactants. In some embodiments, surfactants are nonionic. Nonionic surfactants do not have charged groups in their heads. Exemplary nonionic surfactants include, but are not limited to, fatty alcohols, cetyl alcohol, stearyl alcohol, cetearyl alcohol, and oleyl alcohol. Exemplary nonionic surfactants include, but are not limited to, polyethylene glycol alkyl ethers (such as octaethylene glycol monododecyl ether, pentaethylene glycol monododecyl ether), polypropylene glycol alkyl ethers, glucoside alkyl ethers (such as decyl glucoside, lauryl glucoside, octyl glucoside), polyethylene glycol octylphenyl ether (such as Triton X-100), polyethylene glycol alkylphenyl ether (such as nonoxynol-9), glycerol alkyl esters (such as lauric acid glyceryl), polyoxyethylene glycol sorbitan alkyl esters (such as polysorbates), sorbitan alkyl esters (such as Spans), cocamide MEA, cocamide DEA, dodecyl dimethylamine oxide, tocosolane (TPGS), block copolymers of polyethylene glycol and polypropylene glycol (such as poloxamer) and polyethoxylated tallow amine (POEA). In some embodiments, the surfactant is a nonionic surfactant comprising polyethylene glycol. In some embodiments, the surfactant is a block copolymer of polyethylene glycol and polypropylene glycol. In some embodiments, the surfactant comprises a poloxamer.

[0146] In some embodiments, the nonionic surfactant has a number average molecular weight of about 1000 to about 100,000Da, 2000 to about 20,000Da, about 4000 to about 15,000Da, about 6000 to about 12,000Da, or about 7000 to about 10,000Da. In some embodiments, the nonionic surfactant has a number average molecular weight of about 7000 to about 10,000Da. In some embodiments, the nonionic surfactant has an ethylene glycol content of about 30wt% to about 99wt%, about 50wt% to about 95wt%, about 60wt% to about 95wt%, about 75wt% to about 90wt%, or about 80wt% to about 85wt%. In some embodiments, the nonionic surfactant has an ethylene glycol content of about 80wt% to about 85wt%.

[0147] Surfactants used in the present disclosure may include cationic surfactants. Cationic surfactants include primary, secondary or tertiary amines that pH depends on, such as octenidine dihydrochloride; and permanently charged quaternary ammonium salts, such as cetrimide bromide (CTAB), cetylpyridinium chloride (CPC), benzalkonium chloride (BAC), benzethonium chloride (BZT), dimethyldioctadecyl ammonium chloride and dioctadecyl dimethyl ammonium bromide (DODAB).

[0148] Surfactant used in the present disclosure may include anionic surfactants. Anionic surfactants include anionic functional groups in their heads, such as sulfate, sulfonate, phosphate and carboxylate. Exemplary anionic surfactants include but are not limited to ammonium lauryl sulfate, sodium lauryl sulfate (sodium dodecyl sulfate, SLS or SDS) and related alkyl ether sulfates, sodium laureth sulfate (sodium lauryl ether sulfate or SLES), myristyl alcohol polyether sulfate, docusate (dioctyl sodium sulfosuccinate), perfluorooctane sulfonate (PFOS), perfluorobutane sulfonate, docusate sodium, alkyl-aryl ether phosphate and alkyl ether phosphate. In some embodiments, surfactant includes sodium lauryl sulfate (SLS).

[0149] The surfactant used in the present disclosure can be a zwitterionic surfactant. Zwitterionic (amphoteric) surfactants refer to surfactants having a cationic and anionic center connected to the same molecule. Exemplary zwitterionic surfactants include but are not limited to phospholipids phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine and sphingomyelin.

[0150] In some embodiments, the surfactant comprises a cationic surfactant, an anionic surfactant, a nonionic surfactant, or a combination thereof. In some embodiments, the surfactant comprises sodium lauryl sulfate (SLS). In some embodiments, the surfactant comprises poloxamer.

[0151] In some embodiments, one or more pharmaceutically acceptable excipients described herein comprise CTAB. In some embodiments, one or more pharmaceutically acceptable excipients described herein comprise SLS. In some embodiments, one or more pharmaceutically acceptable excipients described herein comprise docusate sodium. In some embodiments, one or more pharmaceutically acceptable excipients described herein comprise Tween 80. In some embodiments, one or more pharmaceutically acceptable excipients described herein comprise Tween 20. In some embodiments, one or more pharmaceutically acceptable excipients described herein comprise poloxamer.

[0152] In some embodiments, the solid formulations described herein include about 0.01wt% to about 10wt% of a surfactant. In some embodiments, the solid formulation includes about 0.02wt% to about 10wt% of a surfactant. In some embodiments, the solid formulation includes about 0.03wt% to about 10wt% of a surfactant. In some embodiments, the solid formulation includes about 0.04wt% to about 10wt% of a surfactant. In some embodiments, the solid formulation includes about 0.05wt% to about 10wt% of a surfactant. In some embodiments, the solid formulation includes about 0.1wt% to about 10wt% of a surfactant. In some embodiments, the solid formulation includes about 0.25wt% to about 10wt% of a surfactant. In some embodiments, the solid formulation includes about 0.5wt% to about 10wt% of a surfactant. In some embodiments, the solid formulation includes about 1wt% to about 10wt% of a surfactant. In some embodiments, the solid formulation includes about 2wt% to about 10wt% of a surfactant. In some embodiments, the solid formulation includes about 3wt% to about 10wt% of a surfactant. In some embodiments, the solid formulation comprises about 4wt% to about 10wt% of a surfactant. In some embodiments, the solid formulation comprises about 5wt% to about 10wt% of a surfactant. In some embodiments, the solid formulation comprises about 6wt% to about 10wt% of a surfactant. In some embodiments, the solid formulation comprises about 7wt% to about 10wt% of a surfactant. In some embodiments, the solid formulation comprises about 8wt% to about 10wt% of a surfactant. In some embodiments, the solid formulation comprises about 9wt% to about 10wt% of a surfactant. In some embodiments, the solid formulation comprises about 0.01wt% to about 9wt% of a surfactant. In some embodiments, the solid formulation comprises about 0.01wt% to about 8wt% of a surfactant. In some embodiments, the solid formulation comprises about 0.01wt% to about 7wt% of a surfactant. In some embodiments, the solid formulation comprises about 0.01wt% to about 6wt% of a surfactant. In some embodiments, the solid formulation comprises about 0.01wt% to about 5wt% of a surfactant. In some embodiments, the solid formulation comprises about 0.01wt% to about 4wt% of a surfactant. In some embodiments, the solid formulation comprises about 0.01wt% to about 3wt% of a surfactant. In some embodiments, the solid formulation comprises about 0.01wt% to about 2wt% of a surfactant. In some embodiments, the solid formulation comprises about 0.01wt% to about 1wt% of a surfactant. In some embodiments, the solid formulation comprises about 0.01wt% to about 0.5wt% of a surfactant.In some embodiments, the solid formulation comprises about 0.01wt% to about 0.25wt% of a surfactant. In some embodiments, the solid formulation comprises about 0.01wt% to about 0.1wt% of a surfactant. In some embodiments, the solid formulation is a powder. In some embodiments, the solid formulation is in the form of flakes, granules, or pellets.

[0153] In some embodiments, a solid formulation such as a pharmaceutical powder comprises about 0.01 wt%, about 0.02 wt%, about 0.03 wt%, about 0.04 wt%, about 0.05 wt%, 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, about 1.5 wt%, about 2 wt%, about 2.5 wt%, about 3 wt%, about 3.5 wt%, about 4 wt%, about 4.5 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, or about 10 wt% of a surfactant. In some embodiments, the solid formulation comprises at least 0.01 wt%, at least 0.02 wt%, at least 0.03 wt%, at least 0.04 wt%, at least 0.05 wt%, at least 0.1 wt%, at least 0.2 wt%, at least 0.3 wt%, at least 0.4 wt%, at least 0.5 wt%, at least 0.6 wt%, at least 0.7 wt%, at least 0.8 wt%, at least 0.9 wt%, at least 1 wt%, at least 1.1 wt%, at least 1.2 wt%, at least 1.3 wt%, at least 1.4 wt%, at least 1.5 wt%, at least 2 wt%, at least 2.5 wt%, at least 3 wt%, at least 3.5 wt%, at least 4 wt%, at least 4.5 wt%, at least 5 wt%, at least 6 wt%, at least 7 wt%, at least 8 wt%, at least 9 wt%, or at least 10 wt% of a surfactant. In some embodiments, the solid dosage form comprises at most 0.01 wt%, at most 0.02 wt%, at most 0.03 wt%, at most 0.04 wt%, at most 0.05 wt%, at most 0.1 wt%, at most 0.2 wt%, at most 0.3 wt%, at most 0.4 wt%, at most 0.5 wt%, at most 0.6 wt%, at most 0.7 wt%, at most 0.8 wt%, at most 0.9 wt%, at most In some embodiments, the solid formulation is a powder. In some embodiments, the solid formulation is in the form of flakes, granules or pellets.

[0154] In some embodiments, the suspension described herein comprises one or more pharmaceutically acceptable excipients as disclosed herein. In some embodiments, one or more pharmaceutically acceptable excipients comprise a surfactant. In some embodiments, the concentration of the surfactant in the suspension is from about 0.5 mg / mL to about 10 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is from about 1 mg / mL to about 10 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is from about 1.5 mg / mL to about 10 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is from about 2 mg / mL to about 10 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is from about 2.5 mg / mL to about 10 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is from about 3 mg / mL to about 10 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is from about 3.5 mg / mL to about 10 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is from about 4 mg / mL to about 10 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is about 4.5 mg / mL to about 10 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is about 5 mg / mL to about 10 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is about 6 mg / mL to about 10 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is about 7 mg / mL to about 10 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is about 8 mg / mL to about 10 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is about 9 mg / mL to about 10 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is about 0.5 mg / mL to about 10 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is about 0.5 mg / mL to about 9 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is about 0.5 mg / mL to about 8 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is about 0.5 mg / mL to about 7 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is about 0.5 mg / mL to about 6 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is about 0.5 mg / mL to about 5 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is about 0.5 mg / mL to about 4.5 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is about 0.5 mg / mL to about 4 mg / mL.In some embodiments, the concentration of the surfactant in the suspension is about 3.5 mg / mL to about 10 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is about 0.5 mg / mL to about 3 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is about 1 mg / mL to about 2.5 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is about 0.5 mg / mL to about 2.5 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is about 0.5 mg / mL to about 2 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is about 0.5 mg / mL to about 2 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is about 0.5 mg / mL to about 1 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is about 0.5 mg / mL, about 1 mg / mL, about 1.5 mg / mL, about 2 mg / mL, about 2.5 mg / mL, about 3 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, or about 10 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is at least 0.5 mg / mL, at least 1 mg / mL, at least 1.5 mg / mL, at least 2 mg / mL, at least 2.5 mg / mL, at least 3 mg / mL, at least 3.5 mg / mL, at least 4 mg / mL, at least 4.5 mg / mL, at least 5 mg / mL, at least 6 mg / mL, at least 7 mg / mL, at least 8 mg / mL, at least 9 mg / mL, or at least 10 mg / mL. In some embodiments, the concentration of the surfactant in the suspension is at most 0.5 mg / mL, at most 1 mg / mL, at most 1.5 mg / mL, at most 2 mg / mL, at most 2.5 mg / mL, at most 3 mg / mL, at most 3.5 mg / mL, at most 4 mg / mL, at most 4.5 mg / mL, at most 5 mg / mL, at most 6 mg / mL, at most 7 mg / mL, at most 8 mg / mL, at most 9 mg / mL, or at most 10 mg / mL.

[0155] In some embodiments, the pharmaceutical powders of the present disclosure comprise:

[0156] about 10 wt % to about 60 wt % of an amorphous solid dispersion comprising (i) about 40 wt % to about 60 wt % of Compound A and (ii) about 40 wt % to about 60 wt % of PVP-VA, wherein the amorphous solid dispersion is a hot melt extrudate;

[0157] about 30 wt % to about 70 wt % of a filler, wherein the filler comprises microcrystalline cellulose and mannitol;

[0158] about 0.1 wt % to 5 wt % of a surfactant, wherein the surfactant is SLS;

[0159] about 0.25 wt % to 6 wt % of a flow aid, wherein the flow aid is CSD; and

[0160] About 0.5 wt % to 5 wt % of an anti-foaming agent, wherein the anti-foaming agent is simethicone or dimethicone.

[0161] In some embodiments, the solid dosage form comprises:

[0162] (a) an amorphous solid dispersion comprising about 40 wt % to about 60 wt % of Compound A and about 40 wt % to about 60 wt % of PVP-VA, wherein the amorphous solid dispersion is a hot melt extrudate and is present in the solid formulation at about 40 wt % to about 60 wt %;

[0163] (b) about 30 wt % to 70 wt % of a filler, wherein the filler comprises microcrystalline cellulose and mannitol;

[0164] (c) about 0.1 wt % to 5 wt % of a surfactant, wherein the surfactant is SLS;

[0165] (d) about 0.25 wt% to 6 wt% of a flow aid, wherein the flow aid is CSD; and

[0166] (e) about 0.5 wt % to 5 wt % of an anti-foaming agent, wherein the anti-foaming agent is simethicone.

[0167] Sweeteners and flavorings

[0168] Solid formulations and / or liquid formulations described herein may include one or more sweeteners, one or more flavoring agents, or both. In some embodiments, one or more pharmaceutically acceptable excipients described herein include sweeteners. In some embodiments, one or more pharmaceutically acceptable excipients described herein include flavoring agents.

[0169] Sweeteners or sweeteners can include any compound that provides sweet taste to enhance the palatability of preparations, including natural and synthetic sugars and natural and synthetic non-sugar sweeteners. These can include glucose, fructose, sucrose or other pharmaceutically acceptable monosaccharides and disaccharides or sugar alcohols, such as xylitol. In addition, sweeteners can include maltodextrin, polydextrose etc. Other sweeteners can include glycerol, inulin, maltol, acesulfame potassium salt, alitame, aspartame, neotame, sodium cyclamate salt, sucralose, sorbitol solution, saccharin and salts thereof, and other artificial and naturally occurring agents that provide sweet taste individually or in combination.

[0170] Exemplary sweeteners include, but are not limited to, glucose, fructose, sucrose, xylitol, tagatose, sucralose, maltitol, isomalt, TM The sweeteners are hydrogenated isomaltulose, lactitol, sorbitol, erythritol, trehalose, maltodextrin, polydextrose, etc. sold in the market. Other sweeteners illustratively include glycerol, inulin, maltol, acesulfame potassium and its salts (e.g. acesulfame potassium), alitame, aspartame, neotame, sodium cyclamate, saccharin and its salts (e.g. saccharin sodium or saccharin calcium), neohesperidin dihydrochalcone, steviol glycosides, thaumatin, etc. The sweeteners can be used in the form of crude products or refined products (such as hydrogenated starch hydrolysate, maltitol syrup, high fructose corn syrup, etc.), and are used as brand products, for example, by Flavors of North America under the trademark Sweet Am TM A combination of propylene glycol, ethanol, and a proprietary artificial flavor sold as a liquid under the trademark Sweet Am TM The powder is sold as a combination of maltodextrin, sorbitol, and fructose under the product code 918.005 and is marketed by Flavors of North America under the trademark Sweet Am TM The powder is sold under product code 918.010 as a combination of water, propylene glycol, sorbitol, fructose and proprietary natural and artificial flavors and is marketed by Virginia Dare under the trademark ProSweet TM A combination of 1-10% proprietary plant / vegetable extracts and 90-99% dextrose sold by Ingredion under the trademark Maltisweet TM Maltitol solution is sold by SPI Polyols under the trademark Sorbo TM Sorbitol and sorbitol / xylitol solutions are sold by Ingredion under the trademark Invertose TM High fructose corn syrup sold by Tate and Lyle under the trademarks Rebalance M60 and X60, and combinations of sucralose and maltodextrin sold by Paddock Laboratories, Inc. under the trademarks and Sugar-containing and sugar-free flavored syrups are sold. Sweeteners can be used alone or in combinations of two or more. Suitable concentrations of different sweeteners can be selected based on published information, manufacturer's data sheets and by routine testing.

[0171] In some embodiments, solid formulations such as pharmaceutical powders described herein include sweeteners from about 0.01wt% to about 10wt%. In some embodiments, solid formulations such as pharmaceutical powders described herein optionally include sweeteners from about 0.01wt% to about 10wt%. In some embodiments, solid formulations include sweeteners from about 0.01wt% to about 5wt%. In some embodiments, solid formulations include sweeteners from about 0.01wt% to about 1wt%. In some embodiments, solid formulations include sweeteners from about 0.1wt% to about 0.5wt%. In some embodiments, solid formulations include sweeteners from about 0.2wt% to about 0.8wt%. In some embodiments, solid formulations include sweeteners from about 0.5wt% to about 0.6wt%. In some embodiments, solid formulations include sweeteners from about 0.6wt%.

[0172] In some embodiments, solid formulations described herein, such as pharmaceutical powders, contain about 0.01wt% to about 2wt% of flavoring agents. In some embodiments, solid formulations described herein, such as pharmaceutical powders, optionally contain about 0.01wt% to about 2wt% of flavoring agents. In some embodiments, solid formulations contain about 0.01wt% to about 2wt% of flavoring agents. In some embodiments, solid formulations contain about 0.001wt% to about 1wt% of flavoring agents. In some embodiments, solid formulations contain about 0.01wt% to about 0.5wt% of flavoring agents.

[0173] In some embodiments of the present disclosure, pharmaceutical compositions described herein, such as pharmaceutical powders and suspensions, comprise one or more sweeteners (e.g., sucralose and sorbitol solutions). In some embodiments, suspensions described herein comprise sweeteners present in an amount of about 0.01% w / v to about 30% w / v of a liquid formulation. In some embodiments, the sweetener comprises a mixture of two or more sweeteners. In some embodiments, the sweetener comprises sucralose. In some embodiments, the sweetener comprises sorbitol. In some embodiments, the sweetener comprises sucrose. In some embodiments, the suspensions described herein comprise 0.1%-14%, 0.2%-7%, 0.3%-5%, 0.35%-0.5%, 0.35%-1.0%, 0.35%-1.5%, 0.35%-2.0%, 0.35%-2.5%, 0.35%-3.0%, 0.35%-3.5%, 0.5%-1.0%, 0.5%-1.5%, 0.5%-2.0%, 0.5%-2.5%, 0.5%-3.0%, 0.5%-3.5%, 1.0%-1.5%, 1.0%-2.0% In some embodiments, the suspensions described herein comprise 0.1%-1% w / v of a sweetener or any range or value contemplated therein. In some embodiments, the suspensions described herein comprise 0.1%-1% w / v of a sweetener. In some embodiments, the suspension described herein comprises 0.05%-0.5% w / v sweetener. In some embodiments, the suspension described herein comprises 0.2%-0.8% w / v sweetener. In some embodiments, the sweetener or a combination of sweeteners is present in about 0.35% w / v to about 3.5% w / v. In some embodiments, the sweetener or a combination of sweeteners is present in the suspension in about 0.35% w / v to about 3.5% w / v, about 0.2% w / v to about 7.0% w / v, about 0.1% w / v to about 10% w / v, about 1% w / v to about 10% w / v, about 1% w / v to about 15% w / v, about 0.5% w / v to about 12% w / v or about 0.1% w / v to about 15% w / v.

[0174] In some embodiments, the suspension described herein comprises 0.1%-14% w / v sweetener. In some embodiments, the suspension described herein comprises 0.2%-7% w / v sweetener. In some embodiments, the suspension described herein comprises 0.35%-3.5% w / v sweetener. In some embodiments, the suspension described herein comprises 0.05%-0.5% w / v sweetener. In some embodiments, the suspension described herein comprises 0.15%-0.35% w / v sweetener. In some embodiments, the suspension described herein comprises 0.3%-5% w / v sweetener. In some embodiments, the suspension described herein comprises 0.35%-3.5% w / v sweetener. In some embodiments, the suspension described herein comprises 0.35%-3.0% w / v sweetener. In some embodiments, the suspension described herein comprises 0.5%-1.0% w / v sweetener. In some embodiments, the suspension described herein comprises 1.0%-2.5% w / v of sweetener. In some embodiments, the suspension described herein comprises 1.0%-2.5% w / v of sweetener. In some embodiments, the suspension described herein comprises 2.0%-4.0% w / v of sweetener. In some embodiments, the suspension described herein comprises 0.1%-5% w / v of sweetener. In some embodiments, the suspension described herein comprises 0.1%-15% w / v of sweetener. In some embodiments, the suspension described herein comprises 0.1%-10% w / v of sweetener. In some embodiments, the suspension described herein comprises 5%-15% w / v of sweetener. In some embodiments, the suspension described herein comprises 5%-25% w / v of sweetener. In some embodiments, the sweetener comprises sucralose. In some embodiments, the sweetener comprises sorbitol. In some embodiments, the sweetener comprises sucrose. In some embodiments, the sweetener includes glycyrrhizin.

[0175] In some embodiments, pharmaceutical compositions described herein, for example, pharmaceutical powders and suspensions, contain flavoring agents or flavoring agents to enhance the flavor or fragrance of the dosage and improve the overall palatability of the dosage, thereby helping to mask the flavor of the active ingredient that the patient may find unpleasant. This can provide an improved experience for the patient and better comply with the drug regimen desired by the clinician. Suitable natural or artificial flavors can be selected from pharmaceutically acceptable options described in standard pharmaceutical references as known to those skilled in the art. Suitable natural or synthetic flavors can be selected from standard reference books, such as Remington: The Science and Practice of Pharmacy (2000) and Fenaroli's Handbook of Flavor Ingredients (1994).

[0176] Non-limiting examples of suitable natural flavors (some of which can be easily simulated with synthetic agents or combinations thereof) include almonds, anise, apples, apricots, bananas, blackberries, black currants, blueberries, caramel, cherries, chocolate, cinnamon, cranberries, grapes, lemons, limes, oranges, mint, pineapples, raspberries, spearmint, strawberries, vanilla, etc. In some embodiments, flavors that can be easily simulated with synthetic agents or combinations thereof include fat, poultry, fish, beef, and other meats. In some embodiments, vanilla flavors are used. In some embodiments, mint flavors are used. In some embodiments, strawberry flavors (e.g., strawberry flavor CW08) are used. In other embodiments, other pharmaceutically acceptable flavors can be used to mask the flavors of other ingredients (e.g., other APIs), and enhance palatability, and therefore enhance compliance in a range of patient populations. In some embodiments, natural flavors can be natural or synthetic. In some embodiments, synthetic flavors are artificial flavors, such as artificial strawberry flavors. Natural and synthetic flavors can be used and adapted to the tastes of different patient populations, including but not limited to age and culturally related flavor preferences (e.g., bubble gum flavors for pediatric patients).

[0177] In some embodiments, solid formulations such as pharmaceutical powders described herein include about 0.01wt% to about 10wt% of flavoring agents. In some embodiments, solid formulations such as pharmaceutical powders described herein optionally include about 0.01wt% to about 10wt% of flavoring agents. In some embodiments, solid formulations include about 0.01wt% to about 5wt% of flavoring agents. In some embodiments, solid formulations include about 0.01wt% to about 1wt% of flavoring agents. In some embodiments, solid formulations include about 0.1wt% to about 0.5wt% of flavoring agents. In some embodiments, solid formulations include about 1wt% to about 2wt% of flavoring agents. In some embodiments, solid formulations include about 0.5wt% to about 2.5wt% of flavoring agents. In some embodiments, solid formulations include about 0.01wt% to about 2wt% of flavoring agents. In some embodiments, solid formulations include about 0.001wt% to about 1wt% of flavoring agents. In some embodiments, solid formulations include about 0.01wt% to about 0.5wt% of flavoring agents.

[0178] In some embodiments of the present disclosure, the pharmaceutical compositions described herein, e.g., pharmaceutical powders and suspensions, comprise one or more flavoring agents. In some embodiments, the suspensions described herein comprise a flavoring agent present at about 0.01% w / v to about 30% w / v of the liquid formulation. In some embodiments, the suspensions described herein comprise 0.1%-14%, 0.2%-7%, 0.3%-5%, 0.35%-0.5%, 0.35%-1.0%, 0.35%-1.5%, 0.35%-2.0%, 0.35%-2.5%, 0.35%-3.0%, 0.35%-3.5%, 0.5%-1.0%, 0.5%-1.5%, 0.5%-2.0%, 0.5%-2.5%, 0.5%-3.0%, 0.5%-3.5%, 1.0%-1.5%, 1.0%-2.0% %, 1.0%-2.5%, 1.0%-3.0%, 1.0%-3.5%, 1.5%-2.0%, 1.5%-2.5%, 1.5%-3.0%, 1.5%-3.5%, 1.5%-4.0%, 2.0%-2.5%, 2.0%-3.0%, 2.0%-3.5%, 2.0%-4.0%, 2.5%-3.0%, 2.5%-3.5%, 2.5%-4.0%, 3.0%-3.5%, 3.0%-4.0%, 3.5%-4.0% w / v flavoring agent or any range or value expected therein. In some embodiments, the suspensions described herein comprise 0.1%-1% w / v flavoring agent. In some embodiments, the suspensions described herein comprise 0.05%-0.5% w / v flavoring agent. In some embodiments, the suspension described herein comprises 0.2%-2% w / v of flavoring agent. In some embodiments, the flavoring agent or the combination of flavoring agents is present in about 0.35% w / v to about 3.5% w / v. In some embodiments, the flavoring agent or the combination of flavoring agents is present in the suspension in about 0.35% w / v to about 3.5% w / v, about 0.2% w / v to about 7.0% w / v, about 0.1% w / v to about 10% w / v, about 1% w / v to about 10% w / v, about 1% w / v to about 15% w / v, about 0.5% w / v to about 12% w / v or about 0.1% w / v to about 15% w / v.

[0179] Colorants

[0180] Solid preparation as herein described and / or liquid preparation can comprise one or more coloring agents.Many such medicaments are approved for use by the U.S. Food and Drug Administration, and are well known to the technical staff in the field of compound pharmacy.Suitable coloring agents approved by the U.S. Food and Drug Administration (FDA) include FD&C Red No. 3, FD&C Red No. 20, FD&C Red No. 40, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Yellow No. 10, caramel, iron oxide and mixtures thereof.

[0181] In situations where more than one oral dosage form is prepared, stored, transported or used, the use of pigments can enhance the aesthetic appearance of the dosage as well as provide confirmation of the identity of the drug. Enhancing the aesthetic appearance of the dosage increases the overall palatability of the dosage, which can provide benefits to patients and clinicians in terms of improving the patient experience and increasing compliance with the medication regimen. The ability to clearly identify medications in pharmacy, clinical and patient settings provides benefits to patients by reducing the scope for errors in the preparation, storage, handling, transportation and use of medications.

[0182] In some embodiments, solid formulations such as pharmaceutical powders described herein comprise from about 0.0001 wt% to about 1 wt% of a colorant. In some embodiments, solid formulations such as pharmaceutical powders described herein optionally comprise from about 0.0001 wt% to about 1 wt% of a colorant.

[0183] In some embodiments of the present disclosure, coloring agents include FD&C Red 40. However, any FDA-approved coloring agents are contemplated herein. In some embodiments, the concentration of coloring agents in suspension is 0.001%-0.1% w / v or any range or value therein. In some embodiments, the concentration of coloring agents in suspension is 0.001%-1%, 0.01%-2%, 0.002%-0.005%, 0.002%-0.004%, 0.002%-0.003% w / v or any range or value therein. In some embodiments, the concentration of coloring agents in suspension or pharmaceutical powder is less than 0.002%. In some embodiments, the concentration of coloring agents in suspension or pharmaceutical powder is greater than 0.005%. In some embodiments, liquid suspensions described herein include coloring agents of about 0.001%-1% w / v. In some embodiments, liquid suspensions described herein include coloring agents of about 0.01%-2% w / v. In some embodiments, the liquid suspensions described herein comprise about 0.002%-0.005% w / v colorant. In some embodiments, the liquid suspensions described herein comprise about 0.002%-0.003% w / v colorant. In some embodiments, the liquid suspensions described herein comprise about 0.002%-0.004% w / v colorant.

[0184] In some embodiments, the solid dosage forms described herein do not contain any colorants.

[0185] In some embodiments, the pH of the liquid suspension described herein is about 2 to 7. In certain aspects, the present disclosure provides an oral liquid suspension comprising: (a) (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof; (b) one or more pharmaceutically acceptable excipients; and (c) water.

[0186] In some embodiments, the suspension comprises, based on weight of solids:

[0187] (a) from about 10 wt % to about 50 wt % of an amorphous solid dispersion comprising:

[0188] (i) from about 40 wt % to about 60 wt % of Compound A; and

[0189] (ii) from about 40 wt % to about 60 wt % PVP-VA, wherein the amorphous solid dispersion is a hot melt extrudate;

[0190] (b) about 40 wt % to about 70 wt % of a filler, wherein the filler comprises microcrystalline cellulose and mannitol;

[0191] (c) from about 0.25 wt % to about 1 wt % of a surfactant, wherein the surfactant is SLS;

[0192] (d) from about 1 wt % to about 6 wt % of a flow aid, wherein the flow aid is colloidal silicon dioxide (CSD);

[0193] (e) about 1 wt % to about 10 wt % of a defoaming agent (e.g., about 1 wt % to about 5 wt % of a defoaming agent), wherein the defoaming agent comprises simethicone or is simethicone; and

[0194] (f) optionally preservatives, flavoring agents, sweeteners or combinations thereof.

[0195] In some embodiments, the anti-foaming agent comprises simethicone and maltodextrin. In some embodiments, the anti-foaming agent comprises simethicone (about 30 wt%) and maltodextrin (about 70 wt%).

[0196] In some embodiments, the suspension comprises a flavoring agent. In some embodiments, the suspension comprises strawberry flavor.

[0197] In some embodiments, the suspension comprises a sweetener. In some embodiments, the suspension comprises sucralose.

[0198] In some embodiments, the suspension comprises about 25 mg / mL of Compound A or a salt thereof. In some embodiments, the suspension comprises about 25 mg / mL of Compound A.

[0199] In some embodiments, the suspension comprises, based on weight of solids:

[0200] (a) about 10 wt % to 30 wt % (e.g., about 25 wt %) of an amorphous solid dispersion comprising:

[0201] (i) about 40 wt % of Compound A; and

[0202] (ii) about 60 wt % copovidone, wherein the amorphous solid dispersion is a hot melt extrudate;

[0203] (b) about 30 wt % to 32 wt % mannitol;

[0204] (c) about 30 wt % to 32 wt % microcrystalline cellulose;

[0205] (d) about 0.5 wt % to 1 wt % SLS;

[0206] (e) about 4 wt % to 5 wt % CSD;

[0207] (f) about 2 wt % to 3 wt % of a defoaming agent;

[0208] optionally a carrier for a defoaming agent;

[0209] and optionally preservatives, flavoring agents, sweeteners or combinations thereof.

[0210] In some embodiments, the suspension comprises, based on weight of solids:

[0211] (a) about 10 wt % to 30 wt % (e.g., about 25 wt %) of an amorphous solid dispersion comprising:

[0212] (i) about 40 wt % of Compound A; and

[0213] (ii) about 60 wt % copovidone, wherein the amorphous solid dispersion is a hot melt extrudate;

[0214] (b) about 30 wt % to 32 wt % mannitol;

[0215] (c) about 30 wt % to 32 wt % microcrystalline cellulose;

[0216] (d) about 0.5 wt % to 1 wt % SLS;

[0217] (e) about 4 wt % to 5 wt % CSD;

[0218] (f) about 2 wt % to 3 wt % of simethicone;

[0219] optionally a carrier for a defoaming agent;

[0220] and optionally preservatives, flavoring agents, sweeteners or combinations thereof.

[0221] In some embodiments, the suspension comprises one or more of the following components based on weight of solids:

[0222] (a) about 10 wt % to 30 wt % (e.g., about 25 wt %) of an amorphous solid dispersion comprising:

[0223] (i) about 40 wt % of Compound A; and

[0224] (ii) about 60 wt % of copovidone;

[0225] (b) about 20 wt % to 40 wt % mannitol;

[0226] (c) about 20 wt % to 40 wt % microcrystalline cellulose;

[0227] (d) about 0.1 wt % to 2 wt % SLS;

[0228] (e) about 1 wt % to 10 wt % CSD;

[0229] (f) about 1 wt % to 5 wt % of simethicone;

[0230] (g) about 1 wt % to 10 wt % maltodextrin;

[0231] and optionally preservatives, flavoring agents, sweeteners or combinations thereof.

[0232] In some embodiments, the suspension comprises one or more of the following components based on weight of solids:

[0233] (a) about 10 wt % to 30 wt % (e.g., about 25 wt %) of an amorphous solid dispersion comprising:

[0234] (i) about 40 wt % of Compound A; and

[0235] (ii) about 60 wt % of copovidone;

[0236] (b) about 20 wt % to 40 wt % mannitol;

[0237] (c) about 20 wt % to 40 wt % microcrystalline cellulose;

[0238] (d) about 0.1 wt % to 2 wt % SLS;

[0239] (e) about 1 wt % to 10 wt % CSD;

[0240] (f) about 1 wt % to 5 wt % of simethicone;

[0241] (g) about 1 wt % to 10 wt % maltodextrin;

[0242] (h) about 0.1 wt % to 5 wt % of a flavoring agent; and

[0243] (i) about 0.1 wt % to 5 wt % of a sweetener.

[0244] In some embodiments, the suspension comprises, based on weight of solids:

[0245] (a) about 10 wt % to 30 wt % (e.g., about 25 wt %) of an amorphous solid dispersion comprising:

[0246] (i) about 40 wt % of Compound A; and

[0247] (ii) about 60 wt % of copovidone;

[0248] (b) about 30 wt % to 32 wt % mannitol;

[0249] (c) about 30 wt % to 32 wt % microcrystalline cellulose;

[0250] (d) about 0.5 wt % to 1 wt % SLS;

[0251] (e) about 4 wt % to 5 wt % CSD;

[0252] (f) about 2 wt % to 3 wt % of simethicone;

[0253] (g) about 3 wt % to 8 wt % maltodextrin;

[0254] and optionally preservatives, flavoring agents, sweeteners or combinations thereof.

[0255] In some embodiments, the oral liquid suspension comprises a carrier for a defoamer. In some embodiments, the oral liquid suspension comprises a carrier for simethicone. In some embodiments, the carrier is starch. In some embodiments, the carrier is a filler. In some embodiments, the carrier is maltodextrin. In some embodiments, the carrier is present at about 1-15wt% based on the weight of the solid. In some embodiments, the carrier is present at about 1-10wt% based on the weight of the solid. In some embodiments, the carrier is present at about 2-8wt% based on the weight of the solid. In some embodiments, the carrier is present at about 4-6wt% based on the weight of the solid. In some embodiments, the carrier is present at about 5wt% based on the weight of the solid. In some embodiments, the weight ratio of the carrier to the defoamer is about 1:9 to 9:1. In some embodiments, the weight ratio of the carrier to the defoamer is about 1:4 to 4:1. In some embodiments, the weight ratio of the carrier to the defoamer is about 1:3 to 3:1. In some embodiments, the weight ratio of carrier to defoamer is about 8:3 to 6:3. In some embodiments, the weight ratio of carrier to defoamer is about 7:3.

[0256] In some embodiments, the oral liquid suspension is bioequivalent to a tablet formulation of Compound A or a pharmaceutically acceptable salt thereof, wherein the tablet composition comprises an amorphous solid dispersion comprising (i) about 40 wt % of Compound A and (ii) about 60 wt % of copovidone, wherein the amorphous solid dispersion is a hot melt extrudate; and one or more pharmaceutically acceptable excipients disclosed herein.

[0257] Pharmaceutical compositions (including pharmaceutical powders and oral formulations) can be formulated using one or more physiologically acceptable carriers (including excipients and adjuvants) that facilitate processing of the medicament into a pharmaceutically useful preparation. Suitable formulations depend on the chosen route of administration. An overview of pharmaceutical compositions can be found in, for example, Remington: The Science and Practice of Pharmacy, 19th Edition (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins, 1999).

[0258] Pharmaceutically acceptable excipients can include physiologically acceptable agents, which act, for example, to stabilize, increase solubility or increase the absorption of compounds (such as medicaments). Such physiologically acceptable agents include, for example, carbohydrates (such as glucose, sucrose or dextran), antioxidants (such as ascorbic acid or glutathione), chelating agents, low molecular weight proteins or other stabilizers or excipients. The selection of pharmaceutically acceptable excipients (including physiologically acceptable agents) depends on, for example, the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) can also be a liposome or other polymer matrix, in which a compound of the present invention can be incorporated, for example. For example, the liposome comprising phospholipids or other lipids is a nontoxic, physiologically acceptable and metabolizable carrier, and its preparation and application are relatively simple.

[0259] Pharmaceutical compositions (including pharmaceutical powders and oral preparations thereof) can be sterile aqueous or non-aqueous solutions, suspensions or emulsions, such as microemulsions. The excipients described herein are exemplary and by no means limiting. An effective amount or therapeutically effective amount refers to the amount of one or more medicaments administered to a subject as a single dose or as part of a series of doses, which is effective to produce the desired therapeutic effect.

[0260] The dosage of the drug powder and oral formulation thereof as described herein for treating a disease or condition can depend on the condition of the subject, i.e., the stage of the disease, the severity of the symptoms caused by the disease, general health, and age, sex, and weight, as well as other factors obvious to a medical technician. The pharmaceutical composition can be administered in a manner suitable for the disease to be treated as determined by a medical technician. In addition to the factors associated with the use of medicaments to treat a disease or condition as described herein and above, the appropriate duration and frequency of administration of the medicament can also be determined or adjusted by factors such as the condition of the patient, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. Experimental models and / or clinical trials can usually be used to determine the optimal dose of the agent. The optimal dose can depend on the body mass, body weight, or blood volume of the subject. It is generally preferred to use the minimum dose sufficient to provide an effective therapy. The design and execution of preclinical studies and clinical studies of the medicaments described herein, including when administered for the benefit of prevention, are completely within the skill range of the technicians in the relevant field. When two or more medicaments are administered to treat a disease or condition, the optimal dose of each medicament can be different, such as less than the dose when any one agent is administered alone as a single agent therapy. In some specific embodiments, the combination of two medicaments can work synergistically or additively, and any reagent can be used with less amount than when used alone.The amount of the medicament that can be used every day can be, for example, between about 0.01mg / kg body weight and 100mg / kg body weight, for example, between about 0.1 to 1mg / kg body weight, between about 1 to 10mg / kg body weight, between about 10-50mg / kg body weight, between about 50-100mg / kg body weight.In other embodiments, the amount of the medicament that can be used every day is between about 0.01mg / kg body weight and 1000mg / kg body weight, between about 100-500mg / kg body weight, or between about 500-1000mg / kg body weight.The optimum dose every day or each course of treatment can be different because of disease to be treated or illness, and can also change with route of administration and treatment regimen.

[0261] In-use and long-term stability

[0262] In one aspect, provided herein is an oral liquid suspension that is stable during reconstitution and use. In certain cases, an oral liquid suspension comprising an amorphous solid dispersion of Compound A and PVP-VA or a salt thereof tends to coagulate and / or form a viscous gel immediately after reconstitution, making it difficult for patients to accurately measure and administer the liquid formulation. Surprisingly, it was found that certain pharmaceutical excipients and combinations thereof reduce and slow the formation of gels, thereby improving the in-use stability of the oral liquid suspension.

[0263] In some embodiments, the suspension remains injectable for at least 15 minutes. In some embodiments, the suspension remains injectable for at least 30 minutes. In some embodiments, the suspension remains injectable for at least 5 minutes. In some embodiments, the suspension remains injectable for at least 10 minutes. In some embodiments, the suspension remains injectable for at least 20 minutes. In some embodiments, the suspension remains injectable for at least 25 minutes. In some embodiments, injectability is tested at room temperature.

[0264] In one aspect, provided herein is a solid form pharmaceutical formulation (e.g., a pharmaceutical powder) that is stable after long-term storage. In some embodiments, the solid form pharmaceutical formulation (e.g., a pharmaceutical powder) described herein retains at least 90% of the initial amount of compound A or its pharmaceutically acceptable salt after storage for 3 months at 20±5°C. In some embodiments, the solid form pharmaceutical formulation (e.g., a pharmaceutical powder) described herein retains at least 90% of the initial amount of compound A or its pharmaceutically acceptable salt after storage for 6 months at 20±5°C. In some embodiments, the solid form pharmaceutical formulation (e.g., a pharmaceutical powder) described herein retains at least 90% of the initial amount of compound A or its pharmaceutically acceptable salt after storage for 12 months at 20±5°C. In some embodiments, the solid form pharmaceutical formulation (e.g., a pharmaceutical powder) described herein retains at least 90% of the initial amount of compound A or its pharmaceutically acceptable salt after storage for 18 months at 20±5°C. In some embodiments, the solid form pharmaceutical formulation (e.g., a pharmaceutical powder) described herein retains at least 90% of the initial amount of compound A or its pharmaceutically acceptable salt after storage for 24 months at 20±5°C. In some embodiments, the amount of Compound A, or a pharmaceutically acceptable salt thereof, in the solid form pharmaceutical formulation is determined by HPLC.

[0265] In some embodiments, the solid form pharmaceutical formulations (e.g., pharmaceutical powders) described herein retain at least 90% of the initial amount of Compound A or its pharmaceutically acceptable salt after storage at 5±3°C for 3 months. In some embodiments, the solid form pharmaceutical formulations (e.g., pharmaceutical powders) described herein retain at least 90% of the initial amount of Compound A or its pharmaceutically acceptable salt after storage at 5±3°C for 6 months. In some embodiments, the solid form pharmaceutical formulations (e.g., pharmaceutical powders) described herein retain at least 90% of the initial amount of Compound A or its pharmaceutically acceptable salt after storage at 5±3°C for 12 months. In some embodiments, the solid form pharmaceutical formulations (e.g., pharmaceutical powders) described herein retain at least 90% of the initial amount of Compound A or its pharmaceutically acceptable salt after storage at 5±3°C for 18 months. In some embodiments, the solid form pharmaceutical formulations (e.g., pharmaceutical powders) described herein retain at least 90% of the initial amount of Compound A or its pharmaceutically acceptable salt after storage at 5±3°C for 24 months.

[0266] In some embodiments, the solid form pharmaceutical formulations (e.g., pharmaceutical powders) described herein retain at least 90% of the initial amount of Compound A or its pharmaceutically acceptable salt after storage for 3 months at about 40°C. In some embodiments, the solid form pharmaceutical formulations (e.g., pharmaceutical powders) described herein retain at least 90% of the initial amount of Compound A or its pharmaceutically acceptable salt after storage for 6 months at about 40°C. In some embodiments, the solid form pharmaceutical formulations (e.g., pharmaceutical powders) described herein retain at least 90% of the initial amount of Compound A or its pharmaceutically acceptable salt after storage for 12 months at about 40°C. In some embodiments, the solid form pharmaceutical formulations (e.g., pharmaceutical powders) described herein retain at least 90% of the initial amount of Compound A or its pharmaceutically acceptable salt after storage for 18 months at about 40°C. In some embodiments, the solid form pharmaceutical formulations (e.g., pharmaceutical powders) described herein retain at least 90% of the initial amount of Compound A or its pharmaceutically acceptable salt after storage for 24 months at about 40°C.

[0267] In some embodiments, the solid form pharmaceutical formulations (e.g., pharmaceutical powders) described herein retain at least 95% of the initial amount of Compound A or its pharmaceutically acceptable salt after storage for 3 months at 20±5°C. In some embodiments, the solid form pharmaceutical formulations (e.g., pharmaceutical powders) described herein retain at least 95% of the initial amount of Compound A or its pharmaceutically acceptable salt after storage for 6 months at 20±5°C. In some embodiments, the solid form pharmaceutical formulations (e.g., pharmaceutical powders) described herein retain at least 95% of the initial amount of Compound A or its pharmaceutically acceptable salt after storage for 12 months at 20±5°C. In some embodiments, the solid form pharmaceutical formulations (e.g., pharmaceutical powders) described herein retain at least 95% of the initial amount of Compound A or its pharmaceutically acceptable salt after storage for 18 months at 20±5°C. In some embodiments, the solid form pharmaceutical formulations (e.g., pharmaceutical powders) described herein retain at least 95% of the initial amount of Compound A or its pharmaceutically acceptable salt after storage for 24 months at 20±5°C.

[0268] In some embodiments, the solid form pharmaceutical formulations (e.g., pharmaceutical powders) described herein retain at least 95% of the initial amount of Compound A or its pharmaceutically acceptable salt after storage at 5±3°C for 3 months. In some embodiments, the solid form pharmaceutical formulations (e.g., pharmaceutical powders) described herein retain at least 95% of the initial amount of Compound A or its pharmaceutically acceptable salt after storage at 5±3°C for 6 months. In some embodiments, the solid form pharmaceutical formulations (e.g., pharmaceutical powders) described herein retain at least 95% of the initial amount of Compound A or its pharmaceutically acceptable salt after storage at 5±3°C for 12 months. In some embodiments, the solid form pharmaceutical formulations (e.g., pharmaceutical powders) described herein retain at least 95% of the initial amount of Compound A or its pharmaceutically acceptable salt after storage at 5±3°C for 18 months. In some embodiments, the solid form pharmaceutical formulations (e.g., pharmaceutical powders) described herein retain at least 95% of the initial amount of Compound A or its pharmaceutically acceptable salt after storage at 5±3°C for 24 months.

[0269] In some embodiments, the solid form pharmaceutical formulations (e.g., pharmaceutical powders) described herein retain at least 95% of the initial amount of Compound A or its pharmaceutically acceptable salt after storage for 3 months at about 40°C. In some embodiments, the solid form pharmaceutical formulations (e.g., pharmaceutical powders) described herein retain at least 95% of the initial amount of Compound A or its pharmaceutically acceptable salt after storage for 6 months at about 40°C. In some embodiments, the solid form pharmaceutical formulations (e.g., pharmaceutical powders) described herein retain at least 95% of the initial amount of Compound A or its pharmaceutically acceptable salt after storage for 12 months at about 40°C. In some embodiments, the solid form pharmaceutical formulations (e.g., pharmaceutical powders) described herein retain at least 95% of the initial amount of Compound A or its pharmaceutically acceptable salt after storage for 18 months at about 40°C. In some embodiments, the solid form pharmaceutical formulations (e.g., pharmaceutical powders) described herein retain at least 95% of the initial amount of Compound A or its pharmaceutically acceptable salt after storage for 24 months at about 40°C.

[0270] Method for preparing oral preparations

[0271] In certain aspects, the present invention provides a method for preparing an aqueous formulation, the method comprising: (a) providing a solid formulation of an amorphous solid dispersion, wherein the amorphous solid dispersion comprises:

[0272] (i) (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof, and

[0273] (ii) one or more polymers; and

[0274] (b) contacting the solid preparation with an aqueous solution.

[0275] In some embodiments, the solid formulation is a pharmaceutical powder as disclosed herein. In some embodiments, contacting includes mixing the solid formulation with an aqueous solution to form a suspension. In some embodiments, mixing includes shaking the solid formulation and the aqueous solution to form a suspension. In some embodiments, mixing includes adding the solid formulation to a container comprising an aqueous solution and then shaking the container to form a suspension. In some embodiments, the container is a container as described herein. In some embodiments, the container is shaken in all directions. In some embodiments, wherein mixing or shaking continues until all solid formulations are dispersed in the aqueous solution.

[0276] In some embodiments, mixing lasts from about 10 seconds to about 240 seconds. Mixing lasts from about 10 seconds to about 60 seconds, from about 60 seconds to about 120 seconds, from about 40 seconds to about 80 seconds, or from about 50 seconds to about 70 seconds. In some embodiments, mixing lasts from about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 seconds, about 60 seconds, about 65 seconds, about 70 seconds, about 75 seconds, about 80 seconds, about 85 seconds, about 90 seconds, about 95 seconds, about 100 seconds, about 105 seconds, about 110 seconds, about 115 seconds, or about 120 seconds. In some embodiments, mixing continues for at least 10 seconds, at least 15 seconds, at least 20 seconds, at least 25 seconds, at least 30 seconds, at least 35 seconds, at least 40 seconds, at least 45 seconds, at least 50 seconds, at least 55 seconds, at least 60 seconds, at least 65 seconds, at least 70 seconds, at least 75 seconds, at least 80 seconds, at least 85 seconds, at least 90 seconds, at least 95 seconds, at least 100 seconds, at least 105 seconds, at least 110 seconds, at least 115 seconds, or at least 120 seconds. In some embodiments, mixing lasts for at most 10 seconds, at most 15 seconds, at most 20 seconds, at most 25 seconds, at most 30 seconds, at most 35 seconds, at most 40 seconds, at most 45 seconds, at most 50 seconds, at most 55 seconds, at most 60 seconds, at most 65 seconds, at most 70 seconds, at most 75 seconds, at most 80 seconds, at most 85 seconds, at most 90 seconds, at most 95 seconds, at most 100 seconds, at most 105 seconds, at most 110 seconds, at most 115 seconds, or at most 120 seconds. In some embodiments, mixing lasts for 60 seconds. In some embodiments, mixing lasts for no more than about 120 seconds.

[0277] In some embodiments, shaking lasts from about 10 seconds to about 240 seconds. Mixing lasts from about 10 seconds to about 60 seconds, from about 60 seconds to about 120 seconds, from about 40 seconds to about 80 seconds, or from about 50 seconds to about 70 seconds. In some embodiments, shaking lasts from about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 seconds, about 60 seconds, about 65 seconds, about 70 seconds, about 75 seconds, about 80 seconds, about 85 seconds, about 90 seconds, about 95 seconds, about 100 seconds, about 105 seconds, about 110 seconds, about 115 seconds, or about 120 seconds. In some embodiments, mixing continues for at least 10 seconds, at least 15 seconds, at least 20 seconds, at least 25 seconds, at least 30 seconds, at least 35 seconds, at least 40 seconds, at least 45 seconds, at least 50 seconds, at least 55 seconds, at least 60 seconds, at least 65 seconds, at least 70 seconds, at least 75 seconds, at least 80 seconds, at least 85 seconds, at least 90 seconds, at least 95 seconds, at least 100 seconds, at least 105 seconds, at least 110 seconds, at least 115 seconds, or at least 120 seconds. In some embodiments, the shaking lasts for at most 10 seconds, at most 15 seconds, at most 20 seconds, at most 25 seconds, at most 30 seconds, at most 35 seconds, at most 40 seconds, at most 45 seconds, at most 50 seconds, at most 55 seconds, at most 60 seconds, at most 65 seconds, at most 70 seconds, at most 75 seconds, at most 80 seconds, at most 85 seconds, at most 90 seconds, at most 95 seconds, at most 100 seconds, at most 105 seconds, at most 110 seconds, at most 115 seconds, or at most 120 seconds. In some embodiments, the shaking lasts for 60 seconds. In some embodiments, the shaking lasts for no more than about 120 seconds.

[0278] In some embodiments, mixing or shaking occurs in increments. In some embodiments, mixing or shaking occurs in increments of 5 seconds, 10 seconds, 15 seconds, 20 seconds, 25 seconds, or 30 seconds. In some embodiments, mixing or shaking occurs in increments of about 5 seconds, about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, or about 30 seconds. In some embodiments, mixing or shaking occurs in increments of 15 seconds.

[0279] In some embodiments, the method further comprises allowing the container to stand for a period of time without mixing or shaking. In some embodiments, the period of time is about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, or about 30 minutes.

[0280] In some embodiments, the method further comprises inverting the container and continuing to mix the suspension. In some embodiments, the inverting container comprises vortexing for about 10 seconds to about 60 seconds, about 20 seconds to about 40 seconds, about 40 seconds to about 80 seconds, or about 15 seconds to about 45 seconds. In some embodiments, the vortexing lasts for about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 seconds, about 60 seconds, about 65 seconds, about 70 seconds, about 75 seconds, or about 80 seconds.

[0281] In some embodiments, the aqueous solution is at high temperature or close to room temperature. In some embodiments, the aqueous solution is close to room temperature. In some embodiments, the aqueous solution has a temperature of about 15°C to about 80°C, about 20°C to about 60°C, or about 20°C to about 50°C. In some embodiments, the aqueous solution has a temperature of about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, or about 85°C. In some embodiments, the aqueous solution has a temperature of at least 15°C, at least 20°C, at least 25°C, at least 30°C, at least 35°C, at least 40°C, at least 45°C, at least 50°C, at least 55°C, at least 60°C, at least 65°C, at least 70°C, at least 75°C, at least 80°C, or at least 85°C. In some embodiments, the aqueous solution has a temperature of at most 15°C, at most 20°C, at most 25°C, at most 30°C, at most 35°C, at most 40°C, at most 45°C, at most 50°C, at most 55°C, at most 60°C, at most 65°C, at most 70°C, at most 75°C, at most 80°C, or at most 85°C. In some embodiments, the aqueous solution is warm water or room temperature water. In some embodiments, the aqueous solution is warm water. In some embodiments, the aqueous solution is room temperature water.

[0282] In some embodiments, the volume of the aqueous solution is about 5 mL to about 200 mL, about 5 mL to 100 mL, about 5 mL to 50 mL, about 5 mL to 25 mL, about 5 mL to 20 mL, about 10 mL to 50 mL, about 10 mL to 25 mL, about 25 mL to 50 mL, about 25 mL to 150 mL, or about 10 mL to about 20 mL. In some embodiments, the volume of the aqueous solution is about 5 mL, about 10 mL, about 15 mL, about 20 mL, about 25 mL, about 30 mL, about 35 mL, about 40 mL, about 45 mL, about 50 mL, about 60 mL, about 70 mL, about 80 mL, about 90 mL, about 100 mL, about 125 mL, about 150 mL, about 175 mL, or about 200 mL. In some embodiments, the volume of the aqueous solution is about 10 mL, about 11 mL, about 12 mL, about 13 mL, about 14 mL, about 15 mL, about 16 mL, about 17 mL, about 18 mL, about 19 mL, or about 20 mL. In some embodiments, the volume of the aqueous solution is about 14 mL.

[0283] In some embodiments, the method further comprises withdrawing the suspension from the container with a syringe. In some embodiments, the suspension is administered directly to the subject from the syringe.

[0284] In some embodiments, an aqueous formulation as disclosed herein is administered with food, before consuming food, or after consuming food. In some embodiments, the aqueous formulation is administered with food. In some embodiments, the aqueous formulation is administered before the subject consumes food. In some embodiments, the aqueous formulation is administered after the subject consumes food.

[0285] Reagent test kit

[0286] In certain aspects, the present disclosure provides a kit comprising a pharmaceutical powder or pharmaceutical composition for reconstitution as disclosed herein. In some embodiments, the pharmaceutical powder or pharmaceutical composition in the kit is reconstituted using a preparation method as disclosed herein.

[0287] In certain aspects, the present disclosure provides a method for preparing an oral liquid suspension of Compound A or a salt thereof, the method comprising reconstituting a solid formulation in a kit as disclosed herein in an aqueous solution.

[0288] In certain aspects, the present disclosure provides a method for preparing an oral liquid suspension of Compound A or a salt thereof, the method comprising reconstituting a pharmaceutical powder as disclosed herein in an aqueous solution.

[0289] In another aspect, the present disclosure provides a method for treating cancer in a subject, the method comprising reconstructing a solid formulation in a kit as disclosed herein, and applying the reconstructed formulation to a subject in need thereof. For compositions of compound A or a pharmaceutically acceptable salt thereof as described herein, including powder and liquid compositions, kits and articles are also described. Such kits may include a carrier, a package or a container, which is separated to accommodate one or more containers (such as vials, tubes, bottles, etc.), each container including one of the independent elements to be used in the methods described herein, including solid formulations or liquid formulations. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The container can be formed of a variety of materials such as glass or plastic (e.g., HDPE).

[0290] In some embodiments, the test kit includes one or more containers, which optionally include a mark indicating the measured value of the volume. In some embodiments, the test kit includes a container, which optionally includes a mark indicating the measured value of the volume. In some embodiments, the test kit includes 1-10 containers, which optionally include a mark indicating the measured value of the volume. In some embodiments, the test kit includes 1,2,3,4,5,6,7,8,9 or 10 containers, which optionally include a mark indicating the measured value of the volume. In some embodiments, the container is reusable after each use. In some embodiments, the container is disposable after use.

[0291] The kit may include one or more additional containers, each container having one or more of the various materials (such as reagents, optionally in concentrated form, and / or devices) required from a commercial and user standpoint for use in the solid or liquid formulations described herein. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; carriers, packages, containers, vials, and / or tube labels listing the contents and / or instructions for use, and package inserts with instructions for use associated with the solid or liquid formulation. A set of instructions may also be included. In some embodiments, the kit includes a set of instructions, such as Figure 1 In some embodiments, the kit may include a dosing syringe and / or a dispensing syringe. In some embodiments, the kit includes a bottle adapter.

[0292] The label may be on or associated with the container. The label may be on the container when the letters, numbers or other characters forming the label are attached, molded or etched into the container itself; the label may be associated with the container when the label is present in a receptacle or carrier that also holds the container, such as as a package insert. The label may be used to indicate that the contents are to be used for a specific therapeutic application. The label may also indicate directions for use of the contents, such as in the methods described herein.

[0293] In some embodiments, the syringe in the kit is used to transfer a predetermined amount of a liquid preparation comprising Compound A or a pharmaceutically acceptable salt thereof from a container to form a suspension. The suspension can be prepared by dispersing Compound A or a pharmaceutically acceptable salt thereof in a powdered form into a single-use reconstitution medium of a predetermined volume or in a bottle used multiple times. The patient's personal dose can be applied by using a dosing syringe. The suspension in the syringe can be directly administered to the child's mouth.

[0294] In certain aspects, the present disclosure provides a kit comprising (a) a solid formulation of an amorphous solid dispersion of (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof, wherein the solid formulation comprises one or more pharmaceutically acceptable excipients; and (b) instructions for aqueous reconstitution of the solid formulation. Figure 1 An example of such instructions is shown in . In some embodiments, the instructions for aqueous reconstitution are in the form of a reference referring to the instructions.

[0295] In some embodiments, the solid formulation is in the form of a powder, granules or pellets. In some embodiments, the solid formulation is in the form of a powder. In some embodiments, the solid formulation is in the form of granules. In some embodiments, the solid formulation is in the form of pellets. In some embodiments, the solid formulation is a tablet, wherein the tablet is orange, film-coated and oval, and is concavely engraved with "100" on one side and concavely engraved with "D101" on the opposite side. In some embodiments, the solid formulation is in the form of a powder, wherein the powder is white to off-white, and is further reconstituted with water to form a uniform, flavored white suspension at a concentration of 25 mg / mL.

[0296] In some embodiments, the kit of the present disclosure includes one or more of the following: a solid formulation of compound A or a pharmaceutically acceptable salt thereof, instructions for aqueous reconstitution of the solid formulation, a bottle, a bottle cap, a bottle adapter and / or a syringe. In some embodiments, the kit includes a solid formulation of compound A or a pharmaceutically acceptable salt thereof, instructions for aqueous reconstitution of the solid formulation, a bottle, a bottle cap, a bottle adapter and a syringe. The syringe can be a dosing syringe with a mark indicating the volume of the liquid therein. The syringe can be optionally packaged separately, for example, in a plastic bag. In some embodiments, the solid formulation of compound A or a pharmaceutically acceptable salt thereof is contained in a bottle, which can be sealed with a bottle cap and / or a seal. In some embodiments, the bottle is configured to contain at least 25mL, at least 50mL, at least 75mL, at least 100mL, at least 125mL, at least 150mL or at least 200mL of liquid volume. In some embodiments, the bottle is configured to contain a liquid volume of about 25mL to about 75mL. In some embodiments, the bottle is configured to contain a liquid volume of about 15mL to about 50mL. In some embodiments, the bottle is configured to include a liquid volume of about 50mL to about 150mL. In some embodiments, the bottle is configured to include a liquid volume of about 100mL to about 200mL. In some embodiments, the bottle adapter is configured to fit into a bottleneck and allow the tip of the syringe to be inserted into the hole of the bottle adapter. In some embodiments, the bottle adapter is configured to allow the syringe to extract liquid from the bottle without overflowing or leaking. In some embodiments, the kit of the present disclosure includes a solid preparation (e.g., drug powder) of 1mg to 5000mg of compound A or its pharmaceutically acceptable salt. In some embodiments, the kit includes a solid preparation (e.g., drug powder) of about 100mg to about 1000mg containing compound A. In some embodiments, the kit includes a solid preparation (e.g., drug powder) of about 300mg to about 600mg containing compound A. In some embodiments, the kit includes a solid preparation (e.g., drug powder) of about 100mg to about 200mg containing compound A. In some embodiments, the kit contains about 500mg to about 1500mg of a solid preparation (e.g., a pharmaceutical powder) comprising Compound A. In some embodiments, the kit contains about 200mg to about 800mg of a solid preparation (e.g., a pharmaceutical powder) comprising Compound A. In some embodiments, the kit contains about 400mg to about 450mg of a solid preparation (e.g., a pharmaceutical powder) comprising Compound A. In some embodiments, the kit contains about 400mg to about 500mg of a solid preparation (e.g., a pharmaceutical powder) comprising Compound A. In some embodiments, the kit contains about 430mg of a solid preparation (e.g., a pharmaceutical powder) comprising Compound A.In some embodiments, the kit contains about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, or about 650 mg of a solid formulation (e.g., a pharmaceutical powder) comprising Compound A.

[0297] Drug administration

[0298] Kits with unit doses of one or more agents described herein are provided, typically oral doses or injectable doses. Such kits may include a container containing the unit dose, an information package insert describing the use of the drug in treating the disease and the attendant benefits, and optionally an implement or device for delivering the composition.

[0299] Described herein are solid and liquid formulations of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, solid and liquid formulations of Compound A or a pharmaceutically acceptable salt thereof are used as a unit dose.

[0300] The present disclosure provides a kit with one or more unit doses. The unit dose contains a certain amount of solid preparations (drug powders) as disclosed herein. In some embodiments, the kit contains multiple unit doses, each unit dose containing compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the kit contains a unit dose, which contains compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the kit contains a single dose, which contains compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the kit contains two or more unit doses, which contain compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the kit contains 1-10 unit doses, each unit dose containing compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the kit contains 1-5 unit doses, each unit dose containing compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the kit contains 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 unit doses, each unit dose containing compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the unit dose is a pediatric dose.

[0301] In some embodiments, each unit dose contains about 25 mg to about 1000 mg of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, each unit dose contains about 25 mg to about 900 mg of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, each unit dose contains about 25 mg to about 800 mg of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, each unit dose contains about 25 mg to about 700 mg of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, each unit dose contains about 25 mg to about 600 mg of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, each unit dose contains about 25 mg to about 500 mg of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, each unit dose contains about 25 mg to about 400 mg of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, each unit dose contains about 25 mg to about 300 mg of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, each unit dose contains about 25 mg to about 200 mg of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, each unit dose contains about 25 mg to about 100 mg of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, each unit dose contains about 100 mg to about 1000 mg of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, each unit dose contains about 200 mg to about 1000 mg of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, each unit dose contains about 300 mg to about 1000 mg of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, each unit dose contains about 400 mg to about 1000 mg of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, each unit dose contains about 500 mg to about 1000 mg of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, each unit dose contains about 600 mg to about 1000 mg of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, each unit dose contains about 700 mg to about 1000 mg of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, each unit dose contains about 800 mg to about 1000 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, each unit dose contains about 900 mg to about 1000 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, each unit dose contains about 200 mg to about 900 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, each unit dose contains about 300 mg to about 800 mg of Compound A or a pharmaceutically acceptable salt thereof.In some embodiments, each unit dose contains about 400 mg to about 700 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, each unit dose contains about 500 mg to about 600 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, each unit dose contains about 400 mg to about 600 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, each unit dose contains about 300 mg to about 600 mg of Compound A or a pharmaceutically acceptable salt thereof.

[0302] In some embodiments, each unit dose contains about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, each unit dose contains at least 25, at least 50 mg, at least 100 mg, at least 150 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg, at least 400 mg, at least 450 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, or at least 1000 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, each unit dose contains at most 25 mg, at most 50 mg, at most 100 mg, at most 150 mg, at most 200 mg, at most 250 mg, at most 300 mg, at most 350 mg, at most 400 mg, at most 450 mg, at most 500 mg, at most 600 mg, at most 700 mg, at most 800 mg, at most 900 mg or at most 1000 mg of Compound A or a pharmaceutically acceptable salt thereof.

[0303] In some embodiments, if a weekly dose is missed by 3 days or less, the missed dose should be taken as soon as possible and the next dose should be taken on a normal day. In some embodiments, if a weekly dose is missed by more than 3 days, the missed dose should be skipped and the next dose should be taken on a normal day. In some embodiments, a minimum of four days should be allowed between doses.

[0304] In some embodiments, the dose is not co-administered with a strong or moderate CYP2C8 inhibitor. In some embodiments, the dose is not co-administered with a strong or moderate CYP2C8 inducer. In some embodiments, the dose is not co-administered with a sensitive CYP3A4 substrate. In some embodiments, the dose is not co-administered with a BCRP substrate. In some embodiments, the dose is not administered to a pregnant subject. In some embodiments, the dose is not administered to a lactating subject. In some embodiments, the dose is not administered to a subject with liver damage.

[0305] Oral preparations for treating cancer

[0306] In certain aspects, the present disclosure provides methods of treating cancer in a subject, the method comprising administering to the subject a pharmaceutical powder as disclosed herein or a reconstituted oral liquid formulation as disclosed herein.

[0307] In certain aspects, the present disclosure provides a method of treating cancer, comprising administering to a subject an oral liquid suspension comprising (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof to achieve a specified pharmacokinetic profile. During or after administration of the oral liquid suspension, the plasma concentration of (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof can be determined using a validated bioanalytical assay. For example, where appropriate, the following pharmacokinetic (PK) parameters can be calculated: maximum observed plasma concentration (Cmax) and area under the concentration versus time curve from time 0 to t (AUC 0-t ).

[0308] In certain aspects, the present disclosure provides methods of treating cancer, comprising administering to a subject an oral liquid suspension comprising (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve a maximum observed plasma concentration (Cmax) of at least 2000 ng / mL of Compound A in the subject. In some embodiments, the oral liquid suspension is reconstituted from a solid formulation described herein (e.g., a pharmaceutical powder comprising Compound A or a pharmaceutically acceptable salt thereof).

[0309] Pharmacokinetic parameters

[0310] In some embodiments, the oral liquid suspension comprising Compound A, or a pharmaceutically acceptable salt thereof, is administered in an amount sufficient to achieve a maximum observed plasma concentration (Cmax) of Compound A of at least 100 ng / mL, at least 200 ng / mL, at least 300 ng / mL, at least 400 ng / mL, at least 500 ng / mL, at least 1000 ng / mL, at least 1500 ng / mL, at least 2000 ng / mL, at least 2500 ng / mL, at least 3000 ng / mL, at least 3500 ng / mL, at least 4000 ng / mL, at least 4500 ng / mL, at least 5000 ng / mL, at least 5500 ng / mL, at least 6000 ng / mL, at least 6500 ng / mL, at least 7000 ng / mL, at least 7500 ng / mL, or at least 8000 ng / mL in a subject. In some embodiments, the oral liquid suspension comprising Compound A, or a pharmaceutically acceptable salt thereof, is administered in an amount sufficient to achieve a maximum observed plasma concentration (Cmax) of Compound A in a subject of at most 100 ng / mL, at most 200 ng / mL, at most 300 ng / mL, at most 400 ng / mL, at most 500 ng / mL, at most 1000 ng / mL, at most 1500 ng / mL, at most 2000 ng / mL, at most 2500 ng / mL, at most 3000 ng / mL, at most 3500 ng / mL, at most 4000 ng / mL, at most 4500 ng / mL, at most 5000 ng / mL, at most 5500 ng / mL, at most 6000 ng / mL, at most 6500 ng / mL, at most 7000 ng / mL, at most 7500 ng / mL, or at most 8000 ng / mL.

[0311] In some embodiments, the oral liquid suspension comprising Compound A, or a pharmaceutically acceptable salt thereof, is administered in an amount sufficient to achieve a maximum observed plasma concentration (Cmax) of Compound A in a subject of about 100 ng / mL, about 200 ng / mL, about 300 ng / mL, about 400 ng / mL, about 500 ng / mL, about 1000 ng / mL, about 1500 ng / mL, about 2000 ng / mL, about 2500 ng / mL, about 3000 ng / mL, about 3500 ng / mL, about 4000 ng / mL, about 4500 ng / mL, about 5000 ng / mL, about 5500 ng / mL, about 6000 ng / mL, about 6500 ng / mL, about 7000 ng / mL, about 7500 ng / mL, or about 8000 ng / mL. In some embodiments, an oral liquid suspension comprising Compound A or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve a Cmax of Compound A within a suitable range in a subject. In some embodiments, Cmax is from about 100 ng / mL to about 8,000 ng / mL. In some embodiments, Cmax is from about 100 ng / mL to about 2,000 ng / mL. In some embodiments, Cmax is from about 2,000 ng / mL to about 8,000 ng / mL. In some embodiments, Cmax is at least about 100 ng / mL. In some embodiments, Cmax is at least about 200 ng / mL. In some embodiments, Cmax is at least about 300 ng / mL. In some embodiments, Cmax is at least about 400 ng / mL. In some embodiments, Cmax is at least about 500 ng / mL. In some embodiments, Cmax is at least about 1000 ng / mL. In some embodiments, Cmax is at least about 2,000 ng / mL. In some embodiments, Cmax is at least about 3,000 ng / mL. In some embodiments, the Cmax is at least about 4,000 ng / mL. In some embodiments, the Cmax is at least about 5,000 ng / mL. In some embodiments, the Cmax is at least about 6,000 ng / mL. In some embodiments, the Cmax is at least about 7,000 ng / mL. In some embodiments, the Cmax is up to about 8,000 ng / mL.

[0312] In some embodiments, the oral liquid suspension comprising Compound A or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve a Cmax of Compound A in a subject of about 100 ng / mL to about 300 ng / mL, about 100 ng / mL to about 500 ng / mL, about 100 ng / mL to about 1,000 ng / mL, about 100 ng / mL to about 1,500 ng / mL, about 100 ng / mL to about 2,000 ng / mL, about 100 ng / mL to about 2,500 ng / mL, about 100 ng / mL to about 3,000 ng / mL, about 100 ng / mL to about 3,500 ng / mL, about 100 ng / mL to about 4,000 ng / mL. ng / mL, about 100 ng / mL to about 4,500 ng / mL, about 100 ng / mL to about 5,000 ng / mL, about 100 ng / mL to about 5,500 ng / mL, about 100 ng / mL to about 6,000 ng / mL, about 100 ng / mL to about 6,500 ng / mL, about 100 ng / mL to about 7,000 ng / mL, about 100 ng / mL to about 8,000 ng / mL, about 2,000 ng / mL to about 2,500 ng / mL, about 2,000 ng / mL to about 3,000 ng / mL, about 2,000 ng / mL to about 3,500 ng / mL, about 2,000 ng / mL to about 4,000 ng / mL, ng / mL, about 2,000 ng / mL to about 4,500 ng / mL, about 2,000 ng / mL to about 5,000 ng / mL, about 2,000 ng / mL to about 5,500 ng / mL, about 2,000 ng / mL to about 6,000 ng / mL, about 2,000 ng / mL to about 6,500 ng / mL, about 2,000 ng / mL to about 7,000 ng / mL, about 2,000 ng / mL to about 8,000 ng / mL, about 2,500 ng / mL to about 3,000 ng / mL, about 2,500 ng / mL to about 3,500 ng / mL, about 2,500 ng / mL to about 4,000 ng / mL, about 2,5 ng / mL to about 4,000 ng / mL, about 2,500 ng / mL to about 5,000 ng / mL, about 2,500 ng / mL to about 5,500 ng / mL, about 2,500 ng / mL to about 6,000 ng / mL, about 2,500 ng / mL to about 6,500 ng / mL, about 2,500 ng / mL to about 7,000 ng / mL, about 2,500 ng / mL to about 8,000 ng / mL, about 3,000 ng / mL to about 3,500 ng / mL, about 3,000 ng / mL to about 4,000 ng / mL, about 3,000 ng / mL to about 4,500 ng / mL, about 3,000 ng / mL to about 5,000 ng / mL,ng / mL, about 3,000 ng / mL to about 5,500 ng / mL, about 3,000 ng / mL to about 6,000 ng / mL, about 3,000 ng / mL to about 6,500 ng / mL, about 3,000 ng / mL to about 7,000 ng / mL, about 3,000 ng / mL to about 8,000 ng / mL, about 3,500 ng / mL to about 4,000 ng / mL, about 3,500 ng / mL to about 4,500 ng / mL, about 3,500 ng / mL to about 5,000 ng / mL, about 3,500 ng / mL to about 5,500 ng / mL, about 3,500 ng / mL to about 6,000 ng / mL , about 3,500 ng / mL to about 6,500 ng / mL, about 3,500 ng / mL to about 7,000 ng / mL, about 3,500 ng / mL to about 8,000 ng / mL, about 4,000 ng / mL to about 4,500 ng / mL, about 4,000 ng / mL to about 5,000 ng / mL, about 4,000 ng / mL to about 5,500 ng / mL, about 4,000 ng / mL to about 6,000 ng / mL, about 4,000 ng / mL to about 6,500 ng / mL, about 4,000 ng / mL to about 8,000 ng / mL, about 4,500 ng / mL ng / mL to about 5,000 ng / mL, about 4,500 ng / mL to about 5,500 ng / mL, about 4,500 ng / mL to about 6,000 ng / mL, about 4,500 ng / mL to about 6,500 ng / mL, about 4,500 ng / mL to about 7,000 ng / mL, about 4,500 ng / mL to about 8,000 ng / mL, about 5,000 ng / mL to about 5,500 ng / mL, about 5,000 ng / mL to about 6,000 ng / mL, about 5,000 ng / mL to about 6,500 ng / mL, about 5,000 ng / mL to about 7,000 ng / mL, about 5,000 ng / mL to about 8,000 ng / mL. ng / mL, about 5,500 ng / mL to about 6,000 ng / mL, about 5,500 ng / mL to about 6,500 ng / mL, about 5,500 ng / mL to about 7,000 ng / mL, about 5,500 ng / mL to about 8,000 ng / mL, about 6,000 ng / mL to about 6,500 ng / mL, about 6,000 ng / mL to about 7,000 ng / mL, about 6,000 ng / mL to about 8,000 ng / mL, about 6,500 ng / mL to about 7,000 ng / mL, about 6,500 ng / mL to about 8,000 ng / mL, or about 7,000 ng / mL to about 8,000 ng / mL.

[0313] In some embodiments, the oral liquid suspension comprising Compound A or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve a specified AUC level of Compound A. In some embodiments, the area under the concentration versus time curve (AUC) from time 0 to t is measured in a subject administered Compound A or a pharmaceutically acceptable salt thereof. 0-t ) or AUCss (steady-state AUC). In some embodiments, AUC 0-t AUC 0-12 (or AUC0-12h), AUC 0-24 (or AUC0-24h) or AUC 0-48 (or AUC0-48h). In some embodiments, AUC 0-t AUC 0-24 In some embodiments, the AUC is AUCss.

[0314] In some embodiments, an oral liquid suspension comprising Compound A or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve a specified steady-state AUC (AUCss) in a subject. In some embodiments, an oral liquid suspension comprising Compound A or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve an AUCss of at least about 100,000 ng*h / mL of Compound A in a subject. In some embodiments, the AUCss is at least about 200,000 ng*h / mL. In some embodiments, the AUCss is at least about 300,000 ng*h / mL. In some embodiments, an oral liquid suspension comprising Compound A or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve an AUCss of at least about 400,000 ng*h / mL of Compound A in a subject. In some embodiments, the AUCss is at least about 500,000 ng*h / mL. In some embodiments, the AUCss is at least about 600,000 ng*h / mL. In some embodiments, the AUCss is at least about 400,000 ng*h / mL to at least about 800,000 ng*h / mL. In some embodiments, the AUCss is at least about 500,000 ng*h / mL to at least about 700,000 ng*h / mL. In some embodiments, the AUCss is at least about 300,000 ng*h / mL to at least about 800,000 ng*h / mL. In some embodiments, the AUCss is at least about 200,000 ng*h / mL to at least about 800,000 ng*h / mL. In some embodiments, the AUCss is about 100,000 ng*h / mL to about 800,000 ng*h / mL. In some embodiments, the AUCss is at most about 600,000 ng*h / mL. In some embodiments, the AUCss is at most about 800,000 ng*h / mL. In some embodiments, the AUCss is at most about 1,000,000 ng*h / mL. In some embodiments, the AUCss is at most about 1,200,000 ng*h / mL. In some embodiments, the AUCss is at most about 1,600,000 ng*h / mL.

[0315] In some embodiments, an oral liquid suspension comprising Compound A or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve an AUCss of Compound A in a subject of about 100,000 ng*h / mL to about 1,600,000 ng*h / mL, about 100,000 ng*h / mL to about 1,000,000 ng*h / mL, about 100,000 ng*h / mL to about 800,000 ng*h / mL, about 100,000 ng*h / mL to about 600,000 ng*h / mL, 200,000 ng*h / mL to about 400,000 ng*h / mL, about 100,000 ng*h / mL to about 600,000 ng*h / mL, about 100,000 ng*h / mL to about 800,000 ng*h / mL, about 100,000 ng*h / mL to about 700,000 ng*h / mL, about 100,000 ng*h / mL to about 800,000 ng*h / mL, about 100,000 ng*h / mL to about 900,000 ng*h / mL, about 100,000 ng*h / mL to about 1,600,000 ng*h / mL, about 100,000 ng*h / mL to about 1,000,000 ng*h / mL, about 100,000 ng*h / mL to about g*h / mL to about 1,600,000 ng*h / mL, about 200,000 ng*h / mL to about 1,000,000 ng*h / mL, about 200,000 ng*h / mL to about 800,000 ng*h / mL, about 200,000 ng*h / mL to about 600,000 ng*h / mL, 300,000 ng*h / mL to about 1,600,000 ng*h / mL, about 300,000 ng*h / mL to about 1,000,000 ng*h / mL, about 300,000 ng*h / mL to about 800,000 ng*h / mL, about 300,000 ng*h / mL to about 600,000 ng*h / mL, 400,000 ng*h / mL to about 1,600,000 ng*h / mL, about 400,000 ng*h / mL to about 1,000,000 ng*h / mL, about 400,000 ng*h / mL to about 800,000 ng*h / mL, about 400,000 ng*h / mL to about 600,000 ng*h / mL, 500,000 ng*h / mL to about 1,600,000 ng*h / mL, about 500,000 ng*h / mL to about 1,000,000 ng*h / mL, about 500,000 ng*h / mL to about 800,000 ng*h / mL, about 500,000 ng*h / mL to about 600,000 ng*h / mL, 600,000 ng*h / mL to about 1,600,000 ng*h / mL, about 600,000 ng*h / mL to about 1,000,000 ng*h / mL or about 600,000 ng*h / mL to about 800,000 ng*h / mL.

[0316] In some embodiments, an oral liquid suspension comprising Compound A or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve an AUCss of Compound A in a subject of about 300,000 ng*h / mL to about 450,000 ng*h / mL, about 300,000 ng*h / mL to about 500,000 ng*h / mL, about 300,000 ng*h / mL to about 550,000 ng*h / mL, about 300,000 ng*h / mL to about 650,000 ng*h / mL, about 350,000 ng*h / mL to about 750,000 ng*h / mL, about 400,000 ng*h / mL to about 650,000 ng*h / mL, about 400,000 ng*h / mL to about 750,000 ng*h / mL, about 400,000 ng*h / mL to about 850,000 ng*h / mL, about 400,000 ng*h / mL to about 950,000 ng*h / mL, or about 400,000 ng*h / mL to about 1,000,000 ng*h / mL.

[0317] In some embodiments, the oral liquid suspension comprises Compound A or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve a specified AUC in a subject. 0-t In some embodiments, AUC 0-t AUC 0-24 In some embodiments, the oral liquid suspension comprises Compound A or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve an AUC of Compound A of at least about 10,000 ng*h / mL in a subject. 0-24 In some embodiments, the oral liquid suspension comprising Compound A or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve an AUC of Compound A of at least about 50,000 ng*h / mL in a subject. 0-24 In some embodiments, the oral liquid suspension comprising Compound A or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve an AUC of Compound A of at least about 100,000 ng*h / mL in a subject. 0-24 In some embodiments, AUC 0-24 In some embodiments, AUC 0-24 In some embodiments, AUC 0-24 is at least about 100,000 ng*h / mL. In some embodiments, AUC 0-24 Up to about 600,000 ng*h / mL.

[0318] In some embodiments, the oral liquid suspension comprises Compound A or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve an AUC of Compound A in a subject. 0-24 The amount administered, the AUC 0-24about 100,000 ng*h / mL to about 150,000 ng*h / mL, about 100,000 ng*h / mL to about 200,000 ng*h / mL, about 100,000 ng*h / mL to about 250,000 ng*h / mL, about 100,000 ng*h / mL to about 300,000 ng*h / mL, about 100,000 ng*h / mL to about 350,000 ng*h / mL, about 100,000 ng*h / mL to about 400,000 ng*h / mL, about 100,000 ng*h / mL to about 450,000 ng*h / mL, about 100,000 ng*h / mL to about 500,000 ng*h / mL ng*h / mL, about 100,000 ng*h / mL to about 550,000 ng*h / mL, about 100,000 ng*h / mL to about 600,000 ng*h / mL, about 150,000 ng*h / mL to about 200,000 ng*h / mL, about 150,000 ng*h / mL to about 250,000 ng*h / mL, about 150,000 ng*h / mL to about 300,000 ng*h / mL, about 150,000 ng*h / mL to about 350,000 ng*h / mL, about 150,000 ng*h / mL to about 400,000 ng*h / mL, about 150,000 ng*h / mL to about 4 50,000 ng*h / mL, about 150,000 ng*h / mL to about 500,000 ng*h / mL, about 150,000 ng*h / mL to about 550,000 ng*h / mL, about 150,000 ng*h / mL to about 600,000 ng*h / mL, about 200,000 ng*h / mL to about 250,000 ng*h / mL, about 200,000 ng*h / mL to about 300,000 ng*h / mL, about 200,000 ng*h / mL to about 350,000 ng*h / mL, about 200,000 ng*h / mL to about 400,000 ng*h / mL, about 200,000 ng*h / mL to about h / mL to about 450,000 ng*h / mL, about 200,000 ng*h / mL to about 500,000 ng*h / mL, about 200,000 ng*h / mL to about 550,000 ng*h / mL, about 200,000 ng*h / mL to about 600,000 ng*h / mL, about 250,000 ng*h / mL to about 300,000 ng*h / mL, about 250,000 ng*h / mL to about 350,000 ng*h / mL, about 250,000 ng*h / mL to about 400,000 ng*h / mL, about 250,000 ng*h / mL to about 450,000 ng*h / mL, about 250,000 ng*h / mL to about 500,000 ng*h / mL, about 250,000 ng*h / mL to about 550,000 ng*h / mL, about 250,000 ng*h / mL to about 600,000 ng*h / mL, about 300,000 ng*h / mL to about 350,000 ng*h / mL, about 300,000 ng*h / mL to about 400,000 ng*h / mL, about 300,000 ng*h / mL to about 450,000 ng*h / mL, about 30 0,000 ng*h / mL to about 500,000 ng*h / mL, about 300,000 ng*h / mL to about 550,000 ng*h / mL, about 300,000 ng*h / mL to about 600,000 ng*h / mL, about 350,000 ng*h / mL to about 400,000 ng*h / mL, about 350,000 ng*h / mL to about 450,000 ng*h / mL, about 350,000 ng*h / mL to about 500,000 ng*h / mL, about 3 50,000 ng*h / mL to about 550,000 ng*h / mL, about 350,000 ng*h / mL to about 600,000 ng*h / mL, about 400,000 ng*h / mL to about 450,000 ng*h / mL, about 400,000 ng*h / mL to about 500,000 ng*h / mL, about 400,000 ng*h / mL to about 550,000 ng*h / mL, about 400,000 ng*h / mL to about 600,000 ng*h / mL, about 450,000 ng*h / mL to about 500,000 ng*h / mL, about 450,000 ng*h / mL to about 550,000 ng*h / mL, about 450,000 ng*h / mL to about 600,000 ng*h / mL, about 500,000 ng*h / mL to about 550,000 ng*h / mL, about 500,000 ng*h / mL to about 600,000 ng*h / mL, or about 550,000 ng*h / mL to about 600,000 ng*h / mL. ,

[0319] In some embodiments, the oral liquid suspension comprises Compound A or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve a specified AUC in a subject. 0-∞ In some embodiments, the AUC of Compound A is 0-∞ In some embodiments, the AUC of Compound A is about 250 μg·h / L to about 1,600 μg·h / L. 0-∞ In some embodiments, the AUC of Compound A is at least about 250 μg·h / L. 0-∞In some embodiments, the AUC of Compound A is 0-∞The present invention comprises about 250 μg·h / L to about 350 μg·h / L, about 250 μg·h / L to about 450 μg·h / L, about 250 μg·h / L to about 550 μg·h / L, about 250 μg·h / L to about 650 μg·h / L, about 250 μg·h / L to about 750 μg·h / L, about 250 μg·h / L to about 850 μg·h / L, about 250 μg·h / L to about 950 μg·h / L, about 250 μg·h / L to about 1,000 μg·h / L, about 250 μg·h / L to about 1,250 μg·h / L, about 250 μg·h / L to about 1,500 μg·h / L, about 250 μg·h / L to about 1,600 μg·h / L, about 350μg·h / L to about 450μg·h / L, about 350μg·h / L to about 550μg·h / L, about 350μg·h / L to about 650μg·h / L, about 350μg·h / L to about 750μg·h / L, about 350μg·h / L to about 850μg·h / L, about 350μg·h / L to about 950μg·h / L, about 350μg·h / L to about 1,000μg·h / L, about 350μg·h / L to about 1,250μg·h / L, about 350μg·h / L to about 1,500μg·h / L, about 350μg·h / L to about 1,600μg·h / L, about 450μg·h / L to about 550μg·h / L, about 450μg·h / L to about 650μg·h / L, about 450μg·h / L to about 750μg·h / L, about 450μg·h / L to about 850μg·h / L, about 450μg·h / L to about 950μg·h / L, about 450μg·h / L to about 1,000μg·h / L, about 450μg·h / L to about 1,250μg·h / L, about 450μg·h / L to about 1,500μg·h / L, about 450μg·h / L to about 1,600μg·h / L, about 550μg·h / L to about 650μg·h / L, about 550μg·h / L to about 750μg·h / L, about 550μg·h / L to about 850μg·h / L h / L, about 550μg·h / L to about 950μg·h / L, about 550μg·h / L to about 1,000μg·h / L, about 550μg·h / L to about 1,250μg·h / L, about 550μg·h / L to about 1,500μg·h / L, about 550μg·h / L to about 1,600μg·h / L, about 650μg·h / L to about 750μg·h / L, about 650μg·h / L to about 850μg·h / L, about 650μg·h / L to about 950μg·h / L, about 650μg·h / L to about 1,000μg·h / L, about 650μg·h / L to about 1,250μg·h / L, about 650μg·h / L to about 1,500μg·h / L, about 650μg·h / L to about 1,600μg·h / L, about 750μg·h / L to about 850μg·h / L, about 750μg·h / L to about 950μg·h / L, about 750μg·h / L to about 1,000μg·h / L, about 750μg·h / L to about 1,250μg·h / L, about 750μg·h / L about 1,500 μg·h / L, about 750 μg·h / L to about 1,600 μg·h / L, about 850 μg·h / L to about 950 μg·h / L, about 850 μg·h / L to about 1,000 μg·h / L, about 850 μg·h / L to about 1,250 μg·h / L, about 850 μg·h / L to about 1,500 μg·h / L, about 850 μg·h / L to about 1,600μg·h / L, about 950μg·h / L to about 1,000μg·h / L, about 950μg·h / L to about 1,250μg·h / L, about 950μg·h / L to about 1,500μg·h / L, about 950μg·h / L to about 1,600μg·h / L, about 1,000μg·h / L to about 1,250μg·h / L g·h / L, about 1,000μg·h / L to about 1,500μg·h / L, about 1,000μg·h / L to about 1,600μg·h / L, about 1,250μg·h / L to about 1,500μg·h / L, about 1,250μg·h / L to about 1,600μg·h / L, or about 1,500μg·h / L to about 1,600μg·h / L. ,

[0320] In some embodiments, the oral liquid suspension, when administered to a human subject in an amount equivalent to about 100 mg of Compound A, is sufficient to achieve a maximum observed plasma concentration (Cmax) of Compound A in the subject of at least 100 ng / mL. In some embodiments, the oral liquid suspension is sufficient to achieve a maximum observed plasma concentration (Cmax) of Compound A of at least 100 ng / mL, at least 200 ng / mL, at least 300 ng / mL, at least 400 ng / mL, at least 500 ng / mL, at least 1000 ng / mL, at least 1,500 ng / mL, at least 2000 ng / mL, at least 2500 ng / mL, at least 3000 ng / mL, at least 3500 ng / mL, at least 4000 ng / mL, at least 4500 ng / mL, at least 5000 ng / mL, at least 5500 ng / mL, at least 6000 ng / mL, at least 6500 ng / mL, at least 7000 ng / mL, at least 7500 ng / mL, or at least 8000 ng / mL in the subject when administered to a human subject in an amount equivalent to about 100 mg of Compound A. In some embodiments, the oral liquid suspension is sufficient to achieve a maximum observed plasma concentration (Cmax) of Compound A in the subject of at most 100 ng / mL, at most 200 ng / mL, at most 300 ng / mL, at most 400 ng / mL, at most 500 ng / mL, at most 1000 ng / mL, at most 1,500 ng / mL, at most 2000 ng / mL, at most 2500 ng / mL, at most 3000 ng / mL, at most 3500 ng / mL, at most 4000 ng / mL, at most 4500 ng / mL, at most 5000 ng / mL, at most 5500 ng / mL, at most 6000 ng / mL, at most 6500 ng / mL, at most 7000 ng / mL, at most 7500 ng / mL, or at most 8000 ng / mL when administered to a human subject in an amount equivalent to about 100 mg of Compound A. In some embodiments, the oral liquid suspension is sufficient to achieve a maximum observed plasma concentration (Cmax) of Compound A in the subject of about 100 ng / mL, about 200 ng / mL, about 300 ng / mL, about 400 ng / mL, about 500 ng / mL, about 1000 ng / mL, about 1,500 ng / mL, about 2000 ng / mL, about 2500 ng / mL, about 3000 ng / mL, about 3500 ng / mL, about 4000 ng / mL, about 4500 ng / mL, about 5000 ng / mL, about 5500 ng / mL, about 6000 ng / mL, about 6500 ng / mL, about 7000 ng / mL, about 7500 ng / mL, or about 8000 ng / mL when administered to a human subject in an amount equivalent to about 100 mg of Compound A.

[0321] In some embodiments, the oral liquid suspension, when administered to a human subject in an amount equivalent to about 75 mg of Compound A, is sufficient to achieve a maximum observed plasma concentration (Cmax) of Compound A in the subject of at least 100 ng / mL. In some embodiments, the oral liquid suspension is sufficient to achieve a maximum observed plasma concentration (Cmax) of Compound A of at least 100 ng / mL, at least 200 ng / mL, at least 300 ng / mL, at least 400 ng / mL, at least 500 ng / mL, at least 1000 ng / mL, at least 1,500 ng / mL, at least 2000 ng / mL, at least 2500 ng / mL, at least 3000 ng / mL, at least 3500 ng / mL, at least 4000 ng / mL, at least 4500 ng / mL, at least 5000 ng / mL, at least 5500 ng / mL, at least 6000 ng / mL, at least 6500 ng / mL, at least 7000 ng / mL, at least 7500 ng / mL, or at least 8000 ng / mL in the subject when administered to a human subject in an amount equivalent to about 75 mg of Compound A. In some embodiments, the oral liquid suspension is sufficient to achieve a maximum observed plasma concentration (Cmax) of Compound A in a human subject of at most 100 ng / mL, at most 200 ng / mL, at most 300 ng / mL, at most 400 ng / mL, at most 500 ng / mL, at most 1000 ng / mL, at most 1,500 ng / mL, at most 2000 ng / mL, at most 2500 ng / mL, at most 3000 ng / mL, at most 3500 ng / mL, at most 4000 ng / mL, at most 4500 ng / mL, at most 5000 ng / mL, at most 5500 ng / mL, at most 6000 ng / mL, at most 6500 ng / mL, at most 7000 ng / mL, at most 7500 ng / mL, or at most 8000 ng / mL when administered to a human subject in an amount equivalent to about 75 mg of Compound A. In some embodiments, the oral liquid suspension is sufficient to achieve a maximum observed plasma concentration (Cmax) of Compound A in a human subject of about 100 ng / mL, about 200 ng / mL, about 300 ng / mL, about 400 ng / mL, about 500 ng / mL, about 1000 ng / mL, about 1,500 ng / mL, about 2000 ng / mL, about 2500 ng / mL, about 3000 ng / mL, about 3500 ng / mL, about 4000 ng / mL, about 4500 ng / mL, about 5000 ng / mL, about 5500 ng / mL, about 6000 ng / mL, about 6500 ng / mL, about 7000 ng / mL, about 7500 ng / mL, or about 8000 ng / mL when administered to a human subject in an amount equivalent to about 75 mg of Compound A.

[0322] In some embodiments, the oral liquid suspension, when administered to a human subject in an amount equivalent to about 50 mg of Compound A, is sufficient to achieve a maximum observed plasma concentration (Cmax) of Compound A in the subject of at least about 2000 ng / mL. In some embodiments, the oral liquid suspension is sufficient to achieve a maximum observed plasma concentration (Cmax) of Compound A of at least 100 ng / mL, at least 200 ng / mL, at least 300 ng / mL, at least 400 ng / mL, at least 500 ng / mL, at least 1000 ng / mL, at least 1,500 ng / mL, at least 2000 ng / mL, at least 2500 ng / mL, at least 3000 ng / mL, at least 3500 ng / mL, at least 4000 ng / mL, at least 4500 ng / mL, at least 5000 ng / mL, at least 5500 ng / mL, at least 6000 ng / mL, at least 6500 ng / mL, at least 7000 ng / mL, at least 7500 ng / mL, or at least 8000 ng / mL in the subject when administered to a human subject in an amount equivalent to about 50 mg of Compound A. In some embodiments, the oral liquid suspension is sufficient to achieve a maximum observed plasma concentration (Cmax) of Compound A in a human subject of at most 100 ng / mL, at most 200 ng / mL, at most 300 ng / mL, at most 400 ng / mL, at most 500 ng / mL, at most 1000 ng / mL, at most 1,500 ng / mL, at most 2000 ng / mL, at most 2500 ng / mL, at most 3000 ng / mL, at most 3500 ng / mL, at most 4000 ng / mL, at most 4500 ng / mL, at most 5000 ng / mL, at most 5500 ng / mL, at most 6000 ng / mL, at most 6500 ng / mL, at most 7000 ng / mL, at most 7500 ng / mL, or at most 8000 ng / mL when administered to a human subject in an amount equivalent to about 50 mg of Compound A. In some embodiments, the oral liquid suspension is sufficient to achieve a maximum observed plasma concentration (Cmax) of Compound A in a human subject of about 100 ng / mL, about 200 ng / mL, about 300 ng / mL, about 400 ng / mL, about 500 ng / mL, about 1000 ng / mL, about 1,500 ng / mL, about 2000 ng / mL, about 2500 ng / mL, about 3000 ng / mL, about 3500 ng / mL, about 4000 ng / mL, about 4500 ng / mL, about 5000 ng / mL, about 5500 ng / mL, about 6000 ng / mL, about 6500 ng / mL, about 7000 ng / mL, about 7500 ng / mL, or about 8000 ng / mL when administered to a human subject in an amount equivalent to about 50 mg of Compound A.

[0323] In some embodiments, the oral liquid suspension, when administered to a human subject in an amount equivalent to about 25 mg of Compound A, is sufficient to achieve a maximum observed plasma concentration (Cmax) of Compound A in the subject of at least about 100 ng / mL. In some embodiments, the oral liquid suspension is sufficient to achieve a maximum observed plasma concentration (Cmax) of Compound A of at least 100 ng / mL, at least 200 ng / mL, at least 300 ng / mL, at least 400 ng / mL, at least 500 ng / mL, at least 1000 ng / mL, at least 1,500 ng / mL, at least 2000 ng / mL, at least 2500 ng / mL, at least 3000 ng / mL, at least 3500 ng / mL, at least 4000 ng / mL, at least 4500 ng / mL, at least 5000 ng / mL, at least 5500 ng / mL, at least 6000 ng / mL, at least 6500 ng / mL, at least 7000 ng / mL, at least 7500 ng / mL, or at least 8000 ng / mL in the subject when administered to a human subject in an amount equivalent to about 25 mg of Compound A. In some embodiments, the oral liquid suspension is sufficient to achieve a maximum observed plasma concentration (Cmax) of Compound A in a human subject of at most 100 ng / mL, at most 200 ng / mL, at most 300 ng / mL, at most 400 ng / mL, at most 500 ng / mL, at most 1000 ng / mL, at most 1,500 ng / mL, at most 2000 ng / mL, at most 2500 ng / mL, at most 3000 ng / mL, at most 3500 ng / mL, at most 4000 ng / mL, at most 4500 ng / mL, at most 5000 ng / mL, at most 5500 ng / mL, at most 6000 ng / mL, at most 6500 ng / mL, at most 7000 ng / mL, at most 7500 ng / mL, or at most 8000 ng / mL when administered to a human subject in an amount equivalent to about 25 mg of Compound A. In some embodiments, the oral liquid suspension is sufficient to achieve a maximum observed plasma concentration (Cmax) of Compound A in a human subject of about 100 ng / mL, about 200 ng / mL, about 300 ng / mL, about 400 ng / mL, about 500 ng / mL, about 1000 ng / mL, about 1,500 ng / mL, about 2000 ng / mL, about 2500 ng / mL, about 3000 ng / mL, about 3500 ng / mL, about 4000 ng / mL, about 4500 ng / mL, about 5000 ng / mL, about 5500 ng / mL, about 6000 ng / mL, about 6500 ng / mL, about 7000 ng / mL, about 7500 ng / mL, or about 8000 ng / mL when administered to a human subject in an amount equivalent to about 25 mg of Compound A.

[0324] The subject can be, for example, a mammal, a human, a pregnant woman, an elderly person, an adult, a teenager, a prepubescent child, a child, a toddler, an infant, a newborn, or a newborn less than four weeks old. The subject can be a patient. In some cases, the subject can be a person. In some cases, the subject can be a child (e.g., a young person below the age of puberty). In some cases, the subject can be an infant. In some cases, the subject can be a formula-fed infant. In some cases, the subject can be an individual participating in a clinical study. In some cases, the subject can be an experimental animal, for example, a mammal or a rodent. In some cases, the subject can be a mouse. In some cases, the subject can be an obese or overweight subject.

[0325] Target age

[0326] In some embodiments, the subject described herein is less than 18 years old. In some embodiments, the subject described herein is one week to 6 months old. In some embodiments, the subject described herein is 28 days to 6 months old. In some embodiments, the subject described herein is at least 6 months old. In some embodiments, the subject described herein is at most 6 months old. In some embodiments, the subject described herein is at least 28 days, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months old. In some embodiments, the subject described herein is at most 28 days, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months old. In some embodiments, the subject described herein is at least 1 year old, 2 years old, 3 years old, 4 years old, 5 years old, 6 years old, 7 years old, 8 years old, 9 years old, 10 years old, 11 years old, 12 years old, 13 years old, 14 years old, 15 years old, 16 years old, 17 years old, or 18 years old. In some embodiments, the subjects described herein are at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 years old. In some embodiments, the subjects described herein are at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 years old. In some embodiments, the subjects described herein are at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 years old. In some embodiments, the subjects described herein are up to 28 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 24 months, 48 ​​months, 60 months, 72 months, 84 months, 96 months, 108 months, 120 months, 132 months, 144 months, 156 months, 168 months, 180 months, 192 months, 204 months, or 216 months. In some embodiments, the subjects described herein are up to 28 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 2 years old, 3 years old, 4 years old, 5 years old, 6 years old, 7 years old, 8 years old, 9 years old, 10 years old, 11 years old, 12 years old, 13 years old, 14 years old, 15 years old, 16 years old, 17 years old, or 18 years old.

[0327] In some embodiments, the subject has been previously treated with one or more different cancer treatment modalities. In some embodiments, the subject has been previously treated with one or more of radiotherapy, chemotherapy, or immunotherapy. In some embodiments, the subject has been treated with a first-line, second-line, third-line, fourth-line, or fifth-line prior therapy. In some embodiments, the prior therapy is a cytotoxic therapy.

[0328] Cancer and tumors

[0329] In certain aspects, provided herein is a method for treating cancer, the method comprising administering a pharmaceutical powder or suspension comprising Compound A disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is selected from colorectal cancer, pancreatic cancer, lung cancer, ovarian cancer, liver cancer, breast cancer, kidney cancer, prostate cancer, gastrointestinal cancer, melanoma, cervical cancer, neuroendocrine cancer, bladder cancer, glioblastoma, and head and neck cancer. In certain embodiments, the cancer is pancreatic cancer. In certain embodiments, the cancer is ovarian cancer. In certain embodiments, the cancer is colorectal cancer. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is prostate cancer. In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is melanoma. In some embodiments, the cancer is a solid cancer.

[0330] In some embodiments, the cancer is a hematological cancer. In some embodiments, the cancer is selected from the group consisting of acute myeloid leukemia (AML), Hodgkin's lymphoma, multiple myeloma, T-cell acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), hairy cell leukemia, chronic myeloid leukemia (CML), non-Hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and cutaneous T-cell lymphoma (CTCL).

[0331] The method and pharmaceutical composition of compound A or its salt can be used to treat any suitable cancer known in the art.Non-limiting examples of cancers to be treated by the method disclosed herein can include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone refractory prostate cancer), pancreatic cancer, breast cancer, colon cancer, lung cancer (e.g., non-small cell lung cancer), esophageal cancer, head and neck squamous cell carcinoma, liver cancer, ovarian cancer, cervical cancer, thyroid cancer, glioblastoma, glioma, leukemia, lymphoma and other neoplastic malignancies. In some embodiments, cancer is low-grade glioma (LGG), for example, pediatric low-grade glioma (pLGG). In some embodiments, the pharmaceutical composition of compound A or its salt is used as a first-line therapy for treating cancer. In some embodiments, the subject has not previously received any standard care therapy for treating cancer. In some embodiments, the pharmaceutical composition of compound A or its salt is used to treat newly diagnosed cancer.

[0332] In some embodiments, the cancer is a low-grade glioma. In some embodiments, the cancer is pLGG. In some embodiments, pLGG is identified as having one or more of the following mutations: RAS positive mutations, RAF positive mutations, MEK positive mutations, and ERK positive mutations. In some embodiments, pLGG has a BRAF mutation. In some embodiments, the BRAF mutation is a non-V600 BRAF mutation. In some embodiments, the BRAF mutation is a V600 BRAF mutation. In some embodiments, the presence of BRAF fusion or rearrangement or BRAF mutation in the subject is confirmed before treatment. In some embodiments, the subject is identified as having one or more of the following wild-type fusions: KIAA1549:BRAF, STARD3NL:BRAF, BCAS1:BRAF, KHDRBS2:BRAF, CCDC6:BRAF, FAM131B:BRAF, SRGAP:BRAF, CLCN6:BRAF, GNAI1:BRAF, MRKN1:BRAF, GIT2:BRAF, GTF21:BRAF, FXR1:BRAF, RNF130:BRAF, BRAF:MACF1, TMEM106B:BRAF, PPC1CC:BRAF, CUX1:BRAF, SRGAP3:RAF1, QK1:RAF1, FYCO:RAF1, ATG7:RAF1, and NFIA:RAF1. In some embodiments, the subject is identified as having a KIAA1549:BRAF wild-type fusion. In some embodiments, pLGG has a gene fusion. In some embodiments, the cancer is pLGG with a RIN2:BRAF gene fusion. In some embodiments, the subject has one or more of the following gene fusions: KIAA1549:BRAF, AGK:BRAF, STARD3NL:BRAF, BCAS1:BRAF, KHDRBS2:BRAF, CCDC6:BRAF, FAM131B:BRAF, SRGAP:BRAF, CLCN6:BRAF, GNAI1:BRAF, MRKN1:BRAF, GIT2:BRAF, GTF2I:BRAF, FXR1:BRAF, RNF130:BRAF , MACF1:BRAF, TMEM106B:BRAF, PPC1CC:BRAF, CUX1:BRAF, CCD6:BRAF, PPP1CC:BRAF, SEPT7:BRAF, PDE10A:BRAF, EPB41L 2:BRAF, OSBP:BRAF, DAAM1:BRAF, TEX41:BRAF, FOXN3:BRAF, TRIPP1:BRAF, TOM1L2:BRAF, TMEM106B:BRAF, SRGAP3:RAF1,QK1:RAF1、FYCO:RAF1、ATG7:RAF1、NFIA-RAF1、TMF1:RAF1、GOLGA3:RAF1、SOX6:RAF1、BMPR1A:RAF1、PDZRN3:RAF1、SLMAP:RAF1、MAP4:RAF1、BCL6-RA F1、SEPT17:BRAF、ZNF767:BRAF、CCDC91:BRAF、DYNC1 / 2:BRAF、ZKSCAN1:BRAF、GTF2I:BRAF、MZT1:BRAF、RAD18:BRAF、CUX1:BRAF、CUX1-RAF1、CUL1:BR AF、SLC12A7:BRAF、TRIM24:BRAF、AGAP3:BRAF、AKAP9:BRAF、TAX1BP1:BRAF、CDC27:BRAF、FKBP15:BRAF、SKAP2:BRAF、TARDBP:BRAF、SEPT3:BRAF、ARMC 10:BRAF、PAPSS1:BRAF、FCHSD1:BRAF、ERC1:BRAF、CDK5RAP2:BRAF、TMEM178B:BRAF、BAIAP2L1:BRAF、CEP89:BRAF、CNTNAP2:BRAF、EML4:BRAF、KCTD7: BRAF、LSM14A:BRAF、NFIC:BRAF、NUDCD3:BRAF、PHTF2:BRAF、PLIN3:BRAF、RP2:BRAF、SOX5:BRAF、SOX6:BRAF、TLK2:BRAF、ZKSCAN5:BRAF、KLC1-RAF1、 DAAM1-RAF1、ZNF444-RAF1、LRCH3-RAF1、GOLGA4-RAF1、CTDSPL-RAF1、PRKAR2A-RAF1、CTNNA1-RAF1、MKRN1-RAF1、DYNC1H1-RAF1、GPHN-RAF1、KLHL7:B RAF、TANK:BRAF、RBMS3:BRAF、FAM114A2:BRAF、AGGF1-RAF1、EPS15:BRAF、NUP214:BRAF、BTF3L4:BRAF、GHR:BRAF、DOCK4:BRAF、ZC3HAV1:BRAF、MKRN1: BRAF、MYRIP:BRAF、SND1:BRAF、TNS3:BRAF、ATG7:BRAF、NUB1:BRAF、STRN3:BRAF、STK35:BRAF、ETFA:BRAF、SVOPL:BRAF、JHDM1D:BRAF、PPFIBP2:BRAF、SCL45A3:BRAF, ESRP1-RAF1, AGTRAP:BRAF, SVIP:BRAF, NRF1:BRAF, RAF1-CCDC176, RAF1-TRAK1, ESYT2:BRAF, PCBP2:BRAF, and SALL2:BRAF. In some embodiments, the subject has a TRIM33:BRAF gene fusion.

[0333] In some embodiments, the subject has one or more of the following gene fusions: AGK:BRAF、STARD3NL:BRAF、BCAS1:BRAF、KHDRBS2:BRAF、CCDC6:BRAF、FAM131B:BRAF、SRGAP:BRAF、CLCN6:BRAF、GNAI1 :BRAF、MRKN1:BRAF、GIT2:BRAF、GTF2I:BRAF、FXR1:BRAF、RNF130:BRAF、MACF1:BRAF、TMEM106B:BRAF、PPC1CC:BRAF、CUX1:BRAF、CCD6:BRAF、PPP1CC:B RAF、SEPT7:BRAF、PDE10A:BRAF、EPB41L2:BRAF、OSBP:BRAF、DAAM1:BRAF、TEX41:BRAF、FOXN3:BRAF、TRIPP1:BRAF、TOM1L2:BRAF、TMEM106B:BRAF、QK1: RAF1、FYCO:RAF1、ATG7:RAF1、NFIA-RAF1、TMF1:RAF1、GOLGA3:RAF1、SOX6:RAF1、BMPR1A:RAF1、PDZRN3:RAF1、SLMAP:RAF1、MAP4:RAF1、BCL6-RAF1、SEP T17:BRAF、ZNF767:BRAF、CCDC91:BRAF、DYNC1 / 2:BRAF、ZKSCAN1:BRAF、GTF2I:BRAF、MZT1:BRAF、RAD18:BRAF、CUX1:BRAF、CUX1-RAF1、CUL1:BRAF、SLC1 2A7:BRAF、TRIM24:BRAF、AGAP3:BRAF、AKAP9:BRAF、TAX1BP1:BRAF、CDC27:BRAF、FKBP15:BRAF、SKAP2:BRAF、TARDBP:BRAF、SEPT3:BRAF、ARMC10:BRAF、 PAPSS1:BRAF、FCHSD1:BRAF、ERC1:BRAF、CDK5RAP2:BRAF、TMEM178B:BRAF、BAIAP2L1:BRAF、CEP89:BRAF、CNTNAP2:BRAF、EML4:BRAF、KCTD7:BRAF、LSM1 4A:BRAF、NFIC:BRAF、NUDCD3:BRAF、PHTF2:BRAF、PLIN3:BRAF、RP2:BRAF、SOX5:BRAF、SOX6:BRAF、TLK2:BRAF、ZKSCAN5:BRAF、KLC1-RAF1、DAAM1-RAF1、ZNF444-RAF1, LRCH3-RAF1, GOLGA4-RAF1, CTDSPL-RAF1, PRKAR2A-RAF1, CTNNA1-RAF1, MKRN1-RAF1, DYNC1H1-RAF1, GPHN-RAF1, KLHL7:BRAF, TANK:BRAF, RBMS3:BRAF, FAM114A2:BRAF, AGGF1-RAF1, EPS15:BRAF, NUP214:BRAF, BTF3L4:BRAF, GHR:BRAF, DOCK4:BRAF, ZC3HAV1:BRAF, MKRN1:BRAF, MYRIP:BRAF, SND1:BRAF, TNS3:BRAF, ATG7:BRAF, NUB1:BRAF, STRN3:BRAF, STK35:BRAF, ETFA:BRAF, SVOPL:BRAF, JHDM1D:BRAF, PPFIBP2:BRAF, SCL45A3:BRAF, ESRP1-RAF1, AGTRAP:BRAF, SVIP:BRAF, NRF1:BRAF, RAF1-CCDC176, RAF1-TRAK1, ESYT2:BRAF, PCBP2:BRAF, and SALL2:BRAF.

[0334] In some embodiments, the gene fusion is a BRAF fusion. In some embodiments, the BRAF fusion is selected from the group consisting of: AGK:BRAF、STARD3NL:BRAF、BCAS1:BRAF、KHDRBS2:BRAF、CCDC6:BRAF、FAM131B:BRAF、SRGAP:BRAF、CLC N6:BRAF、GNAI1:BRAF、MRKN1:BRAF、GIT2:BRAF、GTF2I:BRAF、FXR1:BRAF、RNF130:BRAF、MACF1:BRAF、TMEM106B:BRAF、PPC1CC:BRAF、CUX1:BRAF、CCD6: BRAF、PPP1CC:BRAF、SEPT7:BRAF、PDE10A:BRAF、EPB41L2:BRAF、OSBP:BRAF、DAAM1:BRAF、TEX41:BRAF、FOXN3:BRAF、TRIPP1:BRAF、TOM1L2:BRAF、5BRAF Fusion、TMEM106B:BRAF、SEPT17:BRAF、ZNF767:BRAF、CCDC91:BRAF、DYNC1 / 2:BRAF、ZKSCAN1:BRAF、GTF2I:BRAF、MZT1:BRAF、RAD18:BRAF、CUX1:BRAF、CUL1 :BRAF、SLC12A7:BRAF、TRIM24:BRAF、AGAP3:BRAF、AKAP9:BRAF、TAX1BP1:BRAF、CDC27:BRAF、FKBP15:BRAF、SKAP2:BRAF、TARDBP:BRAF、SEPT3:BRAF、AR MC10:BRAF、PAPSS1:BRAF、FCHSD1:BRAF、ERC1:BRAF、CDK5RAP2:BRAF、TMEM178B:BRAF、BAIAP2L1:BRAF、CEP89:BRAF、CNTNAP2:BRAF、EML4:BRAF、KCTD7 :BRAF、LSM14A:BRAF、NFIC:BRAF、NUDCD3:BRAF、PHTF2:BRAF、PLIN3:BRAF、RP2:BRAF、SOX5:BRAF、SOX6:BRAF、TLK2:BRAF、ZKSCAN5:BRAF、KLHL7:BRAF、 TANK:BRAF、RBMS3:BRAF、FAM114A2:BRAF、EPS15:BRAF、NUP214:BRAF、BTF3L4:BRAF、GHR:BRAF、DOCK4:BRAF、ZC3HAV1:BRAF、MKRN1:BRAF、MYRIP:BRAF、SND1:BRAF, TNS3:BRAF, ATG7:BRAF, NUB1:BRAF, STRN3:BRAF, STK35:BRAF, ETFA:BRAF, SVOPL:BRAF, JHDM1D:BRA F. PPFIBP2:BRAF, SCL45A3:BRAF, AGTRAP:BRAF, SVIP:BRAF, NRF1:BRAF, ESYT2:BRAF, PCBP2:BRAF and SALL2:BRAF. ,

[0335] In some embodiments, the gene fusion is a RAF1 fusion. In some embodiments, the RAF1 fusion is selected from the group consisting of: SRGAP3:RAF1, QK1:RAF1, FYCO:RAF1, ATG7:RAF1, NFIA:RAF1, TMF1:RAF1, GOLGA3:RAF1, SOX6:RAF1, BMPR1A:RAF1, PDZRN3:RAF1, SLMAP:RAF1, MAP4:RAF1, BCL6:RAF1, CUX1:RAF1, KLC 1:RAF1, DAAM1:RAF1, ZNF444:RAF1, LRCH3:RAF1, GOLGA4:RAF1, CTDSPL:RAF1, PRKAR2A:RAF1, CTNNA1:RAF1, MKRN1:RAF1, DYNC1H1:RAF1, AGGF1:RAF1, ESRP1:RAF1, GPHN:RAF1, RAF1-CCDC176, and RAF1-TRAK1.

[0336] In some embodiments, the subject has a CRAF gene fusion. In some embodiments, the CRAF gene fusion is SRGAP3:RAF1, QK1:RAF1, FYCO:RAF1, ATG7:RAF1, NFIA:RAF1, TMF1:RAF1, GOLGA3:RAF1, SOX6:RAF1, BMPR1A:RAF1, PDZRN3:RAF1, SLMAP:RAF1, MAP4:RAF1, BCL6:RAF1, CUX1:RAF1, KLC 1:RAF1, DAAM1:RAF1, ZNF444:RAF1, LRCH3:RAF1, GOLGA4:RAF1, CTDSPL:RAF1, PRKAR2A:RAF1, CTNNA1:RAF1, MKRN1:RAF1, DYNC1H1:RAF1, AGGF1:RAF1, ESRP1:RAF1, GPHN:RAF1, RAF1-CCDC176, or RAF1-TRAK1.

[0337] In some embodiments, the cancer has one or more of the following gene fusions: KIAA1549:BRAF、AGK:BRAF、STARD3NL:BRAF、BCAS1:BRAF、KHDRBS2:BRAF、CCDC6:BRAF、FAM131B:BRAF、SRGAP:BRAF、C LCN6:BRAF、GNAI1:BRAF、MRKN1:BRAF、GIT2:BRAF、GTF2I:BRAF、FXR1:BRAF、RNF130:BRAF、MACF1:BRAF、TMEM106B:BRAF、PPC1CC:BRAF、CUX1:BRAF、CC D6:BRAF、PPP1CC:BRAF、SEPT7:BRAF、PDE10A:BRAF、EPB41L2:BRAF、OSBP:BRAF、DAAM1:BRAF、TEX41:BRAF、FOXN3:BRAF、TRIPP1:BRAF、TOM1L2:BRAF、T MEM106B:BRAF、SRGAP3:RAF1、QK1:RAF1、FYCO:RAF1、ATG7:RAF1、NFIA-RAF1、TMF1:RAF1、GOLGA3:RAF1、SOX6:RAF1、BMPR1A:RAF1、PDZRN3:RAF1、SLMA P:RAF1、MAP4:RAF1、BCL6-RAF1、SEPT17:BRAF、ZNF767:BRAF、CCDC91:BRAF、DYNC1 / 2:BRAF、ZKSCAN1:BRAF、GTF2I:BRAF、MZT1:BRAF、RAD18:BRAF、CUX 1:BRAF、CUX1-RAF1、CUL1:BRAF、SLC12A7:BRAF、TRIM24:BRAF、AGAP3:BRAF、AKAP9:BRAF、TAX1BP1:BRAF、CDC27:BRAF、FKBP15:BRAF、SKAP2:BRAF、TAR DBP:BRAF、SEPT3:BRAF、ARMC10:BRAF、PAPSS1:BRAF、FCHSD1:BRAF、ERC1:BRAF、CDK5RAP2:BRAF、TMEM178B:BRAF、BAIAP2L1:BRAF、CEP89:BRAF、CNTNA P2:BRAF、EML4:BRAF、KCTD7:BRAF、LSM14A:BRAF、NFIC:BRAF、NUDCD3:BRAF、PHTF2:BRAF、PLIN3:BRAF、RP2:BRAF、SOX5:BRAF、SOX6:BRAF、TLK2:BRAF、ZKSCAN5: BRAF, KLC1-RAF1, DAAM1-RAF1, ZNF444-RAF1, LRCH3-RAF1, GOLGA4-RAF1, CTDSPL-RAF1, PRKAR2A-RAF1, CTNNA1-RAF1, MKRN1-RAF1, DYNC1H1-RA F1, GPHN-RAF1, KLHL7:BRAF, TANK:BRAF, RBMS3:BRAF, FAM114A2:BRAF, AGGF1-RAF1, EPS15:BRAF, NUP214:BRAF, BTF3L4:BRAF, GHR:BRAF, DOCK4:BRAF, ZC 3HAV1:BRAF, MKRN1:BRAF, MYRIP:BRAF, SND1:BRAF, TNS3:BRAF, ATG7:BRAF, NUB1:BRAF, STRN3:BRAF, STK35:BRAF, ETFA:BRAF, SVOPL:BRAF, JHDM1D:BRAF , PPFIBP2:BRAF, SCL45A3:BRAF, ESRP1-RAF1, AGTRAP:BRAF, SVIP:BRAF, NRF1:BRAF, RAF1-CCDC176, RAF1-TRAK1, ESYT2:BRAF, PCBP2:BRAF, or SALL2:BRAF. ,

[0338] In some aspects, the present disclosure provides a method of treating a subject having pediatric low-grade glioma (pLGG), the method comprising reconstituting an amorphous solid dispersion of Compound A or a salt thereof in an aqueous solution, and administering a pharmaceutically acceptable dose of the reconstituted Compound A or a salt thereof to the subject in need thereof.

[0339] In addition, the diseases or conditions provided herein include refractory or recurrent malignancies, the growth of which can be inhibited using the methods of treatment disclosed herein. In some embodiments, the cancer to be treated by the methods of treatment disclosed herein is selected from carcinoma, squamous cell carcinoma, adenocarcinoma, malignant sarcoma, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, fallopian tube cancer, primary peritoneal cancer, colon cancer, colorectal cancer, anogenital squamous cell carcinoma, melanoma, renal cell carcinoma, lung cancer, non-small cell lung cancer, lung squamous cell carcinoma, gastric cancer, bladder cancer, gallbladder cancer, liver cancer, thyroid cancer, laryngeal cancer, salivary gland cancer, esophageal cancer, head and neck cancer, glioblastoma, glioma, head and neck squamous cell carcinoma, prostate cancer, pancreatic cancer, mesothelioma, sarcoma, hematological cancer, leukemia, lymphoma, neuroma, and combinations thereof. In some embodiments, cancers to be treated by the methods of the present disclosure include, for example, carcinomas, squamous cell carcinomas (e.g., cervical canal, eyelid, conjunctiva, vagina, lung, oral cavity, skin, bladder, tongue, larynx, and esophagus) and adenocarcinomas (e.g., prostate, small intestine, endometrium, cervical canal, large intestine, lung, pancreas, esophagus, rectum, uterus, stomach, breast, and ovary). In some embodiments, cancers to be treated by the methods of the present disclosure further include malignant sarcomas (e.g., myogenic sarcomas), leukemic hyperplasias, neuromas, melanomas, and lymphomas. In some embodiments, cancers to be treated by the methods of the present disclosure are breast cancer. In some embodiments, cancers to be treated by the methods of the present disclosure are triple-negative breast cancer (TNBC). In some embodiments, cancers to be treated by the methods of the present disclosure are ovarian cancer. In some embodiments, cancers to be treated by the methods of the present disclosure are colorectal cancer. In some embodiments, cancers are non-Spitzoid cutaneous melanomas. In some embodiments, cancers are

[0340] Specific examples of cancers that may be prevented and / or treated according to the present disclosure include, but are not limited to, the following: renal cancer, renal carcinoma, glioblastoma multiforme, metastatic breast cancer; breast cancer; mammary sarcoma; neurofibroma; neurofibromatosis; pediatric tumors; neuroblastoma; malignant melanoma; epidermal cancer; leukemias, such as but not limited to acute leukemias, acute lymphocytic leukemias, acute myeloid leukemias such as myeloblastic leukemia, promyelocytic leukemia, myelomonocytic leukemia, monocytic leukemia, erythroleukemic leukemia, and myelodysplastic syndrome, chronic leukemias such as but not limited to chronic myeloid (granulocytic) leukemia, chronic lymphocytic leukemia, hairy cell leukemia; true Polycythemia; lymphomas, such as but not limited to Hodgkin's disease, non-Hodgkin's disease; multiple myeloma, such as but not limited to smoldering multiple myeloma, non-secretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma, and extramedullary plasmacytoma; Waldenstrom's macroglobulinemia; monoclonal gammopathy of undetermined significance; benign monoclonal gammopathy; heavy chain disease; bone cancer and connective tissue sarcomas, such as but not limited to bonesarcoma, myeloma bone disease, multiple myeloma, cholesteatoma-induced bone osteosarcoma, Paget's disease of bone, osterosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor, fibrosarcoma of bone, spinal cord sarcoma, periosteal sarcoma, soft tissue sarcoma, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, schwannoma, rhabdomyosarcoma, and synovial sarcoma; brain tumors, such as, but not limited to, gliomas, astrocytomas, brain stem gliomas, ependymomas, oligodendrogliomas, non-gliomas, acoustic neuromas, craniopharyngiomas, medulloblastomas, meningiomas, pineal cell tumors, pineoblastomas, and primary brain lymphomas; breast cancer, including, but not limited to, adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, myxomatous breast cancer, tubular breast cancer, papillary breast cancer, Paget's disease (including juvenile Paget's disease), and inflammatory breast cancer; adrenal cancers, such as, but not limited to, pheochromocytoma and adrenocortical carcinoma; thyroid cancers, such as, but not limited to, papillary or follicular thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer; pancreatic cancers, such as, but not limited to, insulinomas, gastrinomas, glucagonomas, vipomamas, 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 cancer, such as squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget's disease; cervical cancer, such as, but not limited to, squamous cell carcinoma and adenocarcinoma; uterine cancer, such as, but not limited to, endometrial carcinoma and uterine sarcoma; ovarian cancer, such as, but not limited to, ovarian epithelial carcinoma, borderline tumors, germ cell tumors, and stromal tumors; cervical cancer; esophageal cancer, such as, but not limited to, squamous carcinoma, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; gastric cancer, such as, but not limited to, but not limited to adenocarcinoma, mycosis fungoides (polypoid), ulcer, superficial spreading, diffuse spreading, malignant lymphoma, liposarcoma, fibrosarcoma and carcinosarcoma; colon cancer; colorectal cancer, colorectal cancer with KRAS mutation; colon cancer; rectal cancer; liver cancer, such as but not limited to hepatocellular carcinoma and hepatoblastoma, gallbladder cancer, such as adenocarcinoma; bile duct cancer, such as but not limited to papillary bile duct carcinoma, nodular bile duct carcinoma and diffuse bile duct carcinoma; lung cancer, such as KRAS mutation non-small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large cell carcinoma testicular cancer, such as but not limited to germinal tissue tumor, seminoma, anaplastic seminoma, classical (typical) seminoma, spermatocytic seminoma, non-seminoma, embryonal carcinoma, teratoma carcinoma, choriocarcinoma (yolk sac tumor), prostate cancer, such as but not limited to androgen-independent prostate cancer, androgen-dependent prostate cancer, adenocarcinoma, leiomyosarcoma and rhabdomyosarcoma; penile cancer; oral cancer, such as but not limited to squamous cell carcinoma; basal carcinoma; 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, lentigo malignant melanoma, acral lentigo melanoma; kidney cancer, such as but not limited to renal cell carcinoma, adenocarcinoma, adrenal tumor, fibrosarcoma, transitional cell carcinoma (renal pelvis and / or uterus); renal cancer; Wilms' tumor; bladder cancer, such as but not limited to transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, carcinosarcoma. In addition, cancers include myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchial carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma and papillary adenocarcinoma. ;

[0341] In some embodiments, the cancer is a tumor. In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor is selected from colorectal tumors, pancreatic tumors, lung tumors, ovarian tumors, liver tumors, breast tumors, kidney tumors, prostate tumors, neuroendocrine tumors, gastrointestinal tumors, melanomas, cervical tumors, bladder tumors, glioblastomas, and head and neck tumors. In some embodiments, the tumor is a colorectal tumor. In some embodiments, the tumor is an ovarian tumor. In some embodiments, the tumor is a breast tumor. In some embodiments, the tumor is a lung tumor. In some embodiments, the tumor is a pancreatic tumor. In some embodiments, the tumor is a melanoma. In some embodiments, the tumor comprises a gene fusion or is characterized as having a gene fusion. In some embodiments, the cancer is a cancerous tumor. In some embodiments, the subject in need thereof has a tumor that has been at least partially resected.

[0342] In some embodiments, the patient or patient group to be treated with the pharmaceutical composition of the present disclosure suffers from solid tumors. In some embodiments, solid tumors are melanoma, renal cell carcinoma, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gallbladder cancer, laryngeal cancer, liver cancer, thyroid cancer, gastric cancer, salivary gland cancer, prostate cancer, pancreatic cancer or Merkel cell carcinoma. In some embodiments, the patient or patient group to be treated with the pharmaceutical composition of the present disclosure suffers from hematological cancer. In some embodiments, the patient suffers from hematological cancer, such as diffuse large B-cell lymphoma ("DLBCL"), Hodgkin lymphoma ("HL"), non-Hodgkin lymphoma ("NHL"), follicular lymphoma ("FL"), acute myeloid leukemia ("AML") or multiple myeloma ("MM"). In some embodiments, the patient to be treated or the patient group suffers from a cancer selected from ovarian cancer, lung cancer and melanoma.

[0343] In some embodiments, the patient or patient population to be treated with the pharmaceutical composition of the present disclosure has not been previously treated with a MEK inhibitor or a MAPK inhibitor. In some embodiments, the pharmaceutical composition of the present disclosure is administered in combination with a MEK inhibitor or a MAPK inhibitor. In some embodiments, the MEK inhibitor is selected from the group consisting of cobimetinib, selumetinib, pimacitinib, PD0325901, refactinib, bimetinib, BI-847325, trametinib, GDC-0623, G-573, CH5126766, CIP-137401, and In some embodiments, the MEK inhibitor is selumetinib, bimetinib or pimacitinib. In some embodiments, the MEK inhibitor is pimacitinib.

[0344] In some embodiments, the MEK inhibitor or a pharmaceutically acceptable salt thereof is selected from cobimetinib, selumetinib, pimacitinib, PD0325901, refactinib, bimetinib, BI-847325, trametinib, GDC-0623, G-573, CH5126766, CI-1040, PD035901, and TAK-933. In some embodiments, the MEK inhibitor or a pharmaceutically acceptable salt thereof is selected from cobimetinib, selumetinib, pimacitinib, PD0325901, refactinib, bimetinib, BI-847325, trametinib, GDC-0623, G-573, CH5126766, CI-1040, PD035901, TAK-933, and CIP-137401.

[0345] In some embodiments, the MEK inhibitor is a MEK inhibitor as described in U.S. Pat. No. 7777050, U.S. Pat. No. 8178693, U.S. Pat. No. 9562016, U.S. Pat. No. 7425637, U.S. Pat. No. 8178693, U.S. Pat. No. 9156795, U.S. Pat. No. 9562017, U.S. Pat. No. 7378423, U.S. Pat. No. 8703781, U.S. Pat. No. 9290468, each of which is hereby individually incorporated by reference in its entirety.

[0346] Example

[0347] Having now generally described the invention, the invention will be more readily understood by reference to the following examples, which are included merely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention in any way.

[0348] Example 1. Patient Mixing Instructions ( Figure 1 ; Steps 1 to 12)

[0349] In step 1, open the bottle containing the powder formulation and remove the seal. Do not throw away the child-resistant cap. Remove the oral syringe from the package. In step 2, fill a cup with warm or room temperature water. Do not use cold water. In step 3, pull up on the plunger to draw water into the oral syringe, past the 14 mL mark. In step 4, remove the oral syringe from the cup. Gently push the plunger to squeeze all bubbles out of the tip. Expel excess water so that the top of the plunger is aligned with the 14 mL mark on the syringe. In step 5, fill the bottle with 14 mL of water. Immediately re-cap and shake the bottle vigorously in all directions for 60 seconds. Continue shaking in 15 second increments until the powder is completely dispersed. Do not shake for >2 minutes total time. Observe whether the powder is completely dispersed into the liquid. In step 6, invert the bottle and vortex for 30 seconds. Remove the child-resistant cap and confirm that there are no solids attached to the neck of the bottle. If there are solids in the neck of the bottle, re-cap the bottle, invert, and vortex for an additional 15 seconds. Then, let the bottle sit for about one minute. In step 7, replace the cap with the bottle adapter. Secure it to the bottle by pressing it into the neck of the bottle. In step 8, insert the tip of the oral syringe into the bottle adapter. The tip of the syringe should fit snugly into the hole of the bottle in the adapter. In step 9, with the syringe in place, vortex the suspension for 30 seconds, invert the bottle, and draw the prescribed volume plus an additional 1 mL into the syringe. In step 10, remove the oral syringe from the bottle. Remove only the bubbles in the tip by gently pushing the plunger upward. In step 11, reinsert the syringe into the bottle and adjust to the prescribed volume. In step 12, gently remove the syringe from the bottle. Place the tip of the syringe in the child's mouth, pressing against the inside of the cheek. Slowly squirt the medication into the mouth by pressing the plunger. Allow the child to swallow.

[0350] Example 2. Part 1 Taste / Palatability Evaluation

[0351] The objective of this study was to evaluate the taste and palatability attributes (odor, sweetness, bitterness, flavor, mouthfeel / texture, and aftertaste) and overall acceptability of a suspension formulation of Compound A powder for hot melt extrusion (HME) reconstitution (PfR).

[0352] Part 1 was a single-center, open-label, randomized, single-period, 6-way crossover design to evaluate the taste and palatability attributes and overall palatability of several Compound A HME-PfR suspension formulations with different flavor and sweetener levels using the puff-and-spit method in 12 volunteers. On the morning of Day 1, subjects were randomly assigned to 1 of 6 sequences (ABFCED, BCADFE, CDBEAF, DECFBA, EFDACB, and FAEBDC), with 2 subjects assigned to each sequence. Each subject received the following regimen in a randomized manner. (Tables 1 and 2)

[0353] Table 1. Description of the protocol in Part 1

[0354]

[0355] The drug product of Compound A used in Part I has been formulated as a powder for reconstitution (PfR) dosage form. This PfR formulation was used herein.

[0356] The drug product is packaged in a bottle equipped with a child-proof cap and an induction seal liner with a 300 mg active substance strength (to be delivered). It is reconstituted to an active substance concentration of 25 mg / mL with water or an aqueous diluent containing the flavorings and / or sweeteners in Table 2b, and administered with a syringe. In one example, the bottle is overfilled to 365 mg of Compound A to allow for the reproducible administration and delivery of 300 mg of Compound A (i.e., 12 mL of 25 mg / mL Compound A concentration). The dosage composition of Compound A PfR is provided in Table 2a below as a basic formulation. The preparation A in Table 1 is identical to the basic formulation in Table 2a, and the preparation BF in Table 1 includes the corresponding flavorings and / or sweeteners as shown in the basic formulation shown in Table 2a and Table 2b.

[0357] Flavoring / sweetening agents were pharmaceutically compounded with water as described in Table 2b below.

[0358] Table 2a. Composition of Compound A powder for reconstitution, 300 mg bottle

[0359]

[0360] 1 Testing was performed in accordance with the USP monograph for simethicone, USP for determination and identification.

[0361] Table 2b. Description of flavor and sweetener levels used in formulations

[0362]

[0363] Example 3. Relative bioavailability and food effect of part 2

[0364] The objectives of this study were to (1) determine the relative bioavailability of a Compound A HME PfR suspension formulation compared to the relative bioavailability of a Compound A HME tablet formulation in healthy subjects; (2) evaluate the pharmacokinetic profiles of a Compound A HME tablet formulation and a Compound A HME PfR suspension formulation in healthy subjects; (3) assess the effect of food on the PK profile of Compound A after a single dose of a Compound A HME tablet formulation in healthy subjects in the fed state; and (4) provide information on the safety and tolerability of Compound A after oral administration.

[0365] Part 2 is a single-center, open-label, randomized, 3-phase crossover design to evaluate the relative bioavailability of the selected compound A HME PfR suspension formulation compared to the HME tablet reference formulation in 12 volunteers. The effect of food on the exposure of compound A HME tablets was also studied. In the 1st phase, before the first dose of compound A was administered, subjects were randomly assigned to 1 of 3 regimen sequences (GHI, HIG and IGH), wherein 4 subjects were assigned to each regimen sequence. On the 1st day of each study period, subjects received the following regimens in Table 2.

[0366] Table 2. Preparations used in Part 2

[0367]

[0368] Compound A drug product is formulated as a powder for reconstruction (PfR) dosage form for clinical research. The drug product is packaged in a glass bottle equipped with a child-proof cover and an induction seal liner with 300mg (active substance strength, to be delivered). It is reconstructed to an active substance concentration of 25mg / mL with water and administered with a syringe. The bottle is overfilled to 430mg Compound A and reconstructed with 14mL of water to allow a reproducible dose delivery of 300mg Compound A (i.e., 12mL of 25mg / mL Compound A concentration). The 100mg dose utilizes the same bottle and reconstruction procedure as the 300mg dose. Utilize 4mL aliquots of 25mg / mL to provide a dose of 100mg. The dosage composition of Compound A PfR is provided in Table 4 below.

[0369] Table 4. Composition of Compound A flavored powder for reconstitution, 100 mg (H2 regimen) and 300 mg bottle (H1 regimen)

[0370]

[0371] 1The 100 mg dose is provided by the 300 mg bottle. After reconstitution to 25 mg / mL, the 100 mg dose is administered in 4 mL aliquots, rather than the 12 mL dose for the 300 mg dose.

[0372] Subjects underwent an initial screening procedure to determine if they were eligible to participate in Part 2 of the study at the screening visit (Day -28 to Day -2). Each period followed the same study design. For all regimens, subjects were admitted in the morning of the day prior to dosing (Day -1).

[0373] Subjects received a single dose of Compound A on the morning of Day 1 after a minimum of 10 h of overnight fasting (Schemes G and H, fasting state) or 30 minutes after the start of a standard high-fat breakfast (Scheme I, fed state). Blood samples were collected at prescribed intervals from pre-dose to 120 h after dosing for PK analysis. After administration of Scheme H (selected Compound A HMEPfR suspension formulations in the fasting state), subjects completed a taste / palatability questionnaire individually and privately.

[0374] Subjects remained at the clinical unit until 96 h after dosing (Day 5). Subjects returned to the clinical unit 120 h after dosing (Day 6) for final PK samples.

[0375] There was a minimum 14-day washout period between each dose of Compound A. Follow-up calls were made 7 to 10 days after the last dose to ensure the subject's continued well-being.

[0376] Example 4 - Taste / Palatability and Pharmacokinetic Evaluation

[0377] Taste / Palatability Results (Part 1 and Part 2 Protocol H only)

[0378] Taste was evaluated on a 9-point system based on palatability attributes (aroma, sweetness, bitterness, flavor, mouthfeel, and aftertaste) and overall. The median (minimum-maximum) ratings for each taste / palatability attribute for Part 1 and Part 2 Protocol H are summarized in Table 5.

[0379] Table 5. Median (minimum-maximum) ratings for different taste / palatability attributes evaluated for Compound A HME PfR suspension formulations administered at different schedules: Taste / Palatability Analysis Set

[0380] (Part 1 and Part 2 Option H only)

[0381]

[0382] Overall taste / palatability evaluation is presented in Figure 5 in a stacked bar chart.

[0383] Taste / Palatability Analysis (Part 1)

[0384] For all taste attributes including overall acceptability, the median scores for the reference (Scheme A) ranged from 3.0 to 5.0, indicating that the subjects had a moderate dislike to neutral opinion of the product. When sweeteners were added, palatability was improved, with median scores ranging from 4.0 to 6.0, indicating a substantially neutral opinion of the product. Flavorings paired with different sweetener levels increased the median scores from 5.0 to 7.0, showing acceptability in the neutral to moderately favorable range.

[0385] Based on the grouping (level 1-3: dislike, level 4-6: neutral, level 7-9: like), 7 subjects indicated that they disliked the reference product based on overall acceptability. For the sweetened product, this was reduced to 2 subjects, and for each flavored solution, no more than 1 subject. The solution with the highest proportion of subjects rating 'like' was Solution C, with 7 subjects selecting this rating.

[0386] Adding individual sweeteners to the Compound A HME PfR suspension formulations provided modest improvements over the reference product, however these improvements were not significant in all cases. Each of the Compound A formulations containing flavorings provided more robust improvements over the reference product in each taste attribute except bitterness. There appeared to be no clear preference between the flavoring regimens, however, regimen F (vanilla, low sucralose) tended to show the least improvement.

[0387] For each taste aspect, including overall acceptability, except bitterness, Friedman's test was statistically significant at the 5% significance level, indicating that at least one of the flavor / sweetener levels had a significantly different taste score than the other solutions (p=<0.001, 0.013, <0.001, <0.001, 0.022, and 0.033 for overall acceptability, aroma, sweetness, flavor, mouthfeel / texture, and aftertaste). For bitterness, the p value was greater than 0.05 (p=0.650), indicating that there was no significant difference between at least 2 solutions for bitterness scores.

[0388] For all pairwise comparisons, the median pairwise differences were positive, indicating that each flavor / sweetener combination showed improved acceptability and overall acceptability for each taste aspect analyzed when compared to the reference with no sweetener or flavoring.

[0389] Statistical analysis of taste / palatability evaluation using Wilcoxon signed rank test for taste / palatability is presented in Table 6.

[0390] Table 6. Taste / Palatability Assessment Results from Wilcoxon Signed Rank Test: Taste / Palatability Analysis Set (Part 1)

[0391]

[0392] (1) Median of the pairwise differences (Test solution - Solution A) for each subject

[0393] (2) P value from the Wilcoxon signed-rank test under the null hypothesis that the median difference is equal to 0

[0394] Subjects tasted 5 mL of Compound A HME PfR Oral Suspension, 6 different formulations (Regimens AF = Formulations 1-6) Regimen A = 25 mg / mL Compound A (no sweetener / flavoring), Regimens B to F = different flavor, sweetener level concentrations (mg / mL)

[0395] In general, the smallest improvements from Protocol A (no flavoring or sucralose) were observed for Protocol B (0.15% sucralose) in taste (except aftertaste), with improvements equivalent to those with flavoring. Protocols C (strawberry flavor and 0.15% sucralose), Protocol D (strawberry flavor and 0.3% sucralose), and Protocol E (vanilla flavor and 0.3% sucralose) all provided similar improvements in taste and overall acceptability when compared to reference Protocol A, with these improvements generally being greater than Protocol F (vanilla flavor and 0.15% sucralose). Among all the protocols, Protocol F had the smallest improvement in aftertaste compared to Protocol A, and also had the smallest overall improvement in sweetness in the case of the unflavored Protocol B.

[0396] Taste / Palatability Analysis (Part 2)

[0397] The overall taste profile rating for Proposal H was comparable to that of Proposal C in Part 1, which used the same flavor and sweetener (strawberry / 0.15%).

[0398] Taste / Palatability Statistics Question

[0399] For the Friedman test, subjects were only included in the comparison of all scenarios if they had a numeric rating for each scenario. Because some subjects rated the taste aspect as "NA" (not applicable) in at least 1 scenario, they were not included, so the number of subjects included was reduced for the taste aspects (number of subjects included in the analysis): smell (4), bitterness (4), sweetness (9), flavor (11), and aftertaste (9). Caution should be used when interpreting results for scenarios with large amounts of missing data.

[0400] Taste / Palatability Conclusion

[0401] For overall acceptability and all taste aspects, taste scores were significantly improved for Compound A HME PfR suspension formulations with added sweetener sucralose alone or additionally including flavoring (strawberry or vanilla), with greater improvements observed with the addition of both sweetener and flavoring.

[0402] Pharmacokinetic Results and Analysis (Part 2)

[0403] In Figures 3(A)-3(D) and the table, after administration of Compound A as a reference HME tablet at 300 mg and 100 mg dose levels in the fasting state, all subjects in regimen G1 reached T 3.00 h after administration. max , and for subjects in regimen G2, T was reached between 2.00 h and 5.00 h after dosing max , where the median value T max For the 300 mg and 100 mg dose levels, the geometric mean T 1 / 2 When Compound A was administered at 300 mg and 100 mg dose levels in a PfR suspension (scheme H1 and H2), the median T max Both occurred at 3.000 h. For the 300 mg and 100 mg dose levels, the geometric mean T 1 / 2 The estimated values ​​are 83.177h and 65.363h respectively.

[0404] In Figures 4(A)-4(D) and Table 7, after administration of Compound A as HME tablets at 300 mg (Scheme H1) and 100 mg (Scheme H2) dose levels in the fed state, for Schemes I1 and I2, the median T max For schemes I1 and I2, the geometric mean T 1 / 2 The estimated values ​​were 85.4 h and 61.7 h, respectively. For the 300 mg tablet administered in the fed state (Scheme I1), C max Inter-subject variability was low to moderate for AUC(0-last) and AUC(0-last), with CVs of 26.5% and 11.7%, respectively, and for the 100 mg tablet administered in the fed state, CVs of 23.4% and 20.7%, respectively (Regimen I2).

[0405]

[0406] Due to T 1 / 2 Relative to the sampling scheme, the area of ​​the extrapolated AUC(0-inf) was large (>20%) and therefore the AUC(0inf) could not be reliably calculated for any subject.

[0407] exist Figure 6-Figure 9 In the log 10 / Linear scale shows the mean plasma concentration of Compound A versus time profile for the regimens (Regimen H1 and G2, Regimen H2 and G2, Regimen I1 and G1, and Regimen I2 and G2).

[0408] Regimen G1 (300 mg HME tablet, fasting) and Regimen G2 (100 mg HME tablet, fasting)

[0409] After single oral administration of Compound A as a reference HME tablet at 300 mg (Schedule G1) and 100 mg (Schedule G2) dose levels to healthy male and female subjects in the fasting state, quantifiable plasma concentrations of Compound A were observed starting from the first time point (0.5 h after dosing) for Schedule G1 and before dosing (due to carryover from the previous period) for all subjects in Schedule G2. Subject 2005 was excluded from the Schedule G2 summary statistics and statistical analysis because their pre-dose value (36.4 ng / mL) represented a quantifiable plasma concentration greater than their corresponding C max For all subjects in regimen G1, the maximum plasma concentration of compound A (C max ) was achieved 3.00 h after dosing and between 2.00 h and 5.00 h after dosing for all subjects on regimen G2, where for regimen G2, the median T max is 3.50h.

[0410] In C max After 4 weeks, plasma concentrations decreased in a multi-stage manner in all subjects in both regimens G1 and G2 and remained quantifiable until the last sampling time point (120 h after dosing). At the 300 mg dose level (regimen G1), for all 4 subjects, T 1 / 2 was reliably calculated, ranging between 56.7 h and 82.6 h, with a geometric mean of 67.4 h. At the 100 mg dose level (regimen G2), T 1 / 2 was reliably calculated and ranged between 58.3 h and 113 h, with a geometric mean of 73.5 h.

[0411] At the 300 mg dose level (Schedule G1), C maxThe range of AUC(0-last) was 2040 ng / mL to 3240 ng / mL, with a geometric mean (geometric CV%) of 2620 ng / mL (24.3%). The range of AUC(0-last) was 103000 ng.h / mL to 183000 ng.h / mL, with a geometric mean (geometric mean CV%) of 133000 ng.h / mL (29.4%). At the 100 mg dose level (Scheme G2), C max The range was 1010 ng / mL to 1670 ng / mL with a geometric mean (geometric mean CV%) of 1180 ng / mL (21.6%). The AUC(0-last) ranged from 44000 ng.h / mL to 66900 ng.h / mL with a geometric mean (geometric mean CV%) of 53500 ng.h / mL (15.0%). In all subjects of both regimens, the AUC(0-inf) could not be reliably calculated because the extrapolated portion of the curve represented >20% of the total area.

[0412] Regimen H1 (300 mg of HME PfR suspension, fasting) and Regimen H2 (100 mg of HME PfR suspension, fasting)

[0413] After single oral administration of Compound A as HME PfR suspension to healthy male and female subjects at 300 mg (Regimen H1) and 100 mg (Regimen H2) dose levels in the fasting state, quantifiable plasma concentrations of Compound A were observed from the first time point of Regimen H1 (0.5 h post-dose), and for 7 of the 8 subjects of Regimen H2, quantifiable plasma concentrations of Compound A were observed before dosing (due to carryover from the previous period), with concentrations in the remaining subjects being quantifiable from the first time point 0.5 h post-dose. Since the pre-dose value for subject 2010 (86.6 ng / mL) represents a value greater than the corresponding C max The maximum plasma concentration of Compound A was reached between 1.50 h and 4.00 h after dosing for all subjects in both regimens, with a median T of 1.50 h and 4.00 h for both regimens. max is 3.00h.

[0414] In C max After 1 h, plasma concentrations decreased in a multi-step manner in all subjects in both regimens and remained quantifiable until the last sampling time point (120 h after dosing). At the 300 mg dose level (regimen H1), for all 4 subjects, T 1 / 2was reliably calculated to range between 71.9 h and 114 h, with a geometric mean of 83.2 h. At the 100 mg dose level (scheme H2), T 1 / 2 was reliably calculated and ranged between 57.3 h and 77.5 h, with a geometric mean of 65.4 h. In cases where the endpoint slope could not be reliably determined, this was a result of an unacceptable coefficient of determination (i.e., R 2 <0.9).

[0415] At the 300 mg dose level (scheme H1), C max The range of AUC(0-last) was 2300 ng / mL to 2940 ng / mL, with a geometric mean (geometric CV%) of 2470 ng / mL (11.7%). The range of AUC(0-last) was 127000 ng.h / mL to 189000 ng.h / mL, with a geometric mean (geometric CV%) of 151000 ng.h / mL (17.9%). At the 100 mg dose level (scheme H2), C max The range of AUC(0-last) was 42500 ng.h / mL to 72500 ng.h / mL with a geometric mean (geometric CV%) of 52400 ng.h / mL (22.3%). In cases where AUC(0-inf) could not be reliably calculated, this was due to the extrapolated portion of the curve representing >20% of the total area and an unacceptable coefficient of determination (i.e., R 2 <0.9).

[0416] Regimen I1 (300 mg HME tablet, taken with food) and Regimen I2 (100 mg HME tablet, taken with food)

[0417] After single oral administration of Compound A as HME tablets to healthy male and female subjects at 300 mg (Scheme I1) and 100 mg (Scheme I2) dose levels in the fed state, quantifiable plasma concentrations of Compound A were observed starting from the first time point of Scheme I1 (0.5 h after dosing), and for 7 of the 8 subjects of Scheme I2, quantifiable plasma concentrations of Compound A were observed before dosing (due to carryover from the previous period), with concentrations quantifiable starting from 0.5 h in the remaining subjects. For both schemes, the maximum plasma concentration of Compound A was reached between 4.00 h and 24.00 h after dosing, with median T values ​​for Schemes I1 and I2. max 6.50h and 5.00h respectively.

[0418] In Cmax After 1 h, plasma concentrations decreased in a multi-step manner in all subjects in both regimens and remained quantifiable until the last sampling time point (120 h after dosing). At the 300 mg dose level (regimen I1), T 1 / 2 T was reliably calculated to range between 58.9 h and 125 h, with a geometric mean of 85.4 h. At the 100 mg dose level (Schedule I2), T was 0.5 h for 7 of 8 subjects. 1 / 2 was reliably calculated and ranged between 51.3 h and 77.2 h, with a geometric mean of 61.7 h. In cases where the endpoint slope could not be reliably determined, this was a result of an unacceptable coefficient of determination (i.e., R 2 <0.9)

[0419] At the 300 mg dose level (Scheme I1), C max In the range of 1650 ng / mL to 2870 ng / mL, the geometric mean (geometric CV%) was 2170 ng / mL (26.5%). AUC(0-last) was in the range of 124000 ng.h / mL to 159000 ng.h / mL, with a geometric mean (geometric CV%) of 143000 ng.h / mL (11.4%). At the 100 mg dose level (Scheme I2), C max The range of AUC(0-last) was 34600 ng.h / mL to 66000 ng.h / mL with a geometric mean (geometric CV%) of 50400 ng.h / mL (20.7%). The extrapolated portion of the curve represented >20% of the total area and unacceptable results for the coefficient of determination (i.e., R 2 <0.9), for subject 2008 in protocol I2, only AUC(0-inf) could be reliably calculated, with a value of 57300 ng.h / mL.

[0420] Statistical results

[0421] Analysis of dose proportionality

[0422] PK parameter C for assessing dose proportionality max The results of the formal statistical analysis of AUC(0last) / D and AUC(0last) / D are presented in Table 8.

[0423] In general, subproportional increases in exposure were observed from the 100 mg to 300 mg dose levels, particularly at the peak exposure level (i.e., C max), so the conclusions are presented for each dose level separately rather than for the two dose levels combined.

[0424] Table 8. Dose Proportionality (GMR 90% CI)

[0425]

[0426] Subjects received Compound A HME formulations fasting (Scheme G1 / G2 and Scheme H1 / H2) or fed (Scheme I1 / I2). Schemes G and I = tablet formulations, Scheme H = PfR suspension formulation. G1 / H1 / I1 = 300 mg, G2 / H2 / I2 = 100 mg. Results were obtained from log-transformed dose-corrected PK parameters using an ANOVA model. Separate models were fitted for each formulation, and the dose term was included as a fixed effect fit. CI = confidence interval for the ratio of adjusted geometric means; adjusted geometric mean = adjusted geometric mean from model; ratio of adjusted geometric means for test / reference.

[0427] The results showed that for the corresponding PK parameters, such as C max The peak and total exposure of Compound A measured by AUC / D and AUC(0-last) / D were 73.79% and 83.13% of the peak and total exposure of 100 mg Compound A HME tablets (Scheme G2, Reference). max / D and AUC(0-last), the 90% CIs associated with this estimate were (56.43%, 96.50%) and (64.45%, 107.22%), respectively.

[0428] The results showed that for the corresponding PK parameters, such as C of the HME PfR suspension formulation (Scheme H1) selected by 300 mg of Compound A, max The peak and total exposure of Compound A measured by AUC(0-last) / D and AUC(0-last) / D were 75.71% and 99.66% of the peak and total exposure of the selected HME PfR suspension formulation (Scheme H2) of 100 mg Compound A. max / D and AUC(0-last) / D, the 90% CIs associated with this estimate were (58.59%, 97.84%) and (75.60%, 131.37%), respectively.

[0429] The results showed that for the corresponding PK parameters, such as C maxThe peak and total exposure of Compound A measured by AUC(0-last) / D and AUC(0-last) / D were 79.48% and 95.78% of that of the 100 mg Compound A HME tablet formulation (Scheme I2) under food. max / D and AUC(0-last) / D, the 90% CIs associated with this estimate were (59.42%, 106.30%) and (76.99%, 119.15%), respectively.

[0430] Dose correction analysis

[0431] PK parameter C for evaluating the relative bioavailability and food effect of compound A max The results of the formal statistical analysis of AUC(0-last) / D and AUC(0-last) / D are presented in Table 9.

[0432] Table 9. Dose-corrected plasma pharmacokinetic parameters of Compound A - Assessment of relative bioavailability: Pharmacokinetic analysis subset (Part 2)

[0433]

[0434] Subjects received Compound A HME formulation fasting (Regimen G1 / G2 and Regimen H1 / H2) or fed (Regimen I1 / I2). Regimens G and I = tablet formulations, Regimen H = PfR suspension formulation. G1 / H1 / I1 = 300 mg, G2 / H2 / I2 = 100 mg. Results were obtained from log-transformed dose-corrected PK parameters using an ANOVA model. Separate models were fitted for each formulation and the dose term was included as a fixed effect. (1) Mean = adjusted geometric mean from model, (2) ratio of adjusted geometric means for test / reference, (3) CI = confidence interval of the ratio of adjusted geometric means, (4) p-value from two-sided test of the null hypothesis that the ratio is equal to 100%, (5) CVw = within-subject variability relative bioavailability

[0435] The results showed that for the corresponding PK parameters, such as C max The peak and total exposure of Compound A measured by AUC(0-last) / D and AUC(0-last) / D were 96.04% and 104.07% of the peak and total exposure of Compound A HME tablet formulation (Scheme G). The 90% CI indicated that for Compound A max / D, the true measurement is unlikely to be less than 82.97% or greater than 111.17%, and for AUC(0-last) / D, the true measurement is unlikely to be less than 94.56% or greater than 114.54%. There was no statistically significant difference in peak exposure between treatments (p=0.64), and there was no statistically significant difference in total exposure between treatments (p=0.48).

[0436] Food Effect

[0437] The results showed that for the corresponding PK parameters, such as C of Compound A HME tablet formulation (Scheme I) under food intake, max The peak and total exposure of Compound A measured by AUC(0-last) / D and AUC(0-last) / D were 78.80% and 97.25% of the peak and total exposure of Compound A HME tablet formulation (Sche...

Claims

1. A kit comprising: a) a solid formulation of an amorphous solid dispersion of (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof, wherein the solid formulation comprises one or more pharmaceutically acceptable excipients; b) instructions for aqueous reconstitution of the solid dosage form.

2. The kit according to claim 1, wherein the solid preparation is in the form of powder, granules or pellets.

3. The kit according to claim 1, wherein the solid preparation is in powder form.

4. The kit according to any one of claims 1 to 3, wherein the amorphous solid dispersion comprises one or more polymers.

5. The kit of claim 4, wherein the one or more polymers comprises polyvinyl pyrrolidone, polyvinyl pyrrolidone-polyvinyl acetate copolymer (PVP-VA), cross-linked polyvinyl N-pyrrolidone, polyvinyl alcohol (PVA), polysaccharides, hydroxypropyl methylcellulose (HPMC or hydroxypropyl methylcellulose), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), polyethylene oxide, hydroxypropyl-β-cyclodextrin (HP-β-CD), sulfobutyl ether-β-cyclodextrin (Captisol), cyclodextrin (e.g., γ-cyclodextrin), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyethylene glycol (PEG), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVAc-PVCap-PEG), polysaccharides, poly(methacrylic acid-co-methyl methacrylate) (Eudragit), poloxamers, silica gel, aluminosilicates, or combinations thereof.

6. The kit of claim 5, wherein the one or more polymers comprises PVP-VA or HPMCAS.

7. The kit according to any one of claims 4 to 6, wherein the amorphous solid dispersion comprises from about 10 wt% to about 90 wt% of the one or more polymers.

8. The kit of claim 7, wherein the amorphous solid dispersion comprises from about 40 wt% to about 80 wt% of the one or more polymers.

9. The kit of claim 8, wherein the amorphous solid dispersion comprises from about 55 wt% to about 65 wt% of the one or more polymers.

10. The kit according to any one of claims 1 to 9, wherein the amorphous solid dispersion comprises about 10 wt% to about 90 wt% of the compound A or a pharmaceutically acceptable salt thereof.

11. The kit according to claim 10, wherein the amorphous solid dispersion comprises about 20 wt% to about 60 wt% of the compound A or a pharmaceutically acceptable salt thereof.

12. The kit according to claim 11, wherein the amorphous solid dispersion comprises about 35 wt% to about 45 wt% of the compound A or a pharmaceutically acceptable salt thereof.

13. The kit according to any one of claims 4 to 12, wherein the weight ratio of the compound A or a pharmaceutically acceptable salt thereof to the one or more polymers is 2:1 to 1:

2. 14 . The kit according to claim 13 , wherein the weight ratio of the compound A or a pharmaceutically acceptable salt thereof to the one or more polymers is about 1:1 to 1:

2.

15. The kit according to any one of claims 1 to 14, wherein the amorphous solid dispersion comprises Compound A.

16. The kit according to any one of claims 1 to 15, wherein the amorphous solid dispersion is a hot melt extrudate (HME). 17 . The kit according to any one of claims 1 to 15 , wherein the amorphous solid dispersion is prepared by dissolving the compound A or a pharmaceutically acceptable salt thereof in a solvent, and then removing at least a portion of the solvent.

18. The kit according to any one of claims 1 to 17, wherein the particles in the amorphous solid dispersion have a D50 value of about 10 μm to about 500 μm.

19. The kit of claim 18, wherein the particles in the amorphous solid dispersion have a D50 value of about 100 μm to about 400 μm.

20. The kit of any one of claims 1 to 19, wherein the solid formulation comprises about 10 wt% to about 80 wt% of the amorphous solid dispersion.

21. The kit of claim 20, wherein the solid formulation comprises about 40 wt% to about 60 wt% of the amorphous solid dispersion.

22. The kit of claim 20, wherein the solid formulation comprises about 15 wt% to about 35 wt% of the amorphous solid dispersion.

23. The kit according to any one of claims 1 to 22, wherein the one or more pharmaceutically acceptable excipients are mixed with the amorphous solid dispersion in the solid formulation.

24. The kit of any one of claims 1 to 22, wherein the amorphous solid dispersion comprises one or more pharmaceutically acceptable excipients.

25. The kit of any one of claims 1 to 24, wherein the solid formulation comprises from about 5 wt% to about 80 wt% of the one or more pharmaceutically acceptable excipients.

26. The kit of claim 25, wherein the solid formulation comprises about 40 wt% to about 60 wt% of the one or more pharmaceutically acceptable excipients.

27. The kit according to any one of claims 1 to 26, wherein the one or more pharmaceutically acceptable excipients are selected from defoamers, flow aids, surfactants, fillers, colorants, preservatives, flavoring agents, sweeteners, and combinations thereof.

28. The kit of claim 27, wherein the one or more pharmaceutically acceptable excipients are selected from the group consisting of antifoaming agents, flow aids, surfactants, fillers, and combinations thereof.

29. The kit of claim 28, wherein the antifoaming agent comprises simethicone.

30. The kit of any one of claims 27 to 29, wherein the solid formulation comprises about 0.1 wt% to about 15 wt% of the antifoaming agent.

31. The kit of claim 30, wherein the solid formulation comprises about 1 wt% to about 8 wt% of the antifoaming agent.

32. The kit of claim 31, wherein the solid formulation comprises about 3 wt% to about 8 wt% of the antifoaming agent.

33. The kit of claim 30, wherein the solid formulation comprises about 0.5 wt% to about 3 wt% simethicone.

34. A kit according to any one of claims 27 to 33, wherein the flow aid is selected from silicon dioxide, magnesium stearate, talc, starch, magnesium silicate, hydrated sodium sulfoaluminate and combinations thereof.

35. The kit of claim 34, wherein the silica comprises fumed silica, colloidal silica (CSD), or both.

36. The kit of any one of claims 27 to 35, wherein the solid formulation comprises from about 0.25 wt% to about 10 wt% of the flow aid.

37. The kit of claim 36, wherein the solid formulation comprises from about 1 wt% to about 5 wt% of the flow aid.

38. The kit according to any one of claims 27 to 37, wherein the surfactant comprises a cationic surfactant, an anionic surfactant, a nonionic surfactant, or a combination thereof.

39. The kit of claim 38, wherein the surfactant comprises sodium lauryl sulfate (SLS).

40. The kit of claim 38, wherein the surfactant comprises a poloxamer.

41. The kit of any one of claims 27 to 40, wherein the solid formulation comprises from about 0.01 wt% to about 10 wt% of the surfactant.

42. The kit of claim 41, wherein the solid formulation comprises about 0.1 wt% to about 2 wt% of the surfactant.

43. The kit of any one of claims 27 to 42, wherein the filler comprises a polysaccharide, a sugar or a derivative thereof, or both.

44. The kit of claim 43, wherein the filler comprises cellulose, starch, synthetic soluble fiber, sugar alcohol, or a combination thereof.

45. A kit according to any one of claims 27 to 44, wherein the filler comprises mannitol.

46. ​​The kit of any one of claims 27 to 45, wherein the filler comprises microcrystalline cellulose, polydextrose, sodium carboxymethylcellulose (sodium CMC), or a combination thereof.

47. The kit of any one of claims 27 to 46, wherein the solid formulation comprises from about 5 wt% to about 80 wt% of the filler.

48. The kit of claim 47, wherein the solid formulation comprises about 30 wt% to about 75 wt% of the filler.

49. The kit of any one of claims 1 to 48, wherein the instructions for aqueous reconstitution are in the form of a reference referring to the instructions.

50. The kit of claim 1, wherein the solid formulation comprises: a) an amorphous solid dispersion comprising from about 10 wt% to about 60 wt% of Compound A and from about 40 wt% to about 60 wt% of PVP-VA, wherein the amorphous solid dispersion is a hot melt extrudate and is present in the solid formulation at from about 10 wt% to about 30 wt%; b) about 30 wt % to 70 wt % of a filler, wherein the filler comprises microcrystalline cellulose and mannitol; c) about 0.1 wt% to 5 wt% of a surfactant, wherein the surfactant is SLS; d) about 0.25 wt% to 6 wt% of a flow aid, wherein the flow aid is CSD; e) about 0.5 wt% to 5 wt% of an anti-foaming agent, wherein the anti-foaming agent is simethicone.

51. The kit of any one of claims 1 to 50, wherein the solid formulation further comprises a carrier for the antifoaming agent.

52. The kit of claim 51, wherein the carrier for the antifoaming agent is present at about 4-6 wt%, 3-7 wt%, or 1-10 wt% of the solid formulation.

53. The kit of any one of claims 1 to 52, wherein the kit comprises one or more doses of Compound A or a pharmaceutically acceptable salt thereof.

54. The kit of claim 53, wherein the kit comprises 1 to 5 unit doses of Compound A or a pharmaceutically acceptable salt thereof.

55. The kit of claim 54, wherein the kit comprises a single unit dose of Compound A or a pharmaceutically acceptable salt thereof.

56. A kit according to any one of claims 53 to 55, wherein the dose is a pediatric dose.

57. The kit of any one of claims 53 to 56, wherein each dose comprises about 50 mg to about 800 mg of Compound A or a pharmaceutically acceptable salt thereof.

58. The kit of claim 57, wherein each dose comprises about 300 mg or about 600 mg of Compound A.

59. The kit of any one of claims 1 to 58, further comprising one or more containers, optionally comprising markings indicating measurements of volume.

60. A pharmaceutical powder comprising: a) an amorphous solid dispersion comprising (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof; and b) one or more pharmaceutically acceptable excipients, wherein the excipients comprise a flow aid and a surfactant.

61. The pharmaceutical powder of claim 60, wherein the pharmaceutical powder is configured to be reconstituted into an oral liquid suspension.

62. The pharmaceutical powder of claim 60 or 61, wherein the amorphous solid dispersion comprises one or more polymers.

63. The pharmaceutical powder of claim 62, wherein the one or more polymers comprises polyvinyl pyrrolidone, vinyl pyrrolidone-vinyl acetate copolymer (PVP-VA), cross-linked polyvinyl N-pyrrolidone, polyvinyl alcohol (PVA), polysaccharides, hydroxypropyl methylcellulose (HPMC or hydroxypropyl methylcellulose), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), polyethylene oxide, hydroxypropyl-β-cyclodextrin (HP-β-CD), sulfobutyl ether-β-cyclodextrin (Captisol), γ-cyclodextrin, hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyethylene glycol (PEG), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVAc-PVCap-PEG), polysaccharides, poly(methacrylic acid-co-methyl methacrylate) (Eudragit), poloxamers, silica gel, aluminosilicates, or combinations thereof.

64. The pharmaceutical composition of claim 62, wherein the one or more polymers comprises PVP-VA or HPMCAS.

65. The pharmaceutical powder of any one of claims 62 to 64, wherein the amorphous solid dispersion comprises from about 10 wt% to about 90 wt% of the one or more polymers.

66. The pharmaceutical powder of any one of claims 60 to 65, wherein the amorphous solid dispersion comprises about 10 wt% to about 90 wt% of the Compound A or a pharmaceutically acceptable salt thereof.

67. The pharmaceutical powder according to any one of claims 62 to 66, wherein the weight ratio of Compound A or a pharmaceutically acceptable salt thereof to the one or more polymers is from 2:1 to 1:

2.

68. The pharmaceutical powder of any one of claims 60 to 67, wherein the amorphous solid dispersion comprises Compound A.

69. The pharmaceutical powder according to any one of claims 60 to 68, wherein the amorphous solid dispersion is a hot melt extrudate (HME).

70. The pharmaceutical powder according to any one of claims 60 to 68, wherein the amorphous solid dispersion is prepared by dissolving the Compound A or a pharmaceutically acceptable salt thereof in a solvent, and then removing at least a portion of the solvent.

71. The pharmaceutical powder according to any one of claims 60 to 70, wherein the Compound A or a pharmaceutically acceptable salt thereof is amorphous.

72. The pharmaceutical powder of any one of claims 60 to 71, wherein the amorphous solid dispersion has a D50 value of about 10 μm to about 500 μm.

73. The pharmaceutical powder of any one of claims 60 to 72, wherein the pharmaceutical powder comprises from about 10 wt% to about 80 wt% of the amorphous solid dispersion.

74. The pharmaceutical powder of claim 73, wherein the pharmaceutical powder comprises from about 20 wt% to about 60 wt% of the amorphous solid dispersion.

75. The pharmaceutical powder of any one of claims 60 to 74, wherein the one or more pharmaceutically acceptable excipients are mixed with the amorphous solid dispersion in the pharmaceutical powder.

76. The pharmaceutical powder of any one of claims 60 to 75, wherein the pharmaceutical powder comprises from about 5 wt% to about 80 wt% of the one or more pharmaceutically acceptable excipients.

77. The pharmaceutical powder of any one of claims 60 to 76, wherein the one or more pharmaceutically acceptable excipients comprise an antifoaming agent, a filler, a colorant, a preservative, a flavoring agent, a sweetener, or a combination thereof.

78. The pharmaceutical powder of claim 77, wherein the antifoaming agent comprises simethicone.

79. The pharmaceutical powder according to claims 77 and 78, wherein the antifoaming agent is present in the pharmaceutical powder at about 0.1 wt% to about 10 wt%.

80. The pharmaceutical powder of any one of claims 77 to 79, wherein the filler comprises a polysaccharide, a sugar or a derivative thereof, or both.

81. The pharmaceutical powder of claim 80, wherein the filler comprises cellulose, starch, synthetic soluble fiber, sugar alcohol, or a combination thereof.

82. The pharmaceutical powder of any one of claims 77 to 81, wherein the filler comprises mannitol.

83. The pharmaceutical powder of any one of claims 77 to 82, wherein the filler comprises microcrystalline cellulose, polydextrose, sodium carboxymethylcellulose (sodium CMC), or a combination thereof.

84. The pharmaceutical powder of any one of claims 77 to 83, wherein the pharmaceutical powder comprises from about 5 wt% to about 80 wt% of the filler.

85. The pharmaceutical powder according to any one of claims 60 to 84, wherein the flow aid is selected from silicon dioxide, magnesium stearate, talc, starch, magnesium silicate, hydrated sodium sulfoaluminate, and combinations thereof.

86. The pharmaceutical powder of claim 85, wherein the silicon dioxide comprises fumed silicon dioxide, colloidal silicon dioxide (CSD), or both.

87. The pharmaceutical powder of any one of claims 60 to 86, wherein the pharmaceutical powder comprises from about 0.25 wt% to about 10 wt% of the flow aid.

88. The pharmaceutical powder of any one of claims 60 to 87, wherein the surfactant comprises a cationic surfactant, an anionic surfactant, a nonionic surfactant, or a combination thereof.

89. The pharmaceutical powder of claim 88, wherein the surfactant comprises sodium lauryl sulfate (SLS).

90. The pharmaceutical powder of claim 88, wherein the surfactant comprises a poloxamer.

91. The pharmaceutical powder of any one of claims 60 to 90, wherein the pharmaceutical powder comprises from about 0.01 wt% to about 10 wt% of the surfactant.

92. The pharmaceutical powder of claim 60, comprising: a) about 10 wt % to about 60 wt % of an amorphous solid dispersion comprising (i) about 40 wt % to about 60 wt % of Compound A and (ii) about 40 wt % to about 60 wt % of PVP-VA, wherein the amorphous solid dispersion is a hot melt extrudate; b) about 30 wt % to about 70 wt % of a filler, wherein the filler comprises microcrystalline cellulose and mannitol; c) about 0.1 wt% to 5 wt% of a surfactant, wherein the surfactant is SLS; d) about 0.25 wt% to 6 wt% of a flow aid, wherein the flow aid is CSD; and e) about 0.5 wt% to 5 wt% of an anti-foaming agent, wherein the anti-foaming agent is simethicone or dimethicone.

93. An oral liquid suspension comprising: a) the solid preparation in the kit according to any one of claims 1 to 59, and b) Aqueous solution.

94. An oral liquid suspension produced by contacting the solid formulation in the kit according to any one of claims 1 to 59 with an aqueous solution.

95. An oral liquid suspension comprising: a) a pharmaceutical powder according to any one of claims 60 to 92, and b) Aqueous solution.

96. An oral liquid suspension produced by contacting a pharmaceutical powder according to any one of claims 60 to 92 with an aqueous solution.

97. An oral liquid suspension comprising: a) (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof; b) one or more pharmaceutically acceptable excipients; and c) Water.

98. The oral liquid suspension of claim 97, wherein Compound A or a pharmaceutically acceptable salt thereof is in the form of an amorphous solid dispersion.

99. The oral liquid suspension of claim 98, wherein the amorphous solid dispersion comprises one or more polymers.

100. The oral liquid suspension of claim 99, wherein the one or more polymers comprise polyvinyl pyrrolidone, vinyl pyrrolidone-vinyl acetate copolymer (PVP-VA), cross-linked polyvinyl N-pyrrolidone, polyvinyl alcohol (PVA), polysaccharides, hydroxypropyl methylcellulose (HPMC or hydroxypropyl methylcellulose), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), polyethylene oxide, hydroxypropyl-β-cyclodextrin (HP-β-CD), sulfobutyl ether-β-cyclodextrin (Captisol), γ-cyclodextrin, hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyethylene glycol (PEG), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVAc-PVCap-PEG), polysaccharides, poly(methacrylic acid-co-methyl methacrylate) (Eudragit), poloxamers, silica gel, aluminosilicates, or combinations thereof.

101. The oral liquid suspension of any one of claims 97 to 100, wherein the one or more pharmaceutically acceptable excipients are selected from the group consisting of defoaming agents, flow aids, surfactants, fillers, colorants, preservatives, flavoring agents, sweeteners, and combinations thereof.

102. The oral liquid suspension of any one of claims 93 to 101, wherein the oral liquid suspension is reconstituted.

103. The oral liquid suspension of any one of claims 93 to 102, wherein the concentration of Compound A or a pharmaceutically acceptable salt thereof in the oral liquid suspension is from about 10 mg / mL to about 125 mg / mL.

104. The oral liquid suspension of any one of claims 93 to 102, wherein the concentration of Compound A or a pharmaceutically acceptable salt thereof in the oral liquid suspension is from about 10 mg / mL to about 50 mg / mL.

105. The oral liquid suspension of any one of claims 93 to 96, wherein the aqueous solution is water.

106. The oral liquid suspension of any one of claims 93 to 105, wherein the pH of the liquid suspension is about 2 to 7.

107. The oral liquid suspension of any one of claims 93 to 106, wherein the suspension remains injectable for at least 15 minutes.

108. The oral liquid suspension of claim 107, wherein the suspension remains injectable for at least 30 minutes.

109. The oral liquid suspension of any one of claims 93 to 108, wherein the concentration of the one or more polymers in the suspension is from about 10 mg / mL to about 200 mg / mL.

110. The oral liquid suspension of claim 109, wherein the concentration of the one or more polymers in the suspension is from about 30 mg / mL to about 50 mg / mL.

111. The oral liquid suspension of claim 109, wherein the concentration of the one or more polymers in the suspension is from about 60 mg / mL to about 80 mg / mL.

112. The oral liquid suspension of any one of claims 93 to 111, wherein the concentration of the filler in the suspension is from about 30 mg / mL to about 500 mg / mL.

113. The oral liquid suspension of claim 112, wherein the concentration of the filler in the suspension is about 50 mg / mL to about 300 mg / mL.

114. The oral liquid suspension of claim 113, wherein the concentration of the filler in the suspension is about 125 mg / mL to about 200 mg / mL.

115. The oral liquid suspension of any one of claims 93 to 114, wherein the concentration of the surfactant in the suspension is from about 0.5 mg / mL to about 10 mg / mL.

116. The oral liquid suspension of claim 115, wherein the concentration of the surfactant in the suspension is about 1 mg / mL to about 2.5 mg / mL.

117. The oral liquid suspension of any one of claims 93 to 116, wherein the concentration of the flow aid in the suspension is about 3 mg / mL to about 30 mg / mL.

118. The oral liquid suspension of claim 117, wherein the concentration of the flow aid in the suspension is about 5 mg / mL to about 15 mg / mL.

119. The oral liquid suspension of claim 118, wherein the concentration of the flow aid in the suspension is about 10 mg / mL to about 15 mg / mL.

120. The oral liquid suspension of any one of claims 93 to 119, wherein the concentration of the antifoaming agent in the suspension is about 1 mg / mL to about 30 mg / mL.

121. The oral liquid suspension of claim 120, wherein the concentration of the antifoaming agent in the suspension is from about 1 mg / mL to about 10 mg / mL.

122. The oral liquid suspension of claim 121, wherein the concentration of the antifoaming agent in the suspension is about 3 mg / mL to about 8 mg / mL.

123. The oral liquid suspension of any one of claims 93 to 108, wherein the suspension comprises, based on the weight of the solids: a) about 10 wt % to about 50 wt % of an amorphous solid dispersion comprising (i) about 40 wt % to about 60 wt % of Compound A and (ii) about 40 wt % to about 60 wt % of PVP-VA, wherein the amorphous solid dispersion is a hot melt extrudate; b) about 40 wt % to about 70 wt % of a filler, wherein the filler comprises microcrystalline cellulose and mannitol; c) from about 0.25 wt % to about 1 wt % of a surfactant, wherein the surfactant is SLS; d) from about 1 wt % to about 6 wt % of a flow aid, wherein the flow aid is colloidal silicon dioxide (CSD); e) from about 1 wt % to about 5 wt % of an anti-foaming agent, wherein the anti-foaming agent comprises simethicone; and f) optionally preservatives, flavoring agents, sweeteners or combinations thereof.

124. The oral liquid suspension of any one of claims 93 to 108, wherein the suspension comprises, based on the weight of the solids: a) about 20-30 wt% (e.g., 25 wt%, or 24%-25%) of an amorphous solid dispersion comprising (i) about 40 wt% of Compound A and (ii) about 60 wt% of copovidone, wherein the amorphous solid dispersion is optionally a hot melt extrudate; b) about 30 wt % to 32 wt % mannitol; c) about 30 wt % to 32 wt % microcrystalline cellulose; d) about 0.5 wt % to 1 wt % SLS; e) about 4 wt % to 5 wt % CSD; f) about 1 wt % to 3 wt % of simethicone; g) about 3 wt % to about 8 wt % maltodextrin; h) optionally preservatives, flavoring agents, sweeteners or combinations thereof.

125. The oral liquid suspension of any one of claims 93 to 108, wherein the suspension comprises, based on the weight of the solids: a) about 10 wt% of an amorphous solid dispersion comprising (i) about 40 wt% of Compound A and (ii) about 60 wt% of copovidone, wherein the amorphous solid dispersion is a hot melt extrudate; b) about 30 wt % to 32 wt % mannitol; c) about 30 wt % to 32 wt % microcrystalline cellulose; d) about 0.5 wt % to 1 wt % SLS; e) about 4 wt % to 5 wt % CSD; f) about 1 wt% to 3 wt% simethicone; and g) optionally preservatives, flavoring agents, sweeteners or combinations thereof.

126. An oral liquid suspension according to any one of claims 93 or 125, wherein the oral liquid suspension is bioequivalent to a tablet formulation of Compound A, wherein the tablet composition comprises an amorphous solid dispersion comprising (i) about 40 wt % of Compound A and (ii) about 60 wt % of copovidone, wherein the amorphous solid dispersion is a hot melt extrudate; and one or more pharmaceutically acceptable excipients.

127. The oral liquid suspension of any one of claims 93 or 125, wherein the oral liquid suspension is sufficient to achieve a maximum observed plasma concentration (Cmax) of Compound A of at least about 100 ng / mL in a human subject when administered to the subject in an amount equivalent to about 100 mg of Compound A.

128. The oral liquid suspension of claim 127, wherein the oral liquid suspension is sufficient to achieve a maximum observed plasma concentration (Cmax) of Compound A of at least about 100 ng / mL in a human subject when administered to the subject in an amount equivalent to about 100 mg of Compound A.

129. A kit comprising a pharmaceutical powder for reconstitution according to any one of claims 60 to 92.

130. A method of treating cancer in a subject, comprising: An oral liquid suspension comprising (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof is administered to the subject in an amount sufficient to achieve a maximum observed plasma concentration (Cmax) of Compound A of at least 2000 ng / mL in the subject.

131. A method of treating cancer in a subject comprising administering to the subject the pharmaceutical powder of any one of claims 60 to 92 or the reconstituted oral liquid formulation of any one of claims 93 to 128.

132. A method of treating cancer in a subject, comprising reconstituting the solid formulation in the kit of any one of claims 1 to 59, and administering the reconstituted formulation to the subject.

133. The method of any one of claims 130 to 132, wherein the subject is 18 years of age or younger.

134. The method of any one of claims 130 to 133, wherein the cancer is a low-grade glioma.

135. A method of treating a subject with pediatric low-grade glioma (pLGG), comprising reconstituting an amorphous solid dispersion of Compound A or a salt thereof in an aqueous solution and administering a pharmaceutically acceptable dose of the reconstituted Compound A or a salt thereof to the subject in need thereof.

136. The method of any one of claims 130 to 135, wherein the subject has not been previously administered a MEK inhibitor or a MAPK inhibitor.

137. The method of any one of claims 130 to 136, wherein the method is administered with food, before consumption of food, or after consumption of food.

138. A method for preparing a liquid preparation, comprising: a) providing a solid preparation of an amorphous solid dispersion, wherein the amorphous solid dispersion comprises: (i) (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof; and (ii) one or more polymers; and b) contacting the solid formulation with an aqueous solution.

139. The method of claim 138, wherein the contacting comprises mixing the solid formulation with the aqueous solution to form a suspension.

140. The method of claim 139, wherein the mixing comprises shaking the solid formulation and the aqueous solution to form a suspension.

141. The method of claim 139, wherein the mixing comprises adding the aqueous solution to a container containing the solid formulation, and then shaking the container to form a suspension.

142. The method of claim 139, wherein the mixing comprises adding the solid formulation to a container containing the aqueous solution and then shaking the container to form a suspension.

143. The method of any one of claims 140 to 142, wherein the shaking lasts from about 10 seconds to about 240 seconds.

144. The method of any one of claims 140 to 142, wherein the shaking lasts from about 10 seconds to about 60 seconds, from about 60 seconds to about 120 seconds, from about 40 seconds to about 80 seconds, or from about 50 seconds to about 70 seconds.

145. The method of any one of claims 140 to 142, wherein the shaking lasts for about 60 seconds.

146. The method of any one of claims 140 to 142, wherein the shaking lasts no more than about 120 seconds in total.

147. The method of any one of claims 141 to 146, wherein the container is shaken in all directions.

148. The method of any one of claims 139 to 146, wherein the mixing or shaking occurs in 15 second increments.

149. The method of any one of claims 139 to 146, wherein the mixing or shaking continues until all of the solid formulation is dispersed in the aqueous solution.

150. The method of any one of claims 138 to 149, wherein the aqueous solution has a temperature of about 15°C to about 80°C, about 20°C to about 60°C, or about 20°C to about 50°C.

151. The method of any one of claims 138 to 149, wherein the aqueous solution is warm or room temperature water.

152. The method of any one of claims 141 to 151, further comprising inverting the container and continuing to mix the suspension.

153. The method of claim 152, comprising inverting the container and vortexing for about 10 seconds to about 60 seconds, about 20 seconds to about 40 seconds, about 40 seconds to about 80 seconds, or about 15 seconds to about 45 seconds.

154. The method of any one of claims 141 to 153, further comprising allowing the container to sit for a period of time without mixing.

155. The method of any one of claims 138 to 154, wherein the volume of the aqueous solution is from about 5 mL to about 200 mL, from about 5 mL to 100 mL, from about 5 mL to 50 mL, from about 5 mL to 25 mL, from about 5 mL to 20 mL, from about 10 mL to 50 mL, from about 10 mL to 25 mL, from about 25 mL to 50 mL, from about 25 mL to 150 mL, or from about 10 mL to about 20 mL.

156. The method of any one of claims 138 to 154, wherein the volume of the aqueous solution is about 10 mL, about 11 mL, about 12 mL, about 13 mL, about 14 mL, about 15 mL, about 16 mL, about 17 mL, about 18 mL, about 19 mL, or about 20 mL.

157. The method of any one of claims 138 to 151, wherein the volume of the aqueous solution is about 14 mL.

158. The method of any one of claims 141 to 157, further comprising removing the suspension from the container with a syringe.

159. The method of claim 158, further comprising administering the suspension to a subject directly from the syringe.

160. The method of any one of claims 138 to 159, wherein the solid formulation is in the form of a pharmaceutical powder.

161. A method for preparing an oral liquid suspension of Compound A or a salt thereof, comprising reconstituting the solid formulation in the kit according to any one of claims 1 to 59 in an aqueous solution.

162. A method of preparing an oral liquid suspension of Compound A or a salt thereof, comprising reconstituting the pharmaceutical powder according to any one of claims 60 to 92 in an aqueous solution.

163. A method of treating pediatric low-grade glioma (pLGG) in a subject, comprising: An oral liquid suspension comprising (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof is administered to the subject in an amount sufficient to achieve a maximum observed plasma concentration (Cmax) of Compound A of at least 2000 ng / mL in the subject, wherein the subject has not been previously administered a MEK inhibitor, a MAPK inhibitor, or a combination thereof.

164. A method of treating pediatric low-grade glioma (pLGG) comprising administering to a subject a pharmaceutical powder according to any one of claims 60 to 92 or a reconstituted oral liquid formulation according to any one of claims 93 to 128, wherein the subject has not been previously administered a MEK inhibitor, a MAPK inhibitor, or a combination thereof.

165. A method of treating pediatric low-grade glioma (pLGG), comprising reconstituting the solid formulation in the kit of any one of claims 1 to 59, and administering the reconstituted formulation to a subject, wherein the subject has not been previously administered a MEK inhibitor, a MAPK inhibitor, or a combination thereof.

166. The method of any one of claims 163 to 165, wherein the subject has not been previously administered a MEK inhibitor.

167. The method of any one of claims 163 to 165, wherein the subject has not been previously administered a MAPK inhibitor.

168. The method of any one of claims 163 to 165, wherein the subject is 6 months of age and older with relapsed or refractory pLGG harboring a BRAF fusion or rearrangement or a BRAF V600 mutation.

169. The method of any one of claims 163 to 165, wherein the subject exhibits the presence of a BRAF fusion or rearrangement or a BRAF mutation prior to initiating treatment.

170. A method of treating pediatric low-grade glioma (pLGG), comprising administering to a subject in need thereof a pharmaceutical powder according to any one of claims 60 to 92 or an oral liquid suspension according to any one of claims 93-128, The subjects described were patients aged 6 months; The pLGG is a recurrent or pLGG carrying BRAF fusion or rearrangement or BRAF V600 mutation.

171. The method of claim 170, wherein the oral liquid suspension is administered orally or enterally via a dosing syringe via a nasal or gastric feeding tube.

172. The method of claim 170 or 171, comprising orally administering about 420 mg / m based on body surface area (BSA) once a week. 2 of compound A (not more than 600 mg).

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