Pharmaceutical compositions of epidermal growth factor receptor inhibitors

Abstract

The present disclosure relates to a pharmaceutical composition comprising (i) an amorphous solid dispersion comprising Compound (I) or a pharma- ceutically acceptable salt thereof and a pharma-ceutically acceptable polymer, and (ii) an intragranular phase comprising a surfactant and an extragranular phase comprising a surfactant.The present disclosure also relates to a method of using the composition in the treatment of various disorders.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 214,099, filed June 23, 2021. The entire contents of the aforementioned application are incorporated herein by reference. [Background technology]

[0002] Compound (I), the structure of which is shown below, has been disclosed in patent application PCT / US2020 / 066629 as one of many EGFR inhibitor compounds. Compound (I) is a potent and selective EGFR inhibitor provided in an oral dosage form to selectively target oncogenic EGFR mutations in certain cancer patients, for example, patients with cancers that harbor EGFR with one or more alterations, including L858R and / or exon 19 deletion mutations, T790M mutations, and / or C797S mutations. Compound (I) may also be referred to as N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, and has the following chemical structure: [ka]

[0003] There is a need to develop pharmaceutical compositions of Compound (I) suitable for medical use. Summary of the Invention

[0004] The disclosure features a pharmaceutical composition that includes (i) an amorphous solid dispersion including Compound (I) or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable polymer; and (ii) an intragranular phase including a surfactant, and an extragranular phase including at least one of a surfactant, a disintegrant, a flow agent, a lubricant, and a filler. [Brief description of the drawings]

[0005] [Figure 1] 1 compares the dissolution profiles of Formulations 1 and 2 compared to 50:50 Compound (I):HPMCAS-M alone (i.e., ASD alone) in biorelevant media, i.e., gastric and intestinal pH. [Diagram 2] 1 compares the dissolution profile of Formulation 3 compared to 50:50 Compound (I):HPMCAS-M alone (i.e., ASD alone) in biorelevant media, i.e., gastric and intestinal pH. [Diagram 3] 1 compares the dissolution profiles of Formulations 4 and 5 compared to 50:50 Compound (I):HPMCAS-M alone (i.e., ASD alone) in biorelevant media, i.e., gastric and intestinal pH. [Figure 4] FIG. 11 compares dog PK plasma concentration profiles between 50:50 Compound (I):HPMCAS-M alone (ie, ASD alone), tablet formulations T1 and T2 and T3. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0006] Compound (I) is a potent kinase inhibitor, but was found to have poor water solubility. To improve bioavailability, Compound (I) was molecularly dispersed in a polymer matrix system to create a solid dispersion and improve dissolution rate. Although dissolving a poorly water-soluble active pharmaceutical ingredient (API) in a polymer improves overall solubility, some polymer matrices may delay the onset of API dissolution as the API must be released from the matrix. The properties of the excipients further affect the dissolution behavior of solid dispersions. However, it was unexpected that the addition of surfactants in the intragranular phase, as well as the extragranular phase consisting of at least one of surfactants, disintegrants, flow agents, lubricants, and fillers of the pharmaceutical composition, would allow for wetting, dispersion, and dissolution of Compound (I) at a rate suitable for an immediate release solid dosage form.

[0007] Pharmaceutical Compositions "Extragranular" has or relates to additional excipients that are incorporated into the formulation after granulation, i.e., ingredients that are located outside the granule structure.

[0008] "Intragranular" refers to having or relating to additional excipients that are incorporated into the formulation prior to granulation, i.e., ingredients that are located within the granule structure.

[0009] A "pharmaceutically acceptable polymer" can be a non-ionic polymer or an ionic polymer. Generally, when selected, the polymer should be selected based on polymer chemistry along with the properties of the API and the manufacturing aspects of the formulation.Suitable polymers for use in the amorphous solid dispersions of the present disclosure include, but are not limited to, homopolymers or copolymers of N-vinyl lactams, such as homopolymers or copolymers of N-vinylpyrrolidone (e.g., polyvinylpyrrolidone (PVP), or copolymers of N-vinylpyrrolidone and vinyl acetate (PVPVA), or copolymers of N-vinylpyrrolidone and vinyl propionate); cellulose esters or ethers, such as alkylcelluloses (e.g., methylcellulose or ethylcellulose), hydroxyalkylcelluloses (e.g., hydroxypropylcellulose), hydroxyalkylalkylcelluloses (e.g., hydroxypropylmethylcellulose), and cellulose phthalates or succinates (e.g., cellulose acetate phthalate, and hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate, or hydroxypropylmethylcellulose acetate succinate); polymers such as cellulose acetate phthalate, ... Polyalkylene oxides, such as polyethylene oxide, polypropylene oxide, and copolymers of ethylene oxide and propylene oxide; polyacrylates or polymethacrylates, such as methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl methacrylate copolymer, butyl methacrylate / 2-dimethylaminoethyl methacrylate copolymer, poly(hydroxyalkyl acrylates), and poly(hydroxyalkyl methacrylates); polyacrylamides; vinyl acetate polymers, such as copolymers of vinyl acetate and crotonic acid, and partially hydrolyzed polyvinyl acetate (also called partially saponified "polyvinyl alcohol"); polyvinyl alcohol; oligosaccharides or polysaccharides, such as carrageenan, galactomannan, and xanthan gum; polyhydroxyalkyl acrylates; polyhydroxyalkyl-methacrylates; copolymers of methyl methacrylate and acrylic acid; polyethylene glycols (PEGs), such as polyvinyl graph copolymers; or any mixtures thereof.In one embodiment, the polymer is hydroxypropyl methylcellulose (HPMC or hypromellose), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), such as HPMCAS-M, HPMCAS-L, and HPMCAS-H, hydroxypropyl methylcellulose E5 (HPMC-E5), hydroxypropyl methylcellulose E3 (HPMC-E3), HPMCAS-M, HPMC E3LV, HPMCP-HP55, vinylpyrrolidone-vinyl acetate copolymer (KOLLIDON VA64 or KOLLIDON K30), dimethylaminoethyl methacrylate copolymer (EUDRAGIT EPO), Eudragrit 100, Eudragrit L, poly(ethylene) oxide (POLYOX), or polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SOLUPLUS). In certain embodiments, the polymer is a 6:4 linear random copolymer of N-vinylpyrrolidone and vinyl acetate (e.g., PVPVA-64), HPMCAS-M, Eudragit L100-55, Eudragit L100, and HPMC E3LV. In certain embodiments, the polymer is PVPVA-64 and HPMCAS. In certain embodiments, the polymer is HPMCAS. In certain embodiments, the polymer is PVPVA-64 and HPMCAS-M. In certain embodiments, the polymer is HPMCAS-M. In certain embodiments, the polymer is HPMCAS-MG.

[0010] HPMC E3 refers to hydroxypropyl methylcellulose having a viscosity of about 2.4-3.6 mPa s (2% in water). HPMC E5 refers to hydroxypropyl methylcellulose having a viscosity of about 4-6 mPa s (2% in water). HPMCAS-M, HPMCAS-L, and HPMCAS-H refer to hydroxypropyl methylcellulose acetate succinate, where M, L, and H are different grades of polymer with different acetyl and succinoyl content. HPMC E3LV refers to low viscosity hydroxypropyl methylcellulose, where E3 is the grade determined by the average content of methoxyl and hydroxypropyl groups. In certain embodiments, the polymer is hydroxypropyl methylcellulose acetate succinate. In certain embodiments, the hydrophilic polymer is hydroxypropyl methylcellulose acetate succinate (HPMC-AS).

[0011] In one aspect, the disclosure features an amorphous solid dispersion comprising Compound (I) or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable polymer. In some embodiments, the polymer is hydroxypropylmethylcellulose (HPMC) (e.g., HPMCAS-M) or polyvinylpyrrolidone (PVP) or a 6:4 linear random copolymer of N-vinylpyrrolidone and vinyl acetate (e.g., PPVVA-64).

[0012] In one aspect, the solvent used to prepare the amorphous solid dispersion is dichloromethane (DCM), methanol (MeOH), or a combination thereof. In some embodiments, the ratio of dichloromethane to methanol is 100:0 (e.g., DCM only); 90:10 DCM:MeOH; 80:20 DCM:MeOH; 70:30 DCM:MeOH; or 60:40 DCM:MeOH.

[0013] In one aspect, the solvent used to prepare the amorphous solid dispersion is acetone or water, or a combination thereof. In some embodiments, the ratio of acetone to water is 100:0 acetone:water (e.g., 100% acetone), 95:5 acetone:water, or 90:10 acetone:water.

[0014] In one embodiment, the solid content of the spray solution for preparing the amorphous solid dispersion (i.e., the total concentration (w / w) of Compound (I) and polymer in the solvent used to prepare the amorphous solid dispersion) is 4 w / w% to 15 w / w%, for example, 4 w / w%, 4.5 w / w%, 5 w / w%, 5.5 w / w%, 6 w / w%, 6.5 w / w%, 7.0 w / w%, 7.5 w / w%, 8.0 w / w%, 8.5 w / w%, 9 w / w%, 9.5 w / w%, 10 w / w%, 10.5 w / w%, 11 w / w%, 11.5 w / w%, 12 w / w%, 12.5 w / w%, 13 w / w%, 13.5 w / w%, 14 w / w%, 14.5 w / w%, or 15 w / w%.

[0015] In one embodiment, the compound (I) free base or an equivalent amount of a pharma- ceutically acceptable salt thereof and the polymer are in a weight percent ratio of about 1:1, for example, the disclosed compositions may contain about 100 mg of compound (I) free base and about 100 mg of a polymer as disclosed herein (or 50 mg of compound (I) and about 50 mg of polymer or 25 mg of compound (I) and about 25 mg of polymer). In another embodiment, the compound (I) free base or an equivalent amount of a pharma- ceutically acceptable salt thereof and the polymer are in a weight percent ratio of about 1:5 to about 5:1. In another embodiment, the compound (I) free base or an equivalent amount of a pharma- ceutically acceptable salt thereof and the polymer are in a weight percent ratio of about 1:3 to about 3:1. In another embodiment, the compound (I) free base or an equivalent amount of a pharma- ceutically acceptable salt thereof and the polymer are in a weight percent ratio of about 1:2 to about 2:1. In another embodiment, the compound (I) free base or an equivalent amount of a pharma- ceutically acceptable salt thereof and the polymer are in a weight percent ratio of about 1:1.5 to about 1.5:1. In another embodiment, the compound (I) free base or an equivalent amount of a pharma- ceutically acceptable salt thereof and the polymer are in a weight percent ratio of about 1:1.1 to about 1.1:1. In another embodiment, the compound (I) free base or an equivalent amount of a pharma- ceutically acceptable salt thereof and the polymer are in a weight percent ratio of about 2:3. In another embodiment, the compound (I) free base or an equivalent amount of a pharma- ceutically acceptable salt thereof and the polymer are in a weight percent ratio of about 3:7.

[0016] In one embodiment, Compound (I) free base or an equivalent amount of a pharma- ceutically acceptable salt thereof and the polymer are in a weight percent ratio of about 10%:90%, 20%:80%, about 30%:70%, 40%:60%, 50%:50%, about 60%:40%, about 70%:30%, about 80%:20%, or about 90%:10%. In certain embodiments, the polymer is PVP-VA, Eudragit 100, HPMCAS-M, HPMCAS-MG, or HPMC E3LV and is about 70%, about 60%, and about 50%, and Compound (I) free base is about 30%, about 40%, and about 50% drug loading.

[0017] In one aspect, the compositions disclosed herein are prepared in an oral dosage form.

[0018] In one embodiment, the compositions or oral dosage forms described herein comprise about 20% to about 80% by weight of the amorphous solid dispersion of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise about 25% to about 75% by weight of the amorphous solid dispersion of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise about 35% to about 65% by weight of the amorphous solid dispersion of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise about 45% to about 55% by weight of the amorphous solid dispersion of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise about 40% to about 50% by weight of the amorphous solid dispersion of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 75% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the amorphous solid dispersion is in the intragranular phase.

[0019] In one embodiment, the amorphous solid dispersion is prepared by hot melt extrusion, freeze drying, co-precipitation, spray drying, hot melt coagulation, solvent casting, or melt quenching. Thus, the solid dispersions prepared from these different methods may differ in properties based on the matrix formed by the dispersion polymer, such as porosity, surface area, density, stability, hygroscopicity, dissolution, and therefore bioavailability. In a particular embodiment, the amorphous solid dispersion is prepared by spray drying.

[0020] In one aspect, the composition or solid dosage form comprises a surfactant. Non-limiting examples of suitable surfactants include cationic, anionic, zwitterionic, or nonionic, and mixtures thereof. Non-limiting examples of surfactants that can be used include quaternary ammonium compounds such as dioctyl sodium sulfosuccinate, polyoxyethylene alkylphenyl ethers such as nonoxynol 9, nonoxynol 10, and octoxynol 9, poloxamers (polyoxyethylene and polypropylene block copolymers, e.g., Poloxamer 407), polyoxyethylene fatty acid glycerides and oils such as polyoxyethylene (8), caprylic / capric acid monoglyceride and diglyceride, polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil, polyethylene alkyl ethers such as polyoxyethylene (20) cetostearyl ether, polyoxyethylene fatty acid esters such as polyoxyethylene (40) stearate, polyoxyethylene sorbitan esters such as polysorbate 20 and polysorbate 80 (e.g., Tween 100). 80), propylene glycol fatty acid esters such as propylene glycol laurate, sodium lauryl sulfate, fatty acids and their salts such as oleic acid, sodium oleate and triethanolamine oleate, glyceryl fatty acid esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate, tyloxapol, and mixtures thereof. In a particular embodiment, the surfactant is a poloxamer, such as poloxamer 407. In a more particular embodiment, the surfactant is poloxamer 407 micro having an average particle size of about 50 μm.

[0021] In one embodiment, the compositions or oral dosage forms described herein comprise from about 0.25% to about 20% by weight of the composition or oral dosage form of a surfactant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 0.25% to about 15% by weight of the composition or oral dosage form of a surfactant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 0.25% to about 10% by weight of the composition or oral dosage form of a surfactant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 0.25% to about 5% by weight of the composition or oral dosage form of a surfactant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 0.25% to about 3% by weight of the composition or oral dosage form of a surfactant, based on the total weight of the composition or oral dosage form. In one aspect, the compositions or oral dosage forms described herein comprise about 0.25%, about 0.4%, about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0022] In one aspect, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0.1% to about 20% by weight of the surfactant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and, in the extragranular phase, from about 0.1% to about 20% by weight of the surfactant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and the total amount of surfactant in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 0.25% to about 20% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0023] In one aspect, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0.1% to about 15% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, a surfactant, and in the extragranular phase, from about 0.1% to about 15% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and the total amount of surfactant in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 0.25% to about 15% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0024] In one aspect, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0.1% to about 10% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, a surfactant, and in the extragranular phase, from about 0.1% to about 10% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, such that the total amount of surfactant in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 0.25% to about 10% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0025] In one aspect, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0.1% by weight to about 5% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and, in the extragranular phase, from about 0.1% by weight to about 5% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and the total amount of surfactant in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 0.25% by weight to about 5% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0026] In one aspect, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0.1% to about 3% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, a surfactant, and in the extragranular phase, from about 0.1% to about 2% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, such that the total amount of surfactant in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 0.25% to about 5% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0027] In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0.1% to about 20% by weight of the composition or oral dosage form of a surfactant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0.1% to about 15% by weight of the composition or oral dosage form of a surfactant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0.1% to about 10% by weight of the composition or oral dosage form of a surfactant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0.1% to about 5% by weight of the composition or oral dosage form of a surfactant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0.1% to about 3% by weight of the composition or oral dosage form of a surfactant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0.1% to about 2% of a surfactant by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0.1%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, about 2%, about 2.25%, about 2.5%, about 2.75%, or about 3% of a surfactant by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0028] In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, from about 0% to about 20% by weight of the composition or oral dosage form of a surfactant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, from about 0% to about 15% by weight of the composition or oral dosage form of a surfactant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, from about 0% to about 10% by weight of the composition or oral dosage form of a surfactant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, from about 0% to about 5% by weight of the composition or oral dosage form of a surfactant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, from about 0.1% to about 2% by weight of the composition or oral dosage form of a surfactant, based on the total weight of the composition or oral dosage form. In one aspect, the compositions or oral dosage forms described herein comprise 0%, about 0.1%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, about 2%, about 2.25%, about 2.5%, about 2.75%, or about 3% by weight of the composition or oral dosage form, in the extragranular phase, based on the total weight of the composition or oral dosage form.

[0029] In one aspect, the composition or solid dosage form further comprises a disintegrant.Non-limiting examples of suitable disintegrants include, individually or in combination, starch, such as sodium starch glycolate and pregelatinized corn starch, clay, cellulose, such as refined cellulose, microcrystalline cellulose, methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose, croscarmellose sodium, alginate, crospovidone, and gum, such as agar, guar, locust bean, karaya, pectin and tragacanth gum.In a particular aspect, the disintegrant is crospovidone.In some embodiments, disintegrant can be added at any suitable step during the preparation of the composition, particularly before granulation or at the lubrication step before compression.

[0030] In one embodiment, the compositions or oral dosage forms described herein comprise from about 0% to about 30% by weight of the composition or oral dosage form of a disintegrant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 0% to about 20% by weight of the composition or oral dosage form of a disintegrant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 0% to about 10% by weight of the composition or oral dosage form of a disintegrant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 1% to about 10% by weight of the composition or oral dosage form of a disintegrant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 1% to about 7% by weight of the composition or oral dosage form of a disintegrant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise about 5% to about 10% by weight of the composition or oral dosage form of a disintegrant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% by weight of the composition or oral dosage form of a disintegrant, based on the total weight of the composition or oral dosage form.

[0031] In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0% to about 30% by weight of the disintegrant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and in the extragranular phase, about 0% to about 30% by weight of the disintegrant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and the total amount of disintegrant in the combined intragranular and extragranular phases of the composition or oral dosage form is about 0.2% to about 30% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0032] In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0% to about 20% by weight of the disintegrant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and in the extragranular phase, about 0% to about 20% by weight of the disintegrant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and the total amount of disintegrant in the combined intragranular and extragranular phases of the composition or oral dosage form is about 0.2% to about 20% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0033] In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0% to about 10% by weight of the disintegrant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and in the extragranular phase, about 0% to about 10% by weight of the disintegrant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and the total amount of disintegrant in the combined intragranular and extragranular phases of the composition or oral dosage form is about 0.2% to about 10% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0034] In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0% to about 10% by weight of the disintegrant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and in the extragranular phase, about 0% to about 10% by weight of the disintegrant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and the total amount of disintegrant in the combined intragranular and extragranular phases of the composition or oral dosage form is about 1% to about 10% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0035] In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0% to about 7% by weight of the disintegrant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and in the extragranular phase, from about 0% to about 7% by weight of the disintegrant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and the total amount of disintegrant in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 1% to about 7% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0036] In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0% to about 10% by weight of the disintegrant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and in the extragranular phase, about 0% to about 10% by weight of the disintegrant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and the total amount of disintegrant in the combined intragranular and extragranular phases of the composition or oral dosage form is about 5% to about 10% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0037] In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0.1% by weight to about 5% by weight of the disintegrant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and, in the extragranular phase, from about 0.1% by weight to about 5% by weight of the disintegrant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and the total amount of disintegrant in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 5.1% by weight to about 10% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0038] In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 2% to about 5% by weight of a disintegrant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and in the extragranular phase, about 2% to about 5% by weight of a disintegrant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and the total amount of disintegrant in the combined intragranular and extragranular phases of the composition or oral dosage form is about 4% to about 10% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0039] In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0% to about 30% by weight of the disintegrant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0% to about 20% by weight of the disintegrant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0% to about 10% by weight of the disintegrant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0.2% to about 10% by weight of the disintegrant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 1% to about 10% by weight of the disintegrant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0% to about 5% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0.1% to about 5% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 1% to about 5% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise a disintegrant in the intragranular phase at about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0040] In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, about 0% to about 30% by weight of the disintegrant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, about 0% to about 20% by weight of the disintegrant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, about 0% to about 10% by weight of the disintegrant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, about 0.2% to about 10% by weight of the disintegrant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, about 1% to about 10% by weight of the disintegrant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, from about 0% to about 5% by weight of the composition or oral dosage form of a disintegrant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, from about 0.1% to about 5% by weight of the composition or oral dosage form of a disintegrant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, from about 1% to about 5% by weight of the composition or oral dosage form of a disintegrant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise a disintegrant in the extragranular phase at about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0041] In one embodiment, the composition or solid dosage form further comprises a flow agent.The flow agent can be used to promote the powder flowability of the solid formulation.Suitable flow agents include colloidal silicon dioxide, starch, talc, tribasic calcium phosphate, powdered cellulose, and magnesium trisilicate, and mixtures thereof.In a particular embodiment, the flow agent is colloidal silicon dioxide.

[0042] In one embodiment, the compositions or oral dosage forms described herein comprise from about 0% to about 5% by weight of the composition or oral dosage form of a fluidizing agent, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 0% to about 4% by weight of the composition or oral dosage form of a fluidizing agent, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 0% to about 3% by weight of the composition or oral dosage form of a fluidizing agent, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 0% to about 2% by weight of the composition or oral dosage form of a fluidizing agent, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 0.5% to about 2% by weight of the composition or oral dosage form of a fluidizing agent, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise about 0.1% to about 1% of a fluidizing agent by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5% of a fluidizing agent by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0043] In one aspect, the compositions or oral dosage forms described herein comprise from about 0% to about 5% by weight of the composition or oral dosage form of a fluidizing agent in the intragranular phase, based on the total weight of the composition or oral dosage form, and from about 0% to about 5% by weight of the composition or oral dosage form of a fluidizing agent in the extragranular phase, based on the total weight of the composition or oral dosage form, such that the total amount of fluidizing agent in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 0.1% to about 5% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0044] In one aspect, the compositions or oral dosage forms described herein comprise from about 0% to about 4% by weight of the composition or oral dosage form of a fluidizing agent in the intragranular phase, based on the total weight of the composition or oral dosage form, and from about 0% to about 4% by weight of the composition or oral dosage form of a fluidizing agent in the extragranular phase, based on the total weight of the composition or oral dosage form, such that the total amount of fluidizing agent in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 0.1% to about 4% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0045] In one aspect, the compositions or oral dosage forms described herein comprise from about 0% to about 3% by weight of the composition or oral dosage form of a fluidizing agent in the intragranular phase, based on the total weight of the composition or oral dosage form, and from about 0% to about 3% by weight of the composition or oral dosage form of a fluidizing agent in the extragranular phase, based on the total weight of the composition or oral dosage form, such that the total amount of fluidizing agent in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 0.1% to about 3% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0046] In one aspect, the compositions or oral dosage forms described herein comprise from about 0% to about 2% by weight of the composition or oral dosage form of a fluidizing agent in the intragranular phase, based on the total weight of the composition or oral dosage form, and from about 0% to about 2% by weight of the composition or oral dosage form of a fluidizing agent in the extragranular phase, based on the total weight of the composition or oral dosage form, such that the total amount of fluidizing agent in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 0.1% to about 2% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0047] In one aspect, the compositions or oral dosage forms described herein comprise from about 0.1% to about 2% by weight of the composition or oral dosage form of a fluidizing agent in the intragranular phase, based on the total weight of the composition or oral dosage form, and from about 0.1% to about 2% by weight of the composition or oral dosage form of a fluidizing agent in the extragranular phase, based on the total weight of the composition or oral dosage form, and the total amount of fluidizing agent in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 0.5% to about 2% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0048] In one aspect, the compositions or oral dosage forms described herein comprise from about 0% to about 1% by weight of the composition or oral dosage form of a fluidizing agent in the intragranular phase, based on the total weight of the composition or oral dosage form, and from about 0% to about 1% by weight of the composition or oral dosage form of a fluidizing agent in the extragranular phase, based on the total weight of the composition or oral dosage form, such that the total amount of fluidizing agent in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 0.1% to about 1% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0049] In one aspect, the compositions or oral dosage forms described herein comprise from about 0.25% to about 0.75% by weight of the composition or oral dosage form of a fluidizing agent in the intragranular phase, based on the total weight of the composition or oral dosage form, and from about 0.25% to about 0.75% by weight of the composition or oral dosage form of a fluidizing agent in the extragranular phase, based on the total weight of the composition or oral dosage form, and the total amount of fluidizing agent in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 0.5% to about 1% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0050] In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0% to about 5% by weight of the composition or oral dosage form of a fluidizer, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0% to about 4% by weight of the composition or oral dosage form of a fluidizer, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0% to about 3% by weight of the composition or oral dosage form of a fluidizer, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0% to about 2% by weight of the composition or oral dosage form of a fluidizer, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0% to about 1% by weight of the composition or oral dosage form of a fluidizer, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0.1% to about 5% by weight of the composition or oral dosage form of a fluidizer, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0.1% to about 4% by weight of the composition or oral dosage form of a fluidizer, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0.1% to about 3% by weight of the composition or oral dosage form of a fluidizer, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0.1% to about 2% by weight of the composition or oral dosage form of a fluidizer, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0.1% to about 1% by weight of the composition or oral dosage form of a fluidizer, based on the total weight of the composition or oral dosage form. In one aspect, the compositions or oral dosage forms described herein comprise from about 0.5% to about 1% of a flow agent in the intragranular phase, based on the total weight of the composition or oral dosage form.In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0.25% to about 0.75% of a flow agent by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5% of a flow agent by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0051] In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, about 0% to about 5% by weight of the composition or oral dosage form of a fluidizer, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, about 0% to about 4% by weight of the composition or oral dosage form of a fluidizer, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, about 0% to about 3% by weight of the composition or oral dosage form of a fluidizer, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, about 0% to about 2% by weight of the composition or oral dosage form of a fluidizer, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, about 0% to about 1% by weight of the composition or oral dosage form of a fluidizer, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, about 0.1% to about 5% by weight of the composition or oral dosage form of a fluidizer, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, about 0.1% to about 4% by weight of the composition or oral dosage form of a fluidizer, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, about 0.1% to about 3% by weight of the composition or oral dosage form of a fluidizer, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, about 0.1% to about 2% by weight of the composition or oral dosage form of a fluidizer, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, about 0.1% to about 1% by weight of the composition or oral dosage form of a fluidizer, based on the total weight of the composition or oral dosage form. In one aspect, the compositions or oral dosage forms described herein comprise from about 0.5% to about 1% by weight of the composition or oral dosage form of a flow agent in the extragranular phase, based on the total weight of the composition or oral dosage form.In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, about 0.25% to about 0.75% of a flow agent by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5% of a flow agent by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0052] In one embodiment, the composition or solid dosage form further comprises a lubricant. Suitable lubricants include, individually or in combination, glyceryl behaptate; stearic acid and its salts, such as magnesium, calcium and sodium stearate; hydrogenated vegetable oils; colloidal silica; talc; wax; boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; polyethylene glycol; sodium oleate; sodium lauryl sulfate; glyceryl dibehenate (Compritol 888 ATO); and magnesium lauryl sulfate. Other non-limiting examples of suitable lubricants include talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, sodium stearyl fumerate, and mixtures thereof. In a particular embodiment, the lubricant is magnesium stearate. Magnesium stearate reduces friction between the equipment and the granulation mixture during compression of tablet formulations.

[0053] In one embodiment, the compositions or oral dosage forms described herein comprise from about 0% to about 5% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 0% to about 3% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 0% to about 2.5% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 0% to about 2% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 0.5% to about 2% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 0% to about 1.5% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 0% to about 1% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, or about 3% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form.

[0054] In one aspect, a composition or oral dosage form described herein comprises, in its intragranular phase, from about 0% to about 5% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and, in its extragranular phase, from about 0% to about 5% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, such that the total amount of lubricant in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 0.1% to about 5% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0055] In one aspect, a composition or oral dosage form described herein comprises, in its intragranular phase, from about 0% to about 3% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form, and, in its extragranular phase, from about 0% to about 3% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form, such that the total amount of lubricant in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 0.1% to about 3% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0056] In one aspect, a composition or oral dosage form described herein comprises, in its intragranular phase, from about 0% to about 2.5% by weight of the composition or oral dosage form, of a lubricant, based on the total weight of the composition or oral dosage form, and in its extragranular phase, from about 0% to about 2.5% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, such that the total amount of lubricant in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 0.1% to about 2.5% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0057] In one aspect, a composition or oral dosage form described herein comprises, in its intragranular phase, from about 0% to about 2% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form, and in its extragranular phase, from about 0% to about 2% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form, such that the total amount of lubricant in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 0.1% to about 2% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0058] In one aspect, a composition or oral dosage form described herein comprises, in the intragranular phase, from about 0.1% to about 2% by weight of the composition or oral dosage form of lubricant, based on the total weight of the composition or oral dosage form, and in the extragranular phase, from about 0.1% to about 2% by weight of the composition or oral dosage form of lubricant, based on the total weight of the composition or oral dosage form, and the total amount of lubricant in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 0.5% to about 2% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0059] In one aspect, a composition or oral dosage form described herein comprises, in its intragranular phase, from about 0% to about 1.5% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form, and in its extragranular phase, from about 0% to about 1.5% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form, such that the total amount of lubricant in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 0.1% to about 1.5% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0060] In one aspect, a composition or oral dosage form described herein comprises, in its intragranular phase, from about 0% to about 1% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form, and in its extragranular phase, from about 0% to about 1% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form, such that the total amount of lubricant in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 0.1% to about 1% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0061] In one aspect, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0.25% to about 0.75% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and, in the extragranular phase, from about 0.25% to about 0.75% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and the total amount of lubricant in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 0.5% to about 1.5% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0062] In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0% to about 5% by weight of the lubricant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0% to about 3% by weight of the lubricant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0% to about 2.5% by weight of the lubricant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0% to about 2% by weight of the lubricant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0% to about 1.5% by weight of the lubricant of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0% to about 1% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0.1% to about 3% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0.1% to about 2.5% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0.1% to about 2% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0.1% to about 1.5% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0.1% to about 1% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form.In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0.5% to about 1% of a lubricant by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0.25% to about 0.75% of a lubricant by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one aspect, the compositions or oral dosage forms described herein comprise about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5% by weight of the composition or oral dosage form, in the intragranular phase, based on the total weight of the composition or oral dosage form.

[0063] In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, about 0% to about 5% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, about 0% to about 3% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, about 0% to about 2.5% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, about 0% to about 2% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, about 0% to about 1.5% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, about 0% to about 1% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, about 0.1% to about 3% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, about 0.1% to about 2.5% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, about 0.1% to about 2% by weight of the composition or oral dosage form of a lubricant, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, from about 0.1% to about 1.5% of a lubricant by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, from about 0.1% to about 1% of a lubricant by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, from about 0.5% to about 1% of a lubricant by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, from about 0.25% to about 0.75% of a lubricant by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one aspect, the compositions or oral dosage forms described herein comprise about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5% by weight of the composition or oral dosage form, in the extragranular phase, based on the total weight of the composition or oral dosage form.

[0064] In one embodiment, the composition further comprises one or more fillers (also called diluents). Suitable fillers may be selected, alone or in combination, from lactose, such as anhydrous lactose or lactose monohydrate; starch, such as starch for direct compression and hydrolyzed starch; mannitol, such as spray dried and crystalline mannitol for direct compression; sorbitol; xylitol; dextrose and dextrose monohydrate; sucrose-based diluents, such as powdered sugar; calcium-based diluents, such as monobasic calcium sulfate monohydrate, anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, calcium sulfate dihydrate, or granular calcium lactate trihydrate; dextran; inositol; hydrolyzed cereal solids; amylose; cellulose, such as food grade sources of amorphous cellulose and powdered cellulose: microcrystalline cellulose, modified or co-processed microcrystalline cellulose, extragranular microcrystalline cellulose, or silicified microcrystalline cellulose; calcium carbonate; glycine; bentonite; polyvinylpyrrolidone, and the like. Other examples of suitable fillers are starches (e.g., cellulose, potato starch or corn starch), salts (e.g., calcium hydrogen phosphate, magnesium oxide), sugars such as lactose (e.g., lactose monohydrate), silicates (e.g., silicon dioxide), talc, isomalt, or polyvinyl alcohol. In a specific embodiment, the composition comprises two fillers selected from mannitol and microcrystalline cellulose (e.g., Avicel® PH 101, Avicel® PH 102).

[0065] The filler(s) selected preferably exhibit suitable flow properties and improve compressibility if tablets are desired. A mixture of fillers can be used to optimize the desired properties. For example, materials are usually compressed either by plastic deformation or brittle fracture. Mannitol is a brittle fracture filler, and when combined with a plastic deformation filler such as microcrystalline cellulose, it results in an optimally compressed formulation that retains its shape after compression and has little looseness / friability. Microcrystalline cellulose (e.g., Avicel® PH 102) was selected as the plastic deformation filler.

[0066] In one embodiment, the compositions or oral dosage forms described herein comprise from about 0% to about 90% by weight of the composition or oral dosage form of one or more fillers, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 5% to about 90% by weight of the composition or oral dosage form of one or more fillers, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 10% to about 80% by weight of the composition or oral dosage form of one or more fillers, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 20% to about 70% by weight of the composition or oral dosage form of one or more fillers, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 30% to about 60% by weight of the composition or oral dosage form of one or more fillers, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 40% to about 50% by weight of the composition or oral dosage form of one or more fillers, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 5% to about 15% by weight of the composition or oral dosage form of one or more fillers, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 10% to about 20% by weight of the composition or oral dosage form of one or more fillers, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 15% to about 25% by weight of the composition or oral dosage form of one or more fillers, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 20% to about 30% by weight of the composition or oral dosage form of one or more fillers, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 25% to about 35% by weight of the composition or oral dosage form of one or more fillers, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 30% to about 50% by weight of the composition or oral dosage form of one or more fillers, based on the total weight of the composition or oral dosage form.In one embodiment, the compositions or oral dosage forms described herein comprise from about 30% to about 40% by weight of one or more fillers, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 35% to about 45% by weight of one or more fillers, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 45% to about 55% by weight of one or more fillers, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 55% to about 65% by weight of one or more fillers, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 65% to about 75% by weight of one or more fillers, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 75% to about 85% by weight of one or more fillers of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 50% to about 60% by weight of one or more fillers of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 60% to about 70% by weight of one or more fillers of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 70% to about 80% by weight of one or more fillers of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 80% to about 90% by weight of one or more fillers of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.In one aspect, a composition or oral dosage form described herein comprises one or more fillers in about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0067] In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, about 0% to about 90% by weight (e.g., about 20% to about 60% by weight) of one or more fillers of the composition or oral dosage form based on the total weight of the composition or oral dosage form, and, in the extragranular phase, about 0% to about 90% by weight (e.g., about 0% to about 20% by weight) of one or more fillers of the composition or oral dosage form based on the total weight of the composition or oral dosage form, and the total amount of one or more fillers in the combined intragranular and extragranular phases of the composition or oral dosage form is about 5% to about 90% by weight (e.g., about 20% to about 60% by weight) of the composition or oral dosage form based on the total weight of the composition or oral dosage form.

[0068] In one aspect, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0% to about 80% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, one or more fillers, in the extragranular phase, from about 0% to about 80% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and ... the total amount of one or more fillers in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 5% to about 80% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0069] In one aspect, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0% to about 70% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, one or more fillers, in the extragranular phase, from about 0% to about 70% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and ... the total amount of one or more fillers in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 5% to about 70% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0070] In one aspect, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0% to about 60% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, one or more fillers, in the extragranular phase, from about 0% to about 60% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and ... the total amount of one or more fillers in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 5% to about 60% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0071] In one aspect, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0% to about 50% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, one or more fillers, in the extragranular phase, from about 0% to about 50% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and ... the total amount of one or more fillers in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 5% to about 50% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0072] In one aspect, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 30% to about 50% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, one or more fillers, in the extragranular phase, from about 0% to about 10% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and the total amount of one or more fillers in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 30% to about 60% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0073] In one aspect, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 30% to about 45% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, one or more fillers, in the extragranular phase, from about 1% to about 10% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and the total amount of one or more fillers in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 31% to about 50% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0074] In one aspect, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0% to about 40% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, one or more fillers, in the extragranular phase, from about 0% to about 40% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and ... the total amount of one or more fillers in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 5% to about 40% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0075] In one aspect, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0% to about 30% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, one or more fillers, in the extragranular phase, from about 0% to about 30% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and ... the total amount of one or more fillers in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 5% to about 30% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0076] In one aspect, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0% to about 20% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, one or more fillers, in the extragranular phase, from about 0% to about 20% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and ... the total amount of one or more fillers in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 5% to about 20% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0077] In one aspect, the compositions or oral dosage forms described herein comprise from about 0% to about 10% by weight of the composition or oral dosage form of one or more fillers in the intragranular phase, based on the total weight of the composition or oral dosage form, and from about 0% to about 10% by weight of the composition or oral dosage form of one or more fillers in the extragranular phase, based on the total weight of the composition or oral dosage form, and the total amount of one or more fillers in the combined intragranular and extragranular phases of the composition or oral dosage form is from about 5% to about 10% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0078] In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0% to about 90% by weight of one or more fillers of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0% to about 80% by weight of one or more fillers of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0% to about 70% by weight of one or more fillers of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0% to about 60% by weight of one or more fillers of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0% to about 50% by weight of one or more fillers of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 10% to about 50% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, of one or more fillers. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 20% to about 50% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, of one or more fillers. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 30% to about 50% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, of one or more fillers. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 35% to about 45% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, of one or more fillers. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0% to about 40% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, of one or more fillers. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 30% to about 40% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, of one or more fillers.In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0% to about 30% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, of one or more fillers. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0% to about 20% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, of one or more fillers. In one embodiment, the compositions or oral dosage forms described herein comprise, in the intragranular phase, from about 0% to about 10% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, of one or more fillers. In one aspect, the compositions or oral dosage forms described herein comprise one or more fillers in the intragranular phase at about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0079] In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, from about 0% to about 90% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, of one or more fillers. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, from about 0% to about 80% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, of one or more fillers. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, from about 0% to about 70% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, of one or more fillers. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, from about 0% to about 60% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, of one or more fillers. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, from about 0% to about 50% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, of one or more fillers. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, from about 0% to about 40% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, of one or more fillers. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, from about 0% to about 30% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, of one or more fillers. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, from about 0% to about 20% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, of one or more fillers. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, from about 0% to about 10% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, of one or more fillers. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, from about 0.5% to about 10% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, of one or more fillers. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, from about 0.5% to about 5% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, of one or more fillers.In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, from about 1% to about 5% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, of one or more fillers. In one embodiment, the compositions or oral dosage forms described herein comprise, in the extragranular phase, from about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0080] In one embodiment, the compositions or oral dosage forms described herein include one filler. In one embodiment, the compositions or oral dosage forms described herein include two fillers. In one embodiment, one filler is in the intragranular phase and a second filler is in the extragranular phase. In one embodiment, one filler is in both the intragranular and extragranular phases and a second filler is only in the extragranular phase. In one embodiment, one filler is in both the intragranular and extragranular phases and a second filler is only in the intragranular phase. In one embodiment, both fillers are in both the intragranular and extragranular phases.

[0081] In one aspect, in a composition or oral dosage form described herein, the intragranular phase comprises two fillers selected from mannitol and microcrystalline cellulose, and the extragranular phase comprises a filler selected from mannitol.

[0082] In one aspect, in a composition or oral dosage form described herein, both the intragranular and extragranular phases comprise both two fillers selected from mannitol and microcrystalline cellulose.

[0083] In one aspect, a composition or oral dosage form described herein comprises two fillers, a first filler being from about 5% to about 30% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and a second filler being from about 10% to about 30% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0084] In one aspect, a composition or oral dosage form described herein comprises two fillers, a first filler being about 15% to about 30% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and a second filler being about 15% to about 25% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0085] In one aspect, the compositions or oral dosage forms described herein further comprise a non-functional polymer coating. "Non-functional film coatings" are used to modify the appearance, swallowability of the tablet, mask the taste of the active pharmaceutical ingredient (API), protect the tablet from negative environmental effects such as the effects of humidity, oxidation, and light, and potentially improve the stability of the drug product. However, they do not modify (extend or delay) the release rate of the drug molecules from the tablet. Suitable non-functional polymer coatings may be selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone-polyvinyl acetate copolymer, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymer, acrylic polymers, and polyethylene glycol, alone or in combination. In some embodiments, the non-functional polymer coating is selected from macrogol (PEG) PVA graft copolymer and polyvinyl alcohol. In a specific embodiment, the non-functional polymer coating is polyvinyl alcohol.

[0086] In one aspect, the compositions or oral dosage forms described herein further comprise from about 0% to about 10% (e.g., from about 0.5% to about 6% or from about 2% to about 5% by weight of the composition) of a non-functional coating polymer, based on the total weight of the composition.

[0087] In one aspect, the compositions or oral dosage forms described herein further comprise a non-functional polymer coating, the non-functional polymer coating comprising a pigment. In some embodiments, the pigment is an iron oxide based pigment.

[0088] In one aspect, the compositions or oral dosage forms described herein further comprise a non-functional polymer coating, wherein the non-functional polymer coating does not comprise a pigment.

[0089] In one aspect, a composition or oral dosage form described herein comprises two fillers, a first filler being about 15% to about 25% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and a second filler being about 15% to about 25% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0090] In one embodiment, a composition or oral dosage form described herein comprises two fillers, a first filler being about 10% to about 20% by weight of the composition or oral dosage form in the intragranular phase and about 1% to about 10% by weight of the composition or oral dosage form in the extragranular phase, based on the total weight of the composition or oral dosage form, and a second filler being about 10% to about 30% by weight of the composition or oral dosage form in the intragranular phase, based on the total weight of the composition or oral dosage form.

[0091] In one embodiment, a composition or oral dosage form described herein comprises two fillers, a first filler being about 10% to about 30% by weight of the composition or oral dosage form in the intragranular phase and about 1% to about 10% by weight of the composition or oral dosage form in the extragranular phase, based on the total weight of the composition or oral dosage form, and a second filler being about 10% to about 30% by weight of the composition or oral dosage form in the intragranular phase and about 1% to about 10% by weight of the composition or oral dosage form in the extragranular phase, based on the total weight of the composition or oral dosage form.

[0092] In one embodiment, the composition further comprises a moisture scavenger. Non-limiting examples of suitable moisture scavenger include starch, cellulose, cellulose derivatives, silica and silica derivatives. Specific examples are corn starch, rice starch, cellulose, microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, mesoporous silica, magnesium aluminum silicate, or silica, such as fumed silicon dioxide. In particular, the microcrystalline cellulose can be Avicel™, and / or the fumed silicon dioxide can be Cabosil™. In one embodiment, the moisture scavenger is starch. In a particular embodiment, the starch is pregelatinized starch.

[0093] In one embodiment, the compositions or oral dosage forms described herein comprise from 0% to about 30% by weight of the composition or oral dosage form of a moisture scavenger, based on the total weight of the composition or oral dosage form. In another embodiment, the compositions or oral dosage forms described herein comprise from about 0.5% to about 30% by weight of the composition or oral dosage form of a moisture scavenger, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 0.5% to about 5% by weight of the composition or oral dosage form of a moisture scavenger, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 5% to about 10% by weight of the composition or oral dosage form of a moisture scavenger, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 10% to about 15% by weight of the composition or oral dosage form of a moisture scavenger, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 15% to about 20% by weight of the composition or oral dosage form of a moisture scavenger, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 20% to about 25% by weight of the composition or oral dosage form of a moisture scavenger, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 25% to about 30% by weight of the composition or oral dosage form of a moisture scavenger, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 5% to about 15% by weight of the composition or oral dosage form of a moisture scavenger, based on the total weight of the composition or oral dosage form. In one embodiment, the compositions or oral dosage forms described herein comprise from about 2% to about 4% by weight of the composition or oral dosage form of a moisture scavenger, based on the total weight of the composition or oral dosage form.In one embodiment, the compositions or oral dosage forms described herein comprise about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In an alternative embodiment, the composition does not comprise a moisture scavenger.

[0094] As used herein, "total weight of an oral dosage form" means the material within the oral dosage form (e.g., within a capsule) or without any coating (e.g., without a tablet coating).

[0095] As used herein, the term "about" when used in connection with an amount, weight percentage, or ratio of an ingredient in a composition or dosage form includes the specified amount, weight percentage, or ratio value (or range of amount, weight percentage, or ratio) that is recognized by one of skill in the art to provide an equivalent pharmacological effect to that obtained from the specified amount, weight percentage, or ratio.

[0096] The oral dosage form can be prepared in any suitable dosage form, such as capsules, dragees, granules, powders, or tablets. In certain aspects, the oral dosage form is a capsule. In one embodiment, the capsule size is size 4 to size 0EL. In one embodiment, the capsule size is size 4 to size 00. In another embodiment, the capsule size is size 4 to size 0. In certain embodiments, the capsule size is size 3 to size 0. In some embodiments, the capsule size is 0. In other embodiments, the capsule size is 0EL. In other embodiments, the capsule size is 00. In certain embodiments, the capsule size is 1. In some embodiments, the capsule size is 2. In other embodiments, the capsule size is 3. In certain embodiments, the capsule size is 4. In certain aspects, the oral dosage form is a tablet. In one embodiment, the oral dosage form is a tablet having a non-functional polymer coating. In one embodiment, the tablet size is 6.1 mm circular biconvex, the tablet size is 6.35 mm circular biconvex, the tablet size is 9.0 mm circular biconvex, or the tablet size is 9.5 mm circular biconvex. In one embodiment, the tablet size is 6.9 x 16.9 mm oval biconvex, the tablet size is 8 x 16 mm oval biconvex, the tablet size is 9 x 18 mm oval biconvex, the tablet size is 9.5 x 18.4 mm oval biconvex, or the tablet size is 10 x 19 mm oval biconvex.

[0097] In one aspect, the oral dosage form or composition described herein comprises about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, or about 200 mg of Compound (I) free base or an equivalent amount of a pharma- ceutically acceptable salt thereof. In some embodiments, the oral dosage form (e.g., tablet) comprises about 50 mg of Compound (I) free base or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0098] In some embodiments, the amorphous solid dispersion comprises about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, or about 200 mg of Compound (I) free base or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0099] In some embodiments, the amorphous solid dispersion comprises about 100 mg to 200 mg of Compound (I) free base or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0100] In one aspect, the compositions or oral dosage forms described herein comprise (i) an amorphous solid dispersion comprising Compound (I) or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable polymer; and (ii) an intragranular phase comprising a surfactant and an extragranular phase comprising at least one of a surfactant, a disintegrant, a flow agent, a lubricant, and a filler, wherein the intragranular phase is about 80% to about 95% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and the extragranular phase is about 5% to about 20% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form.

[0101] In one embodiment, the intragranular phase is about 85% to about 95% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and the extragranular phase is about 5% to about 15% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In a specific embodiment, the oral dosage form is a capsule.

[0102] In one embodiment, the intragranular phase is about 80% to about 90% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form, and the extragranular phase is about 10% to about 20% by weight of the composition or oral dosage form, based on the total weight of the composition or oral dosage form. In a specific embodiment, the oral dosage form is a tablet.

[0103] In one embodiment, the disclosure features an oral dosage form that includes: (a) an amorphous solid dispersion of Compound (I) free base or a pharma- ceutically acceptable salt thereof; and a polymer; (b) a surfactant; (c) a disintegrant; (d) a flow agent; (e) a lubricant; and (f) one or more fillers. In one aspect, the amount of the amorphous solid dispersion is as described above (e.g., about 40% to about 60%). In one aspect, the amount of the surfactant is as described above for the surfactant (e.g., about 0.25% to about 5%). In one aspect, the amount of the disintegrant is as described above for the disintegrant (e.g., about 5.1% to about 10%). In one aspect, the amount of the flow agent is as described above for the flow agent (e.g., about 0.5% to about 2%). In one aspect, the amount of the lubricant is as described above for the lubricant (e.g., about 0.5% to about 2%). In one embodiment, the amount of filler is as described above for fillers (eg, about 31% to about 50%).

[0104] In one embodiment, the disclosure features an oral dosage form that includes: (a) an amorphous solid dispersion of Compound (I) free base or a pharma- ceutically acceptable salt thereof; and hydroxypropyl methylcellulose acetate succinate (HPMCAS); (b) poloxamer 407; (c) crospovidone; (d) colloidal silicon dioxide; (e) magnesium stearate; (f) microcrystalline cellulose (MCC); and (g) mannitol. In one aspect, the amount of the amorphous solid dispersion is as described above (e.g., about 40% to about 60%). In one aspect, the amount of the poloxamer 407 is as described above for the surfactant (e.g., about 0.25% to about 5%). In one aspect, the amount of the crospovidone is as described above for the disintegrant (e.g., about 5.1% to about 10%). In one aspect, the amount of the colloidal silicon dioxide is as described above for the flow agent (e.g., about 0.5% to about 2%). In one embodiment, the amount of magnesium stearate is as described above for the lubricant (e.g., about 0.5% to about 2%). In one embodiment, the amount of microcrystalline cellulose and mannitol is as described above for the filler (e.g., about 31% to about 50%).

[0105] In one aspect, the present disclosure provides an oral dosage form comprising: a) an amorphous solid dispersion comprising Compound (I) free base or an equivalent amount of a pharma- ceutically acceptable salt thereof and hydroxypropyl methylcellulose acetate succinate, wherein the Compound (I) free base or an equivalent amount of a pharma- ceutically acceptable salt thereof and the hydroxypropyl methylcellulose acetate succinate are in a weight ratio of about 1:1; b) a surfactant; and, optionally, c) a filler; a disintegrant, a glidant, and / or a lubricant.

[0106] In one aspect, the disclosure provides an oral dosage form comprising: a) an amorphous solid dispersion comprising Compound (I) free base or an equivalent amount of a pharma- ceutically acceptable salt thereof and hydroxypropyl methylcellulose acetate succinate, wherein the Compound (I) free base or an equivalent amount of a pharma- ceutically acceptable salt thereof and the hydroxypropyl methylcellulose acetate succinate are in a weight ratio of about 1:1; b) a surfactant, wherein the composition comprises an intragranular phase and an extragranular phase, and the surfactant is present in the intragranular phase and the extragranular phase; c) a disintegrant; d) a flow agent; e) a lubricant; and f) one or more fillers.

[0107] In one aspect, in the oral dosage form disclosed herein, the intragranular phase comprises (a) an amorphous solid dispersion of Compound (I) free base or a pharma- ceutically acceptable salt thereof; and hydroxypropyl methylcellulose acetate succinate (HPMCAS), (b) poloxamer 407, (c) crospovidone, (d) colloidal silicon dioxide, (e) magnesium stearate, (f) microcrystalline cellulose (MCC), and (g) mannitol, and the extragranular phase comprises (b) poloxamer 407, (c) crospovidone, (d) colloidal silicon dioxide, (e) magnesium stearate, and (g) mannitol.

[0108] In one aspect, in the oral dosage form disclosed herein, the intragranular phase comprises (a) an amorphous solid dispersion of Compound (I) free base or a pharma- ceutically acceptable salt thereof; and hydroxypropyl methylcellulose acetate succinate (HPMCAS), (b) poloxamer 407, (c) crospovidone, (d) colloidal silicon dioxide, (e) magnesium stearate, (f) microcrystalline cellulose (MCC), and (g) mannitol, and the extragranular phase comprises (b) poloxamer 407, (c) crospovidone, (d) colloidal silicon dioxide, (e) magnesium stearate, (f) microcrystalline cellulose (MCC), and (g) mannitol.

[0109] In one aspect, in the oral dosage form disclosed herein, the intragranular phase comprises (a) an amorphous solid dispersion of Compound (I) free base or a pharma- ceutically acceptable salt thereof; and hydroxypropyl methylcellulose acetate succinate (HPMCAS); (b) poloxamer 407; (c) crospovidone; (d) colloidal silicon dioxide; (e) magnesium stearate; (f) microcrystalline cellulose (MCC); and mannitol; the extragranular phase comprises (b) poloxamer 407; (c) crospovidone; (d) colloidal silicon dioxide; (e) magnesium stearate; and (f) microcrystalline cellulose (MCC) and mannitol; and the non-functional coating comprises polyvinyl alcohol.

[0110] In certain embodiments, the dosage form is <701> in less than 15 minutes (e.g., 3 minutes, e.g., about 5 minutes, about 7 minutes, about 10 minutes, about 15 minutes) using a procedure for uncoated or plain coated tablets, where the capsules were placed into each of the 6 tubes of a basket (basket type A) along with a disk, analytical grade water was added, and the temperature was maintained at 37° C.±2° C. In certain embodiments, the capsules disintegrate in less than 15 minutes.

[0111] In some embodiments, the dosage form is a capsule or tablet, and at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of Compound (I) is released in about 30 minutes using a USP II apparatus with a biorelevant medium (0.01 N HCl; or FaSSIF 2.24 mg / mL in 100 mM PBS buffer pH 6.8), a reservoir volume of 100 mL, and a paddle speed of 100 rpm±2 rpm, and a temperature of 37.0±0.5° C.

[0112] In some embodiments, the dosage form is a capsule and at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of Compound (I) is released in about 30 minutes in a biorelevant medium following dissolution protocol. [Table 1]

[0113] Another embodiment of the disclosure features a method for preparing an amorphous solid dispersion as described herein, the method including mixing Compound (I) free base or an equivalent amount of a pharma- ceutically acceptable salt thereof with a polymer in about a 1:1 ratio, adding one or more solvents, and removing the solvent(s) by heating.

[0114] Treatment method Another embodiment of the disclosure features a method of treating EGFR-altered cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the compositions and oral dosage forms disclosed herein.

[0115] Another embodiment of the present disclosure features a method of inhibiting a specific mutant form of epidermal growth factor receptor (EGFR) in a subject in need thereof, comprising administering to a patient in need thereof a therapeutically effective amount of the compositions and oral dosage forms disclosed herein. Mutant forms of EGFR include, for example, EGFR with LRTMCS mutations (exon 19 deletion (del19) or exon 21 (L858R) substitution mutations, T790M mutations, and C797S mutations). A subject "in need of inhibiting EGFR" is a subject with a disease in which inhibition of at least one mutant EGFR can achieve a beneficial therapeutic effect, for example, delaying disease progression, alleviating one or more symptoms associated with the disease, or extending the lifespan of the subject in view of the disease.

[0116] In some embodiments, the disclosure provides a method of treating a disease / condition / or cancer associated with or regulated by mutant EGFR, where inhibition of the mutant EGFR has a therapeutic benefit, including but not limited to, treating cancer in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of the compositions and oral dosage forms disclosed herein.

[0117] In another embodiment, the present disclosure provides a method of treating a subject with cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the compositions and oral dosage forms disclosed herein.Cancers that may be treated according to the disclosed methods include lung cancer, colon cancer, urothelial cancer, breast cancer, prostate cancer, brain cancer, ovarian cancer, gastric cancer, pancreatic cancer, head and neck cancer, bladder cancer, and mesothelioma, including metastases (particularly brain metastases) of all listed cancers.Typically, the cancer is characterized by one or more EGFR mutations as described herein.In a specific embodiment, the cancer has progressed during or after EGFR tyrosine kinase inhibitor (TKI) therapy.In a specific embodiment, the disease has progressed during or after first-line treatment with osimertinib.

[0118] In a specific embodiment, the cancer to be treated is lung cancer. In a more specific embodiment, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is locally advanced or metastatic NSCLC, NSCLC adenocarcinoma, NSCLC with squamous histology, and NSCLC with non-squamous histology. In another embodiment, the lung cancer is NSCLC adenocarcinoma. In another specific embodiment, the lung cancer (or non-small cell lung cancer) metastasizes to the brain.

[0119] The exact amount of compound administered to provide a "therapeutically effective amount" to a subject depends on the mode of administration, the type and severity of the cancer, and the characteristics of the subject, such as overall health, age, sex, weight, and tolerance to the drug. Those skilled in the art will be able to determine the appropriate dosage depending on these and other factors. When administered in combination with other therapeutic agents, for example, in combination with an anti-cancer drug, the "therapeutically effective amount" of any additional therapeutic agent(s) will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by those skilled in the art depending on the subject's condition, the type of condition(s) being treated, and the amount of compound of formula (I) used according to, for example, dosages reported in the literature and recommended in the Physician's Desk Reference (57th ed., 2003).

[0120] "Treating" or "treatment" refers to obtaining a desired pharmacological and / or physiological effect. The effect may be therapeutic, which includes partially or substantially achieving one or more of the following results: partially or substantially reducing the extent of the disease, condition, or cancer; ameliorating or relieving clinical symptoms or indicators associated with the disease, condition, or cancer; delaying, inhibiting, or reducing the likelihood of progression of the disease, condition, or cancer; or reducing the likelihood of recurrence of the disease, condition, or cancer.

[0121] The following examples are intended to be illustrative and not to limit the scope of the disclosure in any way. EXAMPLES

[0122] Example 1: Synthesis of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [Compound (I)] 1.1 Synthesis of (2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidine: [ka]

[0123] Step 1: Synthesis of (2R,3S)-1-benzhydryl-2-methylazetidin-3-yl methanesulfonate:

[0124] (2R,3S)-1-Benzhydryl-2-methylazetidin-3-ol (Pharmablock, 20 g, 78.9 mmol) was dissolved in 300 mL of DCM, TEA (9.55 g, 94.6 mmol) was added and the reaction mixture was cooled in an ice bath. Mesyl chloride (9.93 g, 86.7 mmol) was added dropwise, stirred, slowly warmed to room temperature and stirred overnight. The mixture was diluted with DCM, washed with water, the organic phase was dried over sodium sulfate, filtered and evaporated to give 26 g (98%) of the title compound as a viscous yellow oil. Analytical data: LC-MS: (ES, m / z) = 332 [M+1].

[0125] Step 2: Synthesis of (S)-methyl 2-((2R,3S)-1-benzhydryl-2-methylazetidin-3-yl)-2-(methylsulfonyl)acetate:

[0126] (2R,3S)-1-Benzhydryl-2-methylazetidin-3-yl methanesulfonate (26 g, 78.4 mmol) and methyl 2-(methylsulfonyl)acetate (15.3 g, 101 mmol) were dissolved in 260 mL of DMF, then NaH (3.75 g of a 60% dispersion in mineral oil, 6.63 mmol) was added and stirred for about 15 min until hydrogen evolution ceased. The reaction mixture was heated to 80° C. overnight. The reaction was cooled, then diluted with about 200 mL of water, extracted with EtOAc, and the combined organics were washed with water, brine, dried over sodium sulfate, filtered, and evaporated to give the crude product. The residue was purified by chromatography (0-7% MeOH / DCM). Pure fractions were combined and evaporated to give 24 g (80%) of the title compound as a pale yellow foam.

[0127] Step 3: Synthesis of (2R,3S)-1-benzhydryl-2-methyl-3-(methylsulfonylmethyl)azetidine:

[0128] (S)-Methyl-2-((2R,3S)-1-benzhydryl-2-methylazetidin-3-yl)-2-(methylsulfonyl)acetate (24 g, 61.9 mmol) was dissolved in 240 mL of DMA, lithium chloride (20.9 g, 495 mmol) was added and the flask was placed in a preheat block maintained at 150 °C. LC / MS showed the starting material was consumed after 1.5 h. Cooled to room temperature, diluted with water, extracted with EtOAc, and the combined organics were washed with water, brine and dried over sodium sulfate. Filtration and evaporation gave the crude product which was further purified by chromatography (0-5% MeOH / DCM). Pure fractions were combined and evaporated to give 19 g (93%) of the title compound as a pale yellow foam. Analytical data: LC-MS: (ES, m / z) = 330 [M+1].

[0129] Step 4: Synthesis of (2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidine:

[0130] To a solution of (2R,3S)-1-(diphenylmethyl)-3-(methanesulfonylmethyl)-2-methylazetidine (19 g, 57.3 mmol) in MeOH (270 mL) was added TFA (9 mL) and Pd(OH)2 (5.7 g) and the reaction was stirred overnight at room temperature under H2 atmosphere. The reaction mixture was filtered and evaporated to give the crude title compound (17 g) as a light brown oil. Analytical data: LC-MS: (ES, m / z) = 164 [M+1]. 1.2 Synthesis of 2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine [ka]

[0131] Step 1: Synthesis of (3S,4R)-tert-butyl 3-fluoro-4-methoxypiperidine-1-carboxylate:

[0132] Sodium hydride (218.90 mg, 9.122 mmol, 4 equiv.) was added to tert-butyl (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (500 mg, 2.280 mmol, 1 equiv.) in THF (10 mL) at 0° C. After stirring for 20 min, methyl iodide (1294.73 mg, 9.122 mmol, 4 equiv.) was added. The resulting solution was stirred at 0° C. for an additional hour. The reaction was then quenched by adding 10 mL of water. The solids were filtered off. The resulting solution was extracted with EtOAc and concentrated under vacuum. This afforded 500 mg (94.1%) of the title compound as a pale yellow oil. Analytical data: LC-MS: (ES, m / z) = 178 [M+1-56].

[0133] Step 2: Synthesis of (3S,4R)-3-fluoro-4-methoxypiperidine:

[0134] A solution of tert-butyl (3S,4R)-3-fluoro-4-methoxypiperidine-1-carboxylate (500 mg, 2.143 mmol, 1 equiv.) in TFA / DCM (3 / 10 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo to give 500 mg (crude) of the title compound as a solid.

[0135] Step 3: Synthesis of 2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine

[0136] A mixture of (3S,4R)-3-fluoro-4-methoxypiperidine (3 g, 22.528 mmol, 1 eq.), 2-chloropyrimidin-4-amine (2.33 g, 0.018 mmol, 0.8 eq.) and TEA (6.84 g, 0.068 mmol, 3 eq.) in IPA (3 mL) was stirred at 100° C. for 12 h. The solvent was removed under vacuum and the residue was purified by FLASH (5% MeOH in DCM) to give 3.3 g (66%) of the title compound as a pale yellow solid. Analytical data: LC-MS: (ES, m / z) = 227 [M+1]. 1 H-NMR (400 MHz, 6d-DMSO) δ ppm 7.72 (d, 1H, J=5.6 Hz), 6.39 (s, 2H), 5.71 (d, 1H, J=5.6 Hz), 4.83 (d, 1H, J=49.3 Hz), 4.60 - 4.49 (m, 1H), 4.29 (d, 1H, J=13.3 Hz), 3.55 - 3.42 (m, 1H), 3.28 (d, 1H, J=13.3 Hz), 3.20 - 3.04 (m, 1H), 1.76 - 1.48 (m, 2H) 1.3 Synthesis of 8-bromo-3-chloro-5-isopropylisoquinoline [ka]

[0137] Step 1: Synthesis of 8-bromo-3-chloroisoquinolin-5-yl trifluoromethanesulfonate:

[0138] Trifluoromethanesulfonyl trifluoromethanesulfonate (45.7 g, 162 mmol) was added dropwise to 8-bromo-3-chloroisoquinolin-5-ol (14 g, 54.1 mmol) and TEA (21.8 g, 216 mmol) in DCM (400 mL) at -60°C. The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 1 h. The mixture was concentrated under vacuum. The residue was purified by silica gel column with PE:EA=5:1 to give 18 g (85%) of the title compound as a white solid. Analytical data: LC-MS: (ES, m / z) = 392 [M+1];1H NMR (400 MHz, DMSO-d6) δ 9.46 (d, 1H, J = 0.8 Hz), 8.20 (d, 1H, J = 8.3 Hz), 8.02 (d, 1H, J = 8.4 Hz), 7.93 (d, 1H, J = 0.7 Hz).

[0139] Step 2: Synthesis of 8-bromo-3-chloro-5-(prop-1-en-2-yl)isoquinoline:

[0140] A mixture of K2CO3 (6 g, 43.5 mmol), 8-bromo-3-chloroisoquinolin-5-yl trifluoromethanesulfonate (17 g, 43.5 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (7.30 g, 43.5 mmol) and Pd(dppf)Cl2.CH2Cl2 (2.83 g, 3.48 mmol) in dioxane / H2O (200 / 20 mL) was stirred at 45 °C for 3 h. The mixture was diluted with 500 mL of EA and washed with 200 mL*2 of brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column with PE:EtOAc=20:1 to give 8.0 g (67%) of the title compound as an off-white solid. Analytical data: LC-MS: (ES, m / z) = 282 [M+1].

[0141] Step 3: Synthesis of 8-bromo-3-chloro-5-isopropylisoquinoline:

[0142] PtO2 (1.7 g, 7.04 mmol) and 8-bromo-3-chloro-5-(prop-1-en-2-yl)isoquinoline (7.1 g, 25.1 mmol) in EA (300 mL) were stirred under an atmosphere of H2 balloon at room temperature and stirred for 1 h. The solid was filtered off. The mother solvent was concentrated under vacuum. The crude product was purified by silica gel column with PE:EtOAc=10:1 to give 6.7 g (93%) of the title compound as a brown solid. Analytical data: LC-MS: (ES, m / z) = 284 [M+1]. 1.4 Synthesis of 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline [ka]

[0143] To a solution of 8-bromo-3-chloro-5-(propan-2-yl)isoquinoline (9 g, 31.6 mmol) in 1,4-dioxane (130 mL) was added (2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidine (5.15 g, 31.6 mmol,), Cs2CO3 (20.6 g, 63.2 mmol) and Xantphos Pd G4 (1.51 g, 1.58 mmol) under nitrogen. The mixture was stirred at 100° C. under nitrogen for 3 h. The reaction mixture was cooled to room temperature and diluted with 300 mL of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by silica gel chromatography (0-60% EtOAc in PE) to give 7.2 g (62.6%) of 3-chloro-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-5-(propan-2-yl)isoquinoline as a yellow solid. 1.5 Synthesis of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0144] To a solution of 2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine (18.50 mg, 0.082 mmol, 1 equiv.), 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline (30 mg, 0.082 mmol, 1 equiv.) and Cs2CO3 (53.3 mg, 0.164 mmol, 2 equiv.) in 1,4-dioxane (0.82 ml) was added BrettPhos precatalyst (Gen IV) (3.76 mg, 4.09 μmol, 0.05 equiv.) under N2 and the mixture was stirred at 90° C. for 16 h. The mixture was filtered and concentrated under vacuum. The crude mixture was purified by reverse phase chromatography (0-60% acetonitrile / water containing 0.1% TFA). The pure fractions were combined, neutralized with saturated sodium bicarbonate solution, and then extracted with 10% MeOH / DCM (5 mL x 3). The combined organic phases were dried over sodium sulfate, filtered, and evaporated to give 17.4 mg of the title compound (38%) as a yellow solid. The XRPD diffractogram of the resulting product showed the solid to be a crystalline material, which was designated as Form A.

[0145] Example 2: Preparation of Crystalline Form B of Compound (I) Free Base Approximately 25-35 mg of amorphous Compound (I) was dissolved in dimethylacetamide (solvent) primarily at room temperature. Two volumes of water (antisolvent) were placed in a separate vial to which the solution was added in one move with rapid stirring. For example, if the solid dissolved in 0.5 mL of solvent, the solution was added to 1.0 mL of antisolvent in one move with vigorous stirring. Once the solid had formed, the thick pale yellow slurry was filtered, washed with 1×2.0 volumes of water, and left on the filter paper for 5 minutes with active suction from an aspirator. The sample was then placed in a 50°C oven under active vacuum for 15 minutes, then left on a benchtop overnight to dry. An XRPD diffractogram of the resulting product showed the solid to be a crystalline material, which was designated as Form B.

[0146] Example 3: Compound (I) Amorphous Solid Dispersion Preparation (ASD) Dichloromethane:methanol (80:20) was added to a supply vessel, to which Compound (I) free base (e.g., in any of the crystalline forms described herein (e.g., Forms A and B) or as an amorphous form) and hydroxypropyl methylcellulose acetate succinate (HPMCAS) were added in a 1:1 w / w ratio, the mixture was stirred to obtain a solution, and then spray dried to obtain a 50:50 Compound (I):HPMCAS-M SDD (spray dried dispersion). [Table 2] Example 4. Capsules of Compound (I) Formulations 1 and 2 [Table 3]

[0147] The manufacturing processes for Formulation 1 and Formulation 2 are as follows. 1) The intragranular ingredients were blended in a suitable sized container using a Turbula blender at 23 rpm for 10 minutes. 2) The intragranular blend was dry granulated by densification using a single station press equipped with 0.875 inch tooling. 3) The resulting material was milled using a Quadro Comil U5 equipped with a 040G screen. 4) The bulk density of the granules was determined and if it was not within the range of 0.45 + 0.02 g / mL, the densification and milling were repeated until the desired bulk density was achieved. 5) The extragranular ingredients were blended with the granules in a Turbula blender at 20 rpm for 5 minutes. 6) The final blend was hand filled into size 4 and size 0 HPMC capsules (Vcaps® Plus). Disintegration time. The time required for the capsules described as Formulation 1 and Formulation 2 to disintegrate was calculated according to the USP <701> Disintegration was determined using the procedure specifically for uncoated or plain coated tablets. Specifically, a single capsule was placed into each of the six tubes of a basket (basket type A) along with a disk. Analytical grade water was added and the temperature was maintained at 37° C.±2° C. The disintegration time for capsules of formulations 1 and 2 was less than 15 minutes.

[0148] Dissolution Times. The dissolution times of Formulations 1 and 2 were determined in biorelevant media using the following dissolution protocol. [Table 4]

[0149] Figure 1 compares the dissolution profiles of Formulations 1 and 2 compared to 50:50 Compound (I):HPMCAS-M alone (i.e., ASD alone) in biorelevant media, i.e., gastric and intestinal pH. Formulation 2 showed slightly higher solubility in both biorelevant media. Formulation 1 was less soluble than Formulation 2, but still tolerable. When these formulations were evaluated in a dog PK study, this solubility was predictive of in vivo behavior in that Formulation 1 at 25 mg strength and both Formulation 2 at 25 mg and 100 mg achieved greater than 90% relative bioavailability compared to ASD in suspension. [Table 5] The manufacturing processes of T1 and T2 were as follows. 1) The intragranular ingredients were blended in an appropriate size container using a Turbula blender at 25 rpm for 10.5 minutes. After the lubricant was added, the ingredients were further blended using the Turbula blender at 25 rpm for 2.5 minutes. 2) The intragranular blend was dry granulated by densification using a single station press to prepare slugs (hardness: 2-5 kp and thickness about 3-4 mm). 3) The resulting slugs were gently crushed and passed through a 35 mesh sieve to obtain granules. 4) The extragranular ingredients were blended with the granules in a Turbula blender for 10 minutes at 25 rpm without the addition of lubricant. After the addition of the lubricant, the ingredients were further blended for 2.5 minutes at 25 rpm using the Turbula blender. 5) The final blend was used to manufacture tablets using a Korsch tablet press. The manufacturing process of T3 was as follows. 1) The intragranular ingredients were blended in an appropriately sized blender for 250 revolutions at 15 rpm, then delumped by comil and blended again for 250 revolutions. After adding the lubricant, the ingredients were blended an additional 60 revolutions at 15 rpm. 2) The intragranular blend was dry granulated using a Gerteis roller compactor with a roll force of 7.5 kN / cm, roll speed of 1.5 rpm, and roll gap of 1.5 mm to form intragranular ribbons. These ribbons were then milled using a screen size of 0.8 mm to form intragranular granules. 3) The extragranular ingredients were blended with the granules in a blender for 200 minutes at 15 rpm without the addition of lubricant. After the addition of lubricant, the ingredients were blended for an additional 60 revolutions at 15 rpm. 4) The final blend was used to manufacture tablets using a Korsch tablet press. Disintegration Time. The time to disintegrate the tablets described as compositions T1, T2, and T3 was measured according to the USP <701> Disintegration was determined using a procedure specifically for uncoated or plain coated tablets. Specifically, a single tablet was placed in each of the three tubes of a basket (basket type A) along with a disk. Analytical grade water was added and the temperature was maintained at 37°C ± 2°C. The disintegration time of the tablets was less than 1 minute 30 seconds. Dissolution. The dissolution profiles of formulations T1, T2, and T3 in biorelevant media were determined using the following method. [Table 6] Formulation T1 provided slightly longer supersaturation in FaSSIF biorelevant media. Formulation T2 was unable to maintain supersaturation longer than formulation T1, but was still tolerable. These formulations were evaluated in a dog PK study.

[0150] FIG. 4 compares the dog PK plasma concentration profiles between 50:50 Compound (I):HPMCAS-M alone (i.e., ASD alone), tablet formulations T1, T2, and T3. Tablets of 100 mg strength formulations T1 and T2 achieved a relative bioavailability of over 85% compared to ASD in suspension. The PK results of these two formulations suggested that they were not significantly different from each other (p<0.05). However, higher variability was observed in formulation T1 at earlier time points compared to T2, which may be due to different levels of total surfactant present in the formulations. The PK results of formulations T2 and T3 are similar.

[0151] Example 5. Capsules of Compound (I) Formulations 3, 4, and 5 (Formulation Comparison) Capsule Compositions 3, 4, and 5 containing the amorphous solid dispersion of Compound (I) described in Example 1 were also prepared. [Table 7]

[0152] The manufacturing process for formulations 3, 4, and 5 is as follows: 1) The intragranular ingredients (Formulations 3, 4, and 5) were blended in an appropriately sized container using a Turbula blender at 23 rpm for 10 minutes. 2) The intragranular blend was dry granulated by densification using a single station press equipped with 0.875 inch tooling. 3) The resulting material was milled using a Quadro Comil U5 equipped with a 040G screen. 4) The bulk density of the granules was determined and if it was not within the range of 0.45 + 0.02 g / mL, the densification and milling were repeated until the desired bulk density was achieved. 5) The extragranular ingredients (for 4 and 5, not applicable to 3 as it does not contain extragranular ingredients) were blended with the granules in a Turbula blender at 20 rpm for 5 minutes. 6) The final blend was hand filled into size 4 (25 mg strength) and size 0 (100 mg strength) HPMC capsules (Vcaps® Plus).

[0153] Disintegration Time. The time to disintegrate Formulations 3, 4, and 5 was determined as described above for Formulations 1 and 2. The disintegration time of the capsules was less than 15 minutes.

[0154] Dissolution Times. The dissolution profiles of Formulations 3, 4, and 5 in biorelevant media were determined using the same protocol as described above for Formulations 1 and 2.

[0155] Figure 2 compares the dissolution profiles of Formulation 3 at different doses compared to 50:50 Compound (I):HPMCAS-M alone (i.e., ASD alone) in biorelevant media, i.e., gastric and intestinal pH. Formulation 3 performed poorly compared to ASD alone, as evidenced by the lower solubility of Formulation 3 compared to ASD. Formulation 3 was also evaluated in a monkey PK study, achieving only about 42% relative bioavailability.

[0156] Figure 3 compares the dissolution profiles of Formulations 4 and 5 at different doses compared to 50:50 Compound (I):HPMCAS-M alone (i.e., ASD alone) in biorelevant media, i.e., gastric and intestinal pH. Formulations 4 and 5 performed poorly compared to ASD alone, as evidenced by the lower solubility of Formulations 4 and 5 compared to ASD.

Claims

1. (i) An amorphous solid dispersion comprising a compound (I) 【Chemical Formula 1】 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable polymer, and (ii) A surfactant comprising an inner granule phase, and an outer granule phase comprising at least one of a surfactant, a disintegrant, a fluidizing agent, a lubricant, and a filler A pharmaceutical composition comprising the same.

2. The pharmaceutical composition according to claim 1, wherein the outer granule phase contains a surfactant, and the surfactants in the inner granule phase and the outer granule phase are the same.

3. The pharmaceutical composition according to any one of claims 1 to 2, wherein the polymer is: (i) Hydroxypropylmethylcellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone / vinyl acetate copolymer (PVP-VA); (ii) Poly(1-vinylpyrrolidone-co-vinyl acetate) (or polyvinylpyrrolidone / vinyl acetate-64, PVPVA-64) or hydroxypropylmethylcellulose acetate succinate (HPMCAS); (iii) Hydroxypropylmethylcellulose acetate succinate-M (HPMCAS-M); or (iv) Hydroxypropylmethylcellulose acetate succinate-MG (HPMCAS-MG), The pharmaceutical composition.

4. The pharmaceutical composition according to any one of claims 1 to 2, wherein the free base of the compound (I) or an equivalent amount of its pharmaceutically acceptable salt and the polymer are in a weight percentage ratio of about 1:

1.

5. The pharmaceutical composition according to any one of claims 1 to 2, wherein the composition contains about 20% to about 80% by weight (e.g., about 40% to about 60% by weight) of the amorphous solid dispersion based on the total weight of the composition.

6. The pharmaceutical composition according to any one of claims 1 to 2, wherein the surfactant is selected from poloxamer 407, poloxamer 188, and sodium lauryl sulfate, and the surfactant is about 0.25% to about 20% by weight (e.g., about 0.25% to about 5% by weight or about 0.25% to about 3% by weight) of the composition based on the total weight of the composition, and Optionally: (i) The surfactant is present in the inner particle phase at about 0.1% to about 20% by weight (e.g., about 0.1% to about 5% by weight) of the composition based on the total weight of the composition, and in the outer particle phase at about 0% to about 20% by weight (e.g., about 0% to about 5% by weight) of the composition based on the total weight of the composition, and the total amount of the surfactant in the combined inner and outer particle phases in the composition is about 0.25% to about 20% by weight (e.g., about 0.25% to about 10% by weight) of the composition based on the total weight of the composition; or (ii) The surfactant is present in the inner particle phase at about 0.1% to about 3% by weight of the composition based on the total weight of the composition, and in the outer particle phase at about 0.1% to about 2% by weight of the composition based on the total weight of the composition, and the total amount of the surfactant in the combined inner and outer particle phases in the composition is about 0.25% to about 5% by weight of the composition based on the total weight of the composition. The pharmaceutical composition.

7. The pharmaceutical composition according to any one of Claims 1 to 2, wherein the composition further comprises a disintegrant selected from crospovidone, croscarmellose sodium, and sodium starch glycolate, (i) The disintegrant is present at about 0% to about 30% by weight (e.g., about 1% to about 7% by weight or about 5% to about 10% by weight) of the composition based on the total weight of the composition; (ii) The disintegrant is present in the inner particle phase at about 0% to about 30% by weight (e.g., about 0% to about 10% by weight) of the composition based on the total weight of the composition, and in the outer particle phase at about 0% to about 30% by weight (e.g., about 0% to about 10% by weight) of the composition based on the total weight of the composition, and the total amount of the disintegrant in the combined inner and outer particle phases in the composition is about 0.2% to about 30% by weight (e.g., about 0.2% to about 20% by weight) of the composition based on the total weight of the composition; or (iii) The disintegrant is about 0.1% to about 5% by weight of the composition in the inner granule phase based on the total weight of the composition, and about 0.1% to about 5% by weight of the composition in the outer granule phase based on the total weight of the composition, and the total amount of the disintegrant in the combined inner and outer granule phases in the composition is about 5.1% to about 10% by weight of the composition based on the total weight of the composition. The pharmaceutical composition.

8. The pharmaceutical composition according to any one of Claims 1 to 2, wherein the composition contains a fluidizing agent selected from colloidal silicon dioxide, starch, talc, tricalcium phosphate, powdered cellulose, magnesium trisilicate, and mixtures thereof. (i) The fluidizing agent is about 0% to about 5% by weight of the composition (e.g., about 0% to about 3% or about 0.5% to about 2%) based on the total weight of the composition. (ii) The fluidizing agent is about 0% to about 5% by weight of the composition in the inner granule phase based on the total weight of the composition, and about 0% to about 5% by weight of the composition in the outer granule phase based on the total weight of the composition, and the total amount of the fluidizing agent in the combined inner and outer granule phases in the composition is about 0.1% to about 5% by weight of the composition based on the total weight of the composition; or (iii) The fluidizing agent is about 0.1% to about 2% by weight of the composition in the inner granule phase based on the total weight of the composition, and about 0.1% to about 2% by weight of the composition in the outer granule phase based on the total weight of the composition, and the total amount of the fluidizing agent in the combined inner and outer granule phases in the composition is about 0.5% to about 2% by weight of the composition based on the total weight of the composition. The pharmaceutical composition.

9. The pharmaceutical composition according to any one of Claims 1 to 2, wherein the composition further contains a lubricant selected from talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, sodium stearyl fumarate, and mixtures thereof. (i) The lubricant is about 0% to about 5% by weight of the composition (e.g., about 0% to about 3% or about 0.5% to about 2%) based on the total weight of the composition. (ii) the lubricant is from about 0 wt% to about 5 wt% of the composition based on the total weight of the composition in the inner particle phase, and from about 0 wt% to about 5 wt% of the composition based on the total weight of the composition in the outer particle phase, and the total amount of the lubricant in the combined inner and outer particle phases in the composition is from about 0.1 wt% to about 5 wt% of the composition based on the total weight of the composition; or, (iii) the lubricant is from about 0.1 wt% to about 2 wt% of the composition based on the total weight of the composition in the inner particle phase, and from about 0.1 wt% to about 2 wt% of the composition based on the total weight of the composition in the outer particle phase, and the total amount of the lubricant in the combined inner and outer particle phases in the composition is from about 0.5 wt% to about 2 wt% of the composition based on the total weight of the composition, the pharmaceutical composition. [

10. ] The pharmaceutical composition according to any one of Claims 1 to 2, wherein the composition further comprises one or more fillers selected from anhydrous lactose or lactose monohydrate; starches such as direct compression starches and hydrolyzed starches; mannitols such as spray-dried and crystalline mannitols for direct compression; sorbitol; xylitol; dextrose and dextrose monohydrate; sucrose-based diluents such as powdered sugar; calcium-based diluents such as calcium monobasic sulfate monohydrate, dibasic calcium phosphate dihydrate; calcium sulfate dihydrate; granular calcium lactate trihydrate; dextran; inositol; hydrolyzed cereal solids; amylose; cellulose (e.g., food-grade sources of amorphous cellulose and powdered cellulose, microcrystalline cellulose, modified or co-processed microcrystalline cellulose, extra-granular microcrystalline cellulose, and silicified microcrystalline cellulose); calcium carbonate; glycine; bentonite; polyvinylpyrrolidone; and mixtures thereof, (i) the composition comprises from about 0 wt% to about 80 wt% (e.g., from about 30 wt% to about 50 wt% or from about 35 wt% to about 45 wt%) of the one or more fillers based on the total weight of the composition; (ii) the one or more fillers are present in the inner granule phase in an amount of about 0 wt% to about 90 wt% (e.g., about 20 wt% to about 60 wt%) based on the total weight of the composition, in the outer granule phase in an amount of about 0 wt% to about 90 wt% (e.g., about 0 wt% to about 20 wt%) based on the total weight of the composition, and the total amount of the one or more fillers in the combined inner and outer granule phases in the composition is in an amount of about 5 wt% to about 90 wt% (e.g., about 20 wt% to about 60 wt%) based on the total weight of the composition; (iii) the one or more fillers are present in the inner granule phase in an amount of about 30 wt% to about 45 wt% based on the total weight of the composition, in the outer granule phase in an amount of about 1 wt% to about 10 wt% based on the total weight of the composition, and the total amount of the one or more fillers in the combined inner and outer granule phases in the composition is in an amount of about 31 wt% to about 50 wt% based on the total weight of the composition; (iv) the composition comprises two fillers, the first filler being in an amount of about 15 wt% to about 30 wt% based on the total weight of the composition and the second filler being in an amount of about 15 wt% to about 25 wt% based on the total weight of the composition; or (v) the inner granule phase comprises two fillers selected from mannitol and microcrystalline cellulose and the outer granule phase comprises two fillers selected from mannitol and microcrystalline cellulose, the pharmaceutical composition.

11. The pharmaceutical composition according to any one of Claims 1 to 2, wherein the composition further comprises a non-functional polymer coating selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone-polyvinyl acetate copolymer, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymer, acrylic polymer, and polyethylene glycol, the composition comprises the non-functional coating polymer in an amount of about 0 wt% to about 10 wt% (e.g., about 0.5 wt% to about 6 wt% or about 2 wt% to about 5 wt%) based on the total weight of the composition, optionally, the non-functional polymer coating contains a pigment which is an iron oxide-based pigment, or the non-functional polymer coating does not contain a pigment, the pharmaceutical composition. [

12. ] The pharmaceutical composition according to any one of claims 1 to 2, wherein the composition is prepared in an oral dosage form, (i) the oral dosage form contains (a) the free base of compound (I) or a pharmaceutically acceptable salt thereof; and an amorphous solid dispersion of a polymer, (b) a surfactant, (c) a disintegrant, (d) a fluidizing agent, (e) a lubricant, (f) one or more fillers; or (ii) the oral dosage form contains (a) the free base of compound (I) or a pharmaceutically acceptable salt thereof; and an amorphous solid dispersion of hydroxypropylmethylcellulose acetate succinate (HPMCAS), (b) poloxamer 407, (c) crospovidone, (d) colloidal silicon dioxide, (e) magnesium stearate, (f) microcrystalline cellulose (MCC) and (g) mannitol, optionally, (i) the inner phase of the granule contains (a) the free base of compound (I) or a pharmaceutically acceptable salt thereof; and an amorphous solid dispersion of hydroxypropylmethylcellulose acetate succinate (HPMCAS), (b) poloxamer 407, (c) crospovidone, (d) colloidal silicon dioxide, (e) magnesium stearate, (f) microcrystalline cellulose (MCC) and mannitol, and the outer phase of the granule contains (b) poloxamer 407, (c) crospovidone, (d) colloidal silicon dioxide, (e) magnesium stearate, (f) mannitol; or (ii) the inner phase of the granule contains (a) the free base of compound (I) or a pharmaceutically acceptable salt thereof; and an amorphous solid dispersion of hydroxypropylmethylcellulose acetate succinate (HPMCAS), (b) poloxamer 407, (c) crospovidone, (d) colloidal silicon dioxide, (e) magnesium stearate, (f) microcrystalline cellulose (MCC), (g) mannitol, and the outer phase of the granule contains (b) poloxamer 407, (c) crospovidone, (d) colloidal silicon dioxide, (e) magnesium stearate, (f) microcrystalline cellulose (MCC) and (g) mannitol, the pharmaceutical composition. **Claim 13**: A pharmaceutical composition according to any one of claims 1 to 2, wherein the composition is prepared in an oral dosage form, and the oral dosage form is a) an amorphous solid dispersion comprising the free base of compound (I) or an equivalent amount of a pharmaceutically acceptable salt thereof and hydroxypropylmethylcellulose acetate succinate, wherein the free base of compound (I) or an equivalent amount of a pharmaceutically acceptable salt thereof and the hydroxypropylmethylcellulose acetate succinate are in a weight ratio of about 1:1, said amorphous solid dispersion; b) a surfactant, wherein the composition comprises an inner granule phase and an outer granule phase, and the surfactant is present in the inner granule phase and the outer granule phase, said surfactant; c) a disintegrant; d) a fluidizing agent; e) a lubricant; f) one or more fillers; and optionally (i) the inner granule phase comprises (a) the free base of compound (I) or a pharmaceutically acceptable salt thereof; and an amorphous solid dispersion of hydroxypropylmethylcellulose acetate succinate (HPMCAS), (b) poloxamer 407, (c) crospovidone, (d) colloidal silicon dioxide, (e) magnesium stearate, (f) microcrystalline cellulose (MCC) and mannitol, and the outer granule phase comprises (b) poloxamer 407, (c) crospovidone, (d) colloidal silicon dioxide, (e) magnesium stearate, (f) mannitol; (ii) the inner granule phase comprises (a) the free base of compound (I) or a pharmaceutically acceptable salt thereof; and an amorphous solid dispersion of hydroxypropylmethylcellulose acetate succinate (HPMCAS), (b) poloxamer 407, (c) crospovidone, (d) colloidal silicon dioxide, (e) magnesium stearate, (f) microcrystalline cellulose (MCC) and mannitol, and the outer granule phase comprises (b) poloxamer 407, (c) crospovidone, (d) colloidal silicon dioxide, (e) magnesium stearate, (f) microcrystalline cellulose (MCC) and mannitol; or (iii) The inner particle phase contains (a) the free base of compound (I) or a pharmaceutically acceptable salt thereof; and an amorphous solid dispersion of hydroxypropyl methylcellulose acetate succinate (HPMCAS), (b) poloxamer 407, (c) crospovidone, (d) colloidal silicon dioxide, (e) magnesium stearate, (f) microcrystalline cellulose (MCC) and mannitol, and the outer particle phase contains (b) poloxamer 407, (c) crospovidone, (d) colloidal silicon dioxide, (e) magnesium stearate, (f) microcrystalline cellulose (MCC) and mannitol, and the non-functional coating contains polyvinyl alcohol. The pharmaceutical composition. **Claim 14** The pharmaceutical composition according to claim 12, wherein the oral dosage form is (i) a capsule, and optionally, the size of the capsule is 0 or 0EL; or (ii) a tablet or a tablet having a non-functional polymer coating, and optionally, (a) the size of the tablet is a circular biconvex of 6.1 mm, the size of the tablet is a circular biconvex of 6.35 mm, the size of the tablet is a circular biconvex of 9.0 mm, or the size of the tablet is a circular biconvex of 9.5 mm; or (b) the size of the tablet is an oval biconvex of 6.9×16.9 mm, the size of the tablet is an oval biconvex of 8×16 mm, the size of the tablet is an oval biconvex of 9×18 mm, the size of the tablet is an oval biconvex of 9.5×18.4 mm, or the size of the tablet is an oval biconvex of 10×19 mm. The pharmaceutical composition. (**Claim 15**) The pharmaceutical composition according to any one of claims 1 to 2, wherein the composition contains the free base of compound (I) or an equivalent amount of a pharmaceutically acceptable salt thereof in an amount of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, or about 200 mg. (**Claim 16**) A method for preparing the amorphous solid dispersion according to any one of claims 1 to 2, comprising mixing the free base of compound (I) or the pharmaceutically acceptable salt thereof with the polymer at a ratio of about 1:1, adding one or more solvents, and removing the solvent(s) by heating.

17. An amorphous solid dispersion comprising a compound (I) 【Chemical 2】 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable polymer which is hydroxypropylmethylcellulose acetate succinate (HPMCAS) (e.g., HPMCAS-M) or polyvinylpyrrolidone (PVP) or a 6:4 linear random copolymer of N-vinylpyrrolidone and vinyl acetate (e.g., PVPVA-64), optionally, wherein the free base of the compound (I) or an equivalent amount of its pharmaceutically acceptable salt and the polymer are in a weight percent ratio of about 1:1, said amorphous solid dispersion.

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