Solid dispersions of pan-raf kinase inhibitors

Abstract

Disclosed herein are solid dispersions of a pan-RAF kinase inhibitor. In particular, provided herein is a pharmaceutical composition comprising a solid dispersion having a mass median diameter of about 75 µm to about 400 µm and one or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridine-2-yl)thiazole-5-carboxamide or a pharmaceutically acceptable salt thereof and a vinylpyrrolidone-vinyl acetate copolymer.

Description

[0001] This application is a divisional application of Chinese patent application No. 202080094798.4, entitled "Solid Dispersion of Pan-RAF Kinase Inhibitor", filed on November 25, 2020 (the corresponding PCT application was filed on November 25, 2020, and has the application number PCT / US2020 / 062307). Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 941,426, filed November 27, 2019, which is hereby incorporated by reference in its entirety. Technical Field

[0003] This disclosure provides a pharmaceutical composition comprising a median diameter (D) having a mass of about 75 µm to about 400 µm. 50 A solid dispersion of (R) and one or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises (R)-2-(1-(6-amino-5-chloropyrimidin-4-carbamoyl)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide or a pharmaceutically acceptable salt thereof and a vinylpyrrolidone-vinyl acetate copolymer. Background Technology

[0004] RAF kinases (A-RAF, BRAF, and C-RAF) are key components of the mitogen-activated protein kinase (MAPK) pathway, which controls cell proliferation and survival signaling. See Downward J. Nature Reviews. Cancer 2003;3(1):11-22; Wellbrock C et al. Nature Reviews Molecular Cell Biology 2004;5(11):875-85.

[0005] The MAP kinase (MAPK) pathway is a central signaling pathway dysregulated in a wide range of developmental disorders. The MAPK pathway, comprised of RAS, RAF, MAPK, or extracellular signal-regulated kinases (MEKs) and extracellular signal-regulated kinases (ERKs), integrates signals from receptors on the cell surface, including cancer-associated receptor tyrosine kinases such as epidermal growth factor receptor, mesenchymal-epithelial transition factor (MET), and vascular endothelial growth factor receptor (VEGF). Biochim Biophys Acta2007;1773(8):1150-60). Genetic alterations in the MAPK pathway are among the most common in human cancers. Up to 60% of melanomas have BRAF mutations (Davies H. et al., 2007;1773(8):1150-60). Nature 2002;417(6892):94954), and it is estimated that KRAS mutations are present in approximately 60%, 30%, and 15% of pancreatic, colonic, and lung tumors, respectively (Vakiani E et al.). J Pathol 2011;223(2):219-29). BRAF mutations are also present in 40% of papillary or undifferentiated thyroid carcinomas (Kimura ET et al.). Cancer Res 2003;63(7):1454-7) and a smaller percentage of several other types of tumors (Vakiani E et al.). Most reported BRAF mutations involve the substitution of valine with glutamic acid at amino acid position 600 (V600E mutation). The BRAF V600E mutation constitutively activates downstream signal transduction in the BRAF and MAPK pathways (Davies H. et al.).

[0006] (R)-2-(1-(6-amino-5-chloropyrimidin-4-carbamate)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazolyl-5-carboxamide (“Compound 1”) is a class II pan Raf kinase inhibitor that can be used to treat Raf-mediated diseases such as cancer. WO 2009 / 006389 discloses Compound 1 and its use in the treatment of Raf-mediated diseases. WO 2015 / 148828 discloses solid dispersion extrusions comprising Compound 1 and pharmaceutical compositions thereof. WO 2013 / 144923 discloses a method of treating non-BRAFV600E mutant melanoma in patients, the method comprising administering Compound 1 and a MEK inhibitor.

[0007] There is a need for an improved formulation of compound 1 for use in treating patients with cancer. Summary of the Invention

[0008] In one aspect, this disclosure provides a pharmaceutical composition comprising: (1) a solid dispersion having a density of about 75 µm to about 400 µm. 50; and (2) one or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises: (a) about 10% w / w to about 70% w / w of compound 1 or a pharmaceutically acceptable salt thereof; and (b) about 30% w / w to about 90% w / w of a vinylpyrrolidone-vinyl acetate copolymer.

[0009] In another aspect, this disclosure provides a pharmaceutical composition comprising: (1) a solid dispersion wherein about 70% w / w or more of the particles have a diameter greater than or equal to about 75 µm but less than or equal to about 500 µm, i.e., a particle size between or equal to about 75 µm and about 500 µm; and (2) one or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises: (a) about 10% w / w to about 70% w / w of (R)-2-(1-(6-amino-5-chloropyrimidin-4-carbamate)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazolyl-5-carboxamide or a pharmaceutically acceptable salt thereof; and (b) about 30% w / w to about 90% w / w of a vinylpyrrolidone-vinyl acetate copolymer.

[0010] In another aspect, this disclosure provides a method for preparing a pharmaceutical composition comprising: (1) a solid dispersion having a density of about 75 µm to about 400 µm. 50 ; and (2) one or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises: (a) about 10% w / w to about 70% w / w of compound 1 or a pharmaceutically acceptable salt thereof; and (b) about 30% w / w to about 90% w / w of a vinylpyrrolidone-vinyl acetate copolymer, the method comprising: (1) mixing compound 1 or a pharmaceutically acceptable salt thereof with the vinylpyrrolidone-vinyl acetate copolymer to obtain a powder mixture; (2) hot-melt extruding the powder mixture to obtain a solid dispersion extrudate; and (3) milling the solid dispersion extrudate to obtain a D having about 75 µm to about 400 µm. 50 (3) a solid dispersion; and (4) mixing the solid dispersion with one or more pharmaceutically acceptable excipients.

[0011] In another aspect, this disclosure provides a solid oral dosage form, such as a tablet, comprising a pharmaceutical composition comprising: (1) a solid dispersion having a density of about 75 µm to about 400 µm. 50; and (2) one or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises: (a) about 10% w / w to about 70% w / w of compound 1 or a pharmaceutically acceptable salt thereof; and (b) about 30% w / w to about 90% w / w of a vinylpyrrolidone-vinyl acetate copolymer.

[0012] In another aspect, this disclosure provides a method for treating a patient with cancer, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition, the pharmaceutical composition comprising: (1) a solid dispersion having a density of about 75 µm to about 400 µm. 50 ; and (2) one or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises: (a) about 10% w / w to about 70% w / w of compound 1 or a pharmaceutically acceptable salt thereof; and (b) about 30% w / w to about 90% w / w of a vinylpyrrolidone-vinyl acetate copolymer.

[0013] In another aspect, this disclosure provides a kit comprising a pharmaceutical composition comprising: (1) a solid dispersion having a density of about 75 µm to about 400 µm. 50 ; and (2) one or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises: (a) about 10% w / w to about 70% w / w of compound 1 or a pharmaceutically acceptable salt thereof; and (b) about 30% w / w to about 90% w / w of a vinylpyrrolidone-vinyl acetate copolymer.

[0014] In one aspect, this disclosure provides a pharmaceutical composition comprising: (1) a solid dispersion having a density of about 75 µm to about 400 µm. 50 (2) and one or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises: about 10% w / w to about 70% w / w of (R)-2-(1-(6-amino-5-chloropyrimidin-4)-carbamate)ethyl)-N-(5-chloro-4-(trifluoromethylpyridin-2-yl)thiazole-5-carboxamide or a pharmaceutically acceptable salt thereof; and about 30% w / w to about 90% w / w of a polymer.

[0015] In one aspect, this disclosure provides a pharmaceutical composition comprising: (1) a solid dispersion wherein about 70% w / w or more of particles have a diameter greater than or equal to about 75 µm but less than or equal to about 500 µm; and (2) one or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises: (a) about 10% w / w to about 70% w / w of (R)-2-(1-(6-amino-5-chloropyrimidin-4-carbamate)ethyl)-N-(5-chloro-4-(trifluoromethylpyridin-2-yl)thiazolyl-5-carboxamide or a pharmaceutically acceptable salt thereof; and (b) about 30% w / w to about 90% w / w of a polymer.

[0016] In one aspect, this disclosure provides a pharmaceutical composition comprising: (1) a solid dispersion; and (2) one or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises (a) compound 1 or a pharmaceutically acceptable salt thereof; and (b) a polymer (e.g., a polymer suitable for hot melt extrusion). In one aspect, this disclosure provides a pharmaceutical composition comprising a solid dispersion comprising (a) compound 1 or a pharmaceutically acceptable salt thereof; and (b) a polymer (e.g., a polymer suitable for hot melt extrusion). In one aspect, this disclosure provides a solid dispersion comprising (a) compound 1 or a pharmaceutically acceptable salt thereof; and (b) a polymer (e.g., a polymer suitable for hot melt extrusion). In some embodiments, the polymer is a high molecular weight hydrophilic polymer. In one aspect, this disclosure provides a pharmaceutical composition comprising: (1) a solid dispersion; and (2) one or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises: (a) compound 1 or a pharmaceutically acceptable salt thereof; and (b) a high molecular weight hydrophilic polymer, such as a vinylpyrrolidone-vinyl acetate copolymer. In some embodiments, the solid dispersion has a D-size of about 75 µm to about 400 µm. 50In some embodiments, about 70% w / w or more of the particles in the solid dispersion have a diameter greater than or equal to about 75 µm but less than or equal to about 500 µm. In some embodiments, the high molecular weight hydrophilic polymer includes at least one of the following: polyvinylpyrrolidone (PVP, e.g., PVP-K30), vinylpyrrolidone-vinyl acetate copolymer (e.g., copovidone), crosslinked polyvinyl N-pyrrolidone, polyvinyl alcohol (PVA), polysaccharides, hydroxypropyl methylcellulose (HPMC or hydroxypropyl methylcellulose; e.g., HPMC-E5), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), polyethylene oxide, hydroxypropyl-β-cyclodextrin (HP-β-CD), sulfobutyl ether-β-cyclodextrin, hydroxypropyl methylcellulose acetate succinate (HPMC-AS-HF), polyethylene glycol (PEG), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVAc-PVCap-PEG, e.g., sold under the trade name Soluplus), polysaccharides, or combinations thereof. In some embodiments, the high molecular weight hydrophilic polymer is PVP, copovidone, cross-linked povidone, HPMC, or a combination thereof. In some embodiments, the high molecular weight hydrophilic polymer includes HPMC and cross-linked povidone. In some embodiments, the high molecular weight hydrophilic polymer includes HPMC and PVP. In some embodiments, the high molecular weight hydrophilic polymer includes HPMC and copovidone. In some embodiments, the high molecular weight hydrophilic polymer includes copovidone and cross-linked povidone.

[0017] In one aspect, this disclosure provides a method of treating a patient with cancer, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition, the pharmaceutical composition comprising: (1) a solid dispersion; and (2) one or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises (a) compound 1 or a pharmaceutically acceptable salt thereof; and (b) a polymer.

[0018] Further embodiments and advantages of this disclosure will be set forth in part in the description which follows, and will be learned from the description or by practice of this disclosure. The embodiments and advantages of this disclosure will be realized and achieved by means of the elements and combinations specifically pointed out in the appended claims.

[0019] It should be understood that both the above overview and the following detailed description are exemplary and illustrative only and do not limit the implementation as requested. Attached Figure Description

[0020] Figure 1 This is a four-line graph showing the dissolution profile of hot melt extrusion (HME) loaded tablets (USP device 2, paddle 75 rpm, 900 mL, 0.3%-0.45% CTAB, pH 1.1).

[0021] Figure 2 This is a two-line graph showing the tablet characteristics of HME-loaded tablets.

[0022] Figure 3 This is a three-line graph showing the dissolution profile of the tablet formulation (USP device 2, paddle 75 rpm, 900 mL, 0.35% CTAB, pH 1.1).

[0023] Figure 4 This is a two-line graph showing the tablet characteristics of a tablet formulation.

[0024] Figure 5 This is a line graph showing the dissolution profile of the prototype 150 mg HME (50%) tablets (USP device 2, paddle 75 rpm, 900 mL, 0.3% CTAB, pH 1.1). "T2" refers to the HME (40%) tablets.

[0025] Figure 6 These are three-line graphs and three-panel graphs showing the dissolution profiles of Compound 1 tablets (100 mg) made with HME of different particle sizes (40% HME in the tablet).

[0026] Figure 7 This is a four-line graph showing the dissolution profiles of prototype HME (50%) (referred to as "T3") core tablets (20 mg, 70 mg, 100 mg, and 150 mg) (USP device 2, paddle 75 rpm, 900 mL, 0.3% CTAB, pH 1.1). "T2" refers to HME (40%) core tablets.

[0027] Figure 8 This is a two-line graph showing the dissolution profiles of HME (50%) core tablets (100 mg and 150 mg) scaled up.

[0028] Figure 9A This is a fourteen-line graph showing the dissolution profiles of some tablet formulations in Table 14. (USP Unit 2, paddle 75 rpm, 900 mL, 0.35% CTAB, pH 1.1).

[0029] Figure 9B This is an eight-line graph showing the dissolution profiles of some tablet formulations in Table 14. (USP device 2, paddle 75 rpm, 900 mL, 0.35% CTAB, pH 1.1). Detailed Implementation

[0030] In one aspect, this disclosure provides a pharmaceutical composition comprising: (1) a solid dispersion, and (2) one or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises compound 1 or a pharmaceutically acceptable salt thereof; and (b) a polymer, such as a high molecular weight hydrophilic polymer. In one aspect, a solid dispersion comprising compound 1 or a pharmaceutically acceptable salt thereof, and a polymer, such as a high molecular weight hydrophilic polymer, is described herein. In some embodiments, the polymer is a polymer for hot melt extrusion. In some embodiments, the solid dispersion has a D as described herein. 50 D 90 and / or D 10 Value. In some embodiments, the solid dispersion comprises a value as described herein. 50 D 90 and / or D 10 The particle size distribution has a specific particle size distribution. In some embodiments, the solid dispersion comprises particles, and at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100% of the particles have a specific particle size distribution as described herein. 50 D 90 and / or D 10 value.

[0031] In one embodiment, this disclosure provides a pharmaceutical composition comprising: (1) a solid dispersion having a D0.05 of about 75 µm to about 400 µm. 50 ; and (2) one or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises: (a) about 10% w / w to about 70% w / w of compound 1 or a pharmaceutically acceptable salt thereof; and (b) about 30% w / w to about 90% w / w of a vinylpyrrolidone-vinyl acetate copolymer.

[0032] In another embodiment, this disclosure provides a pharmaceutical composition comprising: (1) a solid dispersion wherein about 70% w / w or more of the particles have a diameter greater than or equal to about 75 µm; and (2) one or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises: (a) about 10% w / w to about 70% w / w of (R)-2-(1-(6-amino-5-chloropyrimidin-4-carbamate)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide or a pharmaceutically acceptable salt thereof; and (b) about 30% w / w to about 90% w / w of a vinylpyrrolidone-vinyl acetate copolymer.

[0033] In another embodiment, this disclosure provides a pharmaceutical composition comprising: (1) a solid dispersion wherein about 70% w / w or more of the particles have a diameter greater than or equal to about 75 µm but less than or equal to about 500 µm, i.e., a particle size between or equal to about 75 µm and about 500 µm; and (2) one or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises: (a) about 10% w / w to about 70% w / w of (R)-2-(1-(6-amino-5-chloropyrimidin-4-carbamate)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide or a pharmaceutically acceptable salt thereof; and (b) about 30% w / w to about 90% w / w of a vinylpyrrolidone-vinyl acetate copolymer.

[0034] In another embodiment, this disclosure provides a pharmaceutical composition comprising: (1) a solid dispersion having a D0 of about 10 µm to about 200 µm. 10 ; and (2) one or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises: (a) about 10% w / w to about 70% w / w of compound 1 or a pharmaceutically acceptable salt thereof; and (b) about 30% w / w to about 90% w / w of a vinylpyrrolidone-vinyl acetate copolymer.

[0035] In another embodiment, this disclosure provides a pharmaceutical composition comprising: (1) a solid dispersion having a density of about 100 µm to about 1000 µm. 90 ; and (2) one or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises: (a) about 10% w / w to about 70% w / w of compound 1 or a pharmaceutically acceptable salt thereof; and (b) about 30% w / w to about 90% w / w of a vinylpyrrolidone-vinyl acetate copolymer.

[0036] In another embodiment, this disclosure provides a pharmaceutical composition comprising: (1) a solid dispersion having: (i) a Di of about 10 µm to about 200 µm 10 (ii) D from approximately 100 µm to approximately 1000 µm 90 (1) and (2) one or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises: (a) about 10% w / w to about 70% w / w of compound 1 or a pharmaceutically acceptable salt thereof; and (b) about 30% w / w to about 90% w / w of a vinylpyrrolidone-vinyl acetate copolymer.

[0037] In another embodiment, this disclosure provides a pharmaceutical composition comprising: (1) a solid dispersion having: (i) a Di of about 10 µm to about 200 µm 10 ; and (ii) D from about 75 µm to about 400 µm 50 ; and (2) one or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises: (a) about 10% w / w to about 70% w / w of compound 1 or a pharmaceutically acceptable salt thereof; and (b) about 30% w / w to about 90% w / w of a vinylpyrrolidone-vinyl acetate copolymer.

[0038] In another embodiment, this disclosure provides a pharmaceutical composition comprising: (1) a solid dispersion having: (i) a Di of about 75 µm to about 400 µm 50 ; and (ii) D from about 100 µm to about 1000 µm 90 ; and (2) one or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises: (a) about 10% w / w to about 70% w / w of compound 1 or a pharmaceutically acceptable salt thereof; and (b) about 30% w / w to about 90% w / w of a vinylpyrrolidone-vinyl acetate copolymer.

[0039] In another embodiment, this disclosure provides a pharmaceutical composition comprising: (1) a solid dispersion having: (i) a Di of about 10 µm to about 200 µm 10 (ii) D from approximately 75 µm to approximately 400 µm 50 ; and (iii) D from about 100 µm to about 1000 µm 90 ; and (2) one or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises: (a) about 10% w / w to about 70% w / w of compound 1 or a pharmaceutically acceptable salt thereof; and (b) about 30% w / w to about 90% w / w of a vinylpyrrolidone-vinyl acetate copolymer.

[0040] In one aspect, this disclosure provides a pharmaceutical composition comprising a solid dispersion, wherein the solid dispersion comprises (a) compound 1 or a pharmaceutically acceptable salt thereof; and (b) a polymer (e.g., a polymer suitable for hot melt extrusion).

[0041] In general, the above-described pharmaceutical compositions are referred to herein as "the compositions disclosed".

[0042] In another embodiment, this disclosure provides compositions wherein the solid dispersion has a density of about 85 µm to about 250 µm. 50 In another embodiment, the solid dispersion has a D-size of about 95 µm to about 150 µm. 50 In another embodiment, the solid dispersion has a D-size of about 75 µm to about 150 µm. 50 In another embodiment, the solid dispersion has a D-size of about 75 µm to about 250 µm. 50 In another embodiment, the solid dispersion has a D-size of about 75 µm to about 400 µm. 50 In another embodiment, the solid dispersion has a D-size of about 75 µm to about 500 µm. 50 In another embodiment, the solid dispersion has a D-size of about 75 µm to about 600 µm. 50 In another embodiment, the solid dispersion has a D-size of about 150 µm to about 250 µm. 50 In another embodiment, the solid dispersion has a D-size of about 150 µm to about 400 µm. 50 In another embodiment, the solid dispersion has a D-size of about 150 µm to about 600 µm. 50 In another embodiment, the solid dispersion has a D-size of about 100 µm to about 110 µm. 50 . In another embodiment, the solid dispersion has a diameter of about 75 µm, about 80 µm, about 85 µm, about 90 µm, about 95 µm, about 100 µm, about 105 µm, about 110 µm, about 115 µm, about 120 µm, about 125 µm, about 130 µm, about 135 µm, about 140 µm, about 145 µm, about 150 µm, about 155 µm, about 160 µm, about 165 µm, about 170 µm, about 175 µm, about 180 µm, about 185 µm, about 190 µm, about 195 µm, about 200 µm, about 205 µm, about 210 µm, about 220 µm, about 220 µm, about 230 µm, about 240 µm, about 250 µm, about 260 µm, about 270 µm. D μm, approximately 280 µm, approximately 290 µm, approximately 300 µm, approximately 310 µm, approximately 320 µm, approximately 330 µm, approximately 340 µm, approximately 350 µm, approximately 360 µm, approximately 370 µm, approximately 380 µm, approximately 390 µm, or approximately 400 µm 50In another embodiment, the solid dispersion has a Dm of at least about 50 µm, at least about 75 µm, at least about 80 µm, at least about 85 µm, at least about 90 µm, at least about 95 µm, at least about 100 µm, at least about 110 µm, at least about 120 µm, at least about 125 µm, at least about 150 µm, at least about 175 µm, at least about 200 µm, at least about 250 µm, at least about 300 µm, at least about 350 µm, or at least about 400 µm. 50 In another embodiment, the solid dispersion has a Dm of up to about 75 µm, up to about 100 µm, up to about 125 µm, up to about 150 µm, up to about 200 µm, up to about 250 µm, up to about 300 µm, up to about 350 µm, up to about 400 µm, up to about 500 µm, or up to about 800 µm. 50 In another embodiment, the solid dispersion has a D0.5 of approximately 105 µm. 50 In one implementation, D 50 It was determined through particle size analysis by sieving.

[0043] In another embodiment, this disclosure provides compositions wherein the solid dispersion has a density of about 25 µm to about 150 µm. 10 In another embodiment, the solid dispersion has a D-size of about 25 µm to about 100 µm. 10 In another embodiment, the solid dispersion has a D-size of about 25 µm to about 75 µm. 10 In another embodiment, the solid dispersion has a D-size of about 25 µm to about 50 µm. 10 In another embodiment, the solid dispersion has a D-size of about 25 µm to about 50 µm. 10 In another embodiment, the solid dispersion has a density of about 10 µm, about 20 µm, about 25 µm, about 30 µm, about 35 µm, about 40 µm, about 45 µm, about 50 µm, about 60 µm, about 70 µm, about 75 µm, about 80 µm, about 90 µm, about 100 µm, about 110 µm, about 120 µm, about 130 µm, about 140 µm, about 150 µm, about 160 µm, about 170 µm, about 180 µm, about 190 µm, or about 200 µm. 10 In another embodiment, the solid dispersion has a D0 of approximately 30 µm. 10 .

[0044] In another embodiment, this disclosure provides compositions wherein the solid dispersion has a density of about 100 µm to about 500 µm. 90 In another embodiment, the solid dispersion has a D-size of about 100 µm to about 250 µm. 90 In another embodiment, the solid dispersion has a D-size of about 100 µm to about 200 µm. 90 In another embodiment, the solid dispersion has a D-size of about 100 µm to about 400 µm. 90 In another embodiment, the solid dispersion has a D-size of about 150 µm to about 400 µm. 90 In another embodiment, the solid dispersion has a D-size of about 250 µm to about 400 µm. 90 In another embodiment, the solid dispersion has a D-size of about 100 µm to about 600 µm. 90 In another embodiment, the solid dispersion has a D-size of about 250 µm to about 800 µm. 90 In another embodiment, the solid dispersion has a diameter of about 100 µm, about 125 µm, about 150 µm, about 175 µm, about 200 µm, about 225 µm, about 250 µm, about 275 µm, about 300 µm, about 325 µm, about 350 µm, about 375 µm, about 400 µm, about 425 µm, about 450 µm, about 475 µm, about 500 µm, about 525 µm, about 550 µm, about 575 µm, about 600 µm, about 625 µm, about 650 µm, about 675 µm, about 700 µm, about 725 µm, about 750 µm, about 775 µm, about 800 µm, about 825 µm, about 850 µm, about 875 µm, about 900 µm, about 925 µm. D μm, approximately 950 µm, approximately 975 µm, or approximately 1000 µm 90 In another embodiment, the solid dispersion has a D0.05 of approximately 150 µm. 90 .

[0045] In another embodiment, this disclosure provides compositions comprising: (1) a solid dispersion having: (i) a Di of about 30 µm 10 (ii) D approximately 105 µm 50 ; and (iii) D approximately 150 µm 90; and (2) one or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises: (a) about 10% w / w to about 70% w / w of compound 1 or a pharmaceutically acceptable salt thereof; and (b) about 30% w / w to about 90% w / w of a vinylpyrrolidone-vinyl acetate copolymer.

[0046] In another embodiment, this disclosure provides a composition wherein about 75% w / w or more of the particles have a diameter greater than or equal to about 75 µm. In another embodiment, this disclosure provides a composition wherein about 80% w / w or more of the particles have a diameter greater than or equal to about 75 µm. In another embodiment, this disclosure provides a composition wherein about 85% w / w or more of the particles have a diameter greater than or equal to about 75 µm. In another embodiment, this disclosure provides a composition wherein about 90% w / w or more of the particles have a diameter greater than or equal to about 75 µm. In another embodiment, this disclosure provides a composition wherein about 95% w / w or more of the particles have a diameter greater than or equal to about 75 µm.

[0047] In another embodiment, this disclosure provides compositions wherein about 70% w / w or more of the particles have a diameter between or equal to about 75 µm and about 250 µm. In another embodiment, the particle diameter is between or equal to about 75 µm and about 150 µm.

[0048] In another embodiment, this disclosure provides compositions wherein about 75% w / w or more of the particles have a diameter between or equal to about 75 µm and about 500 µm. In another embodiment, the particle diameter is between or equal to about 75 µm and about 250 µm. In yet another embodiment, the particle diameter is between or equal to about 75 µm and about 150 µm.

[0049] In another embodiment, this disclosure provides compositions wherein about 80% w / w or more of the particles have a diameter between or equal to about 75 µm and about 500 µm. In another embodiment, the particle diameter is between or equal to about 75 µm and about 250 µm. In yet another embodiment, the particle diameter is between or equal to about 75 µm and about 150 µm.

[0050] In another embodiment, this disclosure provides compositions wherein about 85% w / w or more of the particles have a diameter between or equal to about 75 µm and about 500 µm. In another embodiment, the particle diameter is between or equal to about 75 µm and about 250 µm. In yet another embodiment, the particle diameter is between or equal to about 75 µm and about 150 µm.

[0051] In another embodiment, this disclosure provides compositions wherein about 90% w / w or more of the particles have a diameter between or equal to about 75 µm and about 500 µm. In another embodiment, the particle diameter is between or equal to about 75 µm and about 250 µm. In yet another embodiment, the particle diameter is between or equal to about 75 µm and about 150 µm.

[0052] In another embodiment, this disclosure provides compositions wherein about 95% w / w or more of the particles have a diameter between or equal to about 75 µm and about 500 µm. In another embodiment, the particle diameter is between or equal to about 75 µm and about 250 µm. In yet another embodiment, the particle diameter is between or equal to about 75 µm and about 150 µm.

[0053] In another embodiment, this disclosure provides a composition of the present disclosure wherein the solid dispersion comprises about 10% w / w to about 90% w / w of compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the solid dispersion comprises about 20% w / w to about 80% w / w of compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the solid dispersion comprises about 30% w / w to about 75% w / w of compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, this disclosure provides a composition of the present disclosure wherein the solid dispersion comprises about 35% w / w to about 65% w / w of compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, this disclosure provides a composition of the present disclosure wherein the solid dispersion comprises about 35% w / w to about 75% w / w of compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the solid dispersion comprises about 40% w / w to about 60% w / w of compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the solid dispersion comprises about 40% w / w to about 70% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the solid dispersion comprises about 45% w / w to about 55% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the solid dispersion comprises about 45% w / w to about 65% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the solid dispersion comprises about 50% w / w to about 60% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the solid dispersion comprises about 55% w / w to about 65% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the solid dispersion comprises about 50% w / w to about 65% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the solid dispersion comprises about 55% w / w to about 60% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the solid dispersion comprises about 50% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

[0054] In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 10% w / w to about 90% w / w of a polymer (e.g., a high molecular weight hydrophilic polymer). In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 20% w / w to about 80% w / w of a polymer (e.g., a high molecular weight hydrophilic polymer). In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 30% w / w to about 75% w / w of a polymer (e.g., a high molecular weight hydrophilic polymer). In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 35% w / w to about 75% w / w of a polymer (e.g., a high molecular weight hydrophilic polymer). In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 25% w / w to about 50% w / w of a polymer. In another embodiment, the solid dispersion comprises about 40% w / w to about 70% w / w of a polymer (e.g., a high molecular weight hydrophilic polymer). In another embodiment, the solid dispersion comprises about 45% w / w to about 65% w / w of a polymer (e.g., a high molecular weight hydrophilic polymer). In another embodiment, this disclosure provides compositions of the present disclosure wherein the solid dispersion comprises about 50% w / w to about 65% w / w of a polymer (e.g., a high molecular weight hydrophilic polymer). In another embodiment, this disclosure provides compositions of the present disclosure wherein the solid dispersion comprises about 50% w / w to about 80% w / w of a polymer. In another embodiment, the solid dispersion comprises about 50% w / w of a polymer (e.g., a high molecular weight hydrophilic polymer). In some embodiments, the polymer is a polymer listed in Table 1, etc. In some embodiments, the polymer is a polymer for hot melt extrusion. In another embodiment, this disclosure provides compositions of the present disclosure wherein the solid dispersion comprises a polymer for hot melt extrusion (HME). Exemplary common polymers and copolymers used for HME include polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate (PVP-VA), poly(ethylene-copoly-vinyl acetate), polyethylene glycol (PEG), cellulose esters, cellulose acrylates, polyethylene oxide (PEO), polymethacrylate derivatives, poloxamer, hydroxypropyl cellulose (HPC), polylactic acid (PLA), poly(glycolic acid) (PGA), and poly(glycolic acid) (PLGA).

[0055] In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 10% w / w to about 90% w / w of a vinylpyrrolidone-vinyl acetate copolymer. In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 20% w / w to about 80% w / w of a vinylpyrrolidone-vinyl acetate copolymer. In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 30% w / w to about 75% w / w of a vinylpyrrolidone-vinyl acetate copolymer. In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 35% w / w to about 65% w / w of a vinylpyrrolidone-vinyl acetate copolymer. In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 35% w / w to about 75% w / w of a vinylpyrrolidone-vinyl acetate copolymer. In another embodiment, the solid dispersion comprises about 40% w / w to about 60% w / w of a vinylpyrrolidone-vinyl acetate copolymer. In another embodiment, the solid dispersion comprises about 40% w / w to about 70% w / w of a vinylpyrrolidone-vinyl acetate copolymer. In another embodiment, the solid dispersion comprises about 45% w / w to about 55% w / w of a vinylpyrrolidone-vinyl acetate copolymer. In another embodiment, the solid dispersion comprises about 45% w / w to about 65% w / w of a vinylpyrrolidone-vinyl acetate copolymer. In another embodiment, this disclosure provides compositions of the present disclosure wherein the solid dispersion comprises about 50% w / w to about 65% w / w of a vinylpyrrolidone-vinyl acetate copolymer. In another embodiment, the solid dispersion comprises about 50% w / w of a vinylpyrrolidone-vinyl acetate copolymer.

[0056] In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 10% w / w to about 90% w / w of chapovidone. In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 20% w / w to about 80% w / w of chapovidone. In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 30% w / w to about 75% w / w of chapovidone. In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 35% w / w to about 75% w / w of chapovidone. In another embodiment, the solid dispersion comprises about 40% w / w to about 70% w / w of chapovidone. In another embodiment, the solid dispersion comprises about 45% w / w to about 65% w / w of chapovidone. In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 50% w / w to about 65% w / w of chapovidone. In another embodiment, the solid dispersion comprises about 50% w / w of cropovidone.

[0057] In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 10% w / w to about 90% w / w HPMCAS-LG. In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 20% w / w to about 80% w / w HPMCAS-LG. In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 30% w / w to about 75% w / w HPMCAS-LG. In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 35% w / w to about 75% w / w HPMCAS-LG. In another embodiment, the solid dispersion comprises about 40% w / w to about 70% w / w HPMCAS-LG. In another embodiment, the solid dispersion comprises about 45% w / w to about 65% w / w HPMCAS-LG. In another embodiment, this disclosure provides compositions wherein the solid dispersion comprises about 50% w / w to about 65% w / w HPMCAS-LG. In another embodiment, the solid dispersion comprises about 50% w / w HPMCAS-LG.

[0058] In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 10% w / w to about 90% w / w HPMCAS-MG. In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 20% w / w to about 80% w / w HPMCAS-MG. In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 30% w / w to about 75% w / w HPMCAS-MG. In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 35% w / w to about 75% w / w HPMCAS-MG. In another embodiment, the solid dispersion comprises about 40% w / w to about 70% w / w HPMCAS-MG. In another embodiment, the solid dispersion comprises about 45% w / w to about 65% w / w HPMCAS-MG. In another embodiment, this disclosure provides compositions wherein the solid dispersion comprises about 50% w / w to about 65% w / w HPMCAS-MG. In another embodiment, the solid dispersion comprises about 50% w / w HPMCAS-MG.

[0059] In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 10% w / w to about 90% w / w HPMCAS-HG. In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 20% w / w to about 80% w / w HPMCAS-HG. In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 30% w / w to about 75% w / w HPMCAS-HG. In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 35% w / w to about 75% w / w HPMCAS-HG. In another embodiment, the solid dispersion comprises about 40% w / w to about 70% w / w HPMCAS-HG. In another embodiment, the solid dispersion comprises about 45% w / w to about 65% w / w HPMCAS-HG. In another embodiment, this disclosure provides compositions wherein the solid dispersion comprises about 50% w / w to about 65% w / w HPMCAS-HG. In another embodiment, the solid dispersion comprises about 50% w / w HPMCAS-HG.

[0060] In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 10% w / w to about 90% w / w of a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, which is sold under the trade name Soluplus®. In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 20% w / w to about 80% w / w of a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 30% w / w to about 75% w / w of a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In another embodiment, this disclosure provides a composition wherein the solid dispersion comprises about 35% w / w to about 75% w / w of a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In another embodiment, the solid dispersion comprises about 40% w / w to about 70% w / w of a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In another embodiment, the solid dispersion comprises about 45% w / w to about 65% w / w of a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In another embodiment, this disclosure provides compositions of the present disclosure wherein the solid dispersion comprises about 50% w / w to about 65% w / w of a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In another embodiment, the solid dispersion comprises about 50% w / w of a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0061] In another embodiment, this disclosure provides compositions wherein the solid dispersion comprises about 45% w / w to about 55% w / w of compound 1 and about 45% w / w to about 55% w / w of vinylpyrrolidone-vinyl acetate copolymer.

[0062] In another embodiment, this disclosure provides compositions wherein the solid dispersion comprises about 40% w / w of compound 1 and about 60% w / w of vinylpyrrolidone-vinyl acetate copolymer.

[0063] In another embodiment, this disclosure provides compositions wherein the solid dispersion comprises about 45% w / w of compound 1 and about 55% w / w of vinylpyrrolidone-vinyl acetate copolymer.

[0064] In another embodiment, this disclosure provides compositions wherein the solid dispersion comprises about 50% w / w of compound 1 and about 50% w / w of vinylpyrrolidone-vinyl acetate copolymer.

[0065] In another embodiment, this disclosure provides compositions wherein the solid dispersion comprises about 55% w / w of compound 1 and about 45% w / w of vinylpyrrolidone-vinyl acetate copolymer.

[0066] In another embodiment, this disclosure provides compositions wherein the solid dispersion comprises about 60% w / w of compound 1 and about 40% w / w of vinylpyrrolidone-vinyl acetate copolymer.

[0067] In another embodiment, this disclosure provides compositions wherein the vinylpyrrolidone-vinyl acetate copolymer is a copolyvinylpyrrolidone. In another embodiment, the vinylpyrrolidone-vinyl acetate copolymer is Kollidon. ® VA 64.

[0068] In one aspect, this disclosure provides a pharmaceutical composition comprising a solid dispersion, wherein the solid dispersion comprises (a) compound 1 or a pharmaceutically acceptable salt thereof; and (b) the polymer described herein.

[0069] The pharmaceutical compositions described herein may comprise from about 5% w / w to about 100% w / w of the solid dispersion. In some embodiments, the composition comprises from about 5% w / w to about 95% w / w of the solid dispersion. In some embodiments, the composition comprises from about 20% w / w to about 80% w / w of the solid dispersion. In some embodiments, the composition comprises from about 30% w / w to about 70% w / w of the solid dispersion. In some embodiments, the composition comprises from about 40% w / w to about 60% w / w of the solid dispersion. In some embodiments, the composition comprises from about 45% w / w to about 55% w / w of the solid dispersion. In some embodiments, the composition comprises from about 30% w / w to about 50% w / w of the solid dispersion. In some embodiments, the composition comprises from about 50% w / w to about 70% w / w of the solid dispersion. In some embodiments, the composition comprises from about 30% w / w to about 60% w / w of the solid dispersion. In some embodiments, the composition comprises about 40% w / w of a solid dispersion. In some embodiments, the composition comprises about 50% w / w of a solid dispersion. In some embodiments, the composition comprises about 60% w / w of a solid dispersion. In some embodiments, the composition comprises at least about 20% w / w, at least about 30% w / w, at least about 35% w / w, at least about 40% w / w, at least about 45% w / w, at least about 50% w / w, at least about 55% w / w, at least about 60% w / w, or at least about 70% w / w of a solid dispersion. In some embodiments, the composition comprises up to about 30% w / w, up to about 35% w / w, up to about 40% w / w, up to about 45% w / w, up to about 50% w / w, up to about 55% w / w, up to about 60% w / w, up to about 70% w / w, up to about 80% w / w, up to about 90% w / w, or up to about 99% w / w of a solid dispersion.

[0070] In another embodiment, this disclosure provides compositions wherein one or more pharmaceutically acceptable excipients include fillers, disintegrants, flow aids, and / or lubricants.

[0071] In another embodiment, this disclosure provides compositions wherein the one or more pharmaceutically acceptable excipients comprise a filler. In another embodiment, the filler is microcrystalline cellulose (MCC), such as MCCPH101, MCC UF702, MCC UF711, MCC OF. In another embodiment, the microcrystalline cellulose is MCC UF711. In some embodiments, the filler is anhydrous dicalcium phosphate. In some embodiments, the filler is sodium dodecyl sulfate. In some embodiments, the filler is a sugar (e.g., glucose, sucrose, mannitol). In some embodiments, the filler is calcium carbonate. The filler may be present in the composition at about 10% w / w to about 90% w / w. The filler may be present in the composition at about 30% w / w to about 80% w / w. The filler may be present in the composition at about 40% w / w to about 70% w / w. The filler may be present in the composition at about 50% w / w to about 60% w / w.

[0072] In another embodiment, this disclosure provides compositions wherein the one or more pharmaceutically acceptable excipients comprise a disintegrant. In some embodiments, the disintegrant is starch (e.g., corn starch, wheat starch, potato starch, mannitol-starch). In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the disintegrant is sodium carboxymethyl cellulose. In some embodiments, the disintegrant is sodium glycolate starch. In some embodiments, the disintegrant is lactose crystals (e.g., milled lactose, crude lactose). In some embodiments, the disintegrant is α-lactose monohydrate. In some embodiments, the disintegrant is a polysaccharide (e.g., soybean polysaccharide). The disintegrant may be present in the composition at about 1% w / w to about 20% w / w. The disintegrant may be present in the composition at about 5% w / w to about 15% w / w. The disintegrant may be present in the composition at about 5% w / w to about 10% w / w. The disintegrant may be present in the composition at about 8% w / w.

[0073] In another embodiment, this disclosure provides compositions wherein the one or more pharmaceutically acceptable excipients comprise a flow aid. In another embodiment, the flow aid is colloidal silica (e.g., fumed silica, silica derivatives, syloid®). In another embodiment, the flow aid is corn starch. In another embodiment, the flow aid is talc. In another embodiment, the flow aid is sodium sulfoaluminate hydrate. The flow aid may be present in the composition at about 0.1% w / w to about 5% w / w. The flow aid may be present in the composition at about 0.2% w / w to about 3% w / w. The flow aid may be present in the composition at about 0.5% w / w.

[0074] In another embodiment, this disclosure provides compositions wherein the one or more pharmaceutically acceptable excipients comprise a lubricant. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is stearic acid. In some embodiments, the lubricant is sodium stearate. In some embodiments, the lubricant is a vegetable stearate. In some embodiments, the lubricant is stearic acid. In some embodiments, the lubricant is glycerol / polyethylene glycol dibehenate. In some embodiments, the lubricant is hydrogenated vegetable oil (e.g., cottonseed oil). The lubricant may be present in the composition at about 0.1% w / w to about 5% w / w. The lubricant may be present in the composition at about 0.2% w / w to about 3% w / w. The lubricant may be present in the composition at about 0.5% w / w.

[0075] In another embodiment, this disclosure provides compositions comprising about 40% w / w to about 90% w / w of one or more pharmaceutically acceptable excipients. In another embodiment, the compositions comprise about 50% w / w to about 80% w / w of one or more pharmaceutically acceptable excipients. In another embodiment, the compositions comprise about 50% w / w to about 70% w / w of one or more pharmaceutically acceptable excipients. In another embodiment, the compositions comprise about 30% w / w to about 50% w / w of one or more pharmaceutically acceptable excipients. In another embodiment, the compositions comprise about 50% w / w of one or more pharmaceutically acceptable excipients.

[0076] In another embodiment, this disclosure provides compositions wherein compound 1 is amorphous.

[0077] In another embodiment, this disclosure provides a method for preparing the compositions of this disclosure, the method comprising: (1) mixing compound 1 or a pharmaceutically acceptable salt thereof with a vinylpyrrolidone-vinyl acetate copolymer to obtain a powder mixture; (2) hot-melt extruding the powder mixture to obtain a solid dispersion extrudate; and (3) milling the solid dispersion extrudate to obtain a desired D 50 For example, D from approximately 75 µm to approximately 400 µm 50 (3) a solid dispersion; and (4) mixing the solid dispersion with one or more pharmaceutically acceptable excipients. In another embodiment, the solid dispersion extrudate is milled to obtain a D-type particle size distribution having a diameter of about 85 µm to about 250 µm. 50 A solid dispersion. In another embodiment, the solid dispersion extrudate is milled to obtain a D-size having a diameter of about 95 µm to about 150 µm. 50A solid dispersion. In another embodiment, the solid dispersion extrudate is milled to obtain a D-size of approximately 105 µm. 50 Solid dispersion.

[0078] In another embodiment, this disclosure provides a solid oral dosage form, such as a tablet, comprising the composition of this disclosure. In another embodiment, the solid oral dosage form comprises about 1 mg to about 300 mg of compound 1. In another embodiment, the solid oral dosage form comprises about 5 mg to about 250 mg of compound 1. In another embodiment, the solid oral dosage form comprises about 20 mg to about 100 mg of compound 1. In another embodiment, the solid oral dosage form comprises about 50 mg to about 150 mg of compound 1. In another embodiment, the solid oral dosage form comprises about 150 mg to about 250 mg of compound 1. In another embodiment, the solid oral dosage form comprises about 20 mg to about 20 mg of compound 1. In another embodiment, the solid oral dosage form comprises at least about 20 mg, at least about 25 mg, at least about 50 mg, at least about 75 mg, at least about 100 mg, at least about 125 mg, at least about 150 mg, at least about 200 mg, at least about 250 mg, at least about 300 mg, or at least about 400 mg of compound 1. In another embodiment, the solid oral dosage form comprises up to about 50 mg, up to about 75 mg, up to about 100 mg, up to about 125 mg, up to about 150 mg, up to about 200 mg, up to about 250 mg, up to about 300 mg, up to about 400 mg, up to about 500 mg, or up to about 600 mg of compound 1. In another embodiment, the solid oral dosage form comprises about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg of compound 1.

[0079] In another embodiment, this disclosure provides a solid oral dosage form comprising the composition of this disclosure and an outer coating. In another embodiment, the outer coating comprises a flow aid. In another embodiment, the flow aid is talc. In yet another embodiment, the outer coating comprises a coating agent, a flow aid, a pigment, and a coloring agent.

[0080] In another embodiment, this disclosure provides a method of treating a patient in need, the method comprising administering to the patient a therapeutically effective amount of the composition of this disclosure, wherein the patient has cancer. In another embodiment, the cancer has a BRAF gene mutation, an NRAS gene mutation, or both a BRAF gene mutation and an NRAS gene mutation. In another embodiment, the cancer has a BRAF gene mutation. In another embodiment, the cancer has a V600BRAF gene mutation. In another embodiment, the cancer has an NRAS gene mutation. In another embodiment, the cancer is selected from skin cancer, eye cancer, gastrointestinal cancer, thyroid cancer, breast cancer, ovarian cancer, lung cancer, brain cancer, laryngeal cancer, cervical cancer, lymphoma, genitourinary cancer, and bone cancer.

[0081] In another embodiment, this disclosure provides a method of treating a patient in need, the method comprising administering to the patient a therapeutically effective amount of the composition of this disclosure, wherein the patient has cancer and the patient's cells contain a biomarker. In another embodiment, the biomarker is a BRAF gene mutation, an NRAS gene mutation, or both a BRAF gene mutation and an NRAS gene mutation. In another embodiment, the cancer is selected from skin cancer, eye cancer, gastrointestinal cancer, thyroid cancer, breast cancer, ovarian cancer, lung cancer, brain cancer, laryngeal cancer, cervical cancer, lymphoma, genitourinary cancer, and bone cancer.

[0082] In another embodiment, this disclosure provides a kit comprising the composition of this disclosure, and instructions for use for administering the composition of this disclosure to a patient suffering from cancer.

[0083] In another embodiment, this disclosure provides personalized medical procedures for patients with cancer and covers the selection of treatment options with the highest probability of a successful outcome for an individual cancer patient. In another aspect, this disclosure relates to the use of measurements to predict the likelihood of treatment outcomes, such as a favorable response or treatment success, in patients with cancer.

[0084] In another embodiment, this disclosure provides a method for selecting a patient, such as a human subject, to treat cancer with a composition of this disclosure, the method comprising obtaining a biological sample, such as blood cells, from the patient; testing for the presence of a biomarker in the biological sample from the patient; and selecting the patient for treatment if the biological sample contains the biomarker. In another embodiment, if the biological sample contains the biomarker, the method further comprises administering a therapeutically effective amount of the composition of this disclosure to the patient. Examples of biomarkers include, but are not limited to, BRAF mutation status and / or NRAS mutation status.

[0085] In another embodiment, this disclosure provides a method for predicting treatment outcomes in a patient with cancer, the method comprising obtaining a biological sample from the patient; testing the biological sample from the patient for the presence of a biomarker (e.g., BRAF mutation and / or NRAS mutation), wherein the detection of the biomarker indicates that the patient will respond favorably to administration of a therapeutically effective amount of the composition of this disclosure.

[0086] In another embodiment, this disclosure provides a method of treating cancer, the method comprising administering a therapeutically effective amount of the composition of this disclosure to a patient suffering from cancer, such as a human subject, wherein the patient's cells contain biomarkers, such as BRAF mutations and / or NRAS mutations. In one embodiment, after it has been determined that the patient's cells contain biomarkers, the patient is selected for treatment with the composition of this disclosure.

[0087] In another embodiment, a method of treating a patient with cancer includes obtaining a biological sample from the patient; determining whether the biological sample contains a BRAF mutation and / or an NRAS mutation; and if the biological sample contains a BRAF mutation and / or an NRAS mutation, administering a therapeutically effective amount of the composition of this disclosure to the patient.

[0088] This disclosure provides the following specific implementation schemes for personalized medicine for patients with cancer: Implementation Scheme I: A method of treating a patient with cancer, the method comprising administering to the patient a therapeutically effective amount of the composition of the present disclosure, wherein the patient’s cells contain a biomarker, and the biomarker is a BRAF mutation status and / or an NRAS mutation status.

[0089] Implementation Scheme II: A method for treating a patient with cancer, the method comprising: (a) Determine the mutation status of BRAF and / or NRAS in biological samples from the patient, and when BRAF and / or NRAS mutations are detected, (b) Administering a therapeutically effective amount of the composition disclosed herein to the patient.

[0090] Implementation Scheme III: A method for treating cancer in a patient with BRAF and / or NRAS mutations, the method comprising administering to the patient a therapeutically effective amount of the composition of this disclosure.

[0091] Implementation Scheme IV: The method as described in any one of Implementation Schemes I-III, wherein at least one additional anticancer agent is administered to the patient.

[0092] Implementation Scheme V: A method for treating a human patient with cancer, the method comprising: (a) Obtaining biological samples from the patient; (b) Determine whether the biological sample has BRAF and / or NRAS mutations; and (c) If the biological sample indicates a BRAF and / or NRAS mutation, then the patient is given a therapeutically effective amount of the composition disclosed herein.

[0093] definition As used herein, the term "Compound 1" refers to (R)-2-(1-(6-amino-5-chloropyrimidin-4-carbamate)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazolyl-5-carboxamide. This compound is also known as MLN2480 and TAK580. The chemical structure of Compound 1 is: Compound 1 As used herein, the term "solid dispersion" refers to an amorphous dispersion containing compound 1 and a solid vinylpyrrolidone-vinyl acetate copolymer prepared by hot melt extrusion.

[0094] As used herein, the term "amorphous" refers to the solid form of Compound 1 or a solid dispersion of Compound 1 containing the long-range ordered features of a lack of crystals; that is, the solid is non-crystalline.

[0095] As used in this article, “micronization” or “grinding” refers to the process or method of reducing the size of a group of particles, typically to the micrometer level.

[0096] As used in this article, the term "micrometer" or "µm" refers to "micrometer," which is 1 x 10⁻⁶. -6 rice.

[0097] As used herein, the term "therapeuticly effective amount" refers to an amount of compound 1 sufficient to treat one or more symptoms of cancer or to induce cancer regression. For example, in one embodiment, a therapeutically effective amount would refer to an amount of compound 1 that reduces tumor growth rate, reduces tumor mass, reduces the number of metastases, increases tumor progression time, or increases survival time by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100%.

[0098] The terms “a” and “one” refer to one or more.

[0099] As used in this article, the term “about” includes ±10% of the enumerated number. Therefore, “about 10” means 9 to 11.

[0100] As used herein, the term "particle size distribution" or "PSD" describes the stratification of particles in a powder dispersion based on the relative amounts of particles present within a specified size range by mass. For example, in Table 8, 4.64 wt% of the powder dispersion has a particle diameter less than 45 micrometers, 25.50 wt% has a particle diameter between 45 and 75 micrometers, and so on. PSD can be measured by sieving with a woven sieve or similar material. PSD can also be measured using laser diffraction or other suitable techniques with a MalvernMaster Sizer Microplus device or its equivalent.

[0101] As used herein, the term "median diameter of mass" or "D" 50 This describes the diameter of a powder dispersion in which 50% by mass of the particles have a larger equivalent diameter, as determined by laser diffraction or other suitable techniques in a Malvern Master Sizer Microplus apparatus or its equivalent. For example, if the D of the powder dispersion... 50 If it is 105 µm, then 50% of the particles are larger than 105 µm, and 50% of the particles are smaller than 105 µm. Similarly, the term "D"... 90 "D" describes the diameter in a powder dispersion where 90% by mass of the particles have a smaller equivalent diameter, while the other 10% by mass of the particles have a larger equivalent diameter. The term "D" 10 "This describes the diameter in a powder dispersion where 10% by mass of the particles have a smaller equivalent diameter, while the other 90% by mass have a larger equivalent diameter."

[0102] As used in this article, the term "patient" refers to a person who has cancer.

[0103] As used herein, the terms “tablet” or “core tablet” refer to tablets that are not film-coated.

[0104] As used herein, the terms "film-coated tablet" or "FC tablet" refer to a tablet having a film coating. In one embodiment, the coating is polymer-based.

[0105] "Cropping polyvinylpyrrolidone" is a crosslinked homopolymer of vinylpyrrolidone (VP). One brand of cropping polyvinylpyrrolidone is Polyplasdone® XL-10.

[0106] As used herein, the term "vinylpyrrolidone-vinyl acetate copolymer" refers to a polymer comprising vinylpyrrolidone and vinyl acetate. Names and abbreviations for vinylpyrrolidone-vinyl acetate copolymers include, but are not limited to, copovidone (copovidone / copovidonum / copolyvidone / copovidon) and PVP-VAc copolymers. Copovidone is a vinylpyrrolidone-vinyl acetate copolymer composed of 6 parts vinylpyrrolidone and 4 parts vinyl acetate, for example, CAS 25086-89-9. Examples of commercial copovidone products are Kollidon® VA 64 and Kollidon® 64 Fine. Another example is "Plasdone S-630," a 60:40 random copolymer of N-vinylpyrrolidone and vinyl acetate.

[0107] "HPMCAS" refers to hydroxypropyl methylcellulose succinate, a polymer containing acetyl and succinyl groups. Different types and grades of HPMCAS exist (e.g., HPMCAS-LG, HPMCAS-MG, HPMCAS-HG), which dissolve at different pH values ​​due to differences in the composition and proportion of their functional groups (e.g., acetyl and succinyl groups).

[0108] "Eudragit® EPO" is a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate.

[0109] "HPMCP" refers to hydroxypropyl methylcellulose phthalate polymer. Different types and grades of HPMCP exist (e.g., HP-55s, HP-50, HP-55), which dissolve at different pH values ​​due to differences in the composition and proportion of their functional groups (e.g., phthaloyl groups).

[0110] "HPC" refers to hydroxypropyl cellulose. Different types and grades of HPC exist (e.g., HPC-SSL, HPC-SL, HOC-SLT).

[0111] "POVACOAT®" refers to polyvinyl alcohol-acrylic acid-methacrylate copolymer. Different types and grades of POVACOAT exist (e.g., MP type, F type, R type) depending on the average molecular weight or average particle diameter.

[0112] "Hydroxypropyl methylcellulose TC-5E" refers to hydroxypropyl methylcellulose.

[0113] "Soluplus®" refers to a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0114] The term "w / w" refers to a quantity by weight. For example, 50% w / w means that the mass of the substance is 50% of the total mass of the solution or mixture.

[0115] As used herein, the term "pharmaceutically acceptable salt" refers to salts suitable for use in human tissues without excessive toxicity, irritation, anaphylactic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. See Berge et al., J. Pharmaceutical Sciences, 1977, 66, 1-19.

[0116] As used in this article, the term "BRAF" refers to the B-Raf proto-oncogene, a serine / threonine kinase. BRAF functions as a serine / threonine kinase, plays a role in regulating the MAP kinase / ERK signaling pathway, and can be found on chromosome 7q.

[0117] As used herein, the term "NRAS" refers to the neuroblastoma RAS virus (v-ras) oncogene homolog. NRAS functions as an oncogene with GTPA enzyme activity and is located on chromosome 1p. NRAS interacts with the cell membrane and various effector proteins, such as Raf and RhoA, which perform their signaling functions via the cytoskeleton and influence cell adhesion (Fotiadou et al. (2007)). Mol. Gel. Biol. 27:6742-6755).

[0118] As used herein, the phrases “BRAF-positive cancer,” “BRAF mutation-positive cancer,” “BRAF-positive mutation cancer,” or “BRAF-positive mutation cancer” refer to cancers that have one or more mutations in the BRAF gene.

[0119] As used herein, “NRAS-positive cancer,” “NRAS-mutant-positive cancer,” “NRAS-positive-mutant cancer,” or “NRAS-positive-mutant cancer” refers to cancers that have one or more mutations in the NRAS gene.

[0120] In some embodiments of this disclosure, the cancer is BRAF wild-type and has one or more mutations in the NRAS gene.

[0121] In some embodiments of this disclosure, the cancer is NRAS wild-type and has one or more mutations in the BRAF gene.

[0122] In some embodiments of this disclosure, the cancer has one or more mutations in both the BRAF gene and the NRAS gene.

[0123] As used herein, the term "biomarker" refers to any biological compound, such as a protein, protein fragment, peptide, polypeptide, nucleic acid, etc., that can be detected and / or quantified in a patient or in a biological sample obtained from the patient. Furthermore, a biomarker can be a whole, intact molecule, or it can be a part or fragment of said molecule. In one embodiment, the expression level of the biomarker is measured. The expression level of said biomarker can be measured, for example, by detecting the level of the protein or RNA (e.g., mRNA) of the biomarker. In some embodiments, a part or fragment of the biomarker can be detected or measured, for example, by an antibody or other specific binding agent. In some embodiments, measurable aspects of the biomarker are associated with a given state of the patient, such as a specific stage of cancer. For biomarkers detected at the protein or RNA level, such measurable aspects may include, for example, the presence, absence, or concentration (i.e., expression level) of the biomarker in or from the patient. For biomarkers detected at the nucleic acid level, such measurable aspects may include, for example, the allelic version of the biomarker or the type, rate, and / or extent of mutations in the biomarker, also referred to herein as mutation status.

[0124] For biomarkers based on protein or RNA expression levels, expression levels measured between different phenotypic states can be considered different if the mean or median expression level of the biomarker in different groups is calculated to be statistically significant. Common tests for statistical significance include t-tests, ANOVA, Kruskal-Wallis, Wilcoxon, Mann-Whitney, microarray significance analysis, and odds ratios. Biomarkers, alone or in combination, provide a measure of the relative probability that an individual belongs to one phenotypic state or another. Therefore, they are particularly useful as disease markers and indicators that specific treatment regimens may lead to beneficial patient outcomes.

[0125] In one embodiment, the biomarker is the BRAF mutation status. In another embodiment, a measurable aspect of the BRAF mutation status is whether the BRAF gene contains at least one mutation.

[0126] In another embodiment, the BRAF mutation is the V600 mutation. In another embodiment, the V600 mutation is V600E, V600G, V600A, or V600K; V600E, V600D, or V600K; or V600E, V600D, V600M, V600G, V600A, V600R, or V600K. In another embodiment, the BRAF mutation is V600E. In another embodiment, the BRAF mutation is V600D. In another embodiment, the BRAF mutation is V600K. The term "V600E mutation" refers to the substitution of valine with glutamic acid at amino acid position 600. The term "V600K mutation" refers to the substitution of valine with lysine at amino acid position 600. The term "V600D mutation" refers to the substitution of valine with aspartic acid at amino acid position 600. The term "V600G mutation" refers to the substitution of valine with glycine at amino acid position 600. The term "V600A mutation" refers to the substitution of valine with alanine at amino acid position 600. The term "V600M mutation" refers to the substitution of valine with methionine at amino acid position 600. The term "V600R mutation" refers to the substitution of valine with arginine at amino acid position 600.

[0127] In another implementation, the BRAF mutation is a non-V600E mutation. In yet another implementation, the non-V600E mutation is G466A, G466V, N581S, D594H, R146W, L613F, D565_splice, S394*, P367R, G469A, G469V, G469*, G466V, G464V, G397S, S113I, A762E, G469L, D594N, G596S, G596R, D594N, D594H, or G327_splice. In one aspect, one or more non-V600E mutations are G469R, R95T, A62l_splice, V639I, Q609H, G464V, or G466V. The asterisk “*” indicates a stop codon.

[0128] In another embodiment, the biomarker is the NRAS mutation status. In yet another embodiment, a measurable aspect of the NRAS mutation status is whether the NRAS gene contains at least one mutation.

[0129] In another implementation, the NRAS mutation is Q61R, Q61K, Q61L, Q61H, or Q61P. In one aspect, the NRAS mutation is Q61R.

[0130] Therefore, in certain aspects of this disclosure, the biomarker BRAF mutation status and / or NRAS mutation status are present differently in subjects with one phenotypic state (e.g., patients with cancer having a BRAF gene mutation) compared to another phenotypic state (e.g., normal, disease-free patients or patients with cancer without a BRAF gene mutation).

[0131] In addition to individual biological compounds (e.g., BRAF or NRAS), the term "biomarker" as used herein is also intended to include a group or collection of multiple biological compounds. For example, a combination of BRAF and NRAS can constitute a biomarker. Therefore, a "biomarker" can include one, two, three, four, five, six, seven, eight, nine, ten, fifteen, twenty, twenty-five, thirty, or more biological compounds.

[0132] The determination of the expression level or mutational status of a biomarker in a patient can be performed using any of the many methods known in the art. In some embodiments, mutations in a biomarker can be identified by sequencing nucleic acids (e.g., DNA, RNA, cDNA) or proteins associated with a marker gene (e.g., a genotype marker gene, such as BRAF or NRAS). Several sequencing methods for sequencing nucleic acids are known in the art. Nucleic acid primers can be designed to bind to regions containing potential mutation sites, or can be designed to be complementary to mutated sequences rather than wild-type sequences. Primer pairs can be designed to enclose regions containing potential mutations in marker genes. Primers or primer pairs can be used to sequence one or both DNA strands corresponding to a marker gene. Primers can be used in conjunction with probes, such as nucleic acid probes, such as hybridization probes, to amplify the region of interest prior to sequencing to increase the amount of sequence available for detecting mutations in marker genes. Examples of sequenceable regions include one or more of the whole gene, transcripts of the gene, and fragments of the gene or transcript, such as exons or untranslated regions, or portions of a biomarker containing mutation sites. Examples of mutations targeted for primer selection and sequence or composition analysis can be found in public databases that collect mutation information, such as the Database of Genotypes and Phenotypes (dbGaP) maintained by the National Centre for Biotechnology Information (Bethesda, MD) and the Catalogue of Somatic Mutations in Cancer (COSMIC) maintained by the Wellcome Trust Sanger Institute (Cambridge, UK).

[0133] Sequencing methods are known to those skilled in the art. Examples of methods include the Sanger method, the SEQENOM™ method, and next-generation sequencing (NGS) methods. The Sanger method involves using electrophoresis, such as capillary electrophoresis, to separate primer-extended labeled DNA fragments, and can be automated for high-throughput applications. Primer extension sequencing can be performed after PCR amplification of the region of interest. Software can assist in sequence base calling and mutation identification. The SEQUENOM™ MASSARRAY® sequencing analysis (San Diego, CA) is a mass spectrometry method that compares the actual quality of a specific fragment of interest with the expected quality to identify mutations. NGS technology (also known as “mass-parallel sequencing” and “second-generation sequencing”) typically offers much higher throughput than previous methods and uses a variety of methods (as described in Zhang et al. (2011)). J. Genet. Genomics 38:95-109 and Shendure and Hanlee (2008) Nature Biotech.(Reviewed in 26:1135-1145). NGS methods can identify low-frequency mutations of markers in samples. Some NGS methods (see, for example, GS-FLX genome sequencer (Roche Applied Science, Branford, CT), genome analyzer (Illumina, Inc. San Diego, CA), SOLID™ analyzer (Applied Biosystems, Carlsbad, CA), Polonator G.007 (Dover Systems, Salem, NH), HELISCOPETM (Helicos Biosciences Corp., Cambridge, NH)). (MA) uses cyclic array sequencing with or without spatially separated PCR products in a flow cell for clonal amplification, and various protocols for detecting labeled modified nucleotides incorporated by sequencing enzymes (e.g., polymerases or ligases). In one NGS method, primer pairs are used in a PCR reaction to amplify the region of interest. The amplified regions can be ligated into tandem products. Clonal libraries are generated in a flow cell from the PCR or ligation products and further amplified (“bridge” or “cluster” PCR) for single-end sequencing as polymerase adds labeled, reversibly terminated bases, depending on the identity of the labeled bases, which are imaged in one of four channels and then removed for the next cycle. Software can help compare with genomic sequences to identify mutations. Another NGS method is exon sequencing, which focuses on sequencing the exons of all genes in the genome. As with other NGS methods, exons can be enriched using capture or amplification methods.

[0134] In some implementations, methods known in the art can be used to [process / conduct / infect biological samples] via [methods / procedures]. In situ and in vitro Both methods analyze DNA, such as genomic DNA corresponding to wild-type or mutant markers. DNA can be isolated directly from the sample or after isolating another cellular component (e.g., RNA or protein). Kits are available for DNA isolation, such as the QIAAMP® DNA Micro Kit (Qiagen, Valencia, CA). Such kits can also be used to amplify DNA.

[0135] In another embodiment, the mRNA corresponding to the biomarker can be detected in a biological sample using methods known in the art. In situ and in vitro Both are analyzed in form. Many expression detection methods use isolated RNA. For in vitroMethods: Any RNA isolation technique that does not target the separation of mRNA can be used to purify RNA from tumor cells (see, for example, Ausubel). et al. Edited, Current Protocols in Molecular Biology John Wiley & Sons, New York 1987–1999. Furthermore, large volumes of tissue samples can be readily processed using techniques well known to those skilled in the art, such as Chomczynski's (1989, U.S. Patent No. 4,843,155) single-step RNA isolation method. RNA can be processed using standard procedures (see, for example, Chomczynski and Sacchi (1987)). Anal. Biochem. 162: 156-159 Total RNA can be isolated using solutions (e.g., trizol, TRI REAGENT® (Molecular Research Center, Inc., Cincinnati, OH; see U.S. Patent No. 5,346,994) or kits (e.g., QIAGEN® Group RNEASY® Isolation Kit (Valencia, CA) or LEUKOLOCK™ Total RNA Isolation System, Ambion division of Applied Biosystems, Austin, TX).

[0136] Additional steps can be used to remove DNA from RNA samples. Cell lysis can be performed using a nonionic detergent, followed by microcentrifugation to remove the cell nucleus and thereby remove most of the cellular DNA. DNA can then be isolated from the cell nucleus for DNA analysis. In one embodiment, RNA is extracted from various cell types of interest using CsC1 centrifugation following guanidine thiocyanate lysis to separate RNA from DNA (Chirgwin). et al. (1979) Biochemistry 18:5294-99). Poly(A)+ RNA is selected by oligomeric dT cellulose (see Sambrook). et al. (1989) Molecular Cloning--A Laboratory Manual(2nd Edition, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY). Alternatively, RNA can be isolated from DNA via organic extraction, such as with hot phenol or phenol / chloroform / isoamyl alcohol. If desired, an RNase inhibitor can be added to the lysis buffer. Similarly, for some cell types, a protein denaturation / digestion step may need to be added to the protocol. For many applications, mRNA needs to be enriched relative to other cellular RNAs, such as transfer RNA (tRNA) and ribosomal RNA (rRNA). Most mRNAs contain a poly(A) tail at their 3' end. This allows them to be enriched by affinity chromatography, for example using oligo(dT) or poly(U) tails coupled to a solid support (such as cellulose or SEPHADEX RTM media) (see Ausubel). et al. (1994) Current Protocols In Molecular Biology (Volume 2, Current Protocols Publishing, New York). Once bound, poly(A)+ mRNA was eluted from the affinity column using 2 mM EDTA / 0.1% SDS.

[0137] For example, after obtaining a sample from a test subject (e.g., a tumor biopsy), the characteristics of the biomarkers of the present invention in the sample can be assessed by any of a variety of well-known methods for detecting or measuring the characteristics of one or more biomarkers (e.g., nucleic acids (e.g., RNA, mRNA, genomic DNA, or cDNA) and / or translated proteins). Non-limiting examples of these methods include immunological methods for detecting secreted, cell surface, cytoplasmic, or nuclear proteins; protein purification methods; protein function or activity assays; and nucleic acid hybridization methods, optionally including a “mismatch cleavage” step for digesting mismatched (i.e., mutated or variant) regions (Myers Squibb). et al. (1985) Science 230:1242) and the isolation and identification of mutants or variants from the resulting digested fragments; nucleic acid reverse transcription methods; and nucleic acid amplification methods and analysis of amplification products. These methods include gene array / microarray technology, RT-PCR, TAQMAN® gene expression assays (AppliedBiosystems, Foster City, CA), for example, under GLP-approved laboratory conditions, In situ Hybridization, immunohistochemistry, Western blotting, FISH (fluorescence) In situHybridization), FACS analysis, northern blot, southern blot, INFINIUM® DNA analysis bead array (Illumina, Inc., San Diego, CA), quantitative PCR, bacterial artificial chromosome array, single nucleotide polymorphism (SNP) array (Affymetrix, Santa Clara, CA), or cytogenetic analysis.

[0138] Examples of techniques for detecting differences of at least one nucleotide between two nucleic acids include, but are not limited to, selective oligonucleotide hybridization, selective amplification, or selective primer extension. For example, oligonucleotide probes can be prepared in which a known polymorphic nucleotide is placed at the center (allele or mutant-specific probes), and then hybridized with target DNA under conditions that allow hybridization only when a perfect match is found (Saiki). et al. (1986) Nature 324:163); Saiki et al. (1989) Proc. Natl Acad. Sci USA 86:6230; and Wallace et al. (1979) Nucl. Acids Res. (6:3543). This allele-specific oligonucleotide hybridization technique can be used to simultaneously detect several nucleotide changes in different polymorphic or mutant regions of NRAS. For example, oligonucleotides with nucleotide sequences of specific allele variants or mutants are attached to a solid carrier, such as a hybridization membrane, which then hybridizes with labeled sample nucleic acids. Therefore, analysis of this hybridization signal can reveal the nucleotide identity of the sample nucleic acids.

[0139] As used herein, the term "pharmaceuticalally acceptable excipient" or "excipient" refers to any component in the compositions of this disclosure other than the solid dispersion of compound 1 and the vinylpyrrolidone-vinyl acetate copolymer. Excipients are generally inert substances added to a composition to facilitate its processing, handling, application, etc. Useful excipients include, but are not limited to, adjuvants, anti-adhesion agents, binders, carriers, disintegrants, fillers, flavoring agents, colorants, diluents, lubricants, flow aids, preservatives, adsorbents, solvents, surfactants, and sweeteners.

[0140] Conventional pharmaceutical excipients are well known to those skilled in the art. In particular, those skilled in the art will recognize that a variety of pharmaceutically acceptable excipients can be mixed with the solid dispersion of compound 1 and the vinylpyrrolidone-vinyl acetate copolymer, including… Handbook of Pharmaceutical Excipients, Pharmaceutical Press, 4th edition (2003) and Remington: The Science and Practice of Pharmacy Those listed in Lippincott Williams & Wilkins, 21st edition (2005).

[0141] This invention provides, but is not limited to, the following embodiments: 1. A pharmaceutical composition comprising: (1) Having a D of approximately 75 µm to approximately 400 µm 50 Solid dispersions; and (2) One or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises: (a) about 10% w / w to about 70% w / w of (R)-2-(1-(6-amino-5-chloropyrimidin-4-carbamate)ethyl)-N-(5-chloro-4-(trifluoromethylpyridin-2-yl)thiazolyl-5-carboxamide or a pharmaceutically acceptable salt thereof; and (b) Polymers of approximately 30% w / w to approximately 90% w / w.

[0142] 2. The pharmaceutical composition as described in Embodiment 1, wherein the polymer is a vinylpyrrolidone-vinyl acetate copolymer.

[0143] 3. The pharmaceutical composition as described in Embodiment 1, wherein the polymer is a high molecular weight hydrophilic polymer.

[0144] 4. The pharmaceutical composition of embodiment 3, wherein the high molecular weight hydrophilic polymer is polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, cross-linked polyvinyl N-pyrrolidone, polyvinyl alcohol (PVA), polysaccharide, hydroxypropyl methylcellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), polyethylene oxide (PEO), hydroxypropyl-β-cyclodextrin (HP-β-CD), sulfobutyl ether-β-cyclodextrin, hydroxypropyl methylcellulose acetate succinate (HPMC-AS-HF), polyethylene glycol (PEG), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVAc-PVCap-PEG), poly(lactide-co-glycolic acid) (PLGA), cellulose ester, cellulose acrylate, poly(ethylene-co-vinyl acetate), polymethacrylate derivatives, poloxamer, polylactic acid (PLA), poly(glycolic acid) (PGA), or any combination thereof.

[0145] 5. A pharmaceutical composition according to any one of embodiments 1-4, wherein the solid dispersion has a density of about 85 µm to about 250 µm. 50 .

[0146] 6. The pharmaceutical composition of embodiment 5, wherein the solid dispersion has a density of about 95 µm to about 150 µm. 50 .

[0147] 7. The pharmaceutical composition as described in Example 6, wherein the solid dispersion has a density of about 105 µm. 50 .

[0148] 8. A pharmaceutical composition comprising: (1) A solid dispersion wherein about 70% w / w or more of the particles have a diameter greater than or equal to about 75 µm but less than or equal to about 500 µm; and (2) One or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises: (a) about 10% w / w to about 70% w / w of (R)-2-(1-(6-amino-5-chloropyrimidin-4-carbamate)ethyl)-N-(5-chloro-4-(trifluoromethylpyridin-2-yl)thiazolyl-5-carboxamide or a pharmaceutically acceptable salt thereof; and (b) Polymers of approximately 30% w / w to approximately 90% w / w.

[0149] 9. The pharmaceutical composition of embodiment 8, wherein the polymer is a vinylpyrrolidone-vinyl acetate copolymer.

[0150] 10. The pharmaceutical composition of embodiment 8, wherein the polymer is a high molecular weight hydrophilic polymer.

[0151] 11. The pharmaceutical composition of embodiment 10, wherein the high molecular weight hydrophilic polymer is polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, cross-linked polyvinyl N-pyrrolidone, polyvinyl alcohol (PVA), polysaccharide, hydroxypropyl methylcellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), polyethylene oxide (PEO), hydroxypropyl-β-cyclodextrin (HP-β-CD), sulfobutyl ether-β-cyclodextrin, hydroxypropyl methylcellulose acetate succinate (HPMC-AS-HF), polyethylene glycol (PEG), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVAc-PVCap-PEG), poly(lactide-co-glycolic acid) (PLGA), cellulose ester, cellulose acrylate, poly(ethylene-co-vinyl acetate), polymethacrylate derivatives, poloxamer, polylactic acid (PLA), poly(glycolic acid) (PGA), or any combination thereof.

[0152] 12. The pharmaceutical composition of any one of embodiments 8-11, wherein about 75% w / w or more of the particles have a diameter greater than or equal to about 75 µm but less than or equal to about 500 µm.

[0153] 13. The pharmaceutical composition of embodiment 9, wherein about 80% w / w or more of the particles have a diameter greater than or equal to about 75 µm but less than or equal to about 500 µm.

[0154] 14. A pharmaceutical composition according to any one of embodiments 1-13, wherein the solid dispersion comprises about 35% w / w to about 65% w / w of (R)-2-(1-(6-amino-5-chloropyrimidin-4-carbamoyl)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazolyl-5-carboxamide or a pharmaceutically acceptable salt thereof.

[0155] 15. The pharmaceutical composition of embodiment 14, wherein the solid dispersion comprises about 40% w / w to about 60% w / w of (R)-2-(1-(6-amino-5-chloropyrimidin-4-carbamoyl)ethyl)-N-(5-chloro-4-(trifluoromethylpyridin-2-yl)thiazole-5-carbamoyl or a pharmaceutically acceptable salt thereof.

[0156] 16. The pharmaceutical composition of embodiment 15, wherein the solid dispersion comprises about 45% w / w to about 55% w / w of (R)-2-(1-(6-amino-5-chloropyrimidin-4-carbamoyl)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazolyl-5-carboxamide or a pharmaceutically acceptable salt thereof.

[0157] 17. The pharmaceutical composition as described in Embodiment 2 or 9, wherein the vinylpyrrolidone-vinyl acetate copolymer is copolyvinyl acetate.

[0158] 18. The pharmaceutical composition of embodiment 17, wherein the vinylpyrrolidone-vinyl acetate copolymer is Kollidon. ® VA 64.

[0159] 19. A pharmaceutical composition according to any one of embodiments 1-18, wherein the one or more pharmaceutically acceptable excipients include fillers.

[0160] 20. The pharmaceutical composition of embodiment 19, wherein the filler is microcrystalline cellulose.

[0161] 21. The pharmaceutical composition of embodiment 19, wherein the filler is microcrystalline cellulose, anhydrous calcium hydrogen phosphate, sodium dodecyl sulfate, calcium carbonate, sugar, or any combination thereof.

[0162] 22. The pharmaceutical composition as described in Embodiment 20 or 21, wherein the microcrystalline cellulose is MCC UF711.

[0163] 23. The pharmaceutical composition of any one of embodiments 1-22, wherein the one or more pharmaceutically acceptable excipients include disintegrants, glidants, lubricants, or combinations thereof.

[0164] 24. The pharmaceutical composition of embodiment 23, wherein the disintegrant is croscarmellose sodium, starch, glycolic acid starch sodium, carboxymethyl cellulose sodium, polysaccharide, lactose crystals, α-lactose monohydrate, or any combination thereof.

[0165] 25. The pharmaceutical composition of embodiment 23, wherein the flow aid is talc, colloidal silica, corn starch, sodium sulfoaluminate hydrate, or any combination thereof.

[0166] 26. The pharmaceutical composition of embodiment 23, wherein the lubricant is glyceryl disorbate, polyethylene glycol disorbate, hydrogenated vegetable oil, magnesium stearate, stearic acid, sodium stearate, sodium stearate, or any combination thereof.

[0167] 27. A pharmaceutical composition according to any one of embodiments 1-26, wherein the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients at about 40% w / w to about 90% w / w.

[0168] 28. The pharmaceutical composition of embodiment 27, wherein the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients at about 50% w / w to about 80% w / w.

[0169] 29. The pharmaceutical composition of embodiment 27, wherein the pharmaceutical composition comprises about 60% w / w to about 70% w / w of one or more pharmaceutically acceptable excipients.

[0170] 30. The pharmaceutical composition of any one of embodiments 1-29, wherein the (R)-2-(1-(6-amino-5-chloropyrimidin-4-carbamoyl)ethyl)-N-(5-chloro-4-(trifluoromethylpyridin-2-yl)thiazole-5-carbamoyl) is amorphous.

[0171] 31. A method for preparing a pharmaceutical composition as described in Embodiment 1, the method comprising: (1) (R)-2-(1-(6-amino-5-chloropyrimidin-4-carbamate)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazolyl-5-carboxamide or a pharmaceutically acceptable salt thereof is mixed with a vinylpyrrolidone-vinyl acetate copolymer to obtain a powder mixture; (2) The powder mixture is subjected to hot melt extrusion to obtain a solid dispersion extruded product; (3) Grind the solid dispersion extrudate to obtain a D with a diameter of about 75 µm to about 400 µm. 50 Solid dispersions; and (4) The solid dispersion is mixed with one or more pharmaceutically acceptable excipients.

[0172] 32. The method as described in embodiment 31, wherein the solid dispersion extruder is milled to obtain a D having a diameter of about 85 µm to about 250 µm. 50 Solid dispersion.

[0173] 33. The method as described in Embodiment 31, wherein the solid dispersion extruder is milled to obtain a D having a diameter of about 75 µm to about 150 µm. 50 Solid dispersion.

[0174] 34. The method as described in Embodiment 31, wherein the solid dispersion extrudate is milled to obtain a D with a diameter of about 105 µm. 50 Solid dispersion.

[0175] 35. A solid oral dosage form comprising a pharmaceutical composition as described in any one of embodiments 1-34.

[0176] 36. A solid oral dosage form as described in Embodiment 35, the solid oral dosage form comprising about 1 mg to about 300 mg of (R)-2-(1-(6-amino-5-chloropyrimidin-4-carbamoyl)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carbamoyl.

[0177] 37. A solid oral dosage form as described in Embodiment 36, the solid oral dosage form comprising about 20 mg to about 200 mg of (R)-2-(1-(6-amino-5-chloropyrimidin-4-carbamoyl)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carbamoyl.

[0178] 38. A solid oral dosage form as described in any one of embodiments 35-37, wherein the solid oral dosage form further comprises an outer coating.

[0179] 39. The solid oral dosage form as described in embodiment 38, wherein the outer coating comprises a flow aid.

[0180] 40. The solid oral dosage form as described in Embodiment 39, wherein the gliding agent is talc.

[0181] 41. A solid oral dosage form as described in any one of embodiments 35-40, wherein the outer coating comprises a coating agent, a pigment, and a coloring agent.

[0182] 42. A method of treating a patient in need, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition as described in any one of embodiments 1-41, wherein the patient has cancer.

[0183] 43. The method of embodiment 42, wherein the cancer has a BRAF gene mutation, an NRAS gene mutation, or a BRAF gene mutation and an NRAS gene mutation.

[0184] 44. The method of embodiment 43, wherein the cancer has a V600 BRAF gene mutation.

[0185] 45. The method of embodiment 44, wherein the patient’s cells contain biomarkers.

[0186] 46. ​​The method of embodiment 45, wherein the biomarker is a BRAF gene mutation, an NRAS gene mutation, or a BRAF gene mutation and an NRAS gene mutation.

[0187] 47. The method of any one of embodiments 42-46, wherein the cancer is selected from skin cancer, eye cancer, gastrointestinal cancer, thyroid cancer, breast cancer, ovarian cancer, lung cancer, brain cancer, laryngeal cancer, cervical cancer, lymphoma, genitourinary cancer, and bone cancer.

[0188] 48. The pharmaceutical composition according to any one of embodiments 1-34 is used for the treatment of cancer.

[0189] 49. A kit comprising a pharmaceutical composition as described in any one of embodiments 1-34, and instructions for administering the pharmaceutical composition to a patient with cancer. Example

[0190] Example 1 Screening of solid dispersions using DSC and oil bath method Solid dispersions prepared by hot melt extrusion are referred to as hot melt extrusions or "HMEs" in the examples and figures.

[0191] Differential scanning calorimetry (DSC) and oil bath calorimetry were used to study solid dispersions containing compound 1. DSC was also used to predict the miscibility and solubility of compound 1 in polymers.

[0192] Material Hydroxypropyl methylcellulose phthalate HPMCP (55, 55s, 50), hydroxypropyl methylcellulose acetate succinate HPMC-AS (LG, MG, HG), and hydroxypropyl methylcellulose TC-5E were obtained from Shin-Etsu. Eudragit EPO was obtained from Evonik. HPC-SSL was obtained from Nippon Soda. Kollidon VA64 and Soluplus were obtained from BASF. POVACOAT TypeMP was obtained from Daido Chemical Corporation.

[0193] DSC Methodology and Evaluation Pure crystalline drug compound 1 was physically mixed with each pure polymer. The following steps were then performed using DSC (Discovery Channel)... TM DSC, TA Instruments) measured the equilibrium solution temperature (T) of compound 1 in each 20% loaded physical mixture (PM) of compound 1. 结束 ) and enthalpy (H) are used for polymer screening; up to 105°C Maintain 105°C for 10 minutes From 105°C to -20°C at a rate of -10°C / min At a rate of 1°C / min, from -20°C to above the MP (melting point) of compound 1 (206°C). Based on the endothermic peak analysis of DSC, H and T 结束 The change ratio ΔE between pure compound 1 and PM is defined as the miscibility parameter (Equation 1). Generally, PM, which shows higher miscibility with compound 1, shifts the endothermic peak of compound 1 to lower temperatures and reduces the peak intensity. Therefore, a lower ΔE indicates higher miscibility.

[0194]

[0195] (A: Compound 1, pm: Physical mixture) Oil bath method and its evaluation Compound 1 was physically mixed with each polymer (the ratio of Compound 1 in the polymer was 20% w / w for polymer screening, and 40%, 50%, and 60% w / w for loading screening). Approximately 100–500 mg of PM was placed in a glass tube and melted and mixed in the tube with a spatula while heating in an oil bath (180–200°C). Visual appearance and endothermic peaks obtained by mDSC (modulated differential scanning calorimetry) were evaluated for polymer screening, and chemical and physical properties were evaluated for loading screening.

[0196] Results of polymer screening using DSC and oil bath methods The results of polymer screening by DSC and oil bath method are summarized in Table 1. By DSC, PM showed relatively low ΔE compared with HPMC-AS, Kollidon VA64 and Soluplus, and all of these oil bath materials showed amorphous form (clear appearance and no API endothermic peak was obtained by mDSC).

[0197] Table 1: Summary of polymer screening results by DSC and oil bath method

[0198] Table 2: Summary of API Load Screening Results in HME Using the Oil Bath Method

[0199] *RoA (Analysis Results) Glass transition temperature Results of API load screening using the oil bath method The results of the oil bath loading screening of Compound 1 are summarized in Table 2. All samples from the oil bath showed higher solubility in both JP1 (pH 1.2) and JP2 (pH 6.8) than Compound 1 itself. The 60% HME measured by the oil bath indicated the presence of crystalline API based on both appearance and mDSC.

[0200] Example 2 Tablet formulation HME loading screening in tablets Tablets were manufactured using a solid dispersion containing 40% Compound 1 and 60% Kollidon VA64, produced by a hot melt extrusion process, at solid dispersion loadings of 40%, 50%, 60%, and 70%. This solid dispersion is referred to as HME (40%). The PSD of this HME (40%) on a 250 µm sieve is shown in Table 3.

[0201] Sample preparation HME (40%) was blended with MCC (microcrystalline cellulose), croscarmellose sodium, and colloidal silica using a mortar and pestle. The blended powder was then placed in a glass bottle containing magnesium stearate and gently shaken 100 times at a rate of 20 tablets. The blended powder was then compressed into tablets using a single-hand tableting machine (HANDTAB-200, Ichihashi Seiki) at various compression forces. Tablet properties and dissolution rates were measured (CTAB concentration depended on the loading of compound 1 in each tablet to maintain the same sedimentation conditions). Tablet formulations with different HME (40%) loadings are shown in Table 4.

[0202] Table 3: HME obtained by screening (40%)

[0203] Table 4: Tablet Formulations Used for HME Loading Screening in Tablets

[0204] result Dissolution profiles and tablet characteristics for each % HME loading tablet are as follows: Figure 1 and Figure 2 As shown. In Figure 1 In the samples, tablets loaded with 60% and 70% HME exhibited slower dissolution profiles at higher compressive forces, due to the formation of a strong hydrogel matrix within the tablets. Furthermore, these two HME tablets showed better dissolution performance than... Figure 2The other two types of tablets exhibited lower hardness, and the hardness did not reach the target hardness of 150 N, taking into account brittleness. Regardless of the compression force, all 40% and 50% HME-loaded tablets showed rapid dissolution profiles, and the hardness could be achieved to 150 N by controlling the compression force.

[0205] Example 3 tablet Prototype tablets are manufactured to select fillers for tablet formulation.

[0206] Sample preparation HME (40%) was blended with various fillers (MCC, DCPA (anhydrous calcium hydrogen phosphate), SDS (sodium dodecyl sulfate), and combinations thereof), croscarmellose sodium, and colloidal silica using a mortar and pestle. The blended powder was then placed in a glass bottle containing magnesium stearate and gently shaken 100 times at a rate of 20 tablets. The blended powder was then compressed into tablets using a single-hand tablet press (HANDTAB-200, Ichihashi Seiki) at various compression forces. The tablet properties and dissolution were then evaluated. In this study, the HME loading in the tablet formulation was fixed at 50%, and the dose strength of each tablet was 125 mg / tablet. The tablet formulations are shown in Table 5.

[0207] Table 5: Tablet Formulations Used for Screening Major Fillers in Tablets

[0208] result Dissolution profiles and tablet characteristics of tablet formulations, such as Figure 3 and Figure 4 As shown. Based on these results, MCC OF grades (CEOLUS, Asashi-Kasei), especially UF711, exhibited higher tablet hardness than PH101 (Avicel, FMC Biopolymer). Regardless of MCC grade and tablet hardness, all tablet formulations showed similar dissolution profiles. UF711 was selected as the filler in high-dose-strength tablet formulations.

[0209] Example 4 Feasibility assessment of the prototype HME (50%) formulation A solid dispersion containing 50% Compound 1 and 50% Kollidon VA64 was prepared using a hot melt extrusion process. This solid dispersion is referred to as prototype HME (50%).

[0210] Preparation of solid dispersion powders using a micro extruder Compound 1 was physically mixed with Kollidon VA64 (50% loading) and HME filaments were obtained using a microextruder (Hybrid 5 / 9 mm, Three Tech). The process conditions for the microextruder used in this study are shown in Table 6. Following the extrusion process, the HME filaments were manually ground using a mortar and pestle to obtain the prototype HME (50%). The chemical / physical properties and stability of the prototype HME (50%) were evaluated. The effect of temperature conditions on the quality of the solid dispersion was also examined.

[0211] Table 6: Process conditions for micro extruders

[0212] Tablet preparation using prototype solid dispersion powder 50% HME-loaded tablets (150 mg) were manufactured using a prototype HME (50%) produced by a micro-extruder (process conditions are shown in Table 6). HME (50%) was blended with MCC (UF711), croscarmellose sodium, and colloidal silica using a mortar and pestle. The blended powder was then placed in a glass vial containing magnesium stearate and gently shaken 100 times at a rate of 20 tablets. The blended powder was compressed into 16 x 9 mm oval tablets using a single-handed tablet press (HANDTAB-200, Ichihashi Seiki), and then film-coated using a micro-coating machine (micro-coating machine / dryer 2, Caleva). The tablet formulation is shown in Table 7.

[0213] Table 7: Tablet Formulations with 50% HME Loading

[0214] result The physicochemical properties of the PSD and prototype HME (50%) obtained by sieving are shown in Tables 8 and 9. The chemical / physical properties and stability of the prototype HME (50%) are comparable to those of HME (40%). A temperature-dependent increase in enantiomers was observed in the comparison between the three temperature conditions, but this increase did not occur during the stability period. Additionally, the dissolution profiles of the prototype 150 mg HME (50%) tablets (Table 8) and the HME (40%) 100 mg film-coated (FC) tablets are shown below. Figure 5 As shown. Despite the different dose intensities, both tablets exhibited very similar dissolution profiles.

[0215] Table 8: PSD of the prototype HME (50%) obtained by screening

[0216] Table 9: Summary of Results for Prototype HME (50%)

[0217] Example 5 HME grinding study To find the optimal PSD, milling studies were conducted using HME (40%) (lot number 11122755) under several milling conditions. Tablets were prepared using each milled HME powder to examine dissolution and tablet characteristics.

[0218] Sample preparation Grinding was performed using a needle mill (Nara Sample Mill SAM T, Nara Machinery). Grinding speed, sieve size, and mill rotor type were optimized. HME PSD was measured by sieving. HME powders ground under various conditions were blended with MCC (UF711), croscarmellose sodium, and colloidal silica using a mortar and pestle. The blended powders were then placed in glass vials containing magnesium stearate and gently shaken 100 times at a scale of 30 tablets. The blended powders were then compressed into tablets with an oval size of 16 x 9 mm using a single-hand tablet press (HANDTAB-200, Ichihashi Seiki) at various compression forces. In this study, the effects of HME loading (50% and 60%) and MCC OF grade (UF702 and UF711) on tablet properties and dissolution were also examined. The grinding conditions and tablet formulations used in this study are shown in Tables 10, 11, and 12.

[0219] Table 10: Grinding conditions used in grinding studies

[0220] Table 11: Tablet formulations and grinding sample allocation used in grinding studies

[0221] Table 12: Tablet Formulations Used in Grinding Studies

[0222] result HME PSD data obtained by sieving for HME ground under various grinding conditions are shown in Table 13. HME (40%) lot number 11122754 represents a sample ground using the conditions described in WO 2015 / 148828.

[0223] Variations in screen size, grinding speed, and rotor type are effective parameters for optimizing HME PSD. Blade rotors (new) work better than pin rotors (old) to achieve a narrow HME PSD and reduce fine HME particles (<75 µm) that affect compression. On the other hand, larger screen sizes may increase the proportion of very large HME particles (>250 µm), which can result in slower dissolution rates.

[0224] A summary of the grinding studies and individual dissolution profiles of the tablets is shown in Table 14 and Figure 9A and Figure 9B Medium. PSD sizes smaller than 75 µm and larger than 250 µm have an impact on the dissolution profile. Figure 6 Therefore, the HME PSD results are presented in three separate ranges: >250 µm, 75–250 µm, and <75 µm. Minimum standards were set for tablet hardness and dissolution to find optimal grinding conditions. In Table 12, tablet formulations (2, 6, 14, 18, 22) with 50% HME-loaded tablets containing MCC (UF711) showed faster dissolution and higher tablet hardness than other formulations with 60% and / or MCC (UF702). The content of fine particles (<75 µm) affected dissolution based on the dissolution and particle size of the stated tablet formulations (9, 11, 33, 35), ideally less than 30% (for grinding samples 4_1, 5_1–6_2). Compared to the dissolution profiles of formulations 33 and 35, other tablet formulations with less fine particles showed improved tablet hardness and dissolution in the HME PSD.

[0225] Table 13: HME PSD Results Obtained Through Screening

[0226] * D x Defined by equations 2) and 3).

[0227]

[0228] D x =10 z. (3) D x It is the particle size of any cumulative percentage. D It refers to particle size. D j Greater than D j+1 and Dx It should be in D j+1 With D j between.

[0229] Q It is for each particle size D The cumulative percentage.

[0230] Table 14: Summary of Grinding Studies

[0231] Table 15: Representative process conditions for HME process optimization

[0232] Example 6 HME (50%) scaled up proportionally A scale-up study using an HME (50%) formulation was conducted. In this study, the HME process was developed to find optimal manufacturing process parameters, and the feasibility of scale-up for GMP manufacturing using a large extruder (Leistritz 18mm) was examined. A long-term HME process with optimized HME process conditions was also performed at a 10 kg scale.

[0233] Sample preparation Compound 1 and copovidone were mixed using a high-shear mixer. The powder mixture was fed into a hot melt extruder (Leistritz 18mm) with various process conditions to optimize the process. The resulting extrudate filament was cooled by a cooling belt with airflow. The extrudate filament from the optimized process was manually ground with a mortar and pestle for analysis, and the filament from the long-term process was ground using a pin mill under the following grinding conditions: screen size: 0.7 mm, grinding speed: 8000 rpm, blade type: blade rotor. During HME manufacturing, the extrudate outlet flow behavior from the die and the visual appearance of the filament were examined on-site. Representative HME process conditions for this study are shown in Table 15.

[0234] result The results of the scale-up study using HME (50%) are summarized in Table 16. No degradation was observed in any of the samples. The effects of various HME process conditions on manufacturability and quality are summarized below: Feed rate: Faster feed rates result in better manufacturability, but white spots can sometimes be observed due to shorter dwell times. The collected samples are very hot due to insufficient cooling system capacity.

[0235] Screw speed: Higher screw speeds result in a lower risk of white spots, but the wire color becomes more brown due to higher mechanical shearing.

[0236] Temperature: Higher temperatures result in a lower risk of white spot, but enantiomers become more abundant and the wire color becomes more brownish. Since HME (50%) is more viscous than HME (40%), a minimum of 180°C is required to achieve good extrusion flow from the die exit.

[0237] The selected HME process conditions for long-term use are (10_2) in Table 15.

[0238] The chemical and physical properties of 40% and 50% HME powders manufactured in the long-term batch and final demo batch, respectively, are shown in Table 17. No API peaks were observed in either mDSC or XRPD (X-ray powder diffraction), and HME showed a trend toward comparability and equivalence with HME (40%). The reproducibility of the grinding process using the new grinding conditions set in the grinding study was confirmed (and HME PSD met the target, "HME particles <75 µm %: <30%)". A summary of the stability studies and solid-state characterization is provided below. HME (50%) powder is stable under any storage conditions (no degradation or recrystallization) and exhibits similar trends to HME (40%), including photostable stability.

[0239] The solid-state properties (XRPD, SEM, PSD, FT Raman, and DSC) of HME (50%) are comparable to those of HME (40%) (20140399), and partial data are shown in Table 17. HME (40%) (20140399) represents a sample milled using the conditions described in WO 2015 / 148828.

[0240] Table 16: Summary of results from the scale-up study used for HME (50%)

[0241] Loss on drying Table 17: Long-term chemical and physical properties of HME (50%) (No. 10_2)

[0242] Example 7 Prototype tablets (20 mg, 70 mg, 100 mg, and 150 mg) were manufactured using HME (50%). Prototype HME (50%) core tablets (20 mg, 70 mg, 100 mg, and 150 mg) were manufactured on a laboratory scale in FD using HME (50%) manufactured in a long-term process. Tablet properties and dissolution were evaluated using tablets with various compression forces to set target tablet hardness and thickness.

[0243] Sample preparation HME (50%) was blended with MCC, croscarmellose sodium, and colloidal silica using a mortar and pestle. The blended powder was then placed in a glass bottle containing magnesium stearate and gently shaken 100 times at a rate of 20 tablets. The blended powder was then compressed into tablets using a single-hand tablet press (HANDTAB-200, Ichihashi Seiki) at various compression forces. Tablet properties and dissolution were evaluated. The prototype HME (50%) core tablet formulations (20 mg, 70 mg, 100 mg, and 150 mg) are shown in Table 18.

[0244] Table 18: Prototype HME (50%) Core Tablet Formulations (20 mg, 70 mg, 100 mg, and 150 mg)

[0245] *Two different tablet shapes for preparing 100 mg core tablets result Tablet characteristics and dissolution profiles are shown in Table 19 and Figure 7 In the medium-high pressure range, tablet hardness increased with increasing compression force, reaching the target hardness range of 150-200 N. Because a linear relationship between compression force and hardness was confirmed, the risk of capping / sticking during compression appears to be low within this pressure range. Furthermore, because HME (50%) core tablets exhibited rapid dissolution profiles regardless of compression force, as HME PSD optimization improved disintegration. No decrease in dissolution rate due to larger HME particles was observed. All of these prototype HME (50%) core tablets are manufacturable in dosage ranges of 20-150 mg.

[0246] Table 19: Tablet characteristics of prototype HME (50%) core tablets (20 mg, 70 mg, 100 mg and 150 mg)

[0247] Table 20: HME (50%) tablet formulations (100 mg and 150 mg) used for scale-up studies

[0248]

[0249] Example 8 Scaling up of HME (50%) tablet formulation The prototype HME (50%) tablets (100 mg and 150 mg) were scaled up using HME (50%) manufactured during the long-term scaling-up process.

[0250] Sample preparation For 100 mg tablets, HME (50%) is blended in a bag with MCC, croscarmellose sodium, colloidal silica, and magnesium stearate at FD. The blended powder is then compressed into tablets using a rotary tablet press at various compression forces on a 1 kg scale.

[0251] For 150 mg tablets, HME (50%) is blended with MCC, croscarmellose sodium, colloidal silica, and magnesium stearate in a mixer. The blended powder is then compressed into tablets using a rotary tablet press at various compression forces of 5 kg.

[0252] Film coating of the two core tablets was performed using film coating agents of different colors to achieve differentiation through color contrast between these dose intensities. The 150 mg tablet was orange (a mixture of Opadry Red and Opadry Yellow), and the 100 mg tablet was white (Opadry White). Stability studies and solid-state analyses were performed to confirm the comparability between the JME (40%) and HME (50%) film-coated tablets. BU (blending uniformity), CU (content uniformity), tablet characteristics, and dissolution profiles were also evaluated to determine suitable ranges of manufacturing process parameters. The HME (50%) tablet formulations (100 mg and 150 mg) used for scale-up studies are shown in Table 20.

[0253] result The results for BU and CU are shown in Table 21.

[0254] Tablet properties and dissolution profiles of HME (50%) tablets (100 mg and 150 mg) compressed at different compression forces are shown in Tables 22, 23, and 24. Figure 8The results show that HME (50%) tablets (100 mg and 150 mg) manufactured using a rotary tablet press exhibited similar tablet properties and dissolution profiles to the prototype HME (50%) tablets manufactured on a laboratory scale, and met the expected quality targets and acceptability criteria. After a friability test, tablets with lower compressibility forces showed fragmentation on the surface and edges of the core tablet. Tablets using higher compressibility forces exhibited slower dissolution profiles and disintegration due to the formation of a hydrogel matrix in the dissolution medium. Therefore, 6.0 kN and 8.9 kN were set as target compressibility forces for the 100 mg and 150 mg core tablets, respectively.

[0255] Table 21: Blending uniformity (BU) and content uniformity (CU) of HME (50%) tablets (100 mg and 150 mg)

[0256] *Mixed in PE bags Table 22: Tablet characteristics of HME (50%) core tablets (100 mg)

[0257] **Fragments Table 23: Tablet characteristics of HME (50%) core tablets (150 mg)

[0258] **Fragments It should be understood that the foregoing embodiments and examples are not intended to limit the scope of this disclosure in any way, and the claims set forth herein are intended to cover all embodiments and examples, whether or not they are expressly set forth herein.

[0259] All patents and publications cited in this article are incorporated herein by reference in their entirety.

Claims

1. A pharmaceutical composition comprising: (1) Having a D of approximately 75 µm to approximately 400 µm 50 Solid dispersions; and (2) One or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises: (a) about 10% w / w to about 70% w / w of (R)-2-(1-(6-amino-5-chloropyrimidin-4-carbamate)ethyl)-N-(5-chloro-4-(trifluoromethylpyridin-2-yl)thiazolyl-5-carboxamide or a pharmaceutically acceptable salt thereof; and (b) Polymers of approximately 30% w / w to approximately 90% w / w.

2. The pharmaceutical composition of claim 1, wherein the polymer is a vinylpyrrolidone-vinyl acetate copolymer.

3. The pharmaceutical composition of claim 1, wherein the polymer is a high molecular weight hydrophilic polymer.

4. The pharmaceutical composition of claim 3, wherein the high molecular weight hydrophilic polymer is polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, cross-linked polyvinyl N-pyrrolidone, polyvinyl alcohol (PVA), polysaccharide, hydroxypropyl methylcellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), polyethylene oxide (PEO), hydroxypropyl-β-cyclodextrin (HP-β-CD), sulfobutyl ether-β-cyclodextrin, hydroxypropyl methylcellulose acetate succinate (HPMC-AS-HF), polyethylene glycol (PEG), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVAc-PVCap-PEG), poly(lactide-co-glycolic acid) (PLGA), cellulose ester, cellulose acrylate, poly(ethylene-co-vinyl acetate), polymethacrylate derivatives, poloxamer, polylactic acid (PLA), poly(glycolic acid) (PGA), or any combination thereof.

5. The pharmaceutical composition according to any one of claims 1-4, wherein the solid dispersion has a density of about 85 µm to about 250 µm. 50 .

6. A pharmaceutical composition comprising: (1) A solid dispersion wherein about 70% w / w or more of the particles have a diameter greater than or equal to about 75 µm but less than or equal to about 500 µm; and (2) One or more pharmaceutically acceptable excipients, wherein the solid dispersion comprises: (a) about 10% w / w to about 70% w / w of (R)-2-(1-(6-amino-5-chloropyrimidin-4-carbamate)ethyl)-N-(5-chloro-4-(trifluoromethylpyridin-2-yl)thiazolyl-5-carboxamide or a pharmaceutically acceptable salt thereof; and (b) Polymers of approximately 30% w / w to approximately 90% w / w.

7. A method for preparing the pharmaceutical composition of claim 1, the method comprising: (1) (R)-2-(1-(6-amino-5-chloropyrimidin-4-carbamate)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazolyl-5-carboxamide or a pharmaceutically acceptable salt thereof is mixed with a vinylpyrrolidone-vinyl acetate copolymer to obtain a powder mixture; (2) The powder mixture is subjected to hot melt extrusion to obtain a solid dispersion extruded product; (3) Grind the solid dispersion extrudate to obtain a D with a diameter of about 75 µm to about 400 µm. 50 Solid dispersions; and (4) The solid dispersion is mixed with one or more pharmaceutically acceptable excipients.

8. A solid oral dosage form comprising the pharmaceutical composition as described in any one of claims 1-7.

9. A method of treating a patient in need, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-8, wherein the patient has cancer.

10. A kit comprising a pharmaceutical composition as described in any one of claims 1-7, and instructions for administering the pharmaceutical composition to a patient suffering from cancer.

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