Claims for Patent: 10,258,622

Summary for Patent: 10,258,622

Title:	Method of treating colorectal cancer by administration of pharmaceutical formulations of (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)pheny1)-1-isopropyl-1H-- pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-yl) carbamate
Abstract:	This invention relates to solid oral pharmaceutical formulations of (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methyl-sulfonamido)phenyl)-1-isopropyl-1H- -pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate (COMPOUND A) and the use of these formulations for treating proliferative diseases, such as solid tumor diseases.
Inventor(s):	Verma; Daya (Edison, NJ), Krishnamachari; Yogita (Springfield, NJ), Shen; Xiaohong (Livingston, NJ), Lee; Hanchen (Teaneck, NJ), Li; Ping (Basking Ridge, NJ), Singh; Rajinder (Sewaren, NJ), Tan; LayChoo (Bridgewater, NJ)
Assignee:	Array BioPharma Inc. (Boulder, CO)
Application Number:	15/452,239
Patent Claims:	1. A method for treating colorectal cancer, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a solid oral pharmaceutical formulation, wherein the formulation comprises: an inner phase which is a solid dispersion comprising amorphous (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-1-isopropyl-1H-- pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate (COMPOUND A); copovidone; and poloxamer 188 or sorbitol; and an external phase which comprises succinic acid, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, and magnesium stearate. 2. The method of claim 1, wherein the colorectal cancer is characterized by a mutation in B-RAF. 3. The method of claim 1, wherein the inner phase comprises from 5% to 40% by weight of amorphous (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methyl sulfonamido)phenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)prop- an-2-yl)carbamate (Compound A), from 50% to 80% by weight of copovidone, and from 5% to 20% by weight of poloxamer 188 or sorbitol. 4. The method of claim 1, wherein the external phase comprises from 2% to 60% by weight of succinic acid, from 30% to 70% by weight of microcrystalline cellulose, from 5% to 20% by weight of crospovidone, from 0.5% to 5% by weight of colloidal silicon dioxide, and from 0.5% to 5% by weight of magnesium stearate. 5. The method of claim 1, comprising a blend of the internal and external phases in a ratio of from 80:20 to 40:60. 6. The method of claim 5, comprising a blend of the internal and external phases in a ratio of from 75:25 to 50:50. 7. The method of claim 1, wherein the formulation comprises 10 mg, 25 mg, 50 mg, or 100 mg of amorphous (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methyl sulfonamido)phenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)prop- an-2-yl)carbamate (Compound A). 8. The method of claim 7, wherein the formulation comprises 50 mg of amorphous (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-1-isopropyl-1H-- pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate (Compound A). 9. The method of claim 7, wherein the formulation comprises 15% by weight of amorphous (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-1-isopropyl-1H-- pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate (Compound A). 10. The method of claim 1, wherein the formulation is selected from the group consisting of: A) TABLE-US-00012 Ingredient % w/w Internal Phase amorphous (S)-methyl (1-((4-(3-(5-chloro-2- 15 fluoro-3-(methylsulfonamido)phenyl)-1- isopropy1-1H-pyrazo1-4-yl)pyrimidin-2- yl)amino)propan-2-yl)carbamate (Compound A) copovidone 45 Poloxamer 188 5 External Phase Succinic acid 13 Microcrystalline cellulose 16 Crosspovidone 5 magnesium Stearate 0.5 Colloidal silicon dioxide 0.5 Total 100 and B) TABLE-US-00013 Ingredient % w/w Internal amorphous (S)-methyl (1-((4-(3-(5-chloro-2- 17 fluoro-3-(methylsulfonamido)phenyl)-1- isopropy1-1H-pyrazo1-4-yl)pyrimidin-2- yl)amino)propan-2-yl)carbamate (Compound A) PVP-K30 51 Sorbitol 5 External Succinic Acid 9 Microcrystalline cellulose 12 Crosspovidone 5 Mg Stearate 0.5 Colloidal silicon dioxide 0.5 Total 100. 11. The method of claim 10, wherein the colorectal cancer is characterized by a mutation in B-RAF. 12. The method of claim 1, wherein the formulation is TABLE-US-00014 Ingredient % w/w Internal Phase amorphous (S)-methyl (1-((4-(3-(5-chloro-2- 15 fluoro-3-(methylsulfonamido)phenyl)-1- isopropy1-1H-pyrazo1-4-yl)pyrimidin-2- yl)amino)propan-2-yl)carbamate (Compound A) copovidone 45 Poloxamer 188 5 External Phase Succinic acid 13 Microcrystalline cellulose 16 Crosspovidone 5 magnesium Stearate 0.5 Colloidal silicon dioxide 0.5 Total 100. 13. The method of claim 12, wherein the colorectal cancer is characterized by a mutation in B-RAF. 14. The method of claim 1, wherein the formulation is selected from the group consisting of: TABLE-US-00015 Ingredient Internal Phase (mg) amorphous (S)-methyl (1-((4-(3-(5- 10.0 chloro-2-fluoro-3- (methylsulfonamido)phenyl)-1- isopropy1-1H-pyrazo1-4-yl)pyrimidin-2- yl)amino)propan-2-yl)carbamate (Compound A) Copovidone 29.9 Poloxamer 188 3.3 External Phase (mg) Succinic acid 8.7 Cellulose microcrystalline 10.7 Crospovidone 3.3 Colloidal silicon dioxide 0.3 Magnesium Stearate 0.3 Total (mg) 66.6, TABLE-US-00016 Ingredient Internal Phase (mg) amorphous (S)-methyl (1-((4-(3-(5- 25.0 chloro-2-fluoro-3- (methylsulfonamido)phenyl)-1- isopropy1-1H-pyrazo1-4-yl)pyrimidin-2- yl)amino)propan-2-yl)carbamate (Compound A) Copovidone 74.8 Poloxamer 188 8.4 External Phase (mg) Succinic acid 21.7 Cellulose microcrystalline 26.7 Crospovidone 8.4 Colloidal silicon dioxide 0.9 Magnesium Stearate 0.9 Total (mg) 166.5, TABLE-US-00017 Ingredient Internal Phase (mg) amorphous (S)-methyl (1-((4-(3-(5- 50.0 chloro-2-fluoro-3- (methylsulfonamido)phenyl)-1- isopropy1-1H-pyrazo1-4-yl)pyrimidin-2- yl)amino)propan-2-yl)carbamate (Compound A) Copovidone 150.0 Poloxamer 188 16.7 External Phase (mg) Succinic acid 43.3 Cellulose microcrystalline 53.3 Crospovidone 16.7 Colloidal silicon dioxide 1.7 Magnesium Stearate 1.7 Total (mg) 333.4, and TABLE-US-00018 Ingredient Internal Phase (mg) amorphous (S)-methyl (1-((4-(3-(5- 100.0 chloro-2-fluoro-3- (methylsulfonamido)phenyl)-1- isopropy1-1H-pyrazo1-4-yl)pyrimidin-2- yl)amino)propan-2-yl)carbamate (Compound A) Copovidone 300.0 Poloxamer 188 33.3 External Phase (mg) Succinic acid 86.7 Cellulose microcrystalline 106.7 Crospovidone 33.3 Colloidal silicon dioxide 3.3 Magnesium Stearate 3.3 Total (mg) 666.6. 15. The method of claim 14, wherein the colorectal cancer is characterized by a mutation in B-RAF. 16. The method of claim 1, wherein the formulation is: TABLE-US-00019 Ingredient Internal Phase (mg) amorphous (S)-methyl (1-((4-(3-(5- 50.0 chloro-2-fluoro-3- (methylsulfonamido)phenyl)-1- isopropy1-1H-pyrazo1-4-yl)pyrimidin-2- yl)amino)propan-2-yl)carbamate (Compound A) Copovidone 150.0 Poloxamer 188 16.7 External Phase (mg) Succinic acid 43.3 Cellulose microcrystalline 53.3 Crospovidone 16.7 Colloidal silicon dioxide 1.7 Magnesium Stearate 1.7 Total (mg) 333.4. 17. The method of claim 14, wherein the colorectal cancer is characterized by a mutation in B-RAF. 18. The method of claim 1, wherein the formulation is formulated as a capsule or a tablet. 19. The method of claim 10, wherein the formulation is formulated as a capsule or a tablet. 20. The method of claim 12, wherein the formulation is formulated as a capsule or a tablet. 21. The method of claim 14, wherein the formulation is formulated as a capsule or a tablet. 22. The method of claim 16, wherein the formulation is formulated as a capsule or a tablet.