Claims for Patent: 11,369,599

Summary for Patent: 11,369,599

Title:	Melt-extruded solid dispersions containing an apoptosis-inducing agent
Abstract:	A pro-apoptotic solid dispersion comprises, in essentially non-crystalline form, a Bcl-2 family protein inhibitory compound of Formula I as defined herein, dispersed in a solid matrix that comprises (a) a pharmaceutically acceptable water-soluble polymeric carrier and (b) a pharmaceutically acceptable surfactant. A process for preparing such a solid dispersion comprises subjecting to elevated temperature the compound of Formula I, the water-soluble polymeric carrier and the surfactant, to provide an extrudable semi-solid mixture; extruding the semi-solid mixture; and cooling the resulting extrudate to provide a solid matrix comprising the polymeric carrier and the surfactant and having the compound dispersed in essentially non-crystalline form therein. The solid dispersion is suitable for oral administration to a subject in need thereof for treatment of a disease characterized by overexpression of one or more anti-apoptotic Bcl-2 family proteins, for example cancer or an immune or autoimmune disease.
Inventor(s):	Birtalan; Esther (Karlsruhe, DE), Hoelig; Peter (Waechtersbach, DE), Lindley; David J. (Antioch, IL), Sanzgiri; Yeshwant D. (Gurnee, IL), Tong; Ping (Libertyville, IL)
Assignee:	AbbVie Inc. (North Chicago, IL) AbbVie Deutschland GMBH & Co KG (Wiesbaden, DE)
Application Number:	14/340,435
Patent Claims:	1. An orally deliverable pharmaceutical tablet comprising 9.42% by weight of a parent compound 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin- -1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony- l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide, 62.8% by weight of copovidone, 5.495% by weight of polysorbate 80, and 0.785% by weight of colloidal silicon dioxide. 2. The orally deliverable pharmaceutical tablet of claim 1, further comprising 20% by weight of dicalcium phosphate, 0.5% by weight of sodium stearyl fumarate, and 1% by weight of colloidal silicon dioxide. 3. The orally deliverable pharmaceutical tablet of claim 2, wherein the tablet comprises about 50 mg of the parent compound. 4. The orally deliverable pharmaceutical tablet of claim 2, wherein the tablet comprises about 100 mg of the parent compound. 5. An orally deliverable pharmaceutical tablet comprising a solid dispersion, the solid dispersion comprising: (a) 5% by weight to 20% by weight of a parent compound, wherein the parent compound is 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin- -1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony- l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide, and wherein the parent compound is in essentially non-crystalline or amorphous form; and (b) 70% by weight to 95% by weight of at least one pharmaceutically acceptable water-soluble polymeric carrier. 6. The orally deliverable pharmaceutical tablet of claim 5, wherein the solid dispersion comprises about 5% by weight to about 15% by weight of the parent compound. 7. The orally deliverable pharmaceutical tablet of claim 5, wherein the solid dispersion comprises about 75% by weight to about 85% by weight of the at least one pharmaceutically acceptable water-soluble polymeric carrier. 8. The orally deliverable pharmaceutical tablet of claim 5, wherein the at least one pharmaceutically acceptable water-soluble polymeric carrier is selected from the group consisting of homopolymers and copolymers of N-vinyl lactams, cellulose esters, cellulose ethers, polyalkylene oxides, polyacrylates, polymethacrylates, polyacrylamides, vinyl acetate polymers, graft copolymers of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate, oligo- and polysaccharides and mixtures thereof. 9. The orally deliverable pharmaceutical tablet of claim 5, wherein the at least one pharmaceutically acceptable water-soluble polymeric carrier is selected from the group consisting of povidones, copovidones, hydroxypropyl methylcelluloses (HPMCs), graft copolymers of polyethylene glycol/polyvinyl caprolactam/polyvinyl acetate, and mixtures thereof. 10. The orally deliverable pharmaceutical tablet of claim 5, wherein the solid dispersion further comprises at least one pharmaceutically acceptable surfactant, wherein the pharmaceutically acceptable surfactant is non-ionic. 11. The orally deliverable pharmaceutical tablet of claim 10, wherein the pharmaceutically acceptable surfactant is selected from the group consisting of polyoxyethylene glycerides, fatty acid monoesters of sorbitan, polysorbates, a-tocopheryl polyethylene glycol succinate (TPGS) and mixtures thereof. 12. The orally deliverable pharmaceutical tablet of claim 5, wherein the solid dispersion further comprises at least one glidant. 13. The orally deliverable pharmaceutical tablet of claim 12, wherein the at least one glidant comprises colloidal silicon dioxide. 14. The orally deliverable pharmaceutical tablet of claim 5, wherein the solid dispersion comprises about 5% by weight to about 15% by weight of the parent compound, and about 75% by weight to about 85% by weight of the at least one pharmaceutically acceptable water-soluble polymeric carrier. 15. The orally deliverable pharmaceutical tablet of claim 14, wherein the at least one pharmaceutically acceptable water-soluble polymeric carrier is copovidone. 16. The orally deliverable pharmaceutical tablet of claim 15, wherein the solid dispersion further comprises at least one pharmaceutically acceptable surfactant, wherein the pharmaceutically acceptable surfactant is a polysorbate. 17. The orally deliverable pharmaceutical tablet of claim 16, wherein the solid dispersion further comprises at least one glidant. 18. The orally deliverable pharmaceutical tablet of claim 17, wherein the at least one glidant comprises colloidal silicon dioxide. 19. The orally deliverable pharmaceutical tablet of claim 5, wherein the solid dispersion comprises: between about 5% by weight and about 12% by weight of the parent compound; and between about 75% by weight and about 85% by weight of the at least one pharmaceutically acceptable water-soluble polymeric carrier. 20. The orally deliverable pharmaceutical tablet of claim 19, wherein the solid dispersion comprises: between about 5% by weight and about 12% by weight of the parent compound; and between about 75% by weight and about 84% by weight of the at least one pharmaceutically acceptable water-soluble polymeric carrier. 21. The orally deliverable pharmaceutical tablet of claim 20, wherein the at least one pharmaceutically acceptable water-soluble polymeric carrier is copovidone. 22. The orally deliverable pharmaceutical tablet of claim 19, wherein the solid dispersion comprises: 12% by weight of the parent compound; 80% by weight of copovidone 60/40; 7% by weight of polysorbate 80; and, 1% by weight of colloidal silicon dioxide. 23. The orally deliverable pharmaceutical tablet of claim 22, wherein the tablet comprises 78.5% by weight of the solid dispersion, and wherein the orally deliverable pharmaceutical tablet further comprises 20.0% by weight of dicalcium phosphate, 0.5% by weight of sodium stearyl fumarate, and 1.0% by weight of colloidal silicon dioxide. 24. The orally deliverable pharmaceutical tablet of claim 5, wherein the solid dispersion comprises at least one pharmaceutically acceptable surfactant. 25. The orally deliverable pharmaceutical tablet of claim 19, wherein the solid dispersion further comprises: between about 5% by weight and about 15% by weight of a pharmaceutically acceptable surfactant; and between about 0.1% by weight and about 2% by weight of a glidant. 26. The orally deliverable pharmaceutical tablet of claim 20, wherein the solid dispersion further comprises: between about 5% by weight and about 12% by weight of a pharmaceutically acceptable surfactant; and between about 0.5% by weight and about 1.5% by weight of a glidant. 27. The orally deliverable pharmaceutical tablet of claim 26, wherein the glidant is colloidal silicon dioxide. 28. The orally deliverable pharmaceutical tablet of claim 5, wherein the orally deliverable pharmaceutical tablet comprises 9.42% by weight of the parent compound, 62.8% by weight of copovidone, 5.495% by weight of polysorbate 80, and 0.785% by weight of colloidal silicon dioxide. 29. The orally deliverable pharmaceutical tablet of claim 28, wherein the orally deliverable pharmaceutical tablet further comprises 20% by weight of dicalcium phosphate, 0.5% by weight of sodium stearyl fumarate, and 1% by weight of colloidal silicon dioxide. 30. The orally deliverable pharmaceutical tablet of claim 5, wherein the orally deliverable pharmaceutical tablet comprises about 50 mg of the parent compound. 31. The orally deliverable pharmaceutical tablet of claim 5, wherein the orally deliverable pharmaceutical tablet comprises about 100 mg of the parent compound. 32. An orally deliverable solid dosage form comprising a solid dispersion, the solid dispersion comprising: (a) 5% by weight to 20% by weight of a parent compound, wherein the parent compound is 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin- -1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony- l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide, and wherein the parent compound is in essentially non-crystalline or amorphous form; and (b) 70% by weight to 95% by weight of at least one pharmaceutically acceptable water-soluble polymeric carrier. 33. The orally deliverable solid dosage form of claim 32, wherein the solid dispersion comprises about 5% by weight to about 15% by weight of the parent compound, and about 75% by weight to about 85% by weight of the at least one pharmaceutically acceptable water-soluble polymeric carrier. 34. The orally deliverable solid dosage form of claim 32, wherein the solid dispersion further comprises at least one pharmaceutically acceptable surfactant, wherein the pharmaceutically acceptable surfactant is a polysorbate. 35. The orally deliverable solid dosage form of claim 32, wherein the solid dispersion comprises: between about 5% by weight and about 12% by weight of the parent compound; and between about 75% by weight and about 84% by weight of the at least one pharmaceutically acceptable water-soluble polymeric carrier. 36. The orally deliverable solid dosage form of claim 32, wherein the solid dispersion comprises: 12% by weight of the parent compound; 80% by weight of copovidone 60/40; 7% by weight of polysorbate 80; and, 1% by weight of colloidal silicon dioxide. 37. The orally deliverable pharmaceutical tablet of claim 7, wherein the solid dispersion further comprises at least one pharmaceutically acceptable surfactant, and between about 5% by weight and about 12% by weight of the parent compound. 38. The orally deliverable pharmaceutical tablet of claim 37, wherein the solid dispersion further comprises between about 5% by weight and about 15% by weight of a pharmaceutically acceptable surfactant. 39. The orally deliverable pharmaceutical tablet of claim 38, wherein the pharmaceutically acceptable surfactant is polysorbate 80. 40. The orally deliverable pharmaceutical tablet of claim 39, wherein the at least one pharmaceutically acceptable water-soluble polymeric carrier is copovidone. 41. The orally deliverable pharmaceutical tablet of claim 40, wherein the solid dispersion further comprises at least one glidant. 42. The orally deliverable pharmaceutical tablet of claim 40, wherein the solid dispersion further comprises between about 0.1% by weight and about 2% by weight of a glidant. 43. The orally deliverable pharmaceutical tablet of claim 42, wherein the at least one glidant comprises colloidal silicon dioxide. 44. The orally deliverable pharmaceutical tablet of claim 38, wherein the tablet comprises about 50 mg of the parent compound. 45. The orally deliverable pharmaceutical tablet of claim 38, wherein the tablet comprises about 100 mg of the parent compound. 46. The orally deliverable pharmaceutical tablet of claim 7, wherein the solid dispersion further comprises at least one pharmaceutically acceptable surfactant, and between about 5% by weight and about 12% by weight of the parent compound. 47. The orally deliverable pharmaceutical tablet of claim 46, wherein the solid dispersion further comprises between about 5% by weight and about 15% by weight of a pharmaceutically acceptable surfactant. 48. The orally deliverable pharmaceutical tablet of claim 47, wherein the pharmaceutically acceptable surfactant is polysorbate 80. 49. The orally deliverable pharmaceutical tablet of claim 48, wherein the at least one pharmaceutically acceptable water-soluble polymeric carrier is copovidone. 50. The orally deliverable pharmaceutical tablet of claim 49, wherein the solid dispersion further comprises at least one glidant. 51. The orally deliverable pharmaceutical tablet of claim 49, wherein the solid dispersion further comprises between about 0.1% by weight and about 2% by weight of a glidant. 52. The orally deliverable pharmaceutical tablet of claim 51, wherein the at least one glidant comprises colloidal silicon dioxide. 53. The orally deliverable pharmaceutical tablet of claim 47, wherein the tablet comprises about 50 mg of the parent compound. 54. The orally deliverable pharmaceutical tablet of claim 47, wherein the tablet comprises about 100 mg of the parent compound.