Claims for Patent: 10,478,400

Summary for Patent: 10,478,400

Title:	Immediate-release tablets containing combimetinib and methods of making and using the same
Abstract:	The present disclosure relates generally to rapid-release pharmaceutical dosage unit tablets containing a drug that is an inhibitor of the mitogen-activated protein kinase enzyme, a filler and a disintegrant, and to processes for forming the tablets. More specifically, the present disclosure relates to pharmaceutical dosage unit tablets containing cobimetinib, a least one filler, at least one lubricant and at least one disintegrant, and to methods for preparing the tablets from granules formed by dry granulation.
Inventor(s):	Kothari; Sanjeev (Foster City, CA), Mantik; Priscilla (San Jose, CA), Mauerer; Alexander (Nuremberg, DE), Rezaei; Hamid (San Ramon, CA)
Assignee:	Genentech, Inc. (South San Francisco, CA)
Application Number:	15/852,125
Patent Claims:	1. A process for preparing a pharmaceutical dosage unit tablet core, the process comprising: (1) blending a particulate pharmaceutical active drug, an intragranular filler, an intragranular disintegrant and an intragranular lubricant to form a pre-blend, wherein the particulate pharmaceutical drug active has a particle size D[v, 0.5] of from about 25 .mu.m to about 65 .mu.m, from about 25 .mu.m to about 50 .mu.m, or from about 30 .mu.m to about 40 .mu.m; (2) compacting the pre-blend by application of a compaction force of from about 1 kN/cm to about 8 kN/cm, from about 2 kN/cm to about 5 kN/cm, or from about 2 kN/cm to about 4 kN/cm; (3) milling and screening the compacted pre-blend to form granules; and (4) tableting the granules by application of a tableting compression force of from about 5 kN to about 20 kN, from about 14 kN to about 19 kN, from about 14 kN to about 18 kN, or from about 8 kN to about 13 kN to form the pharmaceutical dosage unit tablet core, wherein the particulate pharmaceutical active drug is cobimetinib hemifumarate polymorph Form A. 2. The process of claim 1, wherein the pharmaceutical active drug has a particle size D[v, 0.9] of from about 45 .mu.m to about 500 .mu.m, from about 45 .mu.m to about 400 .mu.m, from about 45 .mu.m to about 300 .mu.m, from about 45 .mu.m to about 200 .mu.m, from about 45 .mu.m to about 100 .mu.m, from about 50 .mu.m to about 60 .mu.m, from about 65 .mu.m to about 100 .mu.m, from about 45 .mu.m to about 80 .mu.m, or from about 75 .mu.m to about 100 .mu.m. 3. The process of claim 1, further comprising applying a film coating on the surface of the pharmaceutical dosage unit tablet core. 4. The process of claim 1, further comprising, prior to tableting, blending the granules with extragranular disintegrant and extragranular lubricant to form a final blend, wherein the final blend is tableted. 5. The process of claim 1, wherein the total lubricant content based on pharmaceutical dosage unit tablet core weight is from about 0.5 wt. % to about 5 wt. %, from about 0.5 wt. % to about 3 wt. %, from about 1 wt. % to about 3 wt. %, from about 1 wt. % to about 2.5 wt. %, or from about 1.5 wt. % to about 2 wt. %. 6. The process of claim 4, wherein (1) the intragranular lubricant content based on tablet core weight is from about 0.1 wt. % to about 1 wt. %, from about 0.2 wt. % to about 0.75 wt. %, or from about 0.25 wt. % to about 5 wt. %; and (2) the extragranular lubricant content based on tablet core weight is from about 0.5 wt. % to about 2.5 wt. %, from about 0.75 wt. % to about 2.25 wt. %, from about 0.75 wt. % to about 2 wt. %, from about 1 wt. % to about 1.75 wt. %, or from about 1.25 wt. % to about 1.5 wt. %. 7. The process of claim 1, wherein the total disintegrant content based on pharmaceutical dosage unit tablet core weight is from about 2 wt. % to about 7 wt. %, from about 2 wt. % to about 6 wt. %, from about 2 wt. % to about 5 wt. %, from about 3 wt. % to about 6 wt. %, or from about 3 wt. % to about 5 wt. %. 8. The process of claim 1, wherein the pharmaceutical dosage unit tablet core comprises intragranular disintegrant and extragranular disintegrant, wherein (1) the intragranular disintegrant content based on tablet core weight is from about 0.1 wt. % to about 3 wt. %, from about 0.25 wt. % to about 2.5 wt. %, from about 0.25 wt. % to about 2 wt. %, from about 0.25 wt. % to about 1.5 wt. %, from about 0.25 wt. % to about 1 wt. %, from about 0.5 wt. % to about 3 wt. %, from about 0.5 wt. % to about 2 wt. %, from about 0.5 wt. % to about 1.5 wt. %, from about 1 wt. % to about 3 wt. %, or from about 1.5 wt. % to about 2.5 wt. %; and (2) the extragranular disintegrant content based on tablet core weight is from about 0.5 wt. % to about 3 wt. %, from about 1 wt. % to about 3 wt. %, from about 1.25 wt. % to about 3 wt. %, from about 1.25 wt. % to about 2.5 wt. %, from about 1.25 wt. % to about 2 wt. %, from about 1.25 wt. % to about 1.5 wt. %, from about 1.5 wt. % to about 3 wt. %, or from about 1.5 wt. % to about 2.5 wt. %. 9. The process of claim 8, wherein the weight ratio of the intragranular disintegrant to the extragranular disintegrant is about 1:5, about 1:3, about 1:1, or about 2:1. 10. The process of claim 1, wherein the total filler content based on pharmaceutical dosage unit tablet core weight is from about 60 wt. % to about 78 wt. %, from about 65 wt. % to about 78 wt. %, from about 65 wt. % to about 77 wt. %, from about 70 wt. % to about 77 wt. %, or from about 71 wt. % to about 75 wt. %. 11. The process of claim 1, wherein the bulk density of the final blend is from about 0.4 g/mL to about 0.75 g/mL, from about 0.45 g/mL to about 0.7 g/mL, or from about 0.5 g/mL to about 0.65 g/mL. 12. The process of claim 1, wherein the screen size is from about 0.5 mm to about 2.0 mm, from about 0.5 mm to about 1.5 mm, from about 0.5 mm to about 1.25 mm, from about 0.75 mm to about 2.0 mm, from about 0.75 mm to about 1.5 mm, from about 0.75 mm to about 1.25 mm, or about 1 mm. 13. The process of claim 1, wherein the filler comprises (1) lactose or (2) lactose and microcrystalline cellulose wherein the weight ratio of lactose to microcrystalline cellulose is from about 1:1.5 to about 4:1, from about 1.25 to about 4:1, from about 1:1 to about 4:1, from about 1:1 to about 3:1, from about 1.5:1 to about 3:1, or from about 2:1 to about 2.5:1. 14. The process of claim 1, wherein the disintegrant comprises sodium starch glycolate, croscarmellose sodium, or a combination thereof. 15. The process of claim 1, wherein the lubricant comprises magnesium stearate, sodium stearyl fumarate, or a combination thereof. 16. The process of claim 1, wherein the pre-blend further comprises a binder at a total binder content based on pharmaceutical dosage unit tablet core weight of from about 1 wt. % to about 10 wt. %, from about 1 wt. % to about 7 wt. %, from about 1 wt. % to about 6 wt. %, or from about 1 wt. % to about 5 wt. %. 17. The process of claim 16, wherein the binder comprises povidone, copovidone, pregelatinized starch, hydroxypropyl methylcellulose, or a combination thereof. 18. The process of claim 1, wherein the particulate pharmaceutical active drug content based on the weight of the tablet core is at least 5 wt. %, from about 15 wt. % to about 25 wt. %, or about 20 wt. %. 19. The process of claim 1, wherein the pharmaceutical dosage unit tablet core comprises: (1) from 17.6 wt. % to 19.4 wt. % cobimetinib hemifumarate polymorph Form A; (2) from 43.3 wt. % to 47.9 wt. % microcrystalline cellulose; (3) from 28.9 wt. % to 31.9 wt. % lactose monohydrate; (4) from 3.8 wt. % to 4.2 wt. % croscarmellose sodium; and (5) from 1.4 wt. % to 1.6 wt. % magnesium stearate. 20. The process of claim 1, wherein the pre-blend is compacted between at least two rotating rolls having a gap width of from about 2 mm to about 5 mm, from about 2 mm to about 4 mm, from about 3 mm to about 5 mm, or from about 4 mm to about 5 mm to form a ribbon, wherein the ribbon is milled and screened to form granules. 21. The process of claim 20, wherein the ribbon has an at-gap density selected from: from about 0.85 g/mL to about 0.95 g/mL from about 0.9 g/mL to about 0.95 g/mL, from about 0.95 g/mL to about 1.1 g/mL, from about 0.95 g/mL to about 1.05 g/mL, from about 1 g/mL to about 1.10 g/mL, from about 1 g/mL to about 1.05 g/mL, from about 1.1 g/mL to about 1.3 g/mL, from about 1.1 g/mL to about 1.25 g/mL, from about 1.1 g/mL to about 1.2 g/mL, from about 1.1 g/mL to about 1.15 g/mL, from about 1.15 g/mL to about 1.3 g/mL, from about 1.15 g/mL to about 1.25 g/mL, and from about 1.15 g/mL to about 1.2 g/mL. 22. The process of claim 20, wherein the particulate pharmaceutical active drug has a particle size D[v, 0.5] of from about 27 .mu.m to about 37 .mu.m, the roller compaction gap force is about 2 kN/cm, and the gap width is about 5 mm. 23. The process of claim 20, wherein the particulate pharmaceutical active drug has a particle size D[v, 0.5] of from about 38 .mu.m to about 65 .mu.m, the roller compaction gap force is from about 2 kN/cm to about 4 kN/cm, and the gap width is from about 4 mm to about 5 mm. 24. A pharmaceutical dosage unit tablet core, the tablet core comprising: (1) about 5 wt. % or more of a particulate pharmaceutical active drug; (2) a lubricant at a content based on the pharmaceutical dosage unit tablet core weight of from about 0.5 wt. % to about 5 wt. %, from about 0.5 wt. % to about 3 wt. %, from about 1 wt. % to about 3 wt. %, from about 1 wt. % to about 2.5 wt. %, or from about 1.5 wt. % to about 2 wt. %; (3) a disintegrant at a content based on the pharmaceutical dosage unit tablet core weight of from about 2 wt. % to about 7 wt. %, from about 2 wt. % to about 6 wt. %, from about 2 wt. % to about 5 wt. %, from about 3 wt. % to about 6 wt. %, or from about 3 wt. % to about 5 wt. %; (4) a filler at a content based on the pharmaceutical dosage unit tablet core weight of from about 60 wt. % to about 78 wt. %, from about 65 wt. % to about 78 wt. %, from about 65 wt. % to about 77 wt. %, from about 70 wt. % to about 77 wt. %, or from about 71 wt. % to about 75 wt. %; and (5) optionally, up to 10 wt. % of a binder, wherein the particulate pharmaceutical active drug is cobimetinib hemifumarate polymorph Form A. 25. The pharmaceutical dosage unit tablet core of claim 24, wherein the particulate pharmaceutical active drug content based on the weight of the tablet core is from about 15 wt. % to about 25 wt. %, or about 20 wt. %. 26. The pharmaceutical dosage unit tablet core of claim 24, wherein the particulate pharmaceutical active drug has a particle size D[v, 0.5] of from about 25 .mu.m to about 65 .mu.m, from about 25 .mu.m to about 50 .mu.m, or from about 30 .mu.m to about 40 .mu.m. 27. The pharmaceutical dosage unit tablet core of claim 24, wherein the particulate pharmaceutical active drug has a particle size D[v, 0.5] of from about 45 .mu.m to about 500 .mu.m, from about 45 .mu.m to about 400 .mu.m, from about 45 .mu.m to about 300 .mu.m, from about 45 .mu.m to about 200 .mu.m, from about 44 .mu.m to about 100 .mu.m, from about 50 .mu.m to about 60 .mu.m, from about 65 .mu.m to about 100 .mu.m, from about 45 .mu.m to about 80 .mu.m, or from about 75 .mu.m to about 100 .mu.m. 28. The pharmaceutical dosage unit tablet core of claim 24, wherein said tablet core comprises intragranular lubricant and extragranular lubricant, wherein: (1) the intragranular lubricant content based on said tablet core weight is from about 0.1 wt. % to about 1 wt. %, from about 0.2 wt. % to about 0.75 wt. %, or from about 0.25 wt. % to about 5 wt. %; and (2) the extragranular lubricant content based on said tablet core weight is from about 0.5 wt. % to about 2.5 wt. %, from about 0.75 wt. % to about 2.25 wt. %, from about 0.75 wt. % to about 2 wt. %, from about 1 wt. % to about 1.75 wt. %, or from about 1.25 wt. % to about 1.5 wt. %. 29. The pharmaceutical dosage unit tablet core of claim 24, wherein the lubricant comprises magnesium stearate, sodium stearyl fumarate, or a combination thereof. 30. The pharmaceutical dosage unit tablet core of claim 24, wherein said tablet core comprises intragranular disintegrant and extragranular disintegrant, wherein: (1) the intragranular disintegrant content based on said tablet core weight is from about 0.1 wt. % to about 3 wt. %, from about 0.25 wt. % to about 2.5 wt. %, from about 0.25 wt. % to about 2 wt. %, from about 0.25 wt. % to about 1.5 wt. %, from about 0.25 wt. % to about 1 wt. %, from about 0.5 wt. % to about 3 wt. %, from about 0.5 wt. % to about 2 wt. %, from about 0.5 wt. % to about 1.5 wt. %, from about 1 wt. % to about 3 wt. %, or from about 1.5 wt. % to about 2.5 wt. %; and (2) the extragranular disintegrant content based on said tablet core weight is from about 0.5 wt. % to about 3 wt. %, from about 1 wt. % to about 3 wt. %, from about 1.25 wt. % to about 3 wt. %, from about 1.25 wt. % to about 2.5 wt. %, from about 1.25 wt. % to about 2 wt. %, from about 1.25 wt. % to about 1.5 wt. %, from about 1.5 wt. % to about 3 wt. %, or from about 1.5 wt. % to about 2.5 wt. %. 31. The pharmaceutical dosage unit tablet core of claim 30, wherein the weight ratio of the intragranular disintegrant to the extragranular disintegrant is about 1:5, about 1:3, about 1:1, or about 2:1. 32. The pharmaceutical dosage unit tablet core of claim 24, wherein the disintegrant comprises sodium starch glycolate, croscarmellose sodium, or a combination thereof. 33. The pharmaceutical dosage unit tablet core of claim 24, wherein the filler comprises (1) lactose or (2) lactose and microcrystalline cellulose, wherein the weight ratio of lactose to microcrystalline cellulose is from about 1:1.5 to about 4:1, from about 1:1.25 to about 4:1, from about 1:1 to about 4:1 from about 1:1 to about 3:1, from about 1.5:1 to about 3:1, or from about 2:1 to about 2.5:1. 34. The pharmaceutical dosage unit tablet core of claim 24, wherein the particulate pharmaceutical active drug has a particle size D[v, 0.5] of from about 25 .mu.m to about 40 .mu.m. 35. The pharmaceutical dosage unit tablet core of claim 24, wherein the particulate pharmaceutical active drug has a particle size D[v, 0.5] of from about 40 .mu.m to about 65 .mu.m. 36. The pharmaceutical dosage unit tablet core of claim 24, wherein the tablet core further comprises a binder at a total binder content based on said tablet core weight of from about 1 wt. % to about 10 wt. %, from about 1 wt. % to about 7 wt. %, from about 1 wt. % to about 6 wt. %, or from about 1 wt. % to about 5 wt. %. 37. The pharmaceutical dosage unit tablet core of claim 36, wherein the binder comprises povidone, copovidone, pregelatinized starch, hydroxypropyl methylcellulose, or a combination thereof. 38. The pharmaceutical dosage unit tablet core of claim 24, wherein said tablet core comprises: (1) from about 17.6 wt. % to about 19.4 wt. % cobimetinib hemifumarate polymorph Form A; (2) from about 43.3 wt. % to about 47.9 wt. % microcrystalline cellulose; (3) from about 28.9 wt. % to about 31.9 wt. % lactose monohydrate; (4) from about 3.8 wt. % to about 4.2 wt. % croscarmellose sodium; and (5) from about 1.4 wt. % to about 1.6 wt. % magnesium stearate. 39. The pharmaceutical dosage unit tablet core of claim 24, further comprising a film-coating on the surface of said tablet core, wherein the coated pharmaceutical dosage unit tablet core is characterized by: (1) a dissolution profile such that 80% of the tablet dissolves in 20 minutes; (2) a minimum hardness of 45 N; (3) a disintegration time of no more than 300; and (4) an abrasion of less than 1.0%. 40. The pharmaceutical dosage unit tablet core of claim 39, wherein the coated pharmaceutical dosage unit tablet core comprises from about 2 wt. % to about 6 wt. % or from about 3 wt. % to about 5 wt. % of the film-coating based on the weight of said tablet core, and, wherein the film-coating comprises: (1) from about 38 wt. % to about 42 wt. % polyvinyl alcohol; (2) from about 23.8 wt. % to about 26.3 wt. % titanium dioxide; (3) from about 19.2 wt. % to about 21.2 wt. % macrogol/PEG3350; and (4) from about 14.1 wt. % to about 15.5 wt. % talc. 41. A pharmaceutical product comprising: (1) a first tablet comprising the coated pharmaceutical dosage unit tablet core of claim 39; and (2) a second tablet comprising propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro- -phenyl}-amide (vemurafenib), or a pharmaceutically acceptable salt thereof. 42. The pharmaceutical product of claim 41, wherein the first tablet comprises 20 mg cobimetinib, 40 mg cobimetinib, or 60 mg cobimetinib. 43. A method of treating BRAFV600 mutation-positive unresectable or metastatic melanoma comprising administering to a patient a therapeutically effective amount of the pharmaceutical product of claim 41. 44. The method of claim 43, wherein one or more first tablets are administered to provide a total dose of 60 mg cobimetinib, on days 1-21 of a 28 day cycle, and wherein one or more second tablets are administered to provide a total dose of 960 mg vemurafenib, twice daily each day of the 28 day cycle. 45. The method of claim 43, wherein the first tablet is administered sequentially with the second tablet. 46. The method of claim 43, wherein the first tablet is administered concurrently with the second tablet. 47. The method of claim 43, wherein the unresectable or metastatic melanoma is BRAFV600E mutation-positive melanoma. 48. The method of claim 43, wherein the unresectable or metastatic melanoma is metastatic melanoma. 49. The method of claim 43, wherein the BRAFV600 mutation-positive unresectable or metastatic melanoma has not been previously treated. 50. A pharmaceutical dosage unit tablet core, the tablet core comprising: (1) 18.5 wt. % cobimetinib hemifumarate polymorph Form A; (2) 45.6 wt. % microcrystalline cellulose; (3) 30.4 wt. % lactose monohydrate; (4) 4 wt. % croscarmellose sodium; and (5) 1.5 wt. % magnesium stearate. 51. The pharmaceutical dosage unit tablet core of claim 50, comprising: (1) 2 wt. % intragranular croscarmellose sodium and 2 wt. % extragranular croscarmellose sodium; and (2) 0.25 wt. % intragranular magnesium stearate and 1.25 wt. % extragranular magnesium stearate. 52. The pharmaceutical dosage unit tablet core of claim 50, wherein the microcrystalline cellulose has a bulk density from 0.26 to 0.31 g/mL, a degree of polymerization of not more than 350, and a particle size measured by air jet of not more than 1 wt. %+60 mesh (250 microns) and not more than 30 wt. %+200 mesh (75 microns). 53. A coated pharmaceutical dosage unit tablet core, the coated tablet comprising: (1) 17.79 wt. % cobimetinib hemifumarate polymorph Form A; (2) 43.85 wt. % microcrystalline cellulose; (3) 29.23 wt. % lactose monohydrate; (4) 3.84 wt. % croscarmellose sodium; (5) 1.45 wt. % magnesium stearate; and (6) 3.85 wt. % film coating. 54. The coated pharmaceutical dosage unit tablet of claim 53, comprising: (1) 1.92 wt. % intragranular croscarmellose sodium and 1.92 wt. % extragranular croscarmellose sodium; and (2) 0.24 wt. % intragranular magnesium stearate and 1.21 wt. % extragranular magnesium stearate. 55. The coated pharmaceutical dosage unit tablet of claim 53, wherein the film coating comprises: (1) 40 wt. % polyvinyl alcohol; (2) 25 wt. % titanium dioxide; (3) 20.2 wt. % macrogol/PEG 3350; and (4) 14.8 wt. % talc. 56. A pharmaceutical product comprising: (1) a first tablet comprising the coated tablet of claim 53; and (2) a second tablet comprising propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro- -phenyl}-amide (vemurafenib), or a pharmaceutically acceptable salt thereof. 57. The pharmaceutical product of claim 56, wherein the first tablet comprises 20 mg cobimetinib, 40 mg cobimetinib, or 60 mg cobimetinib. 58. A method of treating BRAFV600 mutation-positive unresectable or metastatic melanoma comprising administering to a patient a therapeutically effective amount of the pharmaceutical product of claim 56. 59. The method of claim 58, wherein one or more first tablets are administered to provide a total dose of 60 mg cobimetinib, on days 1-21 of a 28 day cycle, and wherein one or more second tablets are administered to provide a total dose of 960 mg vemurafenib, twice daily each day of the 28 day cycle. 60. The method of claim 58, wherein the first tablet is administered sequentially with the second tablet. 61. The method of claim 58, wherein the first tablet is administered concurrently with the second tablet. 62. The method of claim 58, wherein the unresectable or metastatic melanoma is BRAFV600E mutation-positive melanoma. 63. The method of claim 58, wherein the unresectable or metastatic melanoma is metastatic melanoma. 64. The method of claim 58, wherein the BRAFV600 mutation-positive unresectable or metastatic melanoma has not been previously treated. 65. A process for preparing a coated pharmaceutical dosage unit tablet, the process comprising the following steps: (1) combining a particulate filler component, a first particulate disintegrant component and cobimetinib hemifumarate polymorph Form A in a blender and admixing said components to form a primary pre-blend; (2) combining a particulate first lubricant component with the primary pre-blend in a blender and admixing said first lubricant component and primary pre-blend to form a finished preblend; (3) dry granulating the finished pre-blend to form granules; (4) combining the granules and a second particulate disintegrant component in a blender and admixing said granules and disintegrant component to form a primary final blend; (5) combining a second particulate lubricant component and the primary final blend in a blender and admixing said second lubricant component and primary final blend to form a finished final blend; (6) tableting the finished final blend to form tablet cores; and (7) coating the tablet cores. 66. The process of claim 65, further comprising suspending a film-coat solid mixture in water to form a coating slurry mixture and coating the tablet cores with the coating mixture slurry. 67. The process of claim 65, wherein: (1) the particulate filler component is selected from lactose, microcrystalline cellulose, and combinations thereof; (2) the first particulate disintegrant and second particulate disintegrant are each selected from sodium starch glycolate, croscarmellose sodium, and combinations thereof; and (3) first lubricant component and the second lubricant component are each selected from magnesium stearate, sodium stearyl fumarate, and combinations thereof.