Immediate-release tablets containing a drug and processes for forming the tablets

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.

What is claimed is: 
     
         1 . A process for preparing a pharmaceutical dosage unit tablet core, the process comprising:
 (1) blending a particulate pharmaceutical drug active, 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 μm to about 65 μm, from about 25μ to about 50 μm, or from about 30μ to about 40 μm;   (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.   
     
     
         2 . 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. 
     
     
         3 . The process of  claim 1  wherein the pharmaceutical drug active has a particle size D[v, 0.9] of from about 45 μm to about 500 μm, from about 45 μm to about 400 μm, from about 45 μm to about 300 μm, from about 45 μm to about 200 μm, from about 45 μm to about 100 μm, from about 50 μm to about 60 μm, from about 65 μm to about 100 μm, from about 45 μm to about 80 μm, from about 75 μm to about 100 μm. 
     
     
         4 . The process of  claim 1  further comprising applying a film coating on the surface of the pharmaceutical dosage unit tablet core. 
     
     
         5 . The process of  claim 2  wherein the ribbon has an at-gap density selected from:
 (1) from about 0.85 g/mL to about 0.95 g/mL and from about 0.9 g/mL to about 0.95 g/mL; 
 (2) from about 0.95 g/mL to from 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 and from about 1 g/mL to about 1.05 g/mL; and 
 (3) 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. 
 
     
     
         6 . 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. 
     
     
         7 . 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. %. 
     
     
         8 . The process of  claim 7  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. %. 
 
     
     
         9 . 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. %. 
     
     
         10 . The process of  claim 9  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. %. 
 
     
     
         11 . The process of  claim 10  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. 
     
     
         12 . The process of  claim 11  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. %. 
     
     
         13 . The process of  claim 12  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. 
     
     
         14 . The process of  claim 13  wherein the screen size 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. 
     
     
         15 . The process of  claim 14  wherein the particulate pharmaceutical active drug has a particle size D[v, 0.5] of from about 27 μm to about 37 μm, the roller compaction gap force is about 2 kN/cm, and the gap width is about 5 mm. 
     
     
         16 . The process of  claim 14  wherein the particulate pharmaceutical active drug has a particle size D[v, 0.5] of from about 38 μm to about 65 μm, 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. 
     
     
         17 . The process of  claim 16  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. 
     
     
         18 . The process of  claim 18  wherein the disintegrant comprises sodium starch glycolate, croscarmellose sodium, and combinations thereof. 
     
     
         19 . The process of  claim 19  wherein the lubricant comprises magnesium stearate, sodium stearyl fumarate, and combinations thereof. 
     
     
         20 . The process of  claim 20  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. %. 
     
     
         21 . The process of  claim 21  wherein the binder comprises povidone, copovidone, pregelatinized starch, hydroxypropyl methylcellulose, and combinations thereof. 
     
     
         22 . The process of claim wherein the particulate pharmaceutical active drug content based on the weight of the table core is at least 5 wt. %, from about 15 wt. % to about 25 wt. %, or about 20 wt. %. 
     
     
         23 . 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.   
     
     
         24 . The pharmaceutical dosage unit tablet core of  claim 25  or  claim 26  wherein the particulate pharmaceutical active drug content based on the weight of the table core is from about 15 wt. % to about 25 wt. %, or about 20 wt. %. 
     
     
         25 . The pharmaceutical dosage unit tablet core of claim wherein the particulate pharmaceutical active drug has a particle size D [v, 0.5] of from about 25 μm to about 65 μm, from about 25μ to about 50 μm, or from about 30μ to about 40 μm. 
     
     
         26 . The pharmaceutical dosage unit tablet core of claim wherein the particulate pharmaceutical active drug has a particle size D [v, 0.9] of from about 45 μm to about 500 μm, from about 45 μm to about 400 μm, from about 45 μm to about 300 μm, from about 45 μm to about 200 μm, from about 44 μm to about 100 μm, from about 50 μm to about 60 μm, from about 65 μm to about 100 μm, from about 45 μm to about 80 μm, or from about 75 μm to about 100 μm. 
     
     
         27 . The pharmaceutical dosage unit tablet core of  claim 26  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. %. 
 
     
     
         28 . The pharmaceutical dosage unit tablet core of  claim 27  wherein the lubricant comprises magnesium stearate, sodium stearyl fumarate, and combinations thereof. 
     
     
         29 . The pharmaceutical dosage unit tablet core of  claim 28  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. %. 
 
     
     
         30 . The pharmaceutical dosage unit tablet core of  claim 29  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. 
     
     
         31 . The pharmaceutical dosage unit tablet core of  claim 30  wherein the disintegrant comprises sodium starch glycolate, croscarmellose sodium, and combinations thereof. 
     
     
         32 . The pharmaceutical dosage unit tablet core of  claim 31  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. 
     
     
         33 . The pharmaceutical dosage unit tablet core of  claim 32  wherein the particulate pharmaceutical active drug has a particle size D [v, 0.5] of from about 25 μm to about 40 μm. 
     
     
         34 . The pharmaceutical dosage unit tablet core of  claim 33  wherein the particulate pharmaceutical active drug has a particle size D [v, 0.5] of from about 40 μm to about 65 μm. 
     
     
         35 . The pharmaceutical dosage unit tablet core of  claim 34  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. %. 
     
     
         36 . The pharmaceutical dosage unit tablet core of  claim 35  wherein the binder comprises povidone, copovidone, pregelatinized starch, hydroxypropyl methylcellulose, and combinations thereof. 
     
     
         37 . The pharmaceutical dosage unit table core of  claim 36  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%. 
 
     
     
         38 . The pharmaceutical dosage unit table core of  claim 37  wherein the coated pharmaceutical dosage unit table 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 table 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. 
 
     
     
         39 . The pharmaceutical dosage unit tablet core of  claim 38  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. 
 
     
     
         40 . The pharmaceutical dosage unit table core of  claim 39  wherein the microcrystalline cellulose is Avicel®PH101 or equivalent. 
     
     
         41 . The coated pharmaceutical dosage unit tablet of  claim 40  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. 
 
     
     
         42 . The coated pharmaceutical dosage unit tablet of  claim 41  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. 
 
     
     
         43 . 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 a particulate active drug component 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 pre-blend;   (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.   
     
     
         44 . The process of  claim 43  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. 
     
     
         45 . The process of  claim 44  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; 
 (3) the active drug component is cobimetinib hemifumarate polymorph Form A; and 
 (4) first lubricant component and the second lubricant component are each selected from magnesium stearate, sodium stearyl fumarate, and combinations thereof.