Claims for Patent: 9,562,016

Summary for Patent: 9,562,016

Title:	Preparation of and formulation comprising a MEK inhibitor
Abstract:	The present invention relates to processes for preparing 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide, processes for preparing crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide, and intermediates useful therefore. Also provided herein are pharmaceutical compositions comprising this crystallized compound.
Inventor(s):	Christoph Max Krell, Marian Misun, Daniel Andreas Niederer, Werner Heinz Pachinger, Marie-Christine Wolf, Daniel Zimmermann, Weidong Liu, Peter J. Stengel, Paul Nichols
Assignee:	Novartis Pharma AG, Array Biopharma Inc
Application Number:	US14/974,655
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,562,016
Patent Claims:	1. Crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide (Compound A): prepared according to a process comprising the steps of: a) dissolving Compound A in a solution comprising (i.) a solvent system comprising an ether and optionally an alcohol, and (ii.) water to provide a solution; b) adding a seed crystal suspension to the solution to provide a suspension mixture; c) cooling the suspension mixture to provide a cooled suspension mixture; d) adding water to the cooled suspension mixture to provide a treated mixture; and e) cooling the treated mixture, to provide the crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide. 2. The crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide of claim 1, further comprising the step of milling the crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide. 3. A pharmaceutical composition comprising crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide, at least one sugar, and at least one cellulose-derivative excipient. 4. The pharmaceutical composition of claim 3, wherein the at least one sugar is lactose monohydrate. 5. The pharmaceutical composition of claim 3, wherein the at least one cellulose-derivative excipient is microcrystalline cellulose, microfine cellulose, powdered cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, or hydroxypropylmethyl cellulose. 6. The pharmaceutical composition of claim 3, wherein at least one cellulose-derivative excipient is microcrystalline cellulose. 7. The pharmaceutical composition of claim 3, further comprising one or more of croscarmellose sodium, magnesium stearate, and silicon dioxide. 8. The pharmaceutical composition of claim 3, comprising 5-35 weight percent crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide. 9. The pharmaceutical composition of claim 3, comprising approximately 15 mg crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide. 10. The pharmaceutical composition of claim 3, comprising approximately 45 mg crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide. 11. A pharmaceutical composition comprising crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide and a pharmaceutically acceptable carrier or excipient. 12. The pharmaceutical composition according to claim 11, formulated for oral administration. 13. The pharmaceutical composition according to claim 12, formulated as a tablet. 14. The pharmaceutical composition according to claim 13, comprising approximately 15 mg crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide. 15. The pharmaceutical composition according to claim 14, comprising crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide, lactose monohydrate, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate. 16. Crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide: prepared according to a process comprising: a) adding Compound A to a solution comprising (i) a solvent system comprising an ether and an alcohol, and (ii) water to provide a suspension; a1) heating the suspension of step a) to an internal temperature between 53° C. and 56° C. to provide a solution; a2) cooling the solution of step a1); b) adding a seed crystal suspension to the cooled solution of step a2) to provide a suspension mixture; c) adding water to the suspension mixture to provide a treated mixture; and d) cooling the treated mixture to provide the crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide.