Solid pharmaceutical compositions and processes for their production

Abstract

This invention provides novel solid pharmaceutical compositions and processes for the bulk production of said compositions. This invention also provides methods of using the pharmaceutical compositions in the treatment of cancer.

1 - 40 . (canceled) 
     
     
         41 . A method for treating cancer, comprising administering in a subject in need thereof a therapeutically effective amount of a pharmaceutical composition in the form of a tablet, comprising as an active ingredient 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid, or a pharmaceutically acceptable salt thereof; and 20% w/w to 40% w/w of sodium bicarbonate as buffer; wherein the active ingredient is in granular form, and the buffer is extragranular to the active ingredient. 
     
     
         42 . The method of  claim 41 , wherein the active ingredient is sodium 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate. 
     
     
         43 . The method of  claim 41 , wherein the pharmaceutical composition comprises about 1% w/w to about 60% w/w of sodium 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate, about 10% w/w to about 80% w/w of microcrystalline cellulose, about 0% w/w to about 5% w/w of sodium stearyl fumarate, about 0% w/w to about 5% w/w of sodium lauryl sulfate, about 0% w/w to about 20% w/w of polyvinylpyrrolidone, and about 0% w/w to about 20% w/w of croscarmellose sodium. 
     
     
         44 . The method of  claim 41 , wherein the pharmaceutical composition comprises about 13.6% w/w of sodium 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate, about 30.0% w/w of sodium bicarbonate, and about 40.4% w/w of microcrystalline cellulose, about 1.0% w/w of sodium stearyl fumarate, about 2.0% w/w of sodium lauryl sulfate, about 5.0% w/w of polyvinylpyrrolidone, and about 8.0% w/w of croscarmellose sodium. 
     
     
         45 . The pharmaceutical composition of  claim 41 , wherein the pharmaceutical composition comprises about 10% w/w to about 16% w/w of sodium 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate, about 28% w/w to about 40% w/w of sodium bicarbonate, about 35% w/w to about 45% w/w of microcrystalline cellulose, about 1% w/w to about 2% w/w of sodium stearyl fumarate, about 1% w/w to about 2% w/w of sodium lauryl sulfate, about 3% w/w to about 7% w/w of polyvinylpyrrolidone, and about 5% w/w to about 10% w/w of croscarmellose sodium. 
     
     
         46 . The method of  claim 44 , wherein the tablet is enterically coated. 
     
     
         47 . The method of  claim 41 , wherein the tablet further comprises a film coat and an enteric coat. 
     
     
         48 . The method of  claim 47 , wherein:
 the film coat is present in the amount from about 0.5% w/w to about 5.5% w/w; and   the enteric coat is present in the amount from about 5% w/w to about 13% w/w.   
     
     
         49 . The method of  claim 47 , wherein:
 the film coat is present in the amount from about 1.0% w/w to about 5.0% w/w; and   the enteric coat is present in the amount from about 7% w/w to about 11% w/w.   
     
     
         50 . The method of  claim 41 , wherein the pharmaceutical composition comprises:
 about 10% w/w to about 16% w/w of active ingredient;   about 28% w/w to about 40% w/w of sodium bicarbonate as buffer;   about 35% w/w to about 45% w/w of filler;   about 1% w/w to about 2% w/w of lubricant;   about 1% w/w to about 2% w/w of surfactant;   about 3% w/w to about 7% w/w of binder; and   about 5% w/w to about 10% w/w of disintegrant.   
     
     
         51 . The method of  claim 50 , wherein the filler is lactose, microcrystalline cellulose, mannitol, ethyl cellulose, sorbitol, starch, sucrose, calcium phosphate, powdered cellulose, silicified microcrystalline cellulose or isomalt. 
     
     
         52 . The method of  claim 51 , wherein the filler is microcrystalline cellulose. 
     
     
         53 . The method of  claim 50 , wherein the surfactant is sodium lauryl sulfate, sodium dodecyl sulfate, polysorbates, poloxamers or glyceryl monooleate. 
     
     
         54 . The method of  claim 53 , wherein the surfactant is sodium lauryl sulfate. 
     
     
         55 . The method of  claim 50 , wherein the binder is polyvinylpyrrolidone, ethyl cellulose, maltose sodium alginate, hydroxypropyl methylcellulose, stearic acid or pregelatinized starch. 
     
     
         56 . The method of  claim 55 , wherein the binder is polyvinylpyrrolidone. 
     
     
         57 . The method of  claim 50 , wherein the disintegrant is colloidal silicon dioxide, powdered cellulose, calcium silicate, crospovidone, calcium alginate, methyl cellulose, chitosan, carboxy methyl cellulose, croscarmellose sodium, carboxymethyl starch, sodium alginate, sodium starch glycolate or pregelatinized starch. 
     
     
         58 . The method of  claim 57 , wherein the disintegrant is croscarmellose sodium. 
     
     
         59 . The method of  claim 50 , wherein the lubricant is talc, magnesium stearate, sodium stearyl fumarate, glyceryl behenate, hydrogenated vegetable oil, zinc stearate, calcium stearate, sucrose stearate, polyvinyl alcohol or magnesium lauryl sulfate. 
     
     
         60 . The method of  claim 59 , wherein the lubricant is sodium stearyl fumarate. 
     
     
         61 . The method of  claim 41 , wherein the active ingredient is sodium 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate monohydrate. 
     
     
         62 . The method of  claim 61 , wherein the tablet further comprises a film coat and an enteric coat. 
     
     
         63 . The method of  claim 62 , wherein the film coat is present in the amount from 0.5% w/w to 5.5% w/w, and the enteric coat is present in the amount from 5% w/w to 13% w/w. 
     
     
         64 . The method of  claim 62 , wherein the film coat is present in the amount from 1.0% w/w to 5.0% w/w, and the enteric coat is present in the amount from 7% w/w to 11% w/w. 
     
     
         65 . The method of  claim 41 , wherein the cancer is colorectal cancer, ovarian cancer, breast cancer, gastric cancer, prostate cancer, or pancreatic cancer.