(z)-2-cyano-3-hydroxy-but-2-enoic acid-(4'-trifluoromethylphenyl)-amide tablet formulations with improved stability

Abstract

The invention relates to solid pharmaceutical compositions comprising (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4′-trifluoromethylphenyl)-amide, as well as a process for the preparation of the same, methods of using such compositions to treat subjects suffering from autoimmune diseases in particular systemic lupus erythematosus or chronic graft-versus-host disease, multiple sclerosis or rheumatoid arthritis.

1 . A solid pharmaceutical composition comprising
 a) 1% to 30% weight:weight Teriflunomide, or a pharmaceutically acceptable basic addition salt thereof,   b) 5% to 20% weight:weight disintegrant,   c) 0% to 40% weight:weight binder,   d) 0.1% to 2% weight:weight lubricant and   e) the remaining percentage comprising diluents,   
       provided that said solid pharmaceutical composition does not contain colloidal silicon dioxide. 
     
     
         2 . The solid pharmaceutical composition according to  claim 1  wherein said disintegrant is selected from the group consisting of carboxymethylcellulose, low substituted hydroxyproyl cellulose, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, methylcellulose, polacrilin potassium, sodium alginate, sodium starch glycolate or a mixture of one or more of said disintegrants. 
     
     
         3 . The solid pharmaceutical composition according to  claim 2  wherein said disintegrant is selected from the group consisting of low substituted hydroxyproyl cellulose, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, sodium starch glycolate or a mixture of one or more of said disintegrants. 
     
     
         4 . The solid pharmaceutical composition according to  claim 1  wherein said binder is selected from the group consisting of acacia, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, dextrin, gelatin, guar gum, hydroxypropyl methylcellulose, maltodextrin, methylcellulose, sodium alginate, pregelatinized starch, potato starch, corn starch or cereal starch and zein or a mixture of one or more of said binders. 
     
     
         5 . The solid pharmaceutical composition according to  claim 4  wherein said binder is selected from the group consisting of hydroxypropylcellulose, hydroxypropyl methylcellulose, pregelatinized starch, starches such as potato starch, corn starch or cereal starch or a mixture of one or more of said binders. 
     
     
         6 . The solid pharmaceutical composition according to  claim 1  wherein said lubricant is selected from the group consisting of calcium stearate, glyceryl palmitostearate, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate and magnesium stearate or a mixture of one or more of said lubricants. 
     
     
         7 . The solid pharmaceutical composition according to  claim 6  wherein said lubricant is selected from the group consisting of sodium stearyl fumarate and magnesium stearate or a mixture of one or more of said lubricants. 
     
     
         8 . The solid pharmaceutical composition according to  claim 1  wherein said diluent is selected from the group consisting of cellulose, cellulose acetate, dextrates, dextrin, dextrose, fructose, 1-O-α-D-Glucopyranosyl-D-mannitol, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactitol, lactose, lactose mono-hydrate, maltitol, mannitol, maltodextrin, maltose, pregelatinized starch, sodium chloride, sorbitol, starches, sucrose, talc and xylitol or a mixture of one or more of said diluents. 
     
     
         9 . The solid pharmaceutical composition according to  claim 8  wherein said diluent is selected from the group consisting of lactose, lactose mono-hydrate, mannitol and starches or a mixture of one or more of said diluents. 
     
     
         10 . A solid pharmaceutical composition comprising
 A) 1% to 20% weight:weight Teriflunomide, or a pharmaceutically acceptable basic addition salt thereof,   B) % to 20% weight:weight disintegrant,   C) 0% to 30% weight:weight binder,   D) 0.1% to 2% weight:weight lubricant,   E) 1% to 20% weight:weight acidic reacting compound wherein said acidic reacting compound is selected from the group consisting of citric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicyclic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, sulfonic acids, methanesulfonic acid and 2-hydroxyethanesulfonic acid or a mixture of one or more of said acidic reacting compound and   F) the remaining percentage comprising diluents.   
     
     
         11 . The solid pharmaceutical composition according to  claim 10  wherein said disintegrant is selected from the group consisting of carboxymethylcellulose, low substituted hydroxyproyl cellulose, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, methylcellulose, polacrilin potassium, sodium alginate, sodium starch glycolate or a mixture of one or more of said disintegrants. 
     
     
         12 . The solid pharmaceutical composition according to  claim 10  wherein said binder is selected from the group consisting of acacia, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, dextrin, gelatin, guar gum, hydroxypropyl methylcellulose, maltodextrin, methylcellulose, pregelatinized starch, sodium alginate, starches such as potato starch, corn starch or cereal starch and zein or a mixture of one or more of said binders. 
     
     
         13 . The solid pharmaceutical composition according to  claim 10  wherein said lubricant is selected from the group consisting of calcium stearate, glyceryl palmitostearate, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate and magnesium stearate or a mixture of one or more of said lubricants. 
     
     
         14 . The solid pharmaceutical composition according to  claim 10  wherein said diluent is selected from the group consisting of cellulose, cellulose acetate, dextrates, dextrin, dextrose, fructose, 1-O-α-D-Glucopyranosyl-D-mannitol, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactitol, lactose, maltitol, mannitol, maltodextrin, maltose, pregelatinized starch, sodium chloride, sorbitol, starches, sucrose, talc and xylitol or a mixture of one or more of said diluents. 
     
     
         15 . The solid pharmaceutical composition according to  claim 10  comprising about 0.1% to 0.5% weight:weight colloidal silicon dioxide. 
     
     
         16 . The solid pharmaceutical composition according to  claim 10 , comprising a pH from 4.5 to 2.0, when water is adsorbed to the pharmaceutical composition or when water is added to the pharmaceutical composition. 
     
     
         17 . A method of treating sepsis, allergy, graft-versus-host-reactions, host-versus-graft-reactions, rheumatoid arthritis, systemic lupus erythematodes, multiple sclerosis, psoriasis, asthma, urticaria, rhinitis, uveitis, lung cancer, leukemia, ovarian cancer, sarcoma, Kaposi's sarcoma, meningioma, intestinal cancer, lymph node cancer, brain tumours, breast cancer, pancreatic cancer, prostate cancer or skin cancer in a patient in need thereof comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of  claim 1 . 
     
     
         18 . A method of treating sepsis, allergy, graft-versus-host-reactions, host-versus-graft-reactions, rheumatoid arthritis, systemic lupus erythematodes, multiple sclerosis, psoriasis, asthma, urticaria, rhinitis, uveitis, lung cancer, leukemia, ovarian cancer, sarcoma, Kaposi's sarcoma, meningioma, intestinal cancer, lymph node cancer, brain tumours, breast cancer, pancreatic cancer, prostate cancer or skin cancer in a patient in need thereof comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of  claim 10 .