Controlled release pharmaceutical compositions comprising a fumaric acid ester

Abstract

The invention features a method of treating a subject in need of treatment for multiple sclerosis. The method involves orally administering to the subject in need thereof a pharmaceutical composition in unit dosage form consisting essentially of (a) from about 120 mg to about 240 mg of dimethylfumarate formulated for delayed release, and (b) one or more pharmaceutically acceptable excipients, wherein following the orally administering of the unit dosage form monomethylfumarate appears in the plasma of the subject upon hydrolysis of dimethylfumarate and the Cmax of the monomethylfumarate in the plasma of the subject is between about 0.4 and about 2 mg/L, and wherein about 480 mg of dimethylfumarate per day is orally administered to the subject.

1 . A method of treating a subject in need of treatment for multiple sclerosis comprising orally administering to the subject in need thereof a pharmaceutical composition in unit dosage form consisting essentially of (a) from about 120 mg to about 240 mg of dimethylfumarate formulated for delayed release, and (b) one or more pharmaceutically acceptable excipients, wherein following the orally administering of the unit dosage form monomethylfumarate appears in the plasma of the subject upon hydrolysis of dimethylfumarate and the Cmaxof the monomethylfumarate in the plasma of the subject is between about 0.4 and about 2 mg/L, and wherein about 480 mg of dimethylfumarate per day is orally administered to the subject. 
     
     
         2 . The method of  claim 1 , wherein the unit dosage form is administered in separate administrations of 1, 2, or 3 doses per day. 
     
     
         3 . The method of  claim 1 , comprising orally administering twice daily to the subject in need thereof a pharmaceutical composition in unit dosage form consisting essentially of (a) about 240 mg of dimethylfumarate formulated for controlled release, and (b) one or more pharmaceutically acceptable excipients, wherein following the orally administering of the unit dosage form the Cmaxof the monomethylfumarate in the plasma of the subject is about 2 mg/L. 
     
     
         4 . The method of  claim 1 , wherein the pharmaceutical composition is administered with a meal. 
     
     
         5 . The method of  claim 1 , wherein the pharmaceutical composition is in the form of a tablet or a capsule. 
     
     
         6 . The method of  claim 5 , wherein the pharmaceutical composition comprises microtablets. 
     
     
         7 . The method of  claim 6 , wherein the microtablets have an enteric coating. 
     
     
         8 . The method of  claim 1 , wherein the pharmaceutical composition comprises pellets. 
     
     
         9 . The method of  claim 1 , wherein the pharmaceutically acceptable excipients comprise one or more of the following: micro crystalline cellulose, cross-linked sodium carboxymethylcellulose, talc, silica, colloidal silicon dioxide, magnesium stearate, or a surfactant having an HLB value above 8. 
     
     
         10 . The method of  claim 9 , wherein the composition comprises from about 1 to about 60% micro crystalline cellulose. 
     
     
         11 . The method of  claim 9 , wherein the composition comprises from about 0.2 to about 3% magnesium stearate. 
     
     
         12 . The method of  claim 9 , wherein the composition comprises from about 0.2 to about 4% silica. 
     
     
         13 . The method of  claim 9 , wherein the composition comprises cross-linked sodium carboxymethylcellulose. 
     
     
         14 . The method of  claim 9 , wherein the composition comprises a surfactant having an HLB value above 8. 
     
     
         15 . The method of  claim 1 , wherein the dimethylfumarate is in the form of micro crystals. 
     
     
         16 . The method of  claim 15 , wherein the pharmaceutical composition is a capsule containing micro crystals that have an enteric coating. 
     
     
         17 . The method of  claim 15 , wherein said unit dosage form comprises micro crystals between 315 and 710 microns. 
     
     
         18 . The method of  claim 1 , wherein said 480 mg dose is administered in two equal doses. 
     
     
         19 . The method of  claim 1 , wherein said dimethylfumarate is administered at least 30 minutes to about two hours after a meal.