Controlled release pharmaceutical compositions comprising a fumaric acid ester

Abstract

The invention relates to a method of treating a subject in need of treatment for multiple sclerosis including orally administering to the subject in need thereof a delayed release pharmaceutical composition using an increasing dose regimen, wherein an initial daily amount of drug administered is increased later to a higher daily amount and the pharmaceutical composition consists essentially of (a) dimethylfumarate and (b) one or more pharmaceutically acceptable excipients.

1 . A method of treating a subject in need of treatment for multiple sclerosis comprising orally administering to the subject in need thereof a delayed release pharmaceutical composition using an increasing dose regimen, wherein an initial daily amount of drug administered is increased later to a higher daily amount and the pharmaceutical composition consists essentially of (a) dimethylfumarate and (b) one or more pharmaceutically acceptable excipients. 
     
     
         2 . The method of  claim 1 , wherein the delayed release pharmaceutical composition is contained in a capsule. 
     
     
         3 . The method of  claim 1 , wherein the delayed release pharmaceutical composition is in the form of a tablet. 
     
     
         4 . The method of  claim 1 , wherein the delayed release pharmaceutical composition is taken with a meal. 
     
     
         5 . The method of  claim 1 , wherein the increasing dose regimen comprises orally administering to the subject about 480 mg of dimethylfumarate a day within the regimen. 
     
     
         6 . The method of  claim 1 , wherein the increasing dose regimen comprises (i) orally administering to the subject in need thereof the pharmaceutical composition an initial dose per day for a period of time and (ii) following step (i), orally administering to the subject in need thereof the pharmaceutical composition at a higher daily dose, wherein the higher daily dose is about twice the initial daily dose. 
     
     
         7 . The method of  claim 6 , wherein the period of time is a week. 
     
     
         8 . The method of  claim 7 , wherein the initial daily dose is about 240 mg per day. 
     
     
         9 . The method of  claim 6 , wherein the pharmaceutical composition is taken with a meal. 
     
     
         10 . The method of  claim 6 , wherein the pharmaceutical composition is contained in a capsule. 
     
     
         11 . The method of  claim 6 , wherein the pharmaceutical composition is in the form of a tablet. 
     
     
         12 . The method of  claim 6 , wherein the pharmaceutical composition comprises microtablets. 
     
     
         13 . The method of  claim 12 , wherein the microtablets have an enteric coating. 
     
     
         14 . The method of  claim 6 , wherein the pharmaceutical composition comprises pellets. 
     
     
         15 . The method of  claim 6 , wherein the increasing dose regimen comprises orally administering to the subject about 480 mg of dimethylfumarate a day within the regimen. 
     
     
         16 . The method of  claim 1 , wherein the pharmaceutically acceptable excipients comprise one or more of any one 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. 
     
     
         17 . The method of  claim 16 , wherein the dosage form comprises from about 1 to about 60% micro crystalline cellulose. 
     
     
         18 . The method of  claim 16 , wherein the dosage form comprises from about 0.2 to about 3% magnesium stearate. 
     
     
         19 . The method of  claim 16 , wherein the dosage form comprises from about 0.2 to about 4% silica. 
     
     
         20 . The method of  claim 16 , wherein the dosage form comprises cross-linked sodium carboxymethylcellulose. 
     
     
         21 . The method of  claim 16 , wherein the dosage form comprises a surfactant having an HLB value above 8. 
     
     
         22 . The method of  claim 1 , wherein the dimethylfumarate is in the form of micro crystals. 
     
     
         23 . The method of  claim 22 , wherein the pharmaceutical composition containing the dimethylfumarate is a capsule comprising enteric coated micro crystals that have one coating layer. 
     
     
         24 . The method of  claim 22 , wherein the micro crystals are between 315 and 710 microns. 
     
     
         25 . The method of  claim 15 , wherein about 240 mg dimethylfumarate is administered in the morning and the remainder is administered later in the day. 
     
     
         26 . The method of  claim 25 , wherein said about 480 mg in a day is administered in two equal doses at different times of the day. 
     
     
         27 . The method of  claim 1 , wherein said dimethylfumarate is administered at least 30 minutes to about two hours after a meal. 
     
     
         28 . The method of  claim 15 , wherein said dimethylfumarate is administered at least 30 minutes to about two hours after a meal. 
     
     
         29 . The method of  claim 6 , wherein the pharmaceutical composition comprises beads. 
     
     
         30 . The method of  claim 29 , wherein the pharmaceutical composition comprises beads in a capsule.