Controlled release pharmaceutical compositions comprising a fumaric acid ester

Abstract

The present invention relates to controlled release pharmaceutical compositions comprising fumaric acid ester(s) as active substance(s). The compositions are suitable for use in the treatment of e.g. psoriasis or other hyperproliferative, inflammatory or autoimmune disorders and are designated to release the fumaric acid ester in a controlled manner so that local high concentrations of the active substance within the gastrointestinal tract upon oral administration can be avoided and, thereby, enabling a reduction in gastro-intestinal related side-effects.

1 . A pharmaceutical composition comprising as an active substance one or more fumaric acid esters selected from di-(C 1 -C 5 )alkylesters of fumaric acid and mono-(C 1 -C 5 )alkylester of fumaric acid, or a pharmaceutically acceptable salt thereof, which—upon oral administration and in comparison to that obtained after oral administration of Fumaderm® tablets in an equivalent dosage—gives a reduction in GI related side effects. 
     
     
         2 - 45 . (canceled) 
     
     
         46 . A delayed release pharmaceutical capsule composition comprising dimethylfumarate that meets the following dissolution criteria according to the United States Pharmacopoeia at 37° C. using a rotating basket at 100 rpm employing 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—is as follows: during the first 3 hours after start of the test at the most about 70% w/w of the dimethylfumarate is released. 
     
     
         47 . The composition of  claim 46 , wherein said dissolution medium is 1 liter. 
     
     
         48 . The composition of  claim 46 , wherein within the first 4 hours after start of the test at the most about 92% w/w of the dimethylfumarate is released. 
     
     
         49 . The composition of  claim 46 , wherein from about 10% to about 70% w/w of the dimethylfumarate is released during 3 hours. 
     
     
         50 . The composition of  claim 48 , wherein from about 10% to about 65% w/w of the dimethylfumarate contained is released during 3 hours. 
     
     
         51 . The composition of  claim 49 , wherein from about 10% to about 60% w/w of the total amount of the dimethylfumarate contained in the composition is released during 3 hours. 
     
     
         52 . The composition of  claim 50 , wherein from about 15% to about 50% w/w of the dimethylfumarate is released during 3 hours. 
     
     
         53 . The composition of  claim 46 , wherein from about 20% to about 30% w/w of the dimethylfumarate contained is released during 3 hours. 
     
     
         54 . The composition of  claim 46 , wherein the composition is a unit dosage form consisting essentially of about 240 mg of dimethylfumarate and one or more pharmaceutically acceptable excipients. 
     
     
         55 . The composition of  claim 54 , wherein following oral administration of the unit dosage form to a human subject monomethylfumarate appears in the plasma of the subject with a C max  between about 0.4 to about 2 mg/L. 
     
     
         56 . The composition of  claim 55 , wherein the plasma concentration of monomethylfumarate is 50% of the C max  or more for a period of at least 2 hours. 
     
     
         57 . The composition of  claim 55 , wherein the plasma concentration of monomethylfumarate is 50% of the C max  or more for a period of from about 2 to about 15 hours. 
     
     
         58 . The composition of  claim 55 , wherein the plasma concentration of monomethylfumarate is 50% of the C max  or more for a period of from about 2.5 to about 10 hours. 
     
     
         59 . The composition of  claim 55 , wherein the plasma concentration of monomethylfumarate is 50% of the C max  or more for a period of from about 3 to about 8 hours. 
     
     
         60 . The composition of  claim 54 , wherein the composition is a unit dosage form consisting essentially of 240 mg of dimethylfumarate and one or more pharmaceutically acceptable excipients. 
     
     
         61 . A method of treating a subject by administering a delayed release composition of  claim 46 , wherein the composition is a unit dosage form comprising about 240 mg of dimethylfumarate and the unit dosage form is administered in a twice daily therapeutic regimen. 
     
     
         62 . The method of  claim 61 , wherein prior to the twice daily therapeutic regimen lower daily doses of dimethylfumarate are administered. 
     
     
         63 . The method of  claim 61 , wherein the unit dosage form comprises 240 mg of dimethylfumarate and the unit dosage form is administered twice daily. 
     
     
         64 . A method of treating a subject in need thereof by administering to the subject a composition of  claim 46 , wherein a daily dosage of 240 to 1080 mg dimethylfumarate is given in one to three doses to said subject. 
     
     
         65 . The method of  claim 64 , wherein a daily dosage from 240 to 360 mg dimethylfumarate given in one to three doses. 
     
     
         66 . The method of  claim 64 , wherein a daily dosage from 360 to 480 mg dimethylfumarate given in one to three doses. 
     
     
         67 . The method of  claim 64 , wherein a daily dosage from 480 to 600 mg dimethylfumarate given in one to three doses. 
     
     
         68 . The method of  claim 64 , wherein a daily dosage from 600 to 720 mg dimethylfumarate given in one to three doses. 
     
     
         69 . The method of  claim 64 , wherein a daily dosage from 720 to 840 mg dimethylfumarate given in one to three doses. 
     
     
         70 . The method of  claim 64 , wherein the dimethylfumarate is administered once daily. 
     
     
         71 . The method of  claim 64 , wherein the dimethylfumarate is administered twice daily. 
     
     
         72 . A delayed release pharmaceutical capsule composition comprising dimethylfumarate that meets the following dissolution criteria according to the United States Pharmacopoeia at 37° C. using a rotating basket at 100 rpm employing 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.5 as dissolution medium—is as follows: during the first 3 hours after start of the test at the most about 70% w/w of the dimethylfumarate is released. 
     
     
         73 . The composition of  claim 72 , wherein said dissolution medium is 1 liter. 
     
     
         74 . The composition of  claim 72 , wherein within the first 4 hours after start of the test at the most about 92% w/w of the dimethylfumarate is released. 
     
     
         75 . The composition of  claim 72 , wherein from about 10% to about 70% w/w of the dimethylfumarate is released during 3 hours. 
     
     
         76 . The composition of  claim 74 , wherein from about 10% to about 65% w/w of the dimethylfumarate contained is released during 3 hours. 
     
     
         77 . The composition of  claim 75 , wherein from about 10% to about 60% w/w of the total amount of the dimethylfumarate contained in the composition is released during 3 hours. 
     
     
         78 . The composition of  claim 76 , wherein from about 15% to about 50% w/w of the dimethylfumarate is released during 3 hours. 
     
     
         79 . The composition of  claim 72 , wherein from about 20% to about 30% w/w of the dimethylfumarate contained is released during 3 hours. 
     
     
         80 . The composition of  claim 72 , wherein the composition is a unit dosage form consisting essentially of about 240 mg of dimethylfumarate and one or more pharmaceutically acceptable excipients. 
     
     
         81 . The composition of  claim 80 , wherein following oral administration of the unit dosage form to a human subject monomethylfumarate appears in the plasma of the subject with a C max  between about 0.4 to about 2 mg/L. 
     
     
         82 . The composition of  claim 81 , wherein the plasma concentration of monomethylfumarate is 50% of the C max  or more for a period of at least 2 hours. 
     
     
         83 . The composition of  claim 81 , wherein the plasma concentration of monomethylfumarate is 50% of the C max  or more for a period of from about 2 to about 15 hours. 
     
     
         84 . The composition of  claim 81 , wherein the plasma concentration of monomethylfumarate is 50% of the C max  or more for a period of from about 2.5 to about 10 hours. 
     
     
         85 . The composition of  claim 81 , wherein the plasma concentration of monomethylfumarate is 50% of the C max  or more for a period of from about 3 to about 8 hours. 
     
     
         86 . The composition of  claim 80 , wherein the composition is a unit dosage form consisting essentially of 240 mg of dimethylfumarate and one or more pharmaceutically acceptable excipients. 
     
     
         87 . A method of treating a subject by administering a delayed release composition of  claim 72 , wherein the composition is a unit dosage form comprising about 240 mg of dimethylfumarate and the unit dosage form is administered in a twice daily therapeutic regimen. 
     
     
         88 . The method of  claim 87 , wherein prior to the twice daily therapeutic regimen lower daily doses of dimethylfumarate are administered. 
     
     
         89 . The method of  claim 87 , wherein the unit dosage form comprises 240 mg of dimethylfumarate and the unit dosage form is administered twice daily. 
     
     
         90 . A method of treating a subject in need thereof by administering to the subject a composition of  claim 72 , wherein a daily dosage of 240 to 1080 mg dimethylfumarate is given in one to three doses to said subject. 
     
     
         91 . The method of  claim 90 , wherein a daily dosage from 240 to 360 mg dimethylfumarate given in one to three doses. 
     
     
         92 . The method of  claim 90 , wherein a daily dosage from 360 to 480 mg dimethylfumarate given in one to three doses. 
     
     
         93 . The method of  claim 90 , wherein a daily dosage from 480 to 600 mg dimethylfumarate given in one to three doses. 
     
     
         94 . The method of  claim 90 , wherein a daily dosage from 600 to 720 mg dimethylfumarate given in one to three doses. 
     
     
         95 . The method of  claim 90 , wherein a daily dosage from 720 to 840 mg dimethylfumarate given in one to three doses. 
     
     
         96 . The method of  claim 90 , wherein the dimethylfumarate is administered once daily. 
     
     
         97 . The method of  claim 90 , wherein the dimethylfumarate is administered twice daily.