Dimethyl fumarate particles and pharmaceutical compositions thereof

Abstract

The present invention provides dimethyl fumarate (DMF) particles and methods of preparing the DMF particles. Also provided is DMF coated particles comprising DMF particles coated with an enteric coating. The invention also provides various dosage forms and methods of treating a disease or disorder (e.g., multiple sclerosis).

1 - 65 . (canceled) 
     
     
         66 . Dimethyl fumarate (DMF) coated particles comprising DMF starting particles coated with an enteric coating, wherein the DMF starting particles having a volume median diameter (D 50 ) between 50 μm and 100 wherein the span ((D 90 −D 10 )/D 50 ) of the starting DMF particles in the composition is in the range of 1.3 to 1.9; and
 wherein when subjected to an in vitro dissolution test employing USP Simulated Gastric Fluid (SGF) without pepsin as dissolution medium, the enteric coated DMF particles release no more than 20% of DMF over 4 to 12 hours. 
 
     
     
         67 . The DMF coated particles of  claim 66 , wherein no more than 15% of DMF is released over 4 to 12 hours. 
     
     
         68 . The DMF coated particles of  claim 66 , wherein the coated particles have a particle size less than 500 μm. 
     
     
         69 . The DMF coated particles of  claim 66 , wherein the coated particles have a median diameter (D 50 ) in the range of 100 μm to 500 μm or in the range of 100 μm to 250 μm. 
     
     
         70 . (canceled) 
     
     
         71 . The DMF coated particles of  claim 66 , wherein the span ((D 90 −D 10 )/D 50 ) for the coated particles is equal to or less than 1.0. 
     
     
         72 . The DMF coated particles of  claim 71 , wherein the span for the coated particles is less than 0.8. 
     
     
         73 . The DMF coated particles of  claim 71 , wherein the span for the coated particles is less than 0.6. 
     
     
         74 . The DMF coated particles of  claim 71 , wherein the span for the coated particles is in the range of 0.5 to 1.0 or 0.6-0.8. 
     
     
         75 . (canceled) 
     
     
         76 . The DMF coated particles of  claim 66 , wherein the weight of the enteric coating is greater than 30%, 50%, or 80% of the weight of the DMF starting particles. 
     
     
         77 . (canceled) 
     
     
         78 . (canceled) 
     
     
         79 . The DMF coated particles of  claim 76 , wherein the weight of the enteric coating is 30-200%, 50-150%, 80-120%, or 90-120% of the weight of the DMF starting particles. 
     
     
         80 - 82 . (canceled) 
     
     
         83 . The DMF coated particles of  claim 66 , wherein the enteric coating comprises an excipient selected from the group consisting of a copolymer of methacrylic acid and methyl methacrylate, a copolymer of methacrylic acid and ethyl acrylate, hypromellose phthalate (HPMCP), cellulose acetate phthalate. 
     
     
         84 . The DMF coated particles of  claim 83 , wherein the enteric coating comprises a copolymer of methacrylic acid and methyl methacrylate. 
     
     
         85 . The DMF coated particles of  claim 84 , wherein the ratio of the methacrylic acid to the methyl methacrylate in the copolymer is 0.8:1 to 1.2:1 or 1:1 (Eudragit L100). 
     
     
         86 . (canceled) 
     
     
         87 . The DMF coated particles of  claim 66 , wherein the enteric coating comprises a plasticizer. 
     
     
         88 . The DMF coated particles of  claim 87 , wherein the plasticizer is selected from the group consisting of acetyltributyl citrate, acetyltriethyl citrate, benzyl benzoate, castor oil, chlorobutanol, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, mannitol, polyethylene glycol, polyethylene glycol monomethyl ether, propylene glycol, pullulan, sorbitol, sorbitol sorbitan solution, triacetin, tributyl citrate, triethyl citrate and vitamin E. 
     
     
         89 . The DMF coated particles of  claim 88 , wherein the plasticizer is triethyl citrate. 
     
     
         90 . The DMF coated particles of  claim 89 , wherein the weight ratio of the triethyl citrate to the copolymer of methacrylic acid and methyl methacrylate is from 1:1 to 1:20. 
     
     
         91 . The DMF coated particles of  claim 90 , wherein weight ratio of the triethyl citrate to the copolymer of methacrylic acid and methyl methacrylate is 1:5. 
     
     
         92 - 212 . (canceled) 
     
     
         213 . A pharmaceutical composition comprising DMF coated particles of  claim 66 . 
     
     
         214 . A method of treating multiple sclerosis in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition of  claim 213 . 
     
     
         215 . (canceled)