Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof

Abstract

Improved oral dosage forms of methyl hydrogen fumarate and prodrugs thereof are disclosed. Methods of treating diseases such as multiple sclerosis and psoriasis using such dosage forms are also disclose.

1 - 49 . (canceled) 
     
     
         50 . An oral dosage form comprising:
 a core comprising a therapeutically effective amount of a (N,N-Diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate, wherein the core comprises an immediate release dosage form or a sustained release dosage form;   a barrier layer surrounding said core; and   an enteric coating surrounding said barrier layer and comprising an enteric polymer, wherein the barrier layer prevents direct contact between the core and the enteric coating.   
     
     
         51 . The oral dosage form of  claim 50 , wherein the core is a compressed tablet and the barrier layer and enteric coating are each a coating on the tablet. 
     
     
         52 . The oral dosage form of  claim 51 , wherein the tablet contains from 100 to 1200 mg of the compound and one or more tableting excipients. 
     
     
         53 . The oral dosage form of  claim 52 , wherein the tableting excipients are selected from binders, diluents, disintegrants, glidants and lubricants. 
     
     
         54 . The oral dosage form of  claim 50 , wherein the dosage form is a capsule containing a multiplicity of said enteric coated cores. 
     
     
         55 . The oral dosage form of  claim 50 , wherein the barrier layer material is a non-ionizable polymer substantially free of carboxylic acid moieties. 
     
     
         56 . The oral dosage form of  claim 50 , wherein the barrier layer material is selected from non-ionizable cellulosic polymers, non-ionizable vinyl polymers, and non-ionizable polyvinyl alcohol polymers. 
     
     
         57 . The oral dosage form of  claim 50 , wherein the barrier layer material is a sugar. 
     
     
         58 . The oral dosage form of  claim 50 , wherein the barrier layer comprises at least 5 wt % of the coated core for cores having a size of 2 mm or less. 
     
     
         59 . The oral dosage form of  claim 50 , wherein the barrier layer comprises at least 0.5 wt % of the coated core for cores having a size greater than 6 mm. 
     
     
         60 . The oral dosage form of  claim 50 , wherein the barrier layer has an average thickness of at least 5 μm. 
     
     
         61 . The oral dosage form of  claim 50 , wherein the barrier layer has an average thickness of at least 15 μm. 
     
     
         62 . The oral dosage form of  claim 50 , wherein the barrier layer material is either (i) a weakly acidic (proton-donating) material having a pKa of greater than 10, or (ii) a weakly basic (proton-accepting) material having a pKa of less than 0. 
     
     
         63 . The oral dosage form of  claim 50 , wherein the enteric polymer is selected from methacrylic acid polymers, cellulose acetate phthalate polymers, hydroxypropylmethyl cellulose acetate succinate polymers, hydroxypropylmethyl cellulose phthalate polymers and polyvinyl acetate phthalate polymers. 
     
     
         64 . The oral dosage form of  claim 50 , wherein the total degradants in the dosage form when stored at 40° C. and 75% relative humidity for 3 months is less than 0.4% w/w of the composition. 
     
     
         65 . The oral dosage form of  claim 50 , wherein the total degradants in the dosage form when stored at 40° C. and 75% relative humidity for 3 months is less than 0.3% w/w of the composition. 
     
     
         66 . A method of treating a disease in a patient, comprising orally administering to a patient in need thereof an oral dosage form comprising:
 a core comprising a therapeutically effective amount of a (N,N-Diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate, wherein the core comprises an immediate release dosage form or an sustained release dosage form;   a barrier layer surrounding said core; and   an enteric coating surrounding said barrier layer and comprising an enteric polymer, wherein the barrier layer prevents direct contact between the core and the enteric coating.   
     
     
         67 . The method of  claim 66 , wherein the oral administration is sufficient to obtain a therapeutic concentration of methyl hydrogen fumarate in blood plasma of the patient of at least 0.7 g/ml at a time within 24 hours after said oral administration. 
     
     
         68 . The method of  claim 66 , wherein the oral administration is sufficient to obtain an area under a concentration of methyl hydrogen fumarate in blood plasma versus time curve (AUC) of at least 12.0 μg·hr/ml over 24 hours after start of the oral administration. 
     
     
         69 . The method of  claim 66 , wherein the disease is selected from multiple sclerosis and psoriasis. 
     
     
         70 . The method of  claim 66 , wherein the disease is selected from Parkinson's disease, ALS, Huntington's disease, Alzheimer's disease, lupus, Crohn's disease, psoriatic arthritis and ankylosing spondilitis.