Pharmaceutical Compositions of Fumaric Acid Esters

Abstract

Pharmaceutical compositions and dosage forms of (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate and/or methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate, containing low levels of certain impurities are disclosed.

1 . A method of treating a disease in a patient, comprising administering to the patient a dosage form comprising: (a) a therapeutically effective amount of (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate; and (b) one or more compounds of Formulae (I), (II), (III), (IV), (V), (VI), (XIII), or (XV): 
       
         
           
           
               
               
           
         
         N,N-diethyl-2-hydroxyacetamide, and salts of any of the foregoing, wherein: each of R 1  through R 4  is independently chosen from hydrogen, methyl and (N,N-diethyl carbamoyl)methyl; each R 5  and R 7  is independently chosen from hydrogen, methyl, and (N,N-diethyl carbamoyl)methyl; Y is chosen from O, S, NH and NR 8 ; R 6  is chosen from hydrogen, lower alkyl, substituted lower alkyl, aryl, and substituted aryl; R 8  is chosen from lower alkyl; each of R 9  and R 10  is independently chosen from hydrogen, methyl, and (N,N-diethylcarbamoyl)methyl; each of and R 12  is independently chosen from hydrogen, methyl, and (N,N-diethyl carbamoyl)methyl; each of R 13  and R 14  is independently chosen from hydrogen, methyl, and (N,N-diethyl carbamoyl)methyl; Q is —O—, —NH—, —N(R′ 7 )— or —C(R 18 ) 2 —; each of R 15  and R 16  is independently chosen from hydrogen, methyl, and (N,N-diethyl carbamoyl)methyl; R 17  is (N,N-diethylcarbamoyl)methyl or alkyl; each R 18  is independently hydrogen or alkyl; each of R 37  and R 38  is independently chosen from hydrogen, methyl, and (N,N-diethylcarbamoyl)methyl; R 41  is (N,N-diethylcarbamoyl)methyl; R 42  is chosen from hydrogen, ethyl, and (N,N-diethylcarbamoyl)methyl; and each of the one or more compounds of Formulae (I), (II), (III), (IV), (V), (VI), (XIII), and (XV), and N,N-diethyl-2-hydroxyacetamide is present in the dosage form in an amount of less than 0.2% by weight based on total weight of the (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. 
       
     
     
         2 . The method of  claim 1 , wherein any one of the one or more compounds of Formulae (I), (II), (III), (IV), (V), (VI), (XIII), and (XV), and N,N-diethyl-2-hydroxyacetamide is present in the dosage form in an amount of less than 0.1% by weight based on total weight of the (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. 
     
     
         3 . The method of  claim 1 , wherein the one or more compounds of Formulae (I), (II), (III), (IV), (V), (VI), (XIII), and (XV), and N,N-diethyl-2-hydroxyacetamide is present in a combined total amount of less than 3% by weight based on total weight of the (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. 
     
     
         4 . The method of  claim 1 , wherein the one or more compounds of Formulae (I), (II), (III), (IV), (V), (VI), (XIII), and (XV), and N,N-diethyl-2-hydroxy acetamide is present in a combined total amount of less than 2% by weight based on total weight of the (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. 
     
     
         5 . The method of  claim 1 , wherein the one or more compounds of Formulae (I), (II), (III), (IV), (V), (VI), (XIII), and (XV) is selected from: Formula (I) compounds 1,2-bis((N,N-diethylcarbamoyl)methoxycarbonyl)-3,4-bis(methoxycarbonyl)cyclobutane; 1,3-((N,N-diethylcarbamoyl)methoxycarbonyl)-2,4-bis(methoxycarbonyl)cyclobutane; 1-(N,N-diethylcarbamoyl)methoxycarbonyl-2-methoxycarbonylcyclobutane-3,4-dicarboxylic acid; 1,2-((N,N-diethylcarbamoyl)methoxycarbonyl)cyclobutane-2,3-dicarboxylic acid; 1,3-((N,N-diethylcarbamoyl)methoxycarbonyl)cyclobutane-2,4-dicarboxylic acid; 1,2-bis(methoxycarbonyl)cyclobutane-3,4-dicarboxylic acid; 1,3-bis(methoxycarbonyl)cyclobutane-2,4-dicarboylic acid; cyclobutane-1,2,3,4-tetracarboxylic acid; 1,2-((N,N-diethylcarbamoyl)methoxycarbonyl)-3-methoxycarbonylcyclobutane-4-carboxylic acid; 1,2-bis(methoxycarbonyl)cyclobutane-3,4-dicarboxylic acid; 1,2-bis(methoxycarbonyl)-3-((N,N-diethylcarbamoyl)methoxycarbonyl)cyclobutane-4-carboxylic acid; 1,2-((N,N-diethylcarbamoyl)methoxycarbonyl)-3-(methoxycarbonyl)cyclobutane-4-carboxylic acid; 1-((N,N-diethylcarbamoyl)methoxycarbonyl)-2,3-bis(methoxycarbonyl)cyclobutane-4-carboxylic acid; 1-((N,N-diethylcarbamoyl)methoxycarbonyl)cyclobutane-2,3,4-tricarboxylic acid; and 1-(methoxycarbonyl)cyclobutane-2,3,4-tricarboxylic acid; Formula (II) compounds (N,N-diethylcarbamoyl)methyl-methyl-hydroxysuccinate; methyl-hydroxysuccinic mono-acid; (N,N-diethylcarbamoyl)methyl-hydroxysuccinic mono-acid; hydroxysuccinic acid; (N,N-diethylcarbamoyl)methyl-methyl-mercaptosuccinate; methylmercaptosuccinic mono-acid; (N,N-diethylcarbamoyl)methyl-mercaptosuccinic mono-acid; mercaptosuccinic acid; (N,N-diethylcarbamoyl)methyl-methyl-aminosuccinate; methylaminosuccinic mono-acid; (N,N-diethylcarbamoyl)methyl-aminosuccinic mono-acid; and aminosuccinic acid; Formula (III) compounds cis-(N,N-diethylcarbamoyl)methyl-methyl oxirane dicarboxylate; cis-(methoxycarbonyl)oxirane carboxylic mono-acid; cis-(N,N-diethylcarbamoyl)methoxycarbonyl oxirane carboxylic mono-acid; cis-oxirane 2,3-dicarboxylic acid; trans-(N,N-diethylcarbamoyl)methyl-methyl oxirane dicarboxylate; trans-(methoxycarbonyl)oxirane carboxylic mono-acid; trans-(N,N-diethylcarbamoyl)methoxycarbonyl oxirane carboxylic mono-acid; and trans-oxirane 2,3-dicarboxylic acid; Formula (IV) compounds (N,N-diethylcarbamoyl)methyl-methyl-succinate; methyl succinic mono-acid; ((N,N-diethylcarbamoyl)methyl)succinic mono-acid; and succinic acid; Formula (V) compounds (N,N-diethylcarbamoyl)methyl-methyl-2,3-dihydroxysuccinate; methyl-2,3-dihydroxysuccinic mono-acid; (N,N-diethylcarbamoyl)methyl-2,3-dihydroxysuccinic mono-acid; and 2,3-dihydroxysuccinic acid (tartaric acid); Formula (VI) compounds wherein: Q is —O—, and each R 15  and R 16  is methyl; Q is —O—, and each R 15  and R 16  is H; Q is —O—, and each R 15  and R 16  is (N,N-diethylcarbamoyl)methyl; Q is —O—, R 15  is H, and R 16  is methyl; Q is —O—, R 15  is H, and R 16  is (N,N-diethylcarbamoyl)methyl; Q is —O—, R 15  is methyl, and R 16  is (N,N-diethylcarbamoyl)methyl; Q is —S—, and each of R 15  and R 16  is methyl; Q is —S—, and each of R 15  and R 16  is H; Q is —S—, and each of R 15  and R 16  is (N,N-diethylcarbamoyl)methyl; Q is —S—, R 15  is H, and R 16  is methyl; Q is —S—, R 15  is H, and R.sup.16 is (N,N-diethylcarbamoyl)methyl; Q is —S—, R 15  is methyl, and R 16  is (N,N-diethylcarbamoyl)methyl; Q is —NH—, and each of R 15  and R 16  is methyl; Q is —NH—, and each of R 15  and R 16  is H; Q is —NH—, and each of R 15  and R 16  is (N,N-diethylcarbamoyl)methyl; Q is —NH—, R 15  is H, and R 16  is methyl; Q is —NH—, R 15  is H, and R 16  is (N,N-diethylcarbamoyl)methyl; Q is —NH—, R 15  is methyl, and R 16  is (N,N-diethylcarbamoyl)methyl; Q is —NMe-, and each of R 15  and R 16  is methyl; Q is —NMe-, and each of R 15  and R 16  is H; Q is —NMe-, and each of R 15  and R 16  is (N,N-diethylcarbamoyl)methyl; Q is —NMe-, R 15  is H, and R 16  is methyl; Q is —NMe-, R 15  is H, and R 16  is (N,N-diethylcarbamoyl)methyl; Q is —NMe-, R 15  is methyl, and R 16  is (N,N-diethylcarbamoyl)methyl; Q is —CH 2 —, and each R 15  and R 16  is methyl; Q is —CH 2 —, and each R 15  and R 16  is H; Q is —CH 2 —, and each R 15  and R 16  is (N,N-diethylcarbamoyl)methyl; Q is —CH 2 —, R 15  is H, and R 16  is methyl; Q is —CH 2 —, R 15  is H, and R 16  is (N,N-diethylcarbamoyl)methyl; and Q is —CH 2 —, R 15  is methyl, and R 16  is (N,N-diethylcarbamoyl)methyl; Formula (XIII) compounds (N,N-diethylcarbamoyl)methyl methyl maleate, (N,N-diethylcarbamoyl)methyl maleic acid, bis((N,N-diethylcarbamoyl)methyl) maleate, dimethyl maleate, methyl maleate, and maleic acid; Formula (XV) compounds (2E)-3-(((N,N-diethylcarbamoyl)methyl)oxycarbonyl)prop-2-enoic acid; (N,N-diethylcarbamoyl)methyl ethyl (2E)but-2-ene-1,4-dioate; and bis(N,N-diethylcarbamoyl)methyl(2E)but-2-ene-1,4-dioate; isomers of any of the foregoing compounds and salts of any of the foregoing compounds. 
     
     
         6 .- 9 . (canceled) 
     
     
         10 . The method of  claim 1 , wherein the dosage form comprises an opaque layer that is free of the (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. 
     
     
         11 . The method of  claim 10 , wherein the opaque layer is a coating. 
     
     
         12 . The method of  claim 10 , wherein the opaque layer comprises a gelatin capsule comprising an opaque material. 
     
     
         13 . The method of  claim 10 , wherein the dosage form is enclosed in a package that limits exposure of the dosage form to ambient light. 
     
     
         14 . The method of  claim 13 , wherein the package is a bottle comprising an opaque polymer. 
     
     
         15 . The method of  claim 13 , wherein the package is a blister pack comprising metal foil, an opaque polymer or a combination thereof. 
     
     
         16 .- 27 . (canceled) 
     
     
         28 . The method of  claim 1 , wherein the disease is selected from multiple sclerosis and psoriasis. 
     
     
         29 . The method of  claim 1 , wherein the disease is selected from adrenal leukodystrophy, AGE-induced genome damage, Alexander Disease, Alper's Disease, Alzheimer's disease, amyotrophic lateral sclerosis, angina pectoris, arthritis, asthma, balo concentric sclerosis, Canavan disease, cardiac insufficiency including left ventricular insufficiency, central nervous system vasculitis, Charcott-Marie-Tooth Disease, childhood ataxia with central nervous system hypomyelination, chronic idiopathic peripheral neuropathy, chronic obstructive pulmonary disease, diabetic retinopathy, graft versus host disease, hepatitis C viral infection, herpes simplex viral infection, human immunodeficiency viral infection, Huntington's disease, irritable bowel disorder, ischemia, Krabbe Disease, lichen planus, macular degeneration, mitochondrial encephalomyopathy, monomelic amyotrophy, multiple sclerosis, myocardial infarction, neurodegeneration with brain iron accumulation, neuromyelitis optica, neurosarcoidosis, NF-KB mediated diseases, optic neuritis, paraneoplastic syndromes, Parkinson's disease, Pelizaeus-Merzbacher disease, primary lateral sclerosis, progressive supranuclear palsy, psoriasis, reperfusion injury, retinopathia pigmentosa, Schilder's Disease, subacute necrotizing myelopathy, Susac's syndrome, transplantation rejection, transverse myelitis, a tumor, ulcerative colitis, Zellweger's syndrome, granulomas including annulaire, pemphigus, bollus pemphigoid, Behcet's disease, contact dermatitis, acute dermatitis, chronic dermatitis, alopecia areata (totalis and universalis), sarcoidosis, cutaneous sarcoidosis, pyoderma gangrenosum, cutaneous lupus, Crohn's disease, and cutaneous Crohn's disease. 
     
     
         30 .- 58 . (canceled)