Pharmaceutical compositions of fumaric acid esters
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 pharmaceutical dosage form for treating a disease in a patient, comprising:
(a) a therapeutically effective amount of (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, wherein the therapeutically effective amount is from 1 mg to 600 mg; 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 R 11 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—, —S—, —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 about 0.001% to about 0.2% by weight based on total weight of the (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.
2. The dosage form 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 about 0.001% to about 0.1% by weight based on total weight of the (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.
3. The dosage form 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 about 0.001% to about 3% by weight based on total weight of the (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.
4. The dosage form 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 about 0.001% to about 2% by weight based on total weight of the (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.
5. The dosage form 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 IC 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 e and R 16 is methyl;
Q is —S—, and each of e and R 16 is H;
Q is —S—, and each of e 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 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 e and R 16 is methyl;
Q is —NH—, and each of e and R 16 is H;
Q is —NH—, and each of e 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 e and R 16 is methyl;
Q is —NMe-, and each of e and R 16 is H;
Q is —NMe-, and each of e 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 e and R 16 is methyl;
Q is —CH 2 —, and each e and R 16 is H;
Q is —CH 2 —, and each e 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. The dosage form of claim 1 containing one or more compounds of Formula (I), wherein the one or more compounds of Formula (I) are 1R,2R,3S,4S-isomers.
7. The dosage form of claim 1 , including a pharmaceutically acceptable vehicle.
8. The dosage form of claim 7 , wherein the pharmaceutically acceptable vehicle is selected from a carrier, a diluent, an excipient, a wetting agent, an emulsifier, a buffer, a stabilizer, a thickener, a lubricant, a coloring agent, and combinations thereof.
9. The dosage form of claim 1 , in the form of a tablet or capsule.
10. The dosage form of claim 9 containing a compound of Formula (I), comprising an opaque layer that is free of the (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.
11. The dosage form of claim 1 containing a compound of Formula (II), wherein the dosage form is substantially free of materials that promote addition reactions of the (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.
12. The dosage form of claim 11 , wherein the dosage form is substantially free of alcohols, mercaptans, alkylamines and dialkylamines.
13. The dosage form of claim 11 , wherein the dosage form is substantially free of R 6 OH, R 6 SH, R 6 NH 2 , and R 6 N(H)R 8 ; wherein each of R 6 and R 8 is alkyl.
14. The dosage form of claim 1 containing a compound of Formula (IV), wherein the dosage form is substantially free of any compound capable of facilitating the reduction of the double bond of (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.
15. The dosage form of claim 14 , wherein the dosage form is substantially free of any compounds containing a hydrazino group.
16. The dosage form of claim 1 containing a compound of Formula (V), comprising an antioxidant, a free radical scavenger or a combination thereof.
17. The dosage form of claim 1 containing a compound of Formula (VI), wherein the dosage form is substantially free of materials that are capable of reacting with (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate to form Diels-Alder products.
18. The dosage form of claim 17 , wherein the dosage form is substantially free of compounds containing cyclopentadiene, furan, thiophene, and pyrrole moieties.
19. The dosage form of claim 1 containing a compound of Formula (III), wherein the dosage form is substantially free of PVP, PEG, and polysorbate surfactant.
20. The dosage form of claim 1 containing a compound of Formula (III), comprising an antioxidant, a free radical scavenger or a combination thereof.
21. The dosage form of claim 1 , wherein the one or more compounds of Formula (III) comprises (N,N-diethylcarbamoyl)methyl methyl oxirane-2,3-dicarboxylate.
22. A method of treating a disease in a patient, comprising administering to the patient a dosage form of claim 1 .
23. The method of claim 22 , wherein the disease is selected from multiple sclerosis and psoriasis.
24. The dosage form of claim 1 , wherein the therapeutically effective amount is 300 mg to 600 mg.
25. The dosage form of claim 1 , wherein the therapeutically effective amount is 400 mg to 500 mg.