Fumarate esters
Described herein are pharmaceutical compositions comprising one or more fumarate esters, processes for making the same, and compositions and methods for treating multiple sclerosis subjects with the compositions. In particular, oral pharmaceutical compositions comprising fumarate esters in liquid vehicles are described. One embodiment is an oral delayed release pharmaceutical dosage form comprising a soft capsule encapsulating an immediate releasing liquid comprising one or more fumarate esters.
1. A pharmaceutical dosage form comprising a soft capsule and matrix fill comprising about 85 mg to about 100 mg of monomethyl fumarate suspended in an immediate releasing single-phase non-aqueous liquid vehicle, wherein contemporaneous administration to a subject of two dosage forms provides one or more of pharmacokinetic parameters: (a) a mean plasma monomethyl fumarate C max of about 1860 ng/mL; (b) a mean plasma monomethyl fumarate T max of about 3.82 hr; (c) a mean plasma monomethyl fumarate AUC 0→τ of about 3060 hr·ng/mL; (d) a mean plasma monomethyl fumarate AUC 0→∞ of about 3080 hr·ng/mL; (e) a mean plasma monomethyl fumarate AUC % ex of about 1.0%; (f) a mean plasma monomethyl fumarate K el of about 1.4 hr −1 ; or (g) a mean plasma monomethyl fumarate t 1/2 of about 0.5 hr.
2. The dosage form of claim 1 , wherein the immediate releasing single-phase non-aqueous liquid vehicle comprises a mixture of mono- and di-glycerides, polyvinylpyrrolidone, polyoxyl 40 hydrogenated castor oil, and lactic acid.
3. The dosage form of claim 1 , wherein the soft capsule is enterically coated.
4. The dosage form of claim 1 , wherein contemporaneous administration of two dosage forms to a subject provides pharmacokinetic parameters that are bioequivalent to a single 240 mg dose of dimethyl fumarate.
5. The dosage form of claim 1 , wherein the dosage form releases about 50% of the monomethyl fumarate after about 50 min to about 65 min in sodium phosphate, pH 6.8, in a USP Apparatus 2 at 37° C.
6. The dosage form of claim 1 , wherein the matrix fill comprises:
(a) about 30% to about 35% by mass monomethyl fumarate;
(b) about 20% to about 50% by mass mono- and di-glycerides;
(c) about 0.75% to about 5% by mass polyvinyl pyrrolidone;
(e) about 2% to about 12% by mass polyoxyl 40 hydrogenated castor oil; and
(e) about 1% to about 5% by mass lactic acid.
7. A pharmaceutical dosage form comprising a soft capsule and matrix fill comprising about 160 mg to about 200 mg of monomethyl fumarate suspended in an immediate releasing single-phase non-aqueous liquid vehicle, wherein administration of one dosage form to a subject provides one or more pharmacokinetic parameters: (a) a mean plasma monomethyl fumarate C max of about 2370 ng/mL; (b) a mean plasma monomethyl fumarate T max of about 3.8 hr; (c) a mean plasma monomethyl fumarate AUC 0→τ of about 3440 hr·ng/mL; (d) a mean plasma monomethyl fumarate AUC 0→∞ of about 3470 hr·ng/mL; (e) a mean plasma monomethyl fumarate AUC % ex of about 0.86%; (f) a mean plasma monomethyl fumarate K el of about 1.4 hr −1 ; or (g) a mean plasma monomethyl fumarate t 1/2 of about 0.5 hr.
8. The dosage form of claim 7 , wherein the immediate releasing single-phase non-aqueous liquid vehicle comprises a mixture of mono- and di-glycerides, polyvinylpyrrolidone, polyoxyl 40 hydrogenated castor oil, and lactic acid.
9. The dosage form of claim 7 , wherein the soft capsule is enterically coated.
10. A method for treating or reducing symptoms of multiple sclerosis in a subject comprising contemporaneously administering to a subject in need thereof two pharmaceutical dosage forms comprising an enterically coated soft capsule comprising a matrix fill comprising about 80 mg to about 100 mg of monomethyl fumarate suspended in an immediate releasing single-phase non-aqueous liquid vehicle that provides one or more pharmacokinetic parameters: (a) a mean plasma monomethyl fumarate C max of about 1860 ng/mL; (b) a mean plasma monomethyl fumarate T max of about 3.82 hr; (c) a mean plasma monomethyl fumarate AUC 0→τ of about 3060 hr·ng/mL; (d) a mean plasma monomethyl fumarate AUC 0→∞ of about 3080 hr·ng/mL; (e) a mean plasma monomethyl fumarate AUC % ex of about 1.0%; (f) a mean plasma monomethyl fumarate K el of about 1.4 hr −1 ; or (g) a mean plasma monomethyl fumarate t 1/2 of about 0.5 hr.
11. The method of claim 10 , wherein contemporaneous administration of two dosage forms to a subject provides pharmacokinetic parameters that are bioequivalent to a single 240 mg dose of dimethyl fumarate.
12. The method of claim 10 , wherein 170 mg to about 200 mg of monomethyl fumarate is administered at each dosage.