Fumarate ester dosage forms
Described herein are pharmaceutical compositions comprising fumarate esters, methods for making the same, and methods for treating subjects in need thereof. In particular, oral controlled release pharmaceutical compositions comprising fumarate esters suspended in liquid matrices are described. One embodiment described herein is a pharmaceutical composition comprising fumarate esters suspended in a lipid or lipophilic liquid with enhanced bioavailability.
1. A method of treating or reducing symptoms of multiple sclerosis in a subject, the method comprising contacting peripheral blood mononuclear cells or monocytes of the subject with monomethyl fumarate by administering an oral immediate release pharmaceutical composition comprising one or more fumarate esters suspended in a single-phase non-aqueous liquid.
2. The method of claim 1 , wherein the fumarate ester comprises dimethyl fumarate, monomethyl fumarate, pro-drugs thereof, or combinations thereof.
3. The method of claim 1 , wherein the single-phase non-aqueous liquid comprises a lipid liquid or lipophilic liquid.
4. The method of claim 1 , wherein the composition comprises about 80 mg to about 115 mg or about 160 mg to about 230 mg of the fumarate ester.
5. The method of claim 1 , wherein the composition comprises about 95 mg to about 100 mg of the fumarate ester.
6. The method of claim 1 , wherein the composition comprises about 180 mg to about 220 mg of the fumarate ester.
7. The method of claim 1 , wherein the composition comprises about 190 mg to about 200 mg of the fumarate ester.
8. The method of claim 1 , wherein the single-phase non-aqueous liquid comprises a lipid, one or more solubility enhancing agents, and a neutralizing agent.
9. The method of claim 8 , wherein the one or more solubility enhancing agents comprise polyvinylpyrrolidone, polyoxyl 40 hydrogenated castor oil, or a combination thereof.
10. The method of claim 1 , wherein the single-phase non-aqueous liquid comprises mono- and di-glycerides, polyvinylpyrrolidone, polyoxyl 40 hydrogenated castor oil, and lactic acid.
11. The method of claim 1 , wherein the fumarate ester to single-phase non-aqueous liquid weight ratio is about 1:1 to about 1:8.
12. The method of claim 1 , wherein the composition comprises:
about 30% to about 40% by weight of the one or more fumarate esters;
about 55% to about 65% by weight of the single-phase non-aqueous liquid; and
about 5% by weight of lactic acid.
13. The method of claim 1 , wherein the composition comprises:
about 12% to about 40% by weight of the one or more fumarate esters;
about 50% to about 80% by weight of mono- and di-glycerides;
about 5% to about 15% by weight of polyoxyl 40 hydrogenated castor oil;
about 1% to about 5% by weight of polyvinylpyrrolidone; and
about 1% to about 5% by weight lactic acid.
14. The method of claim 1 , wherein the administration comprises:
(a) administering two dosage froms simultaneously comprising about 80 mg to about 115 mg of fumarate ester twice per day (BID);
(b) administering one dosage from comprising about 80 mg to about 115 mg of fumarate ester four times per day (QID); or
(c) administering one dosage from comprising about 160 to about 230 mg of fumarate ester twice per day (BID).
15. The method of claim 1 , wherein the administration comprises a total daily dosage of about 160 mg to about 440 mg of the fumarate ester.
16. The method of claim 1 , wherein the administration comprises a total daily dosage of about 160 mg, about 180 mg, about 190 mg, about 200 mg, about 220 mg, about 230 mg, about 360 mg, about 380 mg, about 400 mg, or about 440 mg of the fumarate ester.
17. The method of claim 1 , wherein the subject achieves a reduction of annualized multiple sclerosis relapse rate relative to baseline and experiences one or more of flushing, abdominal pain, diarrhea, or nausea at a rate of less than about 20%.
18. A method of treating multiple sclerosis or psoriasis comprising administering to a subject one or more dosage forms comprising an oral immediate release pharmaceutical composition comprising one or more fumarate esters suspended in a single-phase non-aqueous liquid that cumulatively provide a daily dosage of a fumarate ester from about 160 mg to about 230 mg fumarate ester or from about 360 mg to about 440 mg fumarate ester.
19. The method of claim 18 , wherein the administration is twice per day.
20. The method of claim 18 , wherein two dosage froms comprising between about 80 mg to about 115 mg of fumarate ester are simultaneously administered twice per day.
21. The method of claim 18 , wherein the dosage form exhibits an in vitro dissolution rate comprising about 50% dissolution after about 30 minutes to about 50 minutes at pH 6.8.
22. A method for activating a nuclear factor erythroid-derived 2-like (Nrf2) pathway comprising administering an oral immediate release pharmaceutical composition comprising a single-phase non-aqueous liquid comprising dimethyl fumarate, monomethyl fumarate, a pro-drug thereof, or a combination thereof.