MONOMETHYLFUMARATE PRODRUG COMPOSITIONS

1 . A pharmaceutical composition for once or twice daily administration of a monomethyl fumarate (MMF) prodrug, said composition comprising 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate or a pharmaceutically acceptable salt thereof and a controlled release polymer, wherein the controlled release polymer is in the form of a coating applied to a core containing the 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate or a pharmaceutically acceptable salt thereof.

2 . A pharmaceutical composition according to claim 1 wherein the core is a tablet or pellet comprising 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate or a pharmaceutically acceptable salt thereof.

3 . A pharmaceutical composition according to claim 2 comprising a plurality of tablets or pellets.

4 . A pharmaceutical composition according to claim 2 wherein the controlled release coating is an enteric coating.

5 . A pharmaceutical composition according to claim 3 wherein the controlled release coating is an enteric coating.

6 . A pharmaceutical composition according to claim 5 wherein the controlled release polymer is applied to one or more tablets at a level of from about 2 to about 30% weight gain.

7 . A pharmaceutical composition according to claim 5 wherein the controlled release polymer is applied to one or more tablets at a level of from about 0.95 to about 14.75 mg/cm 2 .

8 . A pharmaceutical composition according to claim 5 wherein the controlled release coating has a thickness of from about 40 to about 60 microns.

9 . A pharmaceutical composition according to claim 4 wherein the 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate or a pharmaceutically acceptable salt thereof is released substantially immediately following removal of the enteric coating.

10 . A pharmaceutical composition according to claim 4 wherein substantially all of the 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate or a pharmaceutically acceptable salt thereof is released from the composition within about 2 hours in pH 6.8 as measured using USP apparatus I 40-mesh basket at a rotation speed of from 100 to 150 rpm.

11 . A pharmaceutical composition according to claim 10 wherein 100% of the 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate or a pharmaceutically acceptable salt thereof is released from the composition within about 2 hours in pH 6.8 as measured using USP apparatus I 40-mesh basket at a rotation speed of from 100 to 150 rpm.

12 . A pharmaceutical composition according to claim 3 wherein the 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate or a pharmaceutically acceptable salt thereof is dispersed throughout a carrier matrix to form a plurality of pellets.

13 . A pharmaceutical composition according to claim 12 wherein the pellets are produced by melt extrusion, and subsequently coated with the controlled release polymer.

14 . A pharmaceutical composition according to claim 13 wherein substantially all of the 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate or a pharmaceutically acceptable salt thereof is released from the composition within about 2 hours in pH 6.8 as measured using USP apparatus I 40-mesh basket at a rotation speed of from 100 to 150 rpm.

15 . A pharmaceutical composition according to claim 14 wherein 100% of the 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate or a pharmaceutically acceptable salt thereof is released from the composition within about 2 hours in pH 6.8 as measured using USP apparatus I 40-mesh basket at a rotation speed of from 100 to 150 rpm.

16 . A solid oral dosage form comprising a plurality of tablets or pellets according to claim 3 in a capsule.

17 . A solid oral dosage form comprising a plurality of tablets according to claim 8 in a capsule.

18 . A solid oral dosage form comprising a plurality of pellets according to claim 13 in a capsule.

19 . A solid oral dosage form according to claim 16 which upon administration to a human subject provides one or more of the following pharmacokinetic parameters:

i) a mean monomethyl fumarate C max of from about 1.8 μg/mL to about 2.5 μg/mL in the plasma of the subject;

ii) a mean monomethyl fumarate AUC last of from about 4.0 μg·hr/mL to about 5.0 μg·hr/mL in the plasma of the subject;

iii) a median monomethyl fumarate T max of from about 2.75 hours to about 3.5 hours in the plasma of the subject;

iv) a median monomethyl fumarate terminal elimination half-life (t 1/2 ) of from about 0.65 hours to about 0.8 hours in the plasma of the subject; and

v) a median monomethyl fumarate T lag for absorption of from about 1 hour to about 2 hours following administration.

20 . A pharmaceutical composition consisting essentially of a core comprising 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate or a pharmaceutically acceptable salt thereof, a diluent and a disintegrant; and a coating comprising a controlled release polymer.

21 . A pharmaceutical composition according to claim 20 wherein the coating further comprises a plasticizer and one or more anti-tack agents

22 . A pharmaceutical composition according to claim 21 wherein the diluent is selected from the group consisting of microcrystalline cellulose, dextrose, lactose, sucrose, mannitol, dicalcium phosphate and combinations thereof; wherein the disintegrant is selected from the group consisting of sodium carboxymethylcellulose, starch, crosslinked polyvinylpyrrolidone (crospovidone) and combinations thereof; wherein the controlled release polymer is an enteric polymer; wherein the plasticizer is selected from the group consisting of triacetin, tributyl citrate, triethyl citrate, dibutyl sebacate, diethyl phthalate and combinations thereof; and wherein the one or more anti-tack agents are selected from the group consisting of colloidal silicon dioxide, talc and combinations thereof.

23 . A method of treating multiple sclerosis, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 1 .

24 . A method of treating multiple sclerosis, comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is C 1 -C 6 alkyl;

m is 1 or 2;

t is 0, 1, 2, 3, 4, 5, or 6;

R 6 , R 7 , R 8 and R 9 are each, independently, H, C 1 -C 6 alkyl, or C(O)OR a ;

R a is H or C 1 -C 6 alkyl; and

each R 10 is, independently, H, halogen, C 1 -C 6 alkyl, C 3 -C 10 carbocycle, heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S;

or, alternatively, two R 10 s attached to the same carbon atom, together with the carbon atom to which they are attached, form a carbonyl;

or, alternatively, two R 10 s attached to adjacent atoms, together with the carbon atoms to which they are attached, form a fused C 3-6 ring; and

further wherein administering the pharmaceutical composition provides one or more of the following pharmacokinetic parameters:

i) a mean monomethyl fumarate C max of from about 1.8 μg/mL to about 2.5 μg/mL in the plasma of the subject;

ii) a mean monomethyl fumarate AUC last of from about 4.0 μg·hr/mL to about 5.0 μg·hr/mL in the plasma of the subject;

iii) a median monomethyl fumarate T max of from about 2.75 hours to about 3.5 hours in the plasma of the subject;

iv) a median monomethyl fumarate terminal elimination half-life (t 1/2 ) of from about 0.65 hours to about 0.8 hours in the plasma of the subject; and a median monomethyl fumarate T lag for absorption of from about 1 hour to about 2 hours.

25 . The method of claim 24 , wherein administering the pharmaceutical composition provides one or more of the following pharmacokinetic parameters:

i) a mean monomethyl fumarate C max of about 2.0 μg/mL in the plasma of the subject;

ii) a mean monomethyl fumarate AUC last of about 4.2 μg·hr/mL in the plasma of the subject;

iii) a median monomethyl fumarate T max of about 3 hours in the plasma of the subject;

iv) a median monomethyl fumarate terminal elimination half-life (t 1/2 ) of about 0.75 hours in the plasma of the subject; and

v) a median monomethyl fumarate T lag for absorption of about 1.5 hours.

26 . The method of claim 25 , wherein administering the pharmaceutical composition provides the following pharmacokinetic parameters:

i) a mean monomethyl fumarate C max of about 2.0 μg/mL in the plasma of the subject;

ii) a mean monomethyl fumarate AUC last of about 4.2 μg·hr/mL in the plasma of the subject; and

iii) a mean monomethyl fumarate T lag for absorption of about 1.5 hours.

27 . The method of claim 24 , wherein the compound is 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate.

28 . A method of reducing the probability of an occurrence of a drug-induced gastrointestinal disorder in a subject who is currently being treated with dimethyl fumarate or who is contemplating treatment with dimethyl fumarate, comprising administering to the subject an effective amount of 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate.

29 . The method of claim 28 , wherein the gastrointestinal disorder is selected from the group comprising diarrhea, eructation, flatulence, nausea, and retching.

30 . The method of claim 29 , wherein the gastrointestinal disorder is nausea.

31 . A method of reducing the probability of an occurrence of a drug-induced gastrointestinal disorder in a subject who is currently being treated with dimethyl fumarate or who is contemplating treatment with dimethyl fumarate, comprising administering to the subject a pharmaceutical composition of claim 1 .

32 . A method of treating a neurological disorder in a patient population, comprising administering to each patient a therapeutically effective amount of 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate;

wherein the inter-patient variability of a monomethyl fumarate pharmacokinetic parameter in the patient population is reduced relative to the patient population when treated with dimethyl fumarate.

33 . A method of treating a neurological disorder in a subject, comprising administering a therapeutically effective amount of 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate;

wherein one or more of the resultant monomethyl fumarate pharmacokinetic parameters exhibits reduced variability relative to a patient population treated with dimethyl fumarate.

34 . The method of claim 32 , wherein the monomethyl fumarate pharmacokinetic parameter is mean C max , and further wherein a mean monomethyl fumarate C max of about 2.0 μg/mL is achieved in the plasma of the subject with a % CV of less than 40%.

35 . The method of claim 32 , wherein the monomethyl fumarate pharmacokinetic parameter is mean AUC last , and further wherein a mean monomethyl fumarate AUC last of about 4.2 μg·hr/mL is achieved in the plasma of the subject with a % CV of less than 35%.

36 . The method of claim 32 , wherein the neurological disorder is multiple sclerosis or psoriasis.

37 . A method of treating a neurological disorder in a patient population, comprising administering to each patient a pharmaceutical composition of claim 1 ;

wherein the inter-patient variability of a monomethyl fumarate pharmacokinetic parameter in the patient population is reduced relative to the patient population when treated with dimethyl fumarate.

38 . A method of treating a neurological disorder in a subject, comprising administering a pharmaceutical composition of claim 1 ;

wherein one or more of the resultant monomethyl fumarate pharmacokinetic parameters exhibits reduced variability relative to a patient population treated with dimethyl fumarate.

39 . The method of claim 33 , wherein the monomethyl fumarate pharmacokinetic parameter is mean C max , and further wherein a mean monomethyl fumarate C max of about 2.0 μg/mL is achieved in the plasma of the subject with a % CV of less than 40%.

40 . The method of claim 33 , wherein the monomethyl fumarate pharmacokinetic parameter is mean AUC last , and further wherein a mean monomethyl fumarate AUC last of about 4.2 μg·hr/mL is achieved in the plasma of the subject with a % CV of less than 35%.

41 . The method of claim 33 , wherein the neurological disorder is multiple sclerosis or psoriasis.