Fumarate esters
Inventors
Vaughn, Jason M. • Hughey, Justin R. • Roberts, Tanesha • Dyakonov, Tatyana • Agnihotri, Sunil • Fatmi, Aqeel A.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10098863-B2
Publication Date
2018-10-16
Expiration Date
Abstract
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.
Core Innovation
The disclosure relates to oral fumarate-ester formulations in which fumarate esters are provided in an immediate releasing single-phase non-aqueous liquid vehicle filled into soft capsules. The formulations include one or more fumarate esters, and the filled soft capsule may be enterically coated. Contemporaneous administration to a subject is characterized by defined pharmacokinetic parameters for plasma monomethyl fumarate.
The formulations cover fumarate ester species including dimethyl fumarate, monomethyl fumarate, and monomethyl fumarate prodrugs. Example vehicle compositions include single-phase non-aqueous liquid fill systems and excipients such as mono- and di-glycerides, polyvinylpyrrolidone, polyoxyl 40 hydrogenated castor oil, and lactic acid. The soft capsule may further include an enteric coating to provide delayed release behavior.
The disclosure addresses gastrointestinal side effects associated with oral fumarate therapies by reducing stomach drug exposure and improving bioavailability. Dissolution behavior is described using two-stage dissolution in pH 1.2 to pH 6.8 conditions and USP Apparatus 2 testing. Comparative pharmacokinetic parameters and bioequivalence are described in relation to TECFIDERA® 240 mg dimethyl fumarate.
Claims Coverage
The partial content includes five independent claims, collectively covering dosage forms and methods for treating or reducing multiple sclerosis symptoms via immediate releasing single-phase non-aqueous liquid fumarate-ester soft capsules, with pharmacokinetic parameter targets for plasma monomethyl fumarate and specified dosing constraints.
Immediate-releasing single-phase non-aqueous liquid soft capsule fumarate ester dosage form with two-dosage pharmacokinetic targets
A pharmaceutical dosage form comprising a soft capsule and about 85 mg to about 100 mg of one or more fumarate esters in an immediate releasing single-phase non-aqueous liquid vehicle, wherein contemporaneous administration to a subject of two dosage forms provides one or more pharmacokinetic parameters for plasma monomethyl fumarate including mean Cmax, mean Tmax, mean AUC0→τ, mean AUC0→∞, mean AUC%ex, mean Kel, and/or mean t1/2.
Immediate-releasing single-phase non-aqueous liquid soft capsule fumarate ester dosage form with single-dosage pharmacokinetic targets
A pharmaceutical dosage form comprising a soft capsule and about 160 mg to about 200 mg of one or more fumarate esters 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 for plasma monomethyl fumarate including mean Cmax, mean Tmax, mean AUC0→τ, mean AUC0→∞, mean AUC%ex, mean Kel, and/or mean t1/2.
Treating or reducing multiple sclerosis symptoms by contemporaneous two-dosage administration with plasma monomethyl fumarate pharmacokinetic targets
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 about 80 mg to about 100 mg of one or more fumarate esters in an immediate releasing single-phase non-aqueous liquid vehicle that provides one or more pharmacokinetic parameters for plasma monomethyl fumarate including mean Cmax, mean Tmax, mean AUC0→τ, mean AUC0→∞, mean AUC%ex, mean Kel, and/or mean t1/2.
Treating or reducing multiple sclerosis symptoms by administering a single dosage form with plasma monomethyl fumarate pharmacokinetic targets
A method for treating or reducing symptoms of multiple sclerosis in a subject comprising administering to a subject in need thereof one pharmaceutical dosage form comprising about 160 mg to about 200 mg of one or more fumarate ester in an immediate releasing single-phase non-aqueous liquid vehicle that provides one or more pharmacokinetic parameters for plasma monomethyl fumarate including mean Cmax, mean Tmax, mean AUC0→τ, mean AUC0→∞, mean AUC%ex, mean Kel, and/or mean t1/2.
Treating or reducing multiple sclerosis symptoms with dimethyl fumarate or monomethyl fumarate in an immediate releasing single-phase non-aqueous liquid vehicle
A method for treating or reducing symptoms of multiple sclerosis in a subject comprising administering to a subject in need thereof about 170 mg to about 200 mg of dimethyl fumarate or monomethyl fumarate in an immediate releasing single-phase non-aqueous liquid vehicle that provides one or more pharmacokinetic parameters for plasma monomethyl fumarate including mean Cmax, mean Tmax, mean AUC0→τ, mean AUC0→∞, mean AUC%ex, mean Kel, and/or mean t1/2.
Across the independent claims, the core coverage is immediate releasing single-phase non-aqueous liquid vehicle soft capsule formulations containing specified amounts of one or more fumarate esters, and treating or reducing multiple sclerosis symptoms by administering one or two such dosage forms, with the administration characterized by specified plasma monomethyl fumarate pharmacokinetic parameter targets.
Stated Advantages
Reduce gastrointestinal (GI) side effects by reducing stomach drug exposure.
Improve bioavailability.
Provide bioequivalence for monomethyl fumarate plasma pharmacokinetic parameters relative to TECFIDERA® 240 mg dimethyl fumarate in the comparative context described in the partial content.
Documented Applications
Oral administration of fumarate-ester soft capsule formulations for treating or reducing symptoms of multiple sclerosis, including methods using contemporaneous administration of two dosage forms and administration of a single dosage form.
Interested in licensing this patent?