Fumarate ester pharmaceutical compositions
Inventors
Dyakonov, Tatyana • Agnihotri, Sunil • Fatmi, Aqeel A.
Assignees
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Publication Number
US-10918616-B2
Publication Date
2021-02-16
Expiration Date
Abstract
Described herein are pharmaceutical compositions comprising fumarate esters, methods for making the same, and methods for treating subjects in need thereof. In particular, oral pharmaceutical compositions comprising fumarate esters are described.
Core Innovation
The disclosure relates to oral pharmaceutical compositions comprising fumarate esters, such as dimethyl fumarate and monomethyl fumarate, formulated as an immediate releasing single phase non-aqueous liquid vehicle with a suspension of a fumarate ester or a salt thereof. The fumarate ester is defined by substituents R1 and R2, where R1 and R2 may be the same or different and independently represent hydrogen or methyl.
The compositions include solid micronized fumarate ester particles suspended in a lipid or lipophilic matrix and encapsulated in an enteric soft capsule having an enteric soft capsule shell. The shell includes a film-forming polymer and an enteric acid-insoluble polymer, and the formulation includes neutralizing agents, surfactants, polymeric and other excipients.
The disclosed compositions are intended to address gastric release and gastrointestinal side effects of fumarate ester therapies, including flushing. By providing enteric protection based on acid insolubility in acidic gastric conditions and promoting release and dissolution in intestinal conditions, the compositions aim to reduce gastric release, reduce flushing and gastrointestinal side effects, support stability during processing and storage by reducing fumarate sublimation, and provide pharmacokinetic characterization including plasma PK parameters such as Cmax, AUC, and Tmax across dose levels and dosing frequencies.
Claims Coverage
The claim coverage presents one independent feature set for treating or reducing symptoms of multiple sclerosis or psoriasis using an oral immediate releasing single phase non-aqueous liquid vehicle with a suspended fumarate ester or salt defined by R1 and R2 as hydrogen or methyl. The claim features are narrowed by weight-percent ranges, specified liquid vehicle excipients, dose ranges, delayed release via a capsule, and Nrf2-dependent pathway activation.
Oral immediate-releasing non-aqueous fumarate ester suspension for MS or psoriasis
A method of treating or reducing symptoms of multiple sclerosis or psoriasis by orally administering an oral pharmaceutical composition comprising an immediate releasing single phase non-aqueous liquid vehicle having a suspension of a fumarate ester or a salt thereof, where R1 and R2 are hydrogen or methyl.
Weight-percent composition constraints for fumarate ester and liquid vehicle
The composition comprises about 30% to about 40% fumarate ester or salt thereof by weight and about 55% to about 65% liquid vehicle by weight.
Specified non-aqueous liquid vehicle excipients
The liquid vehicle comprises mono- and di-glycerides, polyvinylpyrrolidone, and polyoxyl 40 hydrogenated castor oil.
Quantified fumarate ester or salt amount in the composition
The composition comprises about 90 mg to about 100 mg or about 100 mg to about 200 mg of the fumarate ester or salt thereof.
Delayed release from a capsule
The capsule provides delayed release of the fumarate ester or salt thereof.
Nrf2-dependent pathway activation after administration
Upon administration to a subject, the composition activates a nuclear factor erythroid-derived 2-like (Nrf2) dependent pathway.
The claims focus on oral administration of a fumarate ester or salt in a single phase non-aqueous liquid vehicle, with refinements to composition ranges, excipients, dose, delayed release, and an asserted Nrf2-dependent pathway outcome.
Stated Advantages
Reducing symptoms.
Reduction in relapse rate.
Tolerability-related events are described, including flushing, abdominal pain, diarrhea, and nausea.
Dissolution performance at pH 6.8.
Pharmacokinetic characterization including plasma PK parameters such as Cmax, AUC, and Tmax across dose levels and dosing frequencies.
Enteric protection against gastric release via acid insolubility at acidic pH.
Release and dissolution in intestinal conditions.
Reduction of flushing and gastrointestinal side effects.
Prevention or reduction of fumarate sublimation during processing and storage.
Stability at 25°C and 60% RH for up to 1–2 years.
Documented Applications
Treating or reducing symptoms of multiple sclerosis.
Treating or reducing symptoms of psoriasis.
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