Fumarate ester dosage forms
Inventors
Vaughn, Jason M. • Hughey, Justin R. • Roberts, Tanesha • Dyakonov, Tatyana • Agnihotri, Sunil • Fatmi, Aqeel A.
Assignees
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Publication Number
US-10945985-B2
Publication Date
2021-03-16
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 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.
Core Innovation
The invention relates to oral pharmaceutical compositions in which a fumarate ester or a salt thereof is administered as a suspension in an immediate releasing single phase non-aqueous liquid vehicle. The non-aqueous liquid vehicle comprises mono- and di-glycerides, polyvinylpyrrolidone, polyoxyl 40 hydrogenated castor oil, and in some embodiments lactic acid, and the fumarate ester includes dimethyl fumarate, monomethyl fumarate, and monomethyl fumarate prodrugs.
The compositions are configured to reduce stomach-side release to mitigate flushing and gastrointestinal effects, to limit sublimation losses, and to improve stability. The document also describes stability at 25°C/60% RH for at least about 1–2 years.
In some embodiments, the immediate releasing non-aqueous liquid vehicle composition is encapsulated in an enterically coated soft capsule, optionally with additional subcoating/topcoating layers. The resulting dosage form is characterized by enteric acid resistance behavior and by delayed release of the fumarate ester or salt thereof, and administration is associated with activation of an Nrf2-dependent pathway.
Claims Coverage
Two independent claims are present. The claim coverage centers on an immediate releasing single phase non-aqueous liquid vehicle containing a suspended fumarate ester or salt, with specific excipient components, optional lactic acid, enteric encapsulation with delayed release, and a stated Nrf2-dependent pathway effect.
Immediate releasing single phase non-aqueous liquid vehicle with suspended fumarate ester or salt
An oral pharmaceutical composition comprising an immediate releasing single phase non-aqueous liquid vehicle comprising a suspension of a fumarate ester or a salt thereof.
Configured non-aqueous vehicle with mono- and di-glycerides, polyvinylpyrrolidone, polyoxyl 40 hydrogenated castor oil, and lactic acid
The composition comprises an immediate releasing single phase non-aqueous liquid vehicle comprising mono- and di-glycerides, polyvinylpyrrolidone, polyoxyl 40 hydrogenated castor oil, and lactic acid.
Specific fumarate ester or salt load in suspension
The composition comprises a suspension of about 95 mg of a fumarate ester or a salt thereof.
Enteric coated soft capsule providing delayed release
The composition is encapsulated in an enterically coated soft capsule, wherein the enterically coated soft capsule provides delayed release of the fumarate ester or salt thereof.
Activation of an Nrf2-dependent pathway
When administered to a subject, the composition activates an Nrf2-dependent pathway.
Overall, the claims cover an immediate releasing oral formulation using a single phase non-aqueous liquid vehicle that suspends a fumarate ester or salt, with defined non-aqueous vehicle components and lactic acid. The coverage also includes an enterically coated soft capsule that provides delayed release and a stated biological effect via Nrf2-dependent pathway activation.
Stated Advantages
Enhanced bioavailability relative to TECFIDERA®.
Reducing stomach-side release to mitigate flushing and gastrointestinal effects.
Limiting sublimation losses.
Improving stability, including stability at 25°C/60% RH for at least about 1–2 years.
Documented Applications
Treatment use-cases explicitly described include multiple sclerosis and psoriasis.
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