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-11590095-B2
Publication Date
2023-02-28
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 provides oral pharmaceutical compositions comprising one or more fumarate esters in an immediate releasing single phase non-aqueous liquid vehicle. The fumarate esters include dimethyl fumarate, monomethyl fumarate, monomethyl fumarate prodrugs, or a combination thereof. The compositions are described as formulation compositions and design parameters intended to achieve controlled, delayed, or extended release behavior.
The vehicle is described as a liquid matrix that suspends fumarate ester solids, and the compositions further include lipid or lipophilic liquid vehicles and solubility enhancers, including mono- and di-glycerides and oils such as soybean oil, together with polyvinylpyrrolidone (PVP) and polyoxyl 40 hydrogenated castor oil. Neutralizing agents such as lactic acid are described as part of the formulation approach.
Particle size distribution parameters, including d10 and d90 values, and micronized solids are described as formulation features linked to controlled release and stability of fumarate ester performance. Capsule and enteric capsule embodiments are described, including soft and hard capsules, enteric soft capsule shell compositions, and enteric coating approaches intended to resist dissolution in acidic media and release at intestinal pH.
Claims Coverage
The provided claims include three independent claims centered on oral pharmaceutical compositions comprising one or more fumarate esters in an immediate releasing single phase non-aqueous liquid vehicle.
Immediate releasing single phase non-aqueous liquid fumarate esters with NSAIDs
Administering an oral pharmaceutical composition comprising one or more fumarate esters in an immediate releasing single phase non-aqueous liquid vehicle, together with one or more non-steroidal anti-inflammatory drugs (NSAIDs), to treat or reduce symptoms of multiple sclerosis or psoriasis.
Immediate releasing single phase non-aqueous liquid fumarate esters with leukotriene receptor antagonists
Administering an oral pharmaceutical composition comprising one or more fumarate esters in an immediate releasing single phase non-aqueous liquid vehicle, together with one or more leukotriene receptor antagonists, to treat or reduce symptoms of multiple sclerosis or psoriasis.
Oral single phase non-aqueous liquid fumarate esters to activate the Nrf2 cellular signaling transcriptional pathway
Administering a therapeutically effective amount of an oral pharmaceutical composition comprising monomethyl fumarate, dimethyl fumarate, a pro-drug thereof, or a combination thereof in a single phase non-aqueous liquid vehicle to activate a nuclear factor erythroid-derived 2-like (Nrf2) cellular signaling transcriptional pathway in a subject.
Across the independent claims, the central inventive concept is the oral delivery of fumarate esters in an immediate releasing single phase non-aqueous liquid vehicle, used either with NSAIDs, with leukotriene receptor antagonists, or for activating the Nrf2 cellular signaling transcriptional pathway.
Stated Advantages
Reduce occurrence and severity of flushing side effects.
Resist dissolution in acidic media and release at intestinal pH, supporting delayed or extended release behavior.
Provide consistent release and prevent gastric release.
Suppress fumarate sublimation during manufacturing and storage.
Improve formulation performance linked to pharmacokinetic and dissolution parameters.
Enteric capsules remain intact in simulated gastric fluid (pH 1.2) for at least about 2 hours.
Release fumarate ester after shifting to about pH 6.8.
Reduction in annualized relapse rate without substantial flushing and without substantial gastrointestinal side effects.
Documented Applications
Treating or reducing symptoms of multiple sclerosis.
Treating or reducing symptoms of psoriasis.
Activating a nuclear factor erythroid-derived 2-like (Nrf2) cellular signaling transcriptional pathway in a subject.
Reducing flushing side effects associated with administration.
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