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-10105335-B2
Publication Date
2018-10-23
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 disclosed subject matter relates to oral pharmaceutical compositions for fumarate ester delivery, formulated as an immediate releasing single phase non-aqueous liquid vehicle dosage form. The compositions comprise a fumarate ester or a salt thereof, including dimethyl fumarate (DMF), monomethyl fumarate (MMF; methyl hydrogen fumarate), or monomethyl fumarate prodrugs, with a fumarate ester defined by R1 and R2 substituent rules in which each may independently represent hydrogen or a linear, branched, or cyclic saturated or unsaturated C1-20 alkyl radical optionally substituted with halogen, hydroxy, C1-4 alkoxy, nitro, or cyano.
The compositions further include lipid or lipophilic non-aqueous liquid matrix components, suspended micronized solid particles, neutralizing agents, particle-size distribution parameters, and fumarate ester-to-matrix fill ratio. The document also describes capsule technologies, including soft capsule shell materials, enteric soft capsule shells, and enteric coatings employing acid-insoluble polymers such as methacrylic acid copolymers with alkali-neutralizing agents and defined pH targets.
The compositions are associated with treatment, prophylaxis, or amelioration of general autoimmune or neurodegenerative disorders, including multiple sclerosis and psoriasis. The document further discusses an Nrf2-dependent ARE antioxidant response pathway, Keap1/Nrf2 sequestration and translocation, and pharmacokinetic, bioperformance, dissolution, and stability outcomes in the context of oral administration.
Claims Coverage
The consolidated claim coverage centers on an oral pharmaceutical composition combining an immediate releasing single phase non-aqueous liquid vehicle with a fumarate ester or salt defined by a structural formula for R1 and R2. In total, the inventive coverage presents six inventive features, with dependent claim content further specifying dosage and composition ranges, liquid vehicle excipients, capsule encapsulation, and activation of an Nrf2-dependent pathway.
Immediate releasing single phase non-aqueous liquid vehicle with fumarate ester structure
An oral pharmaceutical composition comprising an immediate releasing single phase non-aqueous liquid vehicle and a fumarate ester or a salt thereof having a formula in which R1 and R2 may be the same or different and independently represent hydrogen or a linear, branched, or cyclic saturated or unsaturated C1-20 alkyl radical optionally substituted with halogen, hydroxy, C1-4 alkoxy, nitro, or cyano.
Specific fumarate ester or salt dosage range
The composition contains about 80 mg to about 230 mg of a fumarate ester or its salt.
Specific by-weight composition ranges for fumarate ester and liquid vehicle
The composition includes about 30% to about 40% by weight of a fumarate ester or a salt thereof and about 55% to about 65% by weight of a liquid vehicle.
Liquid vehicle composition with named excipient components
The liquid vehicle comprises mono- and di-glycerides, polyvinylpyrrolidone, and polyoxyl 40 hydrogenated castor oil.
Capsule-encapsulated oral composition
The oral composition is encapsulated in a capsule.
Nrf2-dependent pathway activation upon administration
When administered to a subject, the composition activates an Nrf2-dependent pathway.
The claim coverage combines an oral immediate releasing single phase non-aqueous liquid vehicle with a structurally defined fumarate ester or salt, while dependent features further define dosage, weight percentages, liquid vehicle excipients, capsule form, and an Nrf2-dependent pathway outcome.
Stated Advantages
Reduced gastric release and reduced flushing and gastrointestinal side effects.
Improved bioavailability.
Reduced or eliminated fumarate sublimation during manufacture/storage.
Enhanced stability at 25°C/60% RH.
Enteric films resist dissolution in acidic media for up to 2 hours and release upon a pH shift toward about 6.8.
Embedded enteric polymers reduce DMF release in acid.
Documented Applications
Treating, prophylaxis, or amelioration of general autoimmune or neurodegenerative disorders including multiple sclerosis and psoriasis.
Therapeutic use for multiple sclerosis.
Therapeutic use for psoriasis.
Therapeutic use for autoimmune and neurodegenerative indications.
Oral administration associated with activation or modulation of an Nrf2-dependent ARE antioxidant response pathway.
Enteric soft capsule shells and enteric coating approaches are used to provide pH-dependent release behavior, including for dimethyl fumarate (DMF) context described in dissolution and release observations.
Oral pharmaceutical compositions are formulated as soft capsule fill or encapsulated capsule compositions for fumarate ester delivery with dissolution, stability, and Nrf2-dependent pathway-related outcomes described.
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