Fumarate ester dosage forms with enhanced gastrointestinal tolerability
Inventors
Rousseau, Franck S. F. • Lategan, Thomas Wallace • Sprague, Tiffany Nicole • Vaughn, Jason Michael • Hughey, Justin Roy
Assignees
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Publication Number
US-11903918-B2
Publication Date
2024-02-20
Expiration Date
Abstract
Described herein are pharmaceutical compositions comprising one or more fumarate esters and methods for treating multiple sclerosis subjects with the compositions where the incidence of gastrointestinal side effects is reduced compared to treatments comprising dimethyl fumarate (e.g., TECFIDERA®). In particular, described herein are oral pharmaceutical compositions comprising monomethyl fumarate in a liquid vehicle that have reduced gastrointestinal side effects.
Core Innovation
The disclosed subject matter relates to fumarate-ester pharmaceutical dosage forms for treating or reducing symptoms of multiple sclerosis or psoriasis. The dosage forms comprise monomethyl fumarate about 90 mg to about 100 mg in an immediate releasing single-phase non-aqueous liquid vehicle and provide an effective dosage for the intended treatment.
The compositions use an immediate releasing single-phase non-aqueous liquid vehicle based on lactic acid and a defined vehicle composition including mono- and di-glycerides, polyvinylpyrrolidone, and polyoxyl 40 hydrogenated castor oil. The disclosure further includes embodiments wherein the pharmaceutical dosage forms are encapsulated in an enterically coated soft capsule having a film-forming polymer, an enteric acid-insoluble polymer, a plasticizer, an alkali-neutralizing agent, and additional shell components.
The claimed methods define gastrointestinal tolerability outcomes in terms of incidence comparisons versus dimethyl fumarate and an improved modified Overall Gastrointestinal Symptom Scale (MOGISS) score earlier in treatment. The incidence of an at least moderate severity gastrointestinal adverse event is at least 5% less frequent, and the incidence of vomiting and diarrhea is at least 5% less frequent, when using the specified monomethyl fumarate dosing in the immediate releasing single-phase non-aqueous liquid vehicle compared to the compared dimethyl fumarate doses.
Claims Coverage
The document provides one independent method claim directed to treating or reducing symptoms of multiple sclerosis or psoriasis using orally administered monomethyl fumarate in an immediate releasing single-phase non-aqueous liquid vehicle, with gastrointestinal adverse event and symptom incidence reductions versus specified dimethyl fumarate doses, and an earlier-in-treatment MOGISS outcome. The independent claim includes two alternative administration/dosing structures, corresponding to monomethyl fumarate given as a single dosage form or given as contemporaneously administered two dosage forms.
Immediate releasing single-phase non-aqueous liquid vehicle monomethyl fumarate for ms/psoriasis
Orally administering one or more pharmaceutical dosage forms comprising about 90 mg to about 100 mg of monomethyl fumarate in an immediate releasing single-phase non-aqueous liquid vehicle, providing an effective dosage for treating multiple sclerosis or psoriasis, with at least 5% less frequent incidence of an at least moderate severity gastrointestinal adverse event and at least 5% less frequent incidence of vomiting and diarrhea compared to a 120 mg dose of dimethyl fumarate.
Contemporaneous monomethyl fumarate dosing with reduced gi incidence versus higher-dose dimethyl fumarate
Contemporaneously administering two dosage forms comprising about 85 mg to about 100 mg of monomethyl fumarate or a single dosage form comprising about 170 mg to about 200 mg of monomethyl fumarate in an immediate releasing single-phase non-aqueous liquid vehicle, providing an effective dosage for treating multiple sclerosis or psoriasis, with at least 5% less frequent incidence of an at least moderate severity gastrointestinal adverse event and at least 5% less frequent incidence of vomiting and diarrhea compared to a 240 mg dose of dimethyl fumarate.
Earlier-in-treatment improved mogiss score
Wherein on average the subject experiences a modified Overall Gastrointestinal Symptom Scale (MOGISS) score of ≤4 for GI events earlier in treatment than would occur in treatment with dimethyl fumarate.
Overall, the independent claim(s) cover monomethyl fumarate administered orally in an immediate releasing single-phase non-aqueous liquid vehicle for treating multiple sclerosis or psoriasis, with gastrointestinal adverse event and symptom incidence reduced versus specified dimethyl fumarate doses and with an earlier-in-treatment MOGISS score outcome.
Stated Advantages
Reduced incidence of an at least moderate severity gastrointestinal adverse event versus specified dimethyl fumarate dosing.
Reduced incidence of vomiting versus specified dimethyl fumarate dosing.
Reduced incidence of diarrhea versus specified dimethyl fumarate dosing.
Improved modified Overall Gastrointestinal Symptom Scale (MOGISS) score of ≤4 for GI events earlier in treatment than would occur with dimethyl fumarate.
Documented Applications
Treating or reducing symptoms of multiple sclerosis in a subject by orally administering monomethyl fumarate pharmaceutical dosage forms in an immediate releasing single-phase non-aqueous liquid vehicle with reduced gastrointestinal side effects versus specified dimethyl fumarate dosing and improved earlier-in-treatment MOGISS outcome.
Treating or reducing symptoms of psoriasis in a subject by orally administering monomethyl fumarate pharmaceutical dosage forms in an immediate releasing single-phase non-aqueous liquid vehicle with reduced gastrointestinal side effects versus specified dimethyl fumarate dosing and improved earlier-in-treatment MOGISS outcome.
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