Fumarate ester pharmaceutical compositions
Inventors
Dyakonov, Tatyana • Agnihotri, Sunil • Fatmi, Aqeel A.
Assignees
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Publication Number
US-10105336-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 pharmaceutical compositions comprising fumarate esters are described.
Core Innovation
The disclosed invention relates to an oral pharmaceutical composition for treating or reducing symptoms of multiple sclerosis or psoriasis in a subject. The composition includes an immediate releasing single phase non-aqueous liquid vehicle and a fumarate ester or a salt thereof defined by substituent groups R1 and R2, where R1 and R2 may be the same or different and each independently represents 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 disclosed approach further includes quantitative formulation constraints for the oral pharmaceutical composition comprising the fumarate ester or salt and the non-aqueous liquid vehicle. The composition can include about 60 mg to about 200 mg of a fumarate ester or its salt, and can further include about 30% to about 40% by weight of the fumarate ester or salt together with about 55% to about 65% by weight of the liquid vehicle.
The liquid vehicle can include mono- and di-glycerides, polyvinylpyrrolidone, and polyoxyl 40 hydrogenated castor oil. The composition can be encapsulated in a capsule as part of the oral dosage form, and treatment embodiments include activation of a nuclear factor erythroid-derived 2-like (Nrf2) dependent pathway after administration.
The disclosed invention also relates to controlled-release, enteric soft-capsule oral pharmaceutical compositions for administering fumarate esters to subjects in need thereof. The pharmaceutical composition incorporates the fumarate ester as solid micronized particles suspended in a lipid or lipophilic matrix with excipients, and includes a neutralizing agent for fumarate ester stabilization.
Claims Coverage
The independent claim is clm-00001. It covers treatment or reduction of symptoms of multiple sclerosis or psoriasis using an oral pharmaceutical composition with an immediate releasing single phase non-aqueous liquid vehicle and a fumarate ester or salt defined by R1 and R2 substituent possibilities. Dependent claims add five further features: dosage range, weight percentages, vehicle components, capsule encapsulation, and Nrf2-dependent pathway activation.
Treating or reducing symptoms of multiple sclerosis or psoriasis with an oral fumarate ester composition
A method of treating or reducing symptoms of multiple sclerosis or psoriasis in a subject comprising administering an oral pharmaceutical composition comprising an immediate releasing single phase non-aqueous liquid vehicle and a fumarate ester or a salt thereof defined by substituents R1 and R2 with specified options for the R1 and R2 groups and optional substitutions.
Defined fumarate ester/salt amount in the composition
A method wherein the composition comprises about 60 mg to about 200 mg of a fumarate ester or its salt.
Defined weight percentages of fumarate ester/salt and liquid vehicle
A method wherein the composition includes about 30% to about 40% by weight of the fumarate ester or salt thereof and about 55% to about 65% by weight of the liquid vehicle.
Specific immediate releasing single phase non-aqueous liquid vehicle components
A method wherein the liquid vehicle contains mono- and di-glycerides, polyvinylpyrrolidone, and polyoxyl 40 hydrogenated castor oil.
Capsule encapsulation of the composition
A method wherein the composition is encapsulated in a capsule.
Nrf2-dependent pathway activation upon administration
A method wherein, upon administration to a subject, the composition activates a nuclear factor erythroid-derived 2-like (Nrf2) dependent pathway.
Overall, claim coverage centers on administering an oral pharmaceutical composition with an immediate releasing single phase non-aqueous liquid vehicle and a fumarate ester or salt defined by R1 and R2 substituent possibilities, for treating or reducing symptoms of multiple sclerosis or psoriasis. Dependent features specify quantitative composition ranges, defined vehicle components, capsule encapsulation, and Nrf2-dependent pathway activation upon administration.
Stated Advantages
Reduces gastrointestinal side effects such as flushing and diarrhea, including nausea and abdominal pain.
Prevents or reduces fumarate sublimation during manufacturing and storage.
Improves stability of the compositions under defined storage conditions.
Enteric acid-insoluble shell resists dissolution at gastric conditions and releases at intestinal pH.
Documented Applications
Treatment or reduction of symptoms of multiple sclerosis in a subject using an oral pharmaceutical composition with a fumarate ester or salt.
Treatment or reduction of symptoms of psoriasis in a subject using an oral pharmaceutical composition with a fumarate ester or salt.
A mechanistic embodiment describing activation of an Nrf2-dependent pathway after administration.
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