Pharmaceutical compositions comprising a fumaric acid ester and method for the preparation thereof
Inventors
Karavas, Evangelos • KOUTRIS, EFTHYMIOS • SAMARA, VASILIKI • Koutri, Ioanna • Kalaskani, Anastasia • ABATZIS, MORFIS • FOUSTERIS, MANOLIS
Assignees
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Publication Number
US-10894026-B2
Publication Date
2021-01-19
Expiration Date
Abstract
The present invention relates to a delayed release pharmaceutical composition comprising a fumaric acid ester such as Dimethyl fumarate in the form of gastro-resistant tablets filled into hard gelation capsule.
Core Innovation
The invention relates to a delayed release pharmaceutical composition for oral administration comprising Dimethyl fumarate in a tablet core of diameter 5-10 mm. The tablet core is coated with first and second pH-dependent gastro-resistant polymeric coating layers, with the weight gain of the first polymeric coating layer being 4-8% w/w and the weight gain of the second polymeric coating layer being 5-15% w/w.
The core innovation also defines pH-dependent gastro-resistant behavior through polymeric coating layers that dissolve, swell and/or degrade at pH≤4.5 and at pH=5.0. The dimethyl fumarate core is used to address prevention of dimethyl fumarate sublimation and hydrolysis.
A further aspect of the invention specifies formulation and quality relationships for the delayed release performance, including coating amount constraints, talc in the polymer coatings, and dimethyl fumarate particle size distribution. The documented content includes preferred polymer compositions for each coating layer and defines particle size criteria including D90<300 μm.
Claims Coverage
The independent claims define a delayed-release oral pharmaceutical composition in tablet form and a preparation process. Across the independent claims, there are three main inventive feature groups: the two-layer pH-dependent gastro-resistant coating system with specified weight gains on a 5-10 mm tablet core, in vitro release thresholds, and dimethyl fumarate particle size D90<300 μm, with a process that includes blending, direct tableting, spraying, and filling enteric coated tablets into hard gelatin capsules.
Two pH-dependent gastro-resistant polymeric coating layers with specified weight gains
A delayed release pharmaceutical composition for oral administration comprising Dimethyl fumarate in a tablet core of diameter 5-10 mm, wherein the core is coated with first and second pH-dependent gastro-resistant polymeric coating layers, with the weight gain of the first polymeric coating layer being 4-8% w/w and the weight gain of the second polymeric coating layer being 5-15% w/w.
In vitro release thresholds for delayed release performance
A delayed release pharmaceutical composition for oral administration comprising Dimethyl fumarate in a tablet core of diameter 5-10 mm, coated with first and second gastro-resistant coating layers with the weight gain of the first polymeric coating layer 4-8% w/w and the weight gain of the second polymeric coating layer 5-15% w/w, wherein the core exhibits an in vitro release rate of not more than 85 wt % Dimethyl fumarate released after 140 minutes and more than 90 wt % Dimethyl fumarate released after 150 minutes.
Preparation of coated tablets with blending, direct tableting, and enteric capsule filling
A process for the preparation of a delayed release pharmaceutical composition comprising Dimethyl fumarate in a tablet core of diameter 5-10 mm, wherein the core is coated with first and second gastro-resistant coating layers, comprising blending Dimethyl fumarate with croscarmellose sodium, microcrystalline cellulose and colloidal silicon dioxide; blending with magnesium stearate; direct tableting the powder mixture into round convex tablets; spraying a solution of methacrylic acid methyl methacrylate, talc, triethyl citrate and ethanol onto the tablet cores up to the desired weight gain; spraying a dispersion of methacrylic acid ethyl acrylate, talc, triethyl citrate and water onto the coated tablets up to the desired weight gain; and filling the appropriate amount of enteric coated tablets into hard gelatin capsules, wherein the weight gain of the first polymeric coating layer is 4-8% w/w and that of the second polymeric coating layer is 5-15% w/w.
Dimethyl fumarate particle size D90 below 300 microns
The delayed release pharmaceutical composition and/or process is defined such that the Dimethyl fumarate comprises particle size D90 value of less than 300 microns.
Overall, the independent claims cover a delayed-release oral composition in a 5-10 mm tablet core with a two-layer pH-dependent gastro-resistant polymeric coating system defined by specific coating weight gains. One independent claim adds explicit in vitro release performance limits at 140 minutes and 150 minutes, and the process claim further ties preparation of the coated tablets to the two coating weight gains, hard gelatin capsule filling, and dimethyl fumarate having a particle size D90 below 300 microns.
Stated Advantages
Prevention of dimethyl fumarate sublimation and hydrolysis.
Achievement of delayed release performance defined by in vitro release rates not more than 85 wt % after 140 minutes and more than 90 wt % after 150 minutes.
Documented Applications
Delayed release pharmaceutical composition for oral administration comprising Dimethyl fumarate in tablet core form.
Hard gelatin capsule presentation by filling enteric coated tablets.
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