Development of Amorphous Solid Dispersion Tablet of Sorafenib with Improved Oral Bioavailability

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Development of Amorphous Solid Dispersion Tablet of Sorafenib with Improved Oral Bioavailability

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Song, Sichen

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2021-05

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Abstract

An amorphous solid dispersion (ASD) immediate release tablet of sorafenib (SOR) was developed to improve oral bioavailability. The ASD was produced by coprecipitating both SOR and an enteric polymer, hydroxypropyl methylcellulose acetate succinate (HPMC-AS). The goal of maintaining supersaturation of ASDs was used to guide the selection of drug loading and HPMC-AS grade. The ASD of 40% drug loading with HPMC-AS M grade, which exhibits superior physical stability, enhanced dissolution extent and moderate hygroscopicity, was selected for further tablet development. Tablet formulation composition and dry granulation process were designed to achieve fast disintegration and adequate flow properties, and to mitigate over-granulation that would compromise in vivo performance. A material sparing and expedited approach was used to optimize compaction pressure to manufacture the ASD tablet with low friability and rapid disintegration. The resulting SOR ASD tablet showed enhanced in vitro dissolution rate and extent compared to the marketed product Nexavar®. A pharmacokinetic study in dogs suggested that the SOR ASD tablet exhibited a 1.5-fold improvement in the relative oral bioavailability compared to Nexavar®.

Keywords

Amorphous Solid Dispersion

Coprecipitation

Immediate release

Oral bioavailability

Sorafenib

Tablet

Description

University of Minnesota M.S. thesis. 2021. Major: Pharmaceutics. Advisor: Ronald Siegel. 1 computer file (PDF); 47 pages.

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Song, Sichen. (2021). Development of Amorphous Solid Dispersion Tablet of Sorafenib with Improved Oral Bioavailability. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/226357.

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