Development and Optimization of Sorafenib Nanosuspension By High-pressure Homogenization for Improved Oral Bioavailabilit

초록

Purpose: Sorafenib (SRF) is a multi-kinase inhibitor approved for the treatment of hepatocellular, advanced renal cell, and differentiated thyroid carcinomas. However, oral bioavailability of SRF is excessively low and variable due to its poor aqueous solubility. Herein, we developed and optimized sorafenib nanosuspensions (SRF-NS) by using different hydrophilic polymers and surfactants for improving its dissolution and oral bioavailability. Methods: SRF-NS were prepared by high-pressure homogenization technique, and were optimized by varying the type and ratio of stabilizers and surfactants, and pressure and number of homogenization cycles. SRF-NS with optimal physicochemical properties were further characterized for surface morphology, physical stability, crystallinity, in vitro dissolution, and in vivo pharmacokinetics. Results: SRF-NS with SRF/hydroxypropyl cellulose EXF/Tween 80/sodium lauryl sulfate at weight ratios of 10/5/2/1 showed the smallest particle size (~ 328 nm) and low polydispersity index (< 0.3). The optimized SRF-NS exhibited significantly improved dissolution in simulated gastric fluid and simulated intestinal fluid compared with bulk SRF powder. Furthermore, SRF-NS displayed enhanced oral bioavailability in rats with 1.54- and 1.63-times higher Cmax and AUClast, respectively, compared to SRF powder. Conclusion: NS with reduced particle size and increased solubility could be a promising formulation for enhancing oral bioavailability of SRF.

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