(T1530-12-68) Preparation and Evaluation of Sorafenib Nanosuspensions Using High Pressure Homogenization Technique for Improved Oral Bioavailability

Purpose: The objective of this study was to prepare sorafenib nanosuspensions (SRF-NSs) to enhance dissolution and oral bioavailability with hydrophilic polymers as stabilizers and sodium lauryl sulfate (SLS) as a surfactant.

Methods: SRF-NSs were prepared by combination of ultrasonication and high pressure homogenization technique, followed by lyophilization for storage stability and further processes. To optimize SRF-NSs, the main parameters such as ratios of stabilizers and SLS (w/w), ultrasonication time, homogenization pressure and cycles of high pressure homogenization were investigated. The physicochemical properties of SRF-NSs were evaluated for particle size, polydispersity index and zeta potential. The optimized SRF-NSs were characterized for surface morphology, crystallinity, dissolution in pH 1.2 and pH 6.8, and pharmacokinetics in rats.

Results: Hydroxypropyl cellulose (HPC), a water-soluble cellulose ether, was the most efficient hydrophilic polymer in the preparation of nanosuspensions. In particular, SRF-NSs prepared with SRF, Klucel™ HPC EXF and SLS (10:5:1, weight ratio) showed the smallest particle size near 300 nm and low polydispersity index below 0.3 indicating a narrow particle size distribution. The optimized SRF-NSs provided an about 13 fold enhanced dissolution rate in simulated intestinal fluid and 2 fold enhanced dissolution rate in simulated gastric fluid within 2 h,compared with SRF powder. The improved dissolution profiles of SRF were attributed to particle size reduction and the presence of the amorphous fraction. In pharmacokinetic study, the optimized SRF-NSs provided 1.86 fold AUC value in rats compared with SRF powder.

Conclusion: Thus, SRF-NSs could be a promising strategy to enhance the oral bioavailability of SRF.

In vitro dissolution profile of SRF powder, and SRF-NS formulations prepared in simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 6.8). Each value represents the mean ± S.D. (n=3)


Plasma concentration-time profiles of SRF after oral administration of SRF powder, and SRF-NS-TS in rats. Each value represents the mean ± S.D. (n=3)


SEM images of sorafenib tosylate (A), SRF-NS-TS (B)