Preparation of sorafenib nanosuspension based on high pressure homogenization technique for improved oral bioavailability

Abstract

ABSTRACT

Preparation of sorafenib nanosuspension based on high pressure homogenization technique for improved oral bioavailability

Kyoung-Won Kim Department of Pharmacy The Graduate School Hanyang University

Sorafenib (SRF) is a multiple kinase inhibitor approved for several cancers including hepatocellular carcinoma and advanced renal cell cancer. However, the oral bioavailability of SRF is excessively low (approximately 8.43%) due to its aqueous solubility. The objective of this study was to prepare sorafenib nanosuspensions (SRF-NSs) to improve dissolution and oral bioavailability with hydrophilic polymers as stabilizers and sodium lauryl sulfate (SLS) as a surfactant. 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. 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, Tween 80 and SLS (10:5:2:1, 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 showed an enhanced dissolution and oral bioavailability of SRF compared with SRF powder due to their reduced particle size and amorphous state conversion. Thus, SRF-NSs could be a promising strategy to enhance the oral bioavailability of SRF.

Key words: Sorafenib, Nanosuspension, Dissolution, Oral bioavailability, High pressure homogenization