Preparation Of Trans-Resveratrol Nanosuspensions And Its Preliminary Pharmacokinetic Study

1ObjectiveTrans-resveratrol has certain amount of anticancer activities for liver cancer and stomach cancer. However, the clinical application of trans-resveratrol was severely limited by its low solubility and short in vivo half-time. As one of colloidal drug delivery systems, nanosuspensions have significant effect for improving the solubility,dissolution and in vivo circulation time of poorly soluble drugs. Herein,nanosuspensions techonology was selected to prepare trans-resveratrol nanosuspensions with uniform particle size for improving the solubility, prolonging the in vivo circulation time and increasing drug efficacy of t-Res.2MethodsTrans-resveratrol were prepared by nanoprecipitation method in our study. Malvern laser particle size analyzer, scanning electron microscopy, X-ray diffraction, differential scanning calorimetry and in vitro release were tested to characterize the particle size,morphology, crystal structure and release behavior of the optimized prescription.HepG2 cells were used to investigate the cytotoxicity of trans-resveratrol nanosuspensions and determinate the half inhibitory concentration(IC50). At last, the in vivo pharmacokinetics of trans-resveratrol nanosuspensions in rats including blood concentration and tissue distribution were investigated.3ResultsThe average particle size, PDI and Zeta potential of the optimized prescription was96.9 nm, 0.052 and 20.4 mV, respectively. The encapsulation efficiency and drug loading of trans-resveratrol nanosuspensions were 78% and 28.1%. The results of SEM showed that the trans-resveratrol in nanosuspensions were spherical. DSC and XRD results indicated that trans-resveratrol in nanosuspensions was in amorphous state. Incomparision to trans-resveratrol crude drug, the dissolution of trans-resveratrol nanosuspensions was significantly improved and its release behavior was with fitting Higuchi equation(Q=0.3215t1/2+0.0070). In vitro cytotoxicity study showed that the inhibition concentration of trans-resveratrol nanosuspensions was 1/2 fold of trans-resveratrol solution. In pharmacokinetic experiment, the AUC and MRT of trans-resveratrol nanosuspensions were 3.63-fold and 1.83-fold higher than trans-resveratrol solution. At 5min, 30 min, 1h, 2h, and 4h after intravenous administration to rats, drug concentration of trans-resveratrol nanosuspensions in the tissues of heart, liver, lung, kidney and brain were significantly improved with spleen decreased compared to trans-resveratrol solution. The tropism of trans-resveratrol nanosuspensions for the liver was much higher compared to trans-resveratrol solution.4ConclusionTrans-resveratrol nanosuspensions was successfully prepared by nanoprecipitation method. Compared to trans-resveratrol crude drug, the physicochemical properties of trans-resveratrol in nanosuspensions have changed and the in vivo pharmacokinetic parameters has improved significantly which has certain liver tropism.