棉酚纳米混悬剂的制备、表征和在体单向灌流肠吸收研究

Nanosuspensions Study of Gossypol: Preparation,Characterization and in Situ Single Pass Perfusion Intestinal Absorption

目的制备棉酚纳米混悬剂(gossypol nanosuspensions,GP-Ns),表征其理化性质,并研究其大鼠在体肠吸收行为。方法采用高压匀质法制备了棉酚纳米混悬剂,对其粒径及分布、Zeta电位、粒子形态、结晶状态、贮存稳定性、饱和溶解度、体外释放等制剂学性质进行了表征并对该纳米混悬剂的肠吸收进行研究。结果棉酚纳米混悬剂粒径为(217±23)nm,且分布均匀,Zeta电位为-22.7 mV,粒子多呈棒状或块状,药物以结晶形式存在,在4℃保存3个月能长期维持较高稳定性。棉酚纳米混悬剂能够以被动扩散的形式被小肠吸收,各吸收肠段上存在差异,其吸收过程不受P-糖蛋白(药物溢出泵)外排作用的影响。结论本实验成功制备了棉酚纳米混悬剂,该方法可行。与原料药相比,制剂的水溶性和体外释放度显著的改善,这为棉酚制剂学研究提供了参考。

OBJECTIVE To prepare gossypol nanosuspensions and investigate their physicochemical properties and intestinal absorption behavior in rats. METHODS Gossypol nanosuspensions were prepared by a high pressure homogenization method. Nanosuspensions＇ characteristics were investigated from particle size distribution,Zeta potential,particle morphology,crystal physical state, storage stability,saturation solubility,and in vitro release. Nanosuspensions＇ intestinal absorption characteristics were also observed in rats. RESULTS The nanosuspensions existed as uniform rods. The mean particle size was（ 217 ± 23） nm,and Zeta potential was- 22. 7 mV. Gossypol existed in crystalline form. Long-term stability test showed that gossypol nanosuspensions were stable at 4 ℃ for 3 months. The experiment of intestinal absorption showed that the nanosuspensions could be absorbed through passive diffusion with significant variation at different sections. The experiment also showed that the absorption process was not affected by the efflux of P-glycoprotein（ drug efflux pump）. CONCLUSION Gossypol nanosuspensions are successfully developed. The solubility in water and the release in vitro of the nanosuspensions are enhanced compared with the bulk drug of gossypol. This study provides a reference for the further pharmaceutical study of gossypol.