蛇床子素3种制剂的制备、表征及药动学比较研究

Comparative study of preparation, characterization and pharmacokinetics of three preparations of osthole

目的制备蛇床子素(Ost)固体分散体(Ost-SD)、磷脂复合物(Ost-PC)和纳米混悬剂(Ost-NS),并分别比较3种制剂在SD大鼠体内的药动学。方法溶剂挥发法制备Ost-SD和Ost-PC,采用XRPD技术分析Ost的存在状态。高压均质法制备Ost-NS,并测定Ost-NS粒径分布及Zeta电位。以Ost原料药为参考,分别比较Ost-SD、Ost-PC和Ost-NS的体外溶出情况。SD大鼠分别ig给予Ost、Ost-SD、Ost-PC和Ost-NS混悬液,HPLC法测定Ost血药浓度,计算主要药动学参数,并比较药动学行为及相对生物利用度。结果 Ost在Ost-SD和Ost-PC中以无定型状态存在。Ost-NS平均粒径为(161.37±3.77)nm,Zeta电位为(-29.16±1.83)m V。体外溶出研究结果显示,Ost-SD、Ost-PC和Ost-NS均可提高Ost的体外溶出速率及溶出度。体内药动学结果显示,Ost-SD、Ost-PC和Ost-NS的Cmax、AUC0~t和AUC0~∞均显著提高,且相对生物利用度分别提高至165.92%、138.46%和259.35%。结论 Ost-SD、Ost-PC和Ost-NS均可提高Ost口服吸收生物利用度,但Ost-NS效果更为明显。

Objective To prepare osthole solid dispersions(Ost-SD),osthole phospholipids complex(Ost-PC),and osthole nanosuspensions(Ost-NS),and compare their effects on the pharmacokinetics in SD rats in vivo.Methods Solvent evaporation method was used to prepare Ost-SD and Ost-PC.Their existential state of Ost in Ost-SD and Ost-PC were analyzed by X-ray power diffraction(XRPD).High pressure homogenization method was employed to prepare Ost-NS,its particle size and Zeta potential were studied.The dissolution in vitro of Ost-SD,Ost-PC,and Ost-NS were also studied compared to Ost suspension.SD rats in each group were ig administered with Ost,Ost-SD,Ost-PC,and Ost-NS,respectively.The concentration of Ost in blood was analyzed by HPLC,and the main pharmacokinetic parameters were obtained.The pharmacokinetic behavior and bioavailability were also been compared.Results The results of XRPD indicated that Ost showed an amorphous state in Ost-SD and Ost-PC.The average particle size and Zeta potential of Ost-NS were(161.37±3.77)nm and(-29.16±1.83)mV,respectively.The results of dissolution in vitro indicated that the dissolution of Ost was improved greatly by Ost-SD,Ost-PC,and Ost-NS.The results of pharmacokinetics in vivo showed that Cmax,AUC0~t and AUC0~∞of Ost-SD,Ost-PC,and Ost-NS were enhanced greatly compared to Ost.The bioavailability of Ost-SD,Ost-PC,and Ost-NS were enhanced to 165.92%,138.46%,and 259.35%,respectively.Conclusion Ost-SD,Ost-PC,and Ost-NS can enhance the bioavailability of Ost in SD rats notably.In addition,Ost-NS can give a better effect.