水飞蓟宾自微乳化胶囊剂的制备及大鼠体内药动学

Preparation of silibinin self-micro emulsifying capsule and its pharmacokinetic study in rats

目的研制水飞蓟宾自微乳化胶囊剂并对其进行体内外评价。方法通过正交设计和伪三元相图的绘制,对自微乳化系统中的油相、乳化剂及助乳化剂的组成、用量进行研究,筛选最佳处方组成和组成比例。以自制水飞蓟宾胶囊作对照,RP-HPLC测定大鼠灌胃后的血药浓度,用3p97计算药物动力学参数。结果水飞蓟宾最佳自微乳化给药系统处方组成及其比例为水飞蓟宾-中链甘油三酯-Cremophor RH40-PEG400=3.85∶16.15∶60∶20,所形成的微乳的平均粒径为14.6 nm,在人工胃液和人工肠液中16 min内累积溶出百分率均超过95%,自制水飞蓟宾颗粒胶囊溶出很少。胶囊内容物水飞蓟宾预乳化浓缩液(SLB-PMC)和水飞蓟宾颗粒浓度-时间数据符合一级吸收单室模型,水飞蓟宾预乳化浓缩液的Cmax为0.70μg/mL,而自制水飞蓟宾颗粒仅为0.104μg/mL,水飞蓟宾预乳化浓缩液的AUC比水飞蓟宾颗粒提高了11.7倍,其相对生物利用度为1 265.22%。结论将水飞蓟宾制成自微乳化胶囊能显著提高其体外溶出和体内吸收。

AIM To develop the formulation of silibinin self-microemulsifying capsule and to study its pharmacokinetics in rats.METHODS The optimization composition and the ratio of silibinin-SMEDDS,including oil,emulsifier and co-emulsifier were studied by orthogonal design and pseudo ternary phase diagrams.The silibinin concentrations in rat plasma were determined by RP-HPLC after oral administration of silibinin-PMC capsule and self-made silibinin-suspension.The pharmacokinetic parameters were calculated by software program 3p97.RESULTS The optimal formulations of silibinin-SMEDDS were composed of silibinin,Labrafac lipophile WL 1349,Cremophor RH40 and PEG400,with the ratio of 3.85∶ 16.15∶ 60∶ 20.The particle size was 14.6 nm after emulsifying.The dissolution of silibinin-PMC in artificial gastric juice and artificial intestinal juice were both more than 95% in sixteen min and the self-made silibinin particles capsule did not have dissolution.The data of concentration in plasma with time of silibinin-PMC and silibinin-suspension were best fitted with first-order absorption one compartment model.The Cmax of silibinin-PMC and silibinin-suspension were 0.70 μg/mL and 0.104 μg/mL,respectively.The AUC of silibinin-PMC was 11.7 times higher than silibinin-suspension and the relative bioavailability was 1 265.22%.CONCLUSION The formulation of silibinin-PMC capsule can increase drug dissolution in vitro and absorption in vivo significantly.