通过体外自乳化性能及体内药代动力学评价优化葛根素自乳化制剂

摘要

本文将水不溶性药物葛根素制备成自乳化制剂.测定了葛根素在不同油相及表面活性剂的溶解度,结果表明葛根素在油酸、Tween 80中的溶解度较好,1,2-丙二醇不但能增加药物的溶解度,而且能够提高自乳化能力.以油酸为油相,Tween 80为表面活性剂,1,2-丙二醇为助表面活性剂,配制一系列混合物,通过绘制三元相图得到自乳化区,考察不同自乳化处方的自乳化性质,采用激光粒度散射仪测定乳化后粒子大小,在体外评价基础上选择较好的3个处方进行比格犬体内药动学研究,比较不同处方自乳化制剂在比格犬体内的生物利用度包括药代动力学参数Cmax, Tmax, AUC0-t.结果表明处方2和处方3的AUC0-t值[(5.201±0.511) ng·mL-1·h, (5.174±0.498) ng·mL-1·h]和Cmax值[(1.524±0.125) ng·mL-1, (1.513±0.157) ng·mL-1]显著高于处方4[(3.013±0.623) ng·mL-1·h, (0.939±0.089) ng·mL-1],通过体内研究结果获得较优处方为油酸(17.5%)、Tween 80(34.5%)、1,2-丙二醇(34.5%).自乳化释药系统提供了水不溶性药物口服给药的新途径.%The main purpose of this work is to prepare self-emulsifying drug delivery system (SEDDS) of a poorly water soluble drug, puerarin. Solubility of puerarin was determined in various oils and surfactants. Oleic acid and Tween 80 provided higher solubility. Addition of propylene glycol as cosurfactant improved solubility of puerarin and the spontaneity of self-emulsification. A series of mixtures comprising oleic acid, propylene glycol and Tween 80 were prepared and their self-emulsifying properties were studied. Pseudo-ternary phase diagrams were constructed to identify the efficient self-emulsification region and particle sizes of the resultant emulsions were determined using a laser diffraction sizer. The harmacokinetic behaviors of three different SEDDS formulations (F2, F3, F4) were investigated in Beagle dogs. The bioavailability was compared using the pharmacokinetic parameters, peak plasma concentration (Cmax), time to reach peak plasma concentration (Tmax) and total area under the plasma concentration-time curve (AUC0-t). AUC0-t was significantly higher in formulation F2 group (5.201±0.511) ng·mL-1·h and formulation F3 group (5.174±0.498) ng·mL-1·h than that in formulation F4 group (3.013±0.623) ng·mL-1·h. Also, Cmax was significantly higher in formulation F2 group (1.524±0.125) ng·mL-1 and formulation F3 group (1.513±0.157) ng·mL-1 than that in formulation F4 group (0.939±0.089) ng·mL-1. Further analysis of the data showed a statistically significant difference between F2 and F4 (P<0.01) as well as F3 and F4 (P<0.01) with regard to the values of AUC0-∞ and Cmax for three SEDDS formulations, but not between those of F2 and F3 (P>0.05). From these studies, the SEDDS formulation containing oleic acid (17.5%), Tween 80 (34.5%) and propylene glycol (34.5%) (w/w) was selected as an optimized SEDDS formulation of puerarin. The data suggest the potential use of SEDDS to improve oral absorption of puerarin.