紫杉醇超饱和自微乳化给药系统的制备及大鼠体内药动学研究

Preparation of paclitaxel supersaturatable self-microemulsifying drug delivery system and its pharmacokinetics in rats

目的:制备紫杉醇超饱和自微乳化给药系统(supersaturatable self-microemulsifying drug delivery system,S-SMEDDS),并对其在大鼠体内的药动学进行研究。方法:采用伪三元相图的方法,优化紫杉醇自微乳化给药系统(SMEDDS)的处方。18只大鼠随机分为3组,分别灌胃给予10 mg/kg紫杉醇溶液、SMEDDS和S-SMEDDS,测定紫杉醇的血药浓度c、max、AUC和tmax,计算相对生物利用度。结果:确定紫杉醇SMEDDS最优处方为:油相∶表面活性剂∶助表面活性剂=50∶33∶17。油相为Lauroglycol FCC∶橄榄油(2∶1),表面活性剂为Cremophor EL∶吐温-80(1∶1),助表面活性剂为PEG-400。S-SMEDDS在此处方基础上添加5%羟丙基甲基纤维素。稀释对制剂的粒径无显著影响。SMEDDS和S-SMEDDS的粒径分别为(92.7±47.7)和(93.6±36.8)nm,粒径分布呈高斯分布。SMEDDS和S-SMEDDS的cmax和AUC显著高于溶液剂,tmax<溶液剂,生物利用度分别为333.9%和719.3%。结论:紫杉醇S-SMEDDS的口服吸收强于溶液剂和SMEDDS。

Objective： To prepare paclitaxol supersaturable self-microemulsifying drug delivery system（S-SMEDDS） and study its pharmacokinetics in rats.Methods： Pseudoternary phase diagrams were applied to optimize the formulation of S-SMEDDS.Eighteen rats were randomly divided into 3 groups and 10 mg/kg paclitaxel solution preparation was given by gavage,SMEDDS and S-SMEDDS,respectively.The plasma concentration of paclitaxel was determined by HPLC method.AUC,cmax and tmax were determined and relative bioavailability was calculated.Results： The optimal formulation of SMEDDS consisted of oil phase∶surfactants∶cosurfactant=50∶33∶17.Lauroglycol FCC-olive oil（2∶1） were used as oil phase,cremophor EL∶tween-80（1∶1）were used as surfactants and PEG-400 was used as cosurfactant.Oil phase of S-SMEDDS was obtained by adding 5% hydroxyl-propyl methyl cellulose（HPMC）.Dilution had no significant effects on the particle size of SMEDDS and S-SMEDDS.The grain sizes of SMEDDS and S-SMEDDS were（92.7±47.7） and（93.6±36.8） nm with a Gaussian distribution.The cmax and AUC of SMEDDS and S-SMEDDS were higher than those of solution preparation,while tmax of SMEDDS and S-SMEDDS were lower.Relative bioavailabilities of SMEDDS and S-SMEDDS were 333.9% and 719.3%,respectively.Conclusion： S-SMEDDS significantly enhances the absorption and bioavailability of paclitaxel compared with solution preparation and SMEDDS.