齐墩果酸纳米结构脂质载体的制备与药效学评价

Preparation and pharmacodynamic evaluation of oleanolic acid nanostructured lipid carriers

目的制备齐墩果酸纳米结构脂质载体(oleanolic acid nanostructured lipid carriers,OA-NLCs),并考察其控制糖尿病大鼠血糖的效果。方法采用热熔乳化-超声波法制备OA-NLCs,并在该处方的基础上加入维生素E聚乙二醇1000琥珀酸酯(D-α-tocopherol polyethyleneglycol 1000 succinate,TPGS),对OA-NLCs进行修饰(TPGS-OA-NLCs);分别考察OA-NLCs和TPGS-OA-NLCs的粒径分布、Zeta电位、微观结构以及体外药物释放等性质;用Caco-2细胞单层模型评价齐墩果酸原料药、OA-NLCs和TPGS-OA-NLCs的细胞跨膜转运性质;比较齐墩果酸原料药、OA-NLCs和TPGS-OA-NLCs经大鼠灌胃给药后的药效学。结果OA-NLCs和TPGS-OA-NLCs的粒径分布分别为(124.2±12.4)、(103.6±8.7)nm,PDI分别为(0.189±0.012)、(0.176±0.008),Zeta电位分别为(-37.4±1.4)、(-35.2±2.7)mV,在透射电镜下可观察到OA-NLCs和TPGS-OA-NLCs均呈球状;体外药物释放实验结果显示,OA-NLCs和TPGS-OA-NLCs中的药物均表现出缓慢释放的特征;TPGS-OA-NLCs能够有效提高药物的跨膜转运能力;与齐墩果酸原料药和OA-NLCs比较,大鼠灌胃给予TPGS-OA-NLCs后血糖水平显著降低。结论将齐墩果酸制备成OA-NLCs,并用TPGS进行修饰,降低血糖水平的作用显著,对齐墩果酸的二次开发、利用具有重要意义。

Objective To prepare oleanolic acid nanostructured lipid carriers(OA-NLCs) and investigate their blood sugar control effects in diabetic rats.Methods OA-NLCs were prepared by hot melt emulsification-ultrasonic method, and D-α-tocopherol polyethyleneglycol 1000 succinate(TPGS) was added on the basis of the formulation to modify OA-NLCs(TPGS-OA-NLCs).The microstructure, particle size distribution, Zeta potential, and in vitro drug release properties of OA-NLCs and TPGS-OA-NLCs were analyzed.The Caco-2 cell monolayer model was used to evaluate the cell transmembrane transport properties of oleanolic acid bulk drugs, OA-NLCs and TPGS-OA-NLCs.The pharmacodynamics of oleanolic acid bulk drugs, OA-NLCs and TPGS-OA-NLCs after intragastric administration in rats were compared.Results The particle size distributions of OA-NLCs and TPGS-OA-NLCs were(124.2±12.4) and(103.6±8.7) nm, PDI were(0.189±0.012) and(0.176±0.008),and Zeta potentials were(-37.4±1.4) and(-35.2±2.7) mV,respectively.The OA-NLCs and TPGS-OA-NLCs were both spherical under transmission electron microscope(TEM).The in vitro drug release demonstrated the drugs in OA-NLCs and TPGS-OA-NLCs all showed slowly release characteristics.The TPGS-OA-NLCs could effectively improve the drug’s transmembrane transport ability.Compared with the oleanolic acid bulk drugs and OA-NLCs, TPGS-OA-NLCs significantly lowered the blood glucose level in diabetic rats after intragastric administration of TPGS-OA-NLCs.Conclusion In this study, oleanolic acid was prepared into OA-NLCs and modified with TPGS,which could significantly reduce the blood glucose level.It was of great significance for the secondary development and utilization of oleanolic acid.