聚乳酸-羟基乙酸共聚物负载坎地沙坦酯纳米粒的制备及体内外评价

Preparation,in vitro and in vivo Evaluation of Candesartan Cilexetil-loaded Poly(lacticco-glycolic acid)Nanoparticles

目的:制备坎地沙坦酯纳米粒并考察其生物利用度。方法:以聚乳酸-羟基乙酸共聚物(PLGA)作为载体材料,以聚乙烯醇(PVA)和D-α-维生素E聚乙二醇1000琥珀酸酯(TPGS)共同作为乳化剂,采用乳化溶剂蒸发法制备坎地沙坦酯PLGA-PVA/TPGS纳米粒,通过中心复合设计-效应面法实验设计优化得到PLGA-PVA/TPGS纳米粒的最优处方,在透射电镜下观察坎地沙坦酯PLGA-PVA和PLGA-PVA/TPGS两种纳米粒的微观形态,并比较两种纳米粒的体外药物释放特性;考察坎地沙坦酯PLGA-PVA和PLGA-PVA/TPGS纳米粒经大鼠灌胃给药后的体内药动学特征。结果:坎地沙坦酯PLGA-PVA/TPGS纳米粒的最优处方组成为:PLGA浓度为100 mg·ml^(-1),PVA浓度为15 mg·ml^(-1),TPGS浓度为0.8 mg·ml^(-1),透射电镜下可观察到两种纳米粒分布均匀、无聚集;其体外释药特性均表现为前期释药较快,后期平缓;大鼠体内药动学结果显示,坎地沙坦酯PLGA-PVA和PLGA-PVA/TPGS纳米粒均能提高药物的达峰浓度,增加药物生物利用度,但是坎地沙坦酯PLGA-PVA/TPGS纳米粒提高的更显著(P<0.05)。结论:将坎地沙坦酯制备成PLGA-PVA/TPGS纳米粒能够提高药物在大鼠体内的生物利用度,对坎地沙坦酯的二次开发利用具有重要意义。

Objective:To prepare candesartan cilexetil PLGA-PVA/TPGS nanoparticles and investigate its bioavailability.Methods:Polylactic acid-glycolic acid copolymer(PLGA)was used as the carrier material;polyvinyl alcohol(PVA)and D-α-vitamin E polyethylene glycol 1000 succinate(TPGS)were used as the emulsifiers.Candesartan cilexetil PLGA-PVA/TPGS nanoparticles were prepared by an emulsification solvent evaporation method.The optimal formulation of PLGA-PVA/TPGS nanoparticles was optimized by center composite design(CCD)experimental design.The microscopic morphology of candesartan cilexetil PLGA-PVA nanoparticles and PLGA-PVA/TPGS nanoparticles was observed under a transmission electron microscope.The dialysis method was used to compare the in vitro drug release characteristics of the two nanoparticles.The in vivo pharmacokinetic characteristics of candesartan cilexetil PLGA-PVA nanoparticles and PLGA-PVA/TPGS nanoparticles after intragastric administration in rats were investigated as well.Results:The optimal formulation of candesartan cilexetil PLGA-PVA/TPGS nanoparticles was as follows:PLGA concentration was 100 mg·ml^(-1),PVA concentration was 15 mg·ml^(-1) and TPGS concentration was 0.8 mg·ml^(-1).Under the transmission electron microscope,it could be observed that PLGA-PVA nanoparticles and PLGA-PVA/TPGS nanoparticles were uniformly distributed without aggregation.The in vitro drug release characteristics were fast in the early stage and stable in the later stage.The in vivo pharmacokinetic results showed that both candesartan cilexetil PLGA-PVA nanoparticles and PLGA-PVA/TPGS nanoparticles could increase the drug peak concentration and bioavailability,and the improvement of PLGA-PVA/TPGS nanoparticles was more significant(P<0.05).Conclusion:The candesartan cilexetil was prepared into PLGA-PVA/TPGS nanoparticles,which can improve the bioavailability of the drug in rats,and it is great significance to the development of candesartan cilexetil.