雷公藤甲素聚乳酸纳米粒的制备及毒性

Preparation and toxicity of triptolide-loaded poly (D, L-lactic acid) nanoparticles

目的 探索可生物降解聚乳酸 [poly(D ,L lacticacid) ,PLA]纳米粒口服给药后降低毒性的可能性。方法采用改良的自乳化溶剂蒸发法制备雷公藤甲素聚乳酸纳米粒 ;透射电子显微镜 (TEM)观察纳米粒的形态 ;动态激光粒度分析仪测定其平均粒径大小和分布 ;采用反相高效液相色谱法 (RP HPLC)测定纳米粒的包封率及载药量 ;X 射线粉末衍射 (X ray)初步研究纳米粒中药物的物理状态 ;考察雷公藤甲素的体外释放特性 ;评价口服给予纳米粒对大鼠的降毒性作用。结果 确定适合处方的工艺为 :水相 有机相为 4 0∶15 (v v) ,表面活性剂浓度为 1% (w v) ,药物在有机相中的浓度为 0 3% (w w) ,TP PLA为 1∶15 (w w)。处方条件下制备的纳米粒平均粒径为 14 9 7nm ,多分散指数为0 0 88,平均包封率及载药量分别为 74 2 7%和 1 36 % ;雷公藤甲素的体外释放分为两相 ;纳米粒非常显著降低肝的毒性 (P <0 0 1) ,显著降低肾的毒性 (P <0 0 5 )。

Aim Investigations on reducing the toxicity of triptolide through poly(D,L-lactic acid) nanoparticles as a drug carrier by oral administration to Wistar rats. Methods Triptolide-loaded poly(D,L-lactic acid) nanoparticles (TP-PLA-NPs) were prepared by modified spontaneous emulsification solvent diffusion (modified-SESD). The shape of nanoparticles was observed by transmission electron microscope (TEM). The size distribution and mean diameter were measured by laser light scattering technique. The entrapment efficiency and contents of drug loading were determined by RP-HPLC. The physical state of drug loaded in nanopartiles were primarily investigated by X-ray powder diffractometry. TP-PLA-NPs release behavior in vitro was carried out. After oral administration of the nanoparticles to Wistar rats in 15 d, the toxicity for liver and kidney were studied by determining aspartate transaminase (AST), alanine transaminase (ALT) and blood urea nitrogen in serum and concentration of protein in urine. Results The preparation process adapted to the formulation was as follows: the volume ratio of the aqueous and organic phases was 40/15; the surfactant concentration was 1%; the drug concentration was 0.3%; triptolide-PLA was 1∶15 (w/w). The mean diameter was 149.7 nm and the polydispersity index was 0.088 for the nanoparticles prepared by above conditions. The entrapment efficiency and content of drug loading were 74.27 % and 1.36%, respectively. The release behavior of drug in vitro showed an initial burst effect, subsequently a slower rate stage. The results indicated that the liver toxicity (P<0.01) and kidney toxicity (P<0.05) caused by triptolide could be decreased significantly by nanoparticles carrier. Conclusion PLA-NPs might be used as a new oral carrier for triptolide.