高乌甲素纳米粒的制备及其在大鼠体内药动学

目的:制备可持续释放且能治疗疼痛的载高乌甲素(LA)的聚乳酸(PLA)纳米粒,并考察其体外释药情况和在大鼠体内的药动学特性。方法:采用O/W乳化-溶剂挥发法制备载高乌甲素的聚乳酸纳米粒(LA/PLA NPs),运用激光粒度仪测定其粒径,原子力显微镜观察其形貌,动态透析法考察其体外释药特性,反相高效液相色谱法(RP-HPLC)测定血药浓度,PKSolver程序处理药-时数据,并以LA为参比进行大鼠腹腔注射的药动学研究。结果:LA/PLA NPs外观呈圆形或类圆形,大小均匀,平均粒径(429±9.19)nm,包封率(86.34±2.15)%、载药量(45.85±1.34)%,体外可持续缓慢释放15 d,体内可释药8 d以上,其主要药动学参数为:t_1/2=(103.16±21.57)h,t_max=(3.6±1.34) h,C_max=(3.50±0.69)μg·mL^-1,AUC_(0-t)=(455.14±26.18) μg·mL^-1·h。结论:LA/PLA NPs制备工艺简单,重复性好,体内药-时过程符合非房室模型,具有良好的缓释效果。

Preparation of lappaconitine-loaded nanoparticles and its pharmacokinetic behaviors in rats

OBJECTIVE To prepare lappaconitine(LA)-loaded polylactic acid(PLA) nanoparticles(LA/PLA NPs), investigate its in vitro release property and pharmacokinetics in rats. METHODS LA/PLA NPs were prepared by emulsion-solvent evaporation method with biodegradable PLA as carrier material and polyvinyl alcohol as emulsifier. The mean particle size of LA/PLA NPs was determined by laser particle size analyzer. The morphology was observed by atomic force microscope. The in vitro release behavior was evaluated using dynamic dialysis method. The concentration of LA in plasma sample was determined using RP-HPLC method. The data of drug concentration-time were processed with PKSolver program. Pharmacokinetics were studied in rats following intraperitoneal injection of LA/PLA NPs with lappaconitine injections as the reference drug. RESULTS LA/PLA NPs possessed a spherical or para-spherical appearance and uniform size. The mean particle size, the entrapment efficiency and drug loading capacity were(429±9.19) nm, (86.34±2.15)% and(45.85±1.34)%, respectively. These LA/PLA NPs could provide a continuous release of the entrapped LA for 15 days in vitro and 8 days in vivo. The main pharmacokinetic parameters of LA/PLA NPs following intraperitoneal injection in rats were listed as follows:t_1/2=(103.16±21.57)h, t_max=(3.6±1.34)h, C_max=(3.50±0.69) μg·mL^-1, and AUC_(0-t)=(455.14±26.18) μg·mL^-1·h. CONCLUSION The preparation technology of LA/PLA NPs is feasible with good reproducibility. The drug concentration-time data of LA in mouse plasma are fitted to non-compartment model. LA/PLA NPs show sustained release effects for LA both in vitro and in vivo.