环孢素A生物黏附性纳米脂质载体的制备及在家兔眼部组织分布研究

 目的 制备适于眼部给药的环孢素A生物黏附性纳米脂质载体，考察其在家兔眼组织的分布情况，并进行眼局部刺激性研究。方法 采用熔融-乳化法制备纳米脂质载体，与生物黏附性材料泊洛沙姆407（P407）溶液混合后，得到泊洛沙姆407纳米脂质载体。运用激光粒度仪测定粒径，透射电镜观察形态，流变仪测定黏度，动态透析法研究其在人工泪液中的释药行为，HPLC测定泊洛沙姆407纳米脂质载体在家兔眼部各组织中不同时间点药物浓度，以未加入泊洛沙姆407的纳米脂质载体(CsA-NLC)及药物油滴眼液作对照，采用线性梯形法计算参数。利用家兔研究其眼局部刺激性。结果 泊洛沙姆407纳米脂质载体多为类球形粒子，泊洛沙姆407包覆于纳米脂质载体的外表，其平均粒径（41.2±0.2）nm，Zeta电位(-15.2±0.21) mV，属于非牛顿流体。体外释放表明，泊洛沙姆407纳米脂质载体具有明显的缓释特征，且体外释药行为符合单指数分布模型。含6.0%泊洛沙姆407的泊洛沙姆407纳米脂质载体在角膜、房水、虹膜的AUC_{0-24 h}分别是油滴眼液的10.75、4.45和4.62倍，是环孢素A纳米脂质载体的2.77、1.22和1.54倍，MRT分别是油滴眼液的3.28、2.26和3.46倍，是环孢素A纳米脂质载体的1.69、1.50和1.62倍。泊洛沙姆407纳米脂质载体对家兔眼部无刺激性。结论 泊洛沙姆407纳米脂质载体可延长药物在眼部的作用时间，显著提高药物在眼部各组织中的浓度，减少刺激性，作为眼部给药载体具有良好的应用前景。

Preparation of Bioadhesive Cyclosporine A Ocular Nanostructured Lipid Carriers and Its Ocular Distribution in Rabbits

OBJECTIVE To develop a bioadhesive nanostructured lipid carrier(P407-NLC) for ocular delivery of cyclosporine A and investigate its ocular distribution in rabbits.METHODS Melt-emulsification method was chosen to prepare CsA-NLC.Poloxamer 407(P407) was dissolved in borate buffer solution(pH 8.0),then added into CsA-NLC to prepare P407-NLC.The morphology of P407-NLC was observed by transmission electron microscopy(TEM).The mean particle size and Zeta potential were measured by laser particle size analyzer.The viscosity was measured by rheometer.Dialysis method was employed to investigate the in vitro release of CsA from P407-NLC at 34 ℃.The concentrations of CsA in ocular tissues were studied by RP-HPLC,and the pharmacokinetic parameters were calculated by linear trapezoidal method.The topical ocular irritation study of P407-NLC was carried out in rabbits.RESULTS The obtained P407-NLC was approximately spherical in shape with average particle size of(41.2±0.2) nm and Zeta potential of(-15.2±0.21) mV,and P407 was coated on the appearance of NLC.P407-NLC was non-newtonian fluids.The in vitro release of CsA from P407-NLC was slowed down and fitted well with single exponential distribution model.AUC0-24 h of CsA in cornea,aqueous humor and iris after ocular administration of P407-NLC containing 6.0% P407 were 10.75,4.45 and 4.62 times higher than that of CsA oil solution,and 2.77,1.22 and 1.54 times higher than that of CsA-NLC,respectively.MRTs in aqueous humor,cornea and iris were 3.28,2.26 and 3.46 times higher,respectively,than that of CsA oil solution,and 1.69,1.50 and 1.62 times higher than CsA-NLC,respectively.There was no irritation for P407-NLC to rabbit eyes.CONCLUSION P407-NLC can be used to increase the level of CsA in ocular tissues and would be a promising nanocarrier for ocular drug delivery.