口服胰岛素肠溶聚合物脂质杂化纳米粒的制备与评价

为了提高胰岛素的口服生物利用度，本研究以聚乙二醇聚乳酸共聚物(PEG-PLA)为高分子载体材料、磷脂s75为脂质材料、Eudragit L100为肠溶材料制备口服胰岛素肠溶聚合物脂质杂化纳米粒(INS-NPs L100)，并对其体内外性能进行评价。采用W/O/W复乳溶剂挥发法制备胰岛素聚合物脂质杂化纳米粒(INS-NPs)，以包封率、粒径和释药行为为评价指标，采用单因素法对处方进行优化；将最优INS-NPs与肠溶材料Eudragit^®； L100混合制备成INS-NPs L100，并对其形态、体外释放及健康大鼠灌胃后的降血糖作用进行评价。以最优处方制备的INS-NPs包封率为(62.18±4.51)%，平均粒径为(225.2±94.3)nm，多分散系数为0.191±0.068，Zeta电位为-(14.84±1.26)mV。包裹肠溶材料后所制备的INS-NPs L100，在pH 1.0盐酸溶液中2 h累积释放量为8.01%，在pH 6.8的磷酸盐缓冲液中6 h累积释放量为67.31%。将所制备的INS-NPs L100经口给予健康大鼠(38 IU/kg)后，具有明显的持续降血糖作用，3.5 h时血糖浓度可降至初始值的76%。实验结果表明，本研究所制备的INS-NPs L100可有效减缓胰岛素在胃液中的释放速度，提高蛋白在胃肠道中的稳定性，为多肽、蛋白类药物口服给药提供了新的研究思路。

Preparation and evaluation of an oral insulin enteric preparation based on polymer-lipid hybrid nanoparticles

To improve the oral bioavailability of insulin, an insulin-loaded enteric polymer-lipid hybrid nanoparticles(INS-NPs L100)was prepared using methoxy PEG-poly(D, L-lactide)(PEG-PLA), phospholipid s75 and Eudragit L100; in vitro and in vivo behaviors of INS-NPs L100 were evaluated. Insulin-loaded polymer-lipid hybrid nanoparticles(INS-NPs)were prepared by W/O/W double emulsion solvent evaporation method. INS-NPs formulation was optimized by single factor experiment using encapsulation efficiency, particle size, and in vitro release behavior of the corresponding INS-NPs L100 as evaluation indexes. The morphology, in vitro drug release profile and hypoglycemic effect of the INS-NPs L100 using the optimal INS-NPs and Eudragit^® L100(used as enteric polymer)were assessed. The results showed that the encapsulation efficiency of the optimal INS-NPs was(62. 18±4. 51)%. The average particle size, PDI and Zeta potential was(225. 2±94. 3)nm, 0. 191±0. 068, and -(14. 84±1. 26)mV, respectively. The cumulative drug release from the INS-NPs L100 was only 8. 01% at 2 h in pH 1. 0 HCl solution, exhibiting a slow drug release behavior; while the drug release from INS-NPs L100 was 67. 31% at 6 h in phosphate buffer of pH 6. 8. Mereorer, after oral administration of INS-NPs L100 with a dose of 38 IU/kg, the blood glucose concentration of healthy rats was reduced to 76% of the initial values at 3. 5 h, exhibiting a sustained hypoglycemic effect. In summary, the INS-NPs L100 prepared in this study could effectively decrease the release rate of insulin in gastric juice, improve the stability of protein in the gastrointestinal tract, and provide a new approach for the oral administration of peptides and protein drugs.