装载艾塞那肽聚合物纳微球口服给药系统的研究

发布时间：2018-06-08 18:18

本文选题：艾塞那肽 + 口服给药　；参考：《烟台大学》2014年硕士论文

【摘要】：蛋白多肽类药物口服给药系统具有很好的患者顺应性，但口服给药始终存在生物利用度低的难题。本研究采用快速膜乳化技术，制备粒径均一的载艾塞那肽（Exenatide）的PLGA/SA纳微球用于口服给药的研究。在PLGA(Poly(lactic-co-glycolic acid))中复配一定量的硬脂胺（Stearylamine, SA），使纳微球带有正电荷，既可以降低载药纳微球的突释效应，获得平稳的缓慢释放，又可以通过静电作用延长纳微球在体内的滞留时间，有利于Exenatide的口服吸收，提高口服生物利用度；进一步在纳微球表面进行聚乙二醇（Poly(ethyleneglycol)，PEG）和CSKSSDYQC (CSK)多肽的双修饰：PEG链的修饰可以使纳微球穿透粘液层，到达肠道上皮细胞表面；CSK多肽与肠道杯状细胞具有很好的亲和性，可以改善载体跨肠道粘膜层的转运效率，进一步提高口服生物利用度。本文主要分为以下三个部分：第一部分采用快速膜乳化技术结合溶剂挥发法制备PLGA/SA纳微球。通过优化固化温度、超声功率、SA比例、PLGA分子量、内水相NH4HCO3的浓度等因素，制备出Exenatide的装载量4%、包埋率和累积释放率均达到80%以上带正电荷的纳微球。与带负电荷的PLGA纳微球相比，口服给药后，，带正电的PLGA/SA纳微球能够更好地促进小肠对Exenatide的吸收，获得了更好的降血糖效果。第二部分采用超声结合快速膜乳化的方法制备出粒径分别为300nm、1μm和4μm的PLGA/SA纳微球，比较不同粒径对Exenatide口服吸收的影响，体外细胞实验和体内动物实验均表明，1μm的PLGA/SA纳微球透膜效果、口服生物利用度和降血糖效果均最好。第三部分通过PEG和CSK多肽的修饰，制备出了靶向杯状细胞的PLGA/SA-PEG-CSK纳微球。PEG的引入不仅延长了纳微球在体内的停留时间，也提高了Exenatide的口服生物利用度和降血糖效果；CSK多肽的引入通过纳微球与杯状细胞的特异性结合，促进小肠对纳微球的吸收，进一步提高Exenatide的口服生物利用度和降血糖效果。
[Abstract]:The oral delivery system of protein polypeptide drugs has good compliance with patients, but the problem of low bioavailability always exists in oral administration. In this study, PLGA / SA nanospheres with uniform particle size were prepared by rapid membrane emulsification for oral administration. In PLGAA Polylactic-co-glycolic acidido), a certain amount of stearic amines Stearylamine (SAA) is added to make the nanospheres have positive charge, which can not only reduce the sudden release effect of the drug loaded nanospheres, but also prolong the retention time of the nanospheres through electrostatic action. It is beneficial to the oral absorption of Exenatide and the increase of oral bioavailability, and the modification of PEG and CSKSDYQC) polypeptides on the surface of nanospheres can make the nanospheres penetrate the mucus layer. To reach the surface of intestinal epithelial cells, CSK peptide has good affinity with goblet cells, which can improve the transport efficiency of the carrier through the intestinal mucosal layer, and further improve the oral bioavailability. This paper is divided into three parts: in the first part, PLGA / SA nanospheres were prepared by rapid membrane emulsification combined with solvent volatilization. By optimizing the curing temperature, ultrasonic power and the molecular weight of PLGA, the concentration of NH _ 4HCO _ 3 in aqueous phase, the encapsulation rate and cumulative release rate of Exenatide nanospheres with positive charge were over 80%. Compared with the negatively charged PLGA nanospheres, the positively charged PLGA / SA nanospheres improved the absorption of Exenatide in the small intestine after oral administration. In the second part, PLGA / SA nanospheres with particle sizes of 300 nm 1 渭 m and 4 渭 m were prepared by ultrasonic and rapid membrane emulsification. The effects of different particle sizes on the oral absorption of Exenatide were compared. Cell experiments in vitro and animal experiments in vivo showed that PLGA / SA nanospheres with 1 渭 m had the best permeation effect, oral bioavailability and hypoglycemic effect. The third part was modified by PEG and CSK peptides. PLGA / SA-PEG-CSK nanospheres. PEG targeting goblet cells were prepared. The introduction of PLGA / SA-PEG-CSK nanospheres not only prolonged the residence time of nanospheres in vivo, The oral bioavailability of Exenatide and the hypoglycemic effect of CSK polypeptide were also improved by the specific binding of nanospheres to goblet cells, thus promoting the absorption of nanospheres in the small intestine, and further improving the oral bioavailability and hypoglycemic effect of Exenatide.
【学位授予单位】：烟台大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R944

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