Laboratory of Pharmaceutical Engineering, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
Eur J Pharm Sci. 2011 Apr 18;42(5):445-51. doi: 10.1016/j.ejps.2010.12.007. Epub 2010 Dec 21.
Chitosan nanoparticles (CS NPs) have been commonly regarded as potential carriers for the mucosal delivery of therapeutic peptides because of their biocompatibility, bioadhesion and permeation enhancing properties. However, they have limited colloidal stability and readily dissociate and dissolve in the acidic gastric conditions. In the current study, CS NPs were formulated by ionic cross-linking with hydroxypropyl methylcellulose phthalate (HPMCP) as a pH-sensitive polymer and evaluated for the oral delivery of insulin. In vitro results revealed a superior acid stability of CS/HPMCP NPs with a significant control over insulin release and degradation in simulated acidic conditions with or without pepsin. Furthermore, fluorescently-labeled CS/HPMCP NPs showed a 2- to 4-fold improvement in the intestinal mucoadhesion and penetration compared to CS/TPP NPs as evidenced by quantitative fluorescence analysis and confocal microscopy. After s.c. injection to rats, no significant difference in the hypoglycemic effect of insulin solution or insulin-loaded CS/HPMCP NPs was observed, confirming the physico-chemical stability and biological activity of the entrapped peptide. Following peroral administration, CS/HPMCP NPs increased the hypoglycemic effect of insulin by more than 9.8 and 2.8-folds as compared to oral insulin solution and insulin-loaded CS/tripolyphosphate (TPP) NPs, respectively.
壳聚糖纳米粒子（CS NPs）由于其生物相容性、生物黏附性和渗透增强特性，常被认为是治疗性肽类经黏膜给药的潜在载体。然而，它们的胶体稳定性有限，容易在酸性胃环境中解离和溶解。在本研究中，CS NPs 通过与羟丙基甲基纤维素邻苯二甲酸酯（HPMCP）的离子交联来制备，HPMCP 是一种 pH 敏感聚合物，并评估其用于胰岛素的口服递送。体外结果表明，CS/HPMCP NPs 具有优异的酸稳定性，能够显著控制胰岛素在模拟酸性条件下的释放和降解，无论是否存在胃蛋白酶。此外，荧光标记的 CS/HPMCP NPs 与 CS/TPP NPs 相比，在肠道黏附和穿透方面分别提高了 2-4 倍，这可以通过定量荧光分析和共聚焦显微镜得到证实。将胰岛素溶液或负载胰岛素的 CS/HPMCP NPs 皮下注射给大鼠后，胰岛素溶液或负载胰岛素的 CS/HPMCP NPs 的降血糖效果没有显著差异，这证实了包封肽的物理化学稳定性和生物活性。口服给予 CS/HPMCP NPs 后，与口服胰岛素溶液和负载胰岛素的 CS/三聚磷酸酯（TPP） NPs 相比，胰岛素的降血糖作用分别提高了 9.8 倍和 2.8 倍。
