胰岛素的口服给药一直是药剂学领域的研究热点。其核心问题是同时克服胰岛素吸收的多重屏障，提高胰岛素的口服生物利用度。在前期研究的基础上，针对多重吸收屏障，本项目提出了胰岛素口服给药系统设计的“4P原则”，形象地描述为“活得好”、“钻得深”、“穿得过”和“放得出”。依据“4P原则”，本项目构建了一种新型胰岛素口服纳米给药系统——载胰岛素-鱼精蛋白-冰片的高密度PEG修饰脂质磷酸钙纳米粒。通过高密度 PEG 修饰提高纳米给药系统在胃肠道的稳定性和穿透肠道黏液层的能力，实现“活得好”和“钻得深”；通过将冰片与胰岛素共载药，提高纳米给药系统穿透肠上皮细胞层的能力，实现“穿得过”；通过鱼精蛋白与胰岛素形成复合物既控制胰岛素的释放，又不影响胰岛素药效的发挥，实现“放得出”。本项目对该纳米给药系统跨越多重吸收屏障的能力进行评价，阐明其促进胰岛素吸收的机制，研究结果可望为蛋白多肽药物的口服给药提供新的思路。

Oral delivery of insulin has always been a research highlight in the field of pharmaceutics. The key issue is to improve the bioavailability of orally delivered insulin by overcoming the multiple barriers to absorption of insulin simultaneously. Based on our previous research, the “4Ps rules” is proposed by us to guide the design of nano-carriers suitable for oral delivery of insulin, including “protection from proteolysis”, “penetration through mucus layer”, “permeation through intestinal epithelial layer” and “programmed release from delivery system”. A novel nano-carrier complying the “4Ps rules” is established by us as insulin-protamine-borneol-loaded lipid calcium phosphate nanoparticle with a densely PEGylated surface. By highly-densed PEGylation of the nano-carrier’s surface, enhanced protection of insulin from proteolysis and rapid penetration of the nano-carrier through mucus layer are realized. The boreneol co-encapsulated with insulin molecules by the nano-carrier could facilitate the permeation of the nano-carrier through intestinal epithelia. Moreover, a complex is formed between insulin and protamine in the nano-carrier to postpone the release of insulin until absorption of the nano-carrier. The enhancement of the nano-carrier on oral absorption of insulin is to be evaluated and the mechanism elucidated. The results of the research will provide a promising new platform for oral delivery of proteins and peptides.