A Novel Oral Insulin Enabling Safe and Efficient Gastrointestinal Transport and Absorption

项目摘要 口服胰岛素将改善糖尿病患者的生活质量，但目前的口服蛋白质制剂 在胃肠道转运和吸收过程中面临多重障碍，导致低 治疗功能。尤其是穿透肠道粘液层和上皮细胞 细胞层到达血液仍然是任何口服制剂的两大挑战。尽管 当前口腔粘液渗透和吸收促进技术的进展 蛋白药物的吸收和生物利用度仍然很低，和/或增加了风险 肠道渗漏和自身免疫性疾病、细菌感染等安全问题 炎症性肠病。迫切需要一种安全有效的口服分娩方式 这项技术极大地增强了蛋白质在粘液和肠道上皮中的运输， 并使口服胰岛素具有较高的生物利用度。PI的长期研究目标是 开发一种平台技术，完全解决这些障碍，并实现口服胰岛素 可用于临床翻译。这个项目的目标是探索一种 新型胰岛素给药系统解决粘液转运、上皮吸收和肠道- 相关的安全问题，并有助于高口服生物利用度。具体目标包括 确定有助于优选的交付系统的机制/关键参数 通过体外和体内研究解决这些障碍的特性和性能 (涉及糖尿病小鼠和大鼠)。此外，本项目还将验证OLARAL的可行性 糖尿病小型猪的胰岛素原型，这是一种更相关的预测大动物模型 人体口服生物利用度。这个项目的成功将直接导致 前景看好的口服胰岛素--一种改变糖尿病患者生活的疗法。这个项目将 还提供有关特定交付平台如何解决的基础知识 口服蛋白质传递的多重障碍；这将影响广泛的未来 口服蛋白药物的开发。

Project Summary Oral insulin will improve the life quality of diabetes patients but current oral protein formulations face multiple obstacles during their gastrointestinal transport and absorption resulting in low therapeutic functionality. In particular, penetrating the intestinal mucus layer and the epithelial cell layer to reach the blood remained two major challenges for any oral formulation. Despite advancement in mucus-penetrating and absorption-enhancing technologies, current oral delivery of protein drugs remains low in absorption and bioavailability, and/or increases the risk of leaky gut and safety concerns such as autoimmune disease, bacterial infection and inflammatory bowel diseases. There is an urgent need for a safe and efficient oral delivery technology to drastically enhance protein transport through the mucus and intestinal epithelium, and to enable oral insulin with high bioavailability. The long-term research goal of the PI is to develop a platform technology that addresses these barriers altogether and enables oral insulin feasible for clinical translation. The objective of this project is to explore the mechanism for a novel insulin delivery system in addressing the mucus transport, epithelium absorption, and gut- related safety issues and contributing to a high oral bioavailability. Specific aims include the identification of mechanism/key parameters of the delivery system contributing to the preferred properties and performance in addressing these obstacles through in vitro and in vivo studies (involving diabetic mice and rats). Furthermore, this project will validate the feasibility of the oral insulin prototype on diabetic minipigs, which is a more relevant large animal model for predicting oral bioavailability in humans. The success of this project will directly lead to the development of highly promising oral insulin– a life-changing treatment for diabetes patients. This project will also produce foundational knowledge regarding how the particular delivery platform addresses the multiple barriers for oral protein delivery; this will impact a broad range of future development of oral protein drugs.