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

一种新型口服胰岛素，可实现安全、高效的胃肠道运输和吸收

• 批准号: 10022124
• 负责人: Zhiqiang Cao
• 金额: $ 42.51万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-25 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10022124
• 关键词: Address; Adherence; Amino Acid Transporter; Animal Model; Autoimmune Diseases; Bacterial Infections; Betaine; Biological Availability; Blood; Carrier Proteins; Cell membrane; Chemicals; Climacteric; Clinical; Colloids; Data; Detergents; Development; Diabetes Mellitus; Diabetic mouse; Diffuse; Diffusion; Encapsulated; Enhancement Technology; Enhancers; Enteral; Enzyme Inhibitor Drugs; Epithelial; Epithelial Cells; Epithelium; Face; Fc Receptor; Formulation; Foundations; Freeze Drying; Future; Goals; Health; Human; In Vitro; Inflammatory Bowel Diseases; Injections; Insulin; Intestinal Absorption; Intestinal permeability; Intestines; Knowledge; Lactulose; Lead; Leaky Gut; Liquid substance; Mannitol; Micelles; Miniature Swine; Mucins; Mucous body substance; Nature; Oral; Patients; Penetration; Performance; Pharmaceutical Preparations; Pharmacology; Play; Polychlorinated Biphenyls; Polymers; Powder dose form; Property; Proteins; Protons; Quality of life; Receptor Cell; Recombinants; Reporting; Research; Risk; Safety; Stomach; Structure; System; Technology; Testing; Therapeutic; Tight Junctions; Time; Tissues; Translations; absorption; bile acid transporter; capsule; clinical translation; diabetic; diabetic patient; diabetic rat; ethylene glycol; gastrointestinal; ileum; improved; in vivo; intestinal epithelium; novel; particle; predictive modeling; protein transport; prototype; success; surfactant

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.

项目概要 口服胰岛素将改善糖尿病患者的生活质量，但目前的口服蛋白制剂 在胃肠道运输和吸收过程中面临多重障碍，导致低 特别是，穿透肠粘液层和上皮的治疗功能。 对于任何口服制剂来说，细胞层到达血液仍然是两个主要挑战。 粘液渗透和吸收增强技术的进步，当前的口腔 蛋白质药物的吸收和生物利用度仍然较低，和/或增加了风险 肠漏和安全问题，如自身免疫性疾病、细菌感染和 炎症性肠病迫切需要安全有效的口服给药。 显着增强蛋白质通过粘液和肠上皮转运的技术， 使口服胰岛素具有高生物利用度是PI的长期研究目标。 开发一种平台技术来共同解决这些障碍并使口服胰岛素成为可能 该项目的目的是探索临床转化的机制。 新型胰岛素输送系统解决粘液运输、上皮吸收和肠道 相关的安全问题和有助于提高口服生物利用度的具体目标包括： 确定有助于实现首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，该项目将验证口服的可行性。 糖尿病小型猪的胰岛素原型，这是一种更适合预测的大型动物模型 该项目的成功将直接促进人类口服生物利用度的发展。 非常有前途的口服胰岛素——一种改变糖尿病患者生活的治疗方法。 还提供有关特定交付平台如何解决问题的基础知识 口服蛋白质输送的多重障碍将影响广泛的未来； 口服蛋白质药物的开发。