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: 10163183
• 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/10163183
• 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; Face; Fc Receptor; Formulation; Foundations; Freeze Drying; Future; Goals; 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; gut health; 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，但目前的口服蛋白配方蛋白 在胃肠道运输和遭受痛苦的过程中，面临多个障碍 治疗功能。特别是，穿透肠粘液层和上皮 到达血液的细胞层对于任何口服配方均存在两个主要挑战。尽管 粘液渗透和滥用 - 增强技术的进步，目前的口服 蛋白质药物的递送在缓解和生物利用度方面仍然很低，并且/或增加风险 渗漏的肠道和安全问题，例如自身免疫性疾病，细菌感染和 炎症性肠病。迫切需要安全有效的口头交付 通过粘液和肠上皮的蛋白质转运的技术，可大大增强蛋白质的转运， 并具有高生物利用度的口服胰岛素。 PI的长期研究目标是 开发一种完全解决这些障碍的平台技术，并实现口服胰岛素 可行的临床翻译。该项目的目的是探索一种机制 在解决粘液转运，上皮滥用和肠道方面的新型胰岛素输送系统 相关的安全问题，并导致高口服生物利用度。具体目的包括 识别有助于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，该项目将验证口头的可行性 胰岛素原型在糖尿病小刺激上，这是一个更相关的大型动物模型 人类的口服生物利用度。该项目的成功将直接导致 高度有希望的口服胰岛素 - 一种改变糖尿病患者生活的治疗方法。这个项目将 还产生有关特定交付平台如何解决的基本知识 口服蛋白质递送的多个障碍；这将影响广泛的未来 开发口服蛋白质药物。