Small Intestine Targeted Fast Acting Oral Insulin Formulation

小肠靶向速效口服胰岛素制剂

• 批准号: 10385154
• 负责人: Yuancheng Li
• 金额: $ 29.99万
• 依托单位: 5M BIOMED, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10385154
• 关键词: Adipose tissue; Animals; Biodistribution; Biological; Biological Assay; Biological Availability; Blood; Blood Glucose; C10; Caseins; Cattle; Chronic; Clinical; Collaborations; Development; Diabetes Mellitus; Diabetic mouse; Dose; Encapsulated; Enhancers; Enzymes; Failure; Fasting; Fluorescent Dyes; Food; Formulation; Gastric Emptying; Gastrointestinal tract structure; Gestational Diabetes; Hepatic; Histologic; Hour; Hyperglycemia; Hyperinsulinism; Hypoglycemia; Iatrogenesis; Impairment; Individual; Infusion procedures; Injections; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Intestinal Absorption; Intestinal Mucosa; Intestines; Investigational New Drug Application; Label; Legal patent; Life; Lipodystrophy; Liver; Magnetic Resonance Imaging; Metabolic Diseases; Microvascular Dysfunction; Milk Proteins; Mucous Membrane; Non-Insulin-Dependent Diabetes Mellitus; Oral; Oral Administration; Organ; Patients; Peptide Hydrolases; Peripheral; Permeability; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Physiological; Plasma; Production; Property; Resistance; Risk; Skeletal Muscle; Small Business Technology Transfer Research; Small Intestines; Sodium; Stomach; Streptozocin; Structure of beta Cell of islet; Subcutaneous Injections; Testing; Therapeutic; Therapeutic Effect; Thick; Time; Tissues; Universities; Validation; Water; Weight; absorption; base; biomaterial compatibility; blood glucose regulation; chemical property; compliance behavior; controlled release; cost effective; cytotoxicity; design; diabetes management; diabetic; diabetic patient; efficacy evaluation; high risk; imaging study; in vivo imaging; in vivo monitoring; innovation; insulin secretion; interest; intestinal epithelium; liquid formulation; mouse model; nanocomposite; nanoparticle; nanosized; near infrared dye; non-invasive imaging; pharmacokinetics and pharmacodynamics; physical property; psychologic; scale up; side effect; stem; success; tablet formulation; targeted delivery

PROJECT SUMMARY Diabetes mellitus is a class of metabolic diseases characterized by chronic hyperglycemia due to impaired insulin secretion and/or insulin resistance. Patients are subject to life-long management of their diabetic conditions and the high risk of macro and microvascular complications. Insulin therapy is the most effective means of lowering blood glucose for type 1 diabetes mellitus (T1DM) patients with complete absence of endogenous insulin and type 2 diabetes mellitus (T2DM) patients with progressively depleted insulin secreting pancreatic β-cells and insulin resistant organs and tissue. It is also used for controlling short-term hyperglycemia in gestational diabetes mellitus (GDM). The current therapy is subcutaneous injection or infusion of insulin. However, the poor patient adherence due to inconvenience and psychological insulin resistance (PIR) to routine injection is still a major hindrance in managing diabetic patients. Furthermore, long- term use of insulin injection can cause side effects, including lipodystrophy, iatrogenic hyperinsulinemia, and hypoglycemia. Orally delivered insulin, on the other hand, possesses advantages in patient adherence and therapeutic effect by mimicking the physiological path of endogenous insulin. However, the development of oral insulin formulations has not yet been successful due to low insulin bioavailability, stemming from the degradation in the highly acidic and protease-active stomach and insufficient permeability through the intestinal epithelium and mucosa. This STTR Phase I project aims to develop a fast-acting oral insulin formulation based on the patented innovation of milk protein casein coated drug-carrying nanoparticles (casNP) to encapsulate insulin and the intestinal absorption enhancer, sodium caprate (C10), for small intestine-targeted delivery of insulin by protecting insulin and C10 from the gastric pH and protease action but enabling the enzyme-triggered release of insulin and C10 in the small intestine. The liquid formulation of nano-sized casNP/inslulin/C10 also facilitates rapid gastric emptying and intestinal permeation and absorption as expected in a fast-acting oral insulin agent for controlling the postprandial blood glucose levels. Developed casNP/insulin/C10 nanoconstruct and encapsulated insulin will be labeled with near infrared (NIR) fluorescent dyes for non-invasive tracking of casNP/insulin/C10 delivery and the subsequent insulin release and absorption in the streptozotocin (STZ) induced diabetic mouse model. We will prepare and optimize the casNP/insulin/C10 formulation with desired physiochemical and biological properties, including insulin and C10 loading capacities, stability in the simulated gastric condition and controlled release in the intestine-mimicking condition (Aim 1). We will determine the biodistribution of casNP/insulin/C10, plasma and hepatic insulin bioavailability and the systemic cytotoxicity in STZ-induced diabetic mice using NIR and magnetic resonance imaging along with histopathological analyses and validation, followed by evaluating the efficacy of casNP/insulin/C10 in controlling hyperglycemia (Aim 2).

项目摘要 糖尿病是一类代谢性疾病，其特征在于慢性高血糖， 胰岛素分泌受损和/或胰岛素抗性。患者应接受终身管理， 糖尿病状况以及大血管和微血管并发症的高风险。胰岛素治疗是最 1型糖尿病完全失神患者的有效降糖方法 内源性胰岛素和胰岛素进行性耗竭的2型糖尿病（T2 DM）患者 分泌胰腺β细胞和胰岛素抵抗器官和组织。它也用于控制短期 妊娠期糖尿病（GDM）高血糖。目前的治疗方法是皮下注射或 注射胰岛素。然而，由于患者使用胰岛素的不便和心理因素， 对常规注射的抵抗（PIR）仍然是管理糖尿病患者的主要障碍。此外，长- 长期使用胰岛素注射可引起副作用，包括脂肪营养不良、医源性高胰岛素血症， 低血糖另一方面，口服递送的胰岛素在患者依从性方面具有优势， 通过模拟内源性胰岛素的生理途径来产生治疗效果。但发展 口服胰岛素制剂还没有成功，这是由于胰岛素生物利用度低， 在高度酸性和蛋白酶活性的胃中降解以及通过肠的渗透性不足 上皮和粘膜。该STTR I期项目旨在开发一种速效口服胰岛素制剂， 关于乳蛋白酪蛋白包被的载药纳米颗粒（casNP）的专利创新， 胰岛素和肠吸收促进剂癸酸钠（C10），用于小剂量的靶向递送 通过保护胰岛素和C10免受胃pH和蛋白酶作用，但使酶触发的 小肠中胰岛素和C10的释放。纳米级casNP/胰岛素/C10的液体制剂还 促进快速胃排空和肠渗透和吸收，如在速效口服制剂中所预期的。 用于控制餐后血糖水平的胰岛素剂。开发casNP/胰岛素/C10纳米构建体 并且封装的胰岛素将用近红外（NIR）荧光染料进行标记，用于非侵入性追踪胰岛素。 casNP/胰岛素/C10递送以及随后的胰岛素释放和链脲佐菌素（STZ）中的吸收 糖尿病小鼠模型。我们将制备和优化casNP/胰岛素/C10制剂， 理化和生物学性质，包括胰岛素和C10负载能力，在模拟环境中的稳定性 胃条件和在模拟麻黄碱条件下的控释（目的1）。康贝特人将以 casNP/胰岛素/C10的生物分布、血浆和肝脏胰岛素生物利用度以及在小鼠中的全身细胞毒性。 STZ诱导的糖尿病小鼠的NIR和磁共振成像沿着组织病理学分析 和验证，然后评估casNP/胰岛素/C10在控制高血糖症中的功效（目的2）。