Small Intestine Targeted Fast Acting Oral Insulin Formulation

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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).