SBIR-STTR Award

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 ?-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). Public Health Relevance Statement PROJECT NARRATIVEThe proposed STTR Phase I project is to develop a fast-acting oral insulin formulation using a nanocomposite made from natural milk protein caseins for co-delivery of insulin and a mucosa permeation enhancer, sodium caprate (C10). The developed oral insulin formulation has high stability and can resist the highly acidic gastric condition, enabling delivery of insulin and C10 to the targeted small intestine. With successful development, this fast-acting oral insulin formulation will replace the traditional insulin injection and offer diabetic patients with a safe, convenient, more efficacious and cost-effective insulin therapy to better manage their diabetic conditions.

Project Terms:
efficacy evaluation ; efficacy analysis ; efficacy assessment ; efficacy examination ; evaluate efficacy ; examine efficacy ; diabetes management ; diabetic management ; nanosized ; nano sized ; nanoparticle ; nano particle ; nano-sized particle ; nanosized particle ; Biodistribution ; blood glucose regulation ; glucose control ; glucose homeostasis ; glucose regulation ; targeted delivery ; site targeted delivery ; scale up ; cost effective ; Diabetic mouse ; diabetes mouse model ; innovation ; innovate ; innovative ; Impairment ; Resistance ; resistant ; mouse model ; murine model ; stem ; high risk ; diabetic patient ; liquid formulation ; tablet formulation ; Microvascular Dysfunction ; microvascular complications ; microvascular disease ; small vessel disease ; in vivo imaging ; imaging in vivo ; non-invasive imaging ; noninvasive imaging ; Formulation ; imaging study ; Injections ; in vivo monitoring ; side effect ; pharmacokinetics and pharmacodynamics ; PK/PD ; near infrared dye ; NIR dye ; near IR dye ; absorption ; Adipose tissue ; Fatty Tissue ; adipose ; white adipose tissue ; yellow adipose tissue ; Oral Administration ; Oral Drug Administration ; intraoral drug delivery ; Animals ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Biological Availability ; Bioavailability ; Biologic Availability ; Physiologic Availability ; Blood ; Blood Reticuloendothelial System ; Blood Glucose ; Blood Sugar ; Caseins ; Cattle ; Bovine Species ; bovid ; bovine ; cow ; Diabetes Mellitus ; diabetes ; Insulin-Dependent Diabetes Mellitus ; Brittle Diabetes Mellitus ; IDDM ; Juvenile-Onset Diabetes Mellitus ; Ketosis-Prone Diabetes Mellitus ; Sudden-Onset Diabetes Mellitus ; T1 DM ; T1 diabetes ; T1D ; T1DM ; Type 1 Diabetes Mellitus ; Type 1 diabetes ; Type I Diabetes Mellitus ; insulin dependent diabetes ; juvenile diabetes ; juvenile diabetes mellitus ; ketosis prone diabetes ; type I diabetes ; type one diabetes ; Non-Insulin-Dependent Diabetes Mellitus ; Adult-Onset Diabetes Mellitus ; Ketosis-Resistant Diabetes Mellitus ; Maturity-Onset Diabetes Mellitus ; NIDDM ; Non-Insulin Dependent Diabetes ; Noninsulin Dependent Diabetes ; Noninsulin Dependent Diabetes Mellitus ; Slow-Onset Diabetes Mellitus ; Stable Diabetes Mellitus ; T2 DM ; T2D ; T2DM ; Type 2 Diabetes Mellitus ; Type 2 diabetes ; Type II Diabetes Mellitus ; Type II diabetes ; adult onset diabetes ; ketosis resistant diabetes ; maturity onset diabetes ; type 2 DM ; type II DM ; type two diabetes ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Enzymes ; Enzyme Gene ; Fasting ; fasted ; fasts ; Fluorescent Dyes ; Fluorescence Agents ; Fluorescent Agents ; fluorescent dye/probe ; Food ; Food or Food Product ; Gastric Emptying ; stomach emptying ; Gastrointestinal tract structure ; Alimentary Canal ; Digestive Tract ; GI Tract ; Gastrointestinal Tract ; alimentary tract ; digestive canal ; Hyperglycemia ; hyperglycemic ; Hyperinsulinism ; Hyperinsulinemia ; Hypoglycemia ; hypoglycemic ; hypoglycemic episodes ; Subcutaneous Injections ; subdermal injection ; Insulin ; Humulin R ; Novolin R ; Regular Insulin ; Insulin Resistance ; insulin resistant ; Intestinal Absorption ; gastrointestinal absorption ; Intestinal Mucosa ; Small Intestines ; small bowel ; Intestines ; Intestinal ; bowel ; Lipodystrophy ; Liver ; hepatic body system ; hepatic organ system ; Magnetic Resonance Imaging ; MR Imaging ; MR Tomography ; MRI ; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance ; NMR Imaging ; NMR Tomography ; Nuclear Magnetic Resonance Imaging ; Zeugmatography ; Metabolic Diseases ; Metabolic Disorder ; Thesaurismosis ; metabolism disorder ; Milk Proteins ; Mucous Membrane ; Mucosa ; Mucosal Tissue ; Structure of beta Cell of islet ; Pancreatic beta Cell ; Pancreatic β-Cell ; pancreas beta cell ; pancreas β cell ; pancreatic b-cell ; Legal patent ; Patents ; Patients ; Peptide Hydrolases ; Esteroproteases ; Peptidases ; Protease Gene ; Proteases ; Proteinases ; Proteolytic Enzymes ; Permeability ; Plasma ; Blood Plasma ; Plasma Serum ; Reticuloendothelial System, Serum, Plasma ; Production ; Risk ; Sodium ; Na element ; Stomach ; gastric ; Streptozocin ; STZ ; Streptozotocin ; Zanosar ; Testing ; Time ; Tissues ; Body Tissues ; Universities ; Water ; Hydrogen Oxide ; Weight ; Gestational Diabetes ; Gestational Diabetes Mellitus ; Pregnancy-Induced Diabetes ; pregnancy diabetes ; Enhancers ; Investigational New Drug Application ; base ; Organ ; Label ; Hepatic ; Peripheral ; Chronic ; Clinical ; Encapsulated ; Phase ; Biological ; Histologic ; Histologically ; Physiological ; Physiologic ; psychologic ; psychological ; intestinal epithelium ; Failure ; Individual ; diabetic ; Skeletal Muscle ; Voluntary Muscle ; chemical property ; Collaborations ; Phase III Clinical Trials ; Phase 3 Clinical Trials ; phase III protocol ; Therapeutic ; Life ; Hour ; Oral ; interest ; Infusion ; Infusion procedures ; biocompatibility ; biomaterial compatibility ; Lytotoxicity ; cytotoxicity ; physical property ; success ; controlled release ; Property ; C10 ; insulin secretion ; Thickness ; Thick ; Patient Compliance ; patient adherence ; patient cooperation ; therapy compliance ; therapy cooperation ; treatment compliance ; compliance behavior ; Dose ; iatrogenic ; iatrogenically ; iatrogenicity ; Iatrogenesis ; Small Business Technology Transfer Research ; STTR ; Validation ; Therapeutic Effect ; Development ; developmental ; nanocomposite ; nano composite ; design ; designing ;