Approximately 20.8 million Americans are diagnosed with diabetes. Additionally, nearly 54 million people in the U.S. are diagnosed as being pre-diabetic, meaning to suffer from elevated blood glucose levels. Worldwide, the number of people with diabetes has been estimated to increase over 350 million by 2030. Presently, diabetes is treated with insulin injected either intramuscularly or subcutaneously. Because of poor patient compliance, a strong effort has been aimed at developing oral insulin formulations, which also has the potential to mimic physiological insulin secretion seen in non-diabetic individuals. Nevertheless, oral insulin delivery encounters two major barriers:  the enzyme barrier that leads to rapid insulin degradation, and  the mucosal barrier that limits insulin's bioavailability. Presently, the enzyme barrier has been circumvented to a certain degree by concurrent administration of protease inhibitors or encapsulation of insulin into protective carriers, yet the mucosal barrier remains as a challenge in developing an effective oral insulin delivery system. The recent discovery of a class of cell-penetrating peptides, widely termed as protein transduction domain (PTD) peptides, has provided a tool for finally overcoming the cell membrane barrier. Both cell culture and animal studies demonstrate that by covalently linking PTD to almost any type of cargo, including large proteins (MW >150 kDa), PTD was able to ferry the attached cargo into all types of organ tissues. In this SBIR grant application, we propose an innovative oral insulin delivery approach that could potentially prevail over both the enzyme and mucosal barriers concomitantly. A major component of this system will be a silica-alginate nanocomposite that serves to protect insulin from degradation, target insulin release to the GI tract, and also control drug release rate. Insulin will first be conjugated to LMWP (a proven PTD peptide) by chemical method, and the conjugates will then be encapsulated into a silica-alginate nanocomposite network. Following oral administration, the network structure of the composite would protect entrapped insulin from degradation by proteases in the GI track, whereas the mucoadhesive function of alginate on the surface would provide adsorption of the carriers onto intestinal mucosa. Once accumulated at the mucosal site, the potent cell-penetrating activity of LMWP would allow the released LMWP-insulin conjugates to rapidly cross over the epithelial cell layer, transporting biologically active insulin directly into portal circulation. Promising initial in vitro findings convincingly suggest the plausibility of the proposed system. In this Phase I research, we plan to carry out decisive proof-of-concept animal studies to fully demonstrate the feasibility of this system. Based on the unmatched economical and social impacts of diabetes, the value of the proposed oral insulin delivery technology is far-reaching.
An assessment made by the American Diabetes Association in 2002 indicated that costs attributable to diabetes in that year were approximately $132 billion; including $92 billion in direct medical expenditures and $40 billion in indirect expenditures resulting from lost productivity. Because insulin therapy is required by virtually all patients with type I diabetes, and is also now increasingly used in treating patients with type II diabetes (right now up to 35% of patients with type II diabetes require insulin treatment), effective insulin delivery has become the ultimate goal in clinical management of diabetes. Therefore, the development of this highly effective insulin delivery technology would not only impart tremendous impact on healthcare and social lives but also offer significant benefit to the overall economy of this country. ? ? ?