Synthesis, characterization, and application of polyethylene glycol modified insulin for oral delivery using complexation hydrogels

Therapeutic proteins and peptides represent a major area of research in current pharmaceutical and biotechnology companies. Due to their inherent instability, the vast majority of these drugs require parenteral administration. Such is the case for as many as 6 million patients in the United States who use insulin in the treatment of diabetes mellitus. Oral insulin delivery would is a highly desirable alternative method of administration, though it continues to be an elusive target due the enzymatic digestion of insulin and low levels of absorption from the gastrointestinal tract. Hydrogel polymers have shown promise as potential carriers for oral insulin delivery. In particular, a pH responsive hydrogel composed of poly(methacrylic acid-g-polyethylene glycol), P(MAAg- EG), has shown the ability to protect insulin from enzymes in the gastric environment and release in small intestines. It was also able to induce a hypoglycemic effect in vivo when delivered to isolated ileal segments in rats. However, this material has not shown similar potential for oral protein delivery of other model drugs. To date, the unique interaction between P(MAA-g-EG) and insulin, which give it such potential for oral delivery, are not completely understood.The focus of this research is to investigate how P(MAA-g-EG) hydrogels interact with insulin and to improve upon current designs for oral insulin delivery. An attempt is made to correlate the structure and chemistry of the hydrogel to its interaction with insulin over the pH range exhibited by the gastrointestinal tract in vitro. Further insight is gained by observing the interaction of the hydrogel with insulin-like proteins including insulin glargine, an insulin analog, and polyethylene glycol (PEG) modified insulin. The PEG-insulin conjugate is synthesized and characterized to maintain the bioactivity of the protein, which is confirmed in vivo using intravenous and subcutaneous administration in rats. Finally, the proposed system is tested using an in vivo model in Sprague Dawley rats and related to the potential application of P(MAA-g-EG) to deliver insulin and PEG modified insulin for the treatment of diabetes.Ph.D., Biochemical Engineering -- Drexel University, 200