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150b

Nanoscale Characterization and in Vitro Behavior of Poly(Methacrylic Acid-G-Ethylene Glycol) as an Oral Delivery Device for Insulin

Anthony D. Tuesca and Anthony M. Lowman. Deptartment of Chemical and Biological Engineering, Drexel University, 3141 Chestnut St., Philadelphia, PA 19104

In recent years, a significant number of therapeutic proteins and peptides have been developed for the treatment of diseases. These drugs have significantly lower stability than traditional small molecule therapeutics and generally require delivery directly to the bloodstream via injection. Oral delivery would present a more convenient and less stressful method of delivery; however it continues to be an elusive goal due to two main obstacles. First, there is significant proteolytic degradation of proteins occurring primarily in the stomach. Second, non-specific macromolecular transport is quite slow and limited to only a few areas of the small intestine. Therefore, an oral protein delivery system should be able to greatly reduce exposure to the gastric environment and facilitate absorption across the intestinal epithelium.

In this work we investigate the use of a network copolymer hydrogel of poly(methacrylic acid) grafted with poly(ethylene glycol) (P(MAA-g-EG)) as an oral delivery device for insulin. This material exhibits a pH-responsive swelling behavior with a pKa around 4.8. In acidic environments the copolymer collapses due to hydrogen bonds between the protonated PMAA and pendant PEG chains. The collapsed hydrogel greatly restricts diffusion and has been shown to significantly reduce enzymatic degradation of insulin in simulated gastric fluid in vitro. In neutral environments the hydrogel swells due to repulsion of the anionic MAA groups and insulin rapidly diffuses out of the polymer. This polymer has the potential to protect insulin through the acidic stomach and release it in the neutral environment of the lower intestine where it could be absorbed into the bloodstream. Additionally, the grafted PEG chains are capable of forming hydrogen bonds with the glycocalyx in the small intestine. This mucoadhesive behavior would provied a localized and sustained release of insulin near the surface of the epithelial cell layer, where absorption occurs most rapidly. Previous work has shown that this material has been shown to reduce blood glucose levels and increase plasma insulin levels in rats in vivo.

A series of P(MAA-g-EG) gels are synthesized using a free-radical photopolymerization technique. Difunctional PEG is used to introduce covalent crosslinks into the network. Temporary crosslinks may also exist in the hydrogel due to hydrogen bond formation depending on pH. The monomer and difunctional PEG concentrations are varied in order to alter the network structure of the hydrogel. The effective molecular weight between cross links (Mc) and the network mesh size (ξ) are determined based on the swelling and tensile properties of the gels at various pH levels. The effects of those changes on insulin incorporation and in vitro insulin release are determined using HPLC and correlated to the network mesh size.