Molecular design of advanced oral protein delivery systems using complexation hydrogels

Abstract

A novel class of pH sensitive complexation hydrogels composed of methacrylic acid and functionalized poly(ethylene glycol) tethers, referred to as P(MAA-g-EG) WGA, was investigated as an oral protein delivery system. The PEG tethers were functionalized with wheat germ agglutinin (WGA), a lectin that can bind to carbohydrates in the intestinal mucosa, to improve residence time of the carrier and absorption of the drug at the delivery site. P(MAA-g-EG) WGA created a specific mucoadhesive interaction between mucin and WGA in in vitro experiments. In addition, it improved the overall adhesion of the carrier by 17% to a cellular monolayer, as compared to P(MAA-g-EG). Administration of P(MAA-g-EG) WGA to a rat small intestine demonstrated that 99% of the microparticles still remained in the rat small intestine after 1 hour. These results confirmed that functionalizing P(MAA-g-EG) with WGA improved the mucoadhesive properties of the carrier. Insulin was effectively entrapped within the polymer network with a loading efficiency of 74%. Release studies with insulin-loaded P(MAA-g-EG) WGA showed that the carrier released less than 10% of the insulin at pH 3.2 after 60 minutes and 70% of the insulin at pH 7.0 after 60 minutes. These studies confirmed that P(MAA-g-EG) WGA can protect insulin in the low pH of the stomach and that the pH change between the stomach and the small intestine can be used as a physiologic trigger to quickly release insulin. The ability of P(MAA-g-EG) WGA to improve insulin absorption was investigated in two different intestinal epithelial models and an animal model. In the Caco-2 cells, P(MAA-g-EG) WGA improved insulin permeability by 9-fold as compared to an insulin only solution. P(MAA-g-EG) WGA was also evaluated in a mucussecreting culture that contained Caco-2 and HT29-MTX cells. Insulin permeability was increased by 5-fold in the presence of P(MAA-g-EG) WGA. The final study determined bioavailability of insulin-loaded P(MAA-g-EG) WGA when administered to a rat small intestine. Bioavailability of insulin was 11.9% for insulin-loaded P(MAA-g-EG) WGA, which is a vast improvement over the 0.5% bioavailability of an insulin only solution. Overall, it is clear that P(MAA-gEG) WGA holds great promise as an oral insulin delivery system.