Hydrogels are three-dimensional hydrophilic structures that imbibe water while maintaining structural integrity. A subset of hydrogels, complexation hydrogels, has found utility as microparticulate carriers for the oral delivery of protein therapeutics. P(MAA-co-NVP), a random copolymer composed of methacrylic acid (MAA) and N-vinyl pyrrolidone (NVP), is a complexation hydrogel that has been successfully used for the transmucosal delivery of proteins such as insulin and growth hormone. While successful oral protein delivery has been shown with unmodified P(MAA-co-NVP) microparticles, a cause for concern is the lack of interaction of the particle with the mucus-lining of the upper small intestine. This interaction leads to increased carrier residence time in the intestine and ensures greater protein delivery across the intestinal wall.We have developed dextran- or poly(ethylene glycol)- modified P(MAA-co-NVP) microparticles, as both molecules interact readily with mucus. Dextran tethers have been successfully added in a post-synthesis scheme using carbodiimide-linking chemistry that joins primary amine-containing hydrogels to carboxymethylated-dextran. Poly(ethylene glycol) tethers are incorporated during the UV-initiated bulk radical polymerization hydrogel synthesis. The P((MAA-co-NVP)-g-EG) hydrogels have been synthesized with varying crosslinking type (TEG/PEGDMA) and density (0.75-1.25%) to modulate the swelling profile to better protect the protein in the stomach and prompt release in the intestine (see figure). Furthermore, these systems have pore sizes ~10x greater than the hydrodynamic radius of the proteins of interest, show no cytotoxicity, and can successfully load and release protein therapeutics. 

Surface-modification of P(MAA-co-NVP) microparticles for oral protein delivery

247th National Meeting (2014)

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