(532b) Molecular Analysis of Interpolymer Complexing Hydrogels Based on Poly(Methacrylic Acid) and N-Vinyl Pyrrolidone as Carriers for Protein Delivery by Transmucosal Transport

Two major problems exist in developing oral delivery systems for peptides and proteins. The first problem is the inactivation of sensitive peptides by digestive enzymes in the gastrointestinal (GI) system, mainly in the stomach. This can be overcome by designing carriers which would protect the drugs from the harsh environments of the stomach before releasing the drug into more favorable regions of the GI tract. Additionally, protease inhibitors could be used to retard the action of enzymes which could degrade peptides and proteins present in the GI system. The other problem is the slow transport of large macromolecules across the lining of the intestine into the blood stream.

In this work we examine the use of hydrogen bonding, copolymer networks of poly(methacrylic acid) and N-vinyl-2-pyrrolidone as oral delivery systems for peptides and proteins. These materials exhibit pH-dependent swelling behavior due to the formation/dissociation of interpolymer complexes. In acidic media, interpolymer complexes form due to hydrogen bonding. These complexes serve as temporary, physical crosslinks and cause the gels to be in collapsed conformations. In solutions of pH greater than 5.4, the complexes dissociate due to ionization of the pendant acid groups resulting in a mesh size greater than in the collapsed state. These hydrogels are ideal for the oral delivery of peptides and proteins due to the large change in network structure over a small pH range. In the acidic environment of the stomach, the drugs would be trapped in the collapsed gel and protected from degradation by digestive enzymes in the stomach. However, in the neutral or basic environments in the intestine where the drugs could potentially be absorbed, the peptides and proteins would readily be released.

Copolymer networks of methacrylic acid (MAA) and N-vinyl-2-pyrrolidone (NVP) were synthesized by free radical polymerization using ethylene glycol dimethacrylate as a crosslinking agent. The ensuing hydrogels are sensitive to solvent pH due to ionization of pendant groups and formation of interpolymer complexes as a result of hydrogen bonding. Hydrogels investigated contained between a 1:1 and 4:1 molar feed ratio of MAA and NVP. The effects of copolymer composition, crosslinking ratio and solvent pH on the swelling behavior of these hydrogels were examined by performing equilibrium and dynamic swelling studies. Drug-loaded particles were filtered and washed to remove surface drug and dried under vacuum. Loading efficiencies and release kinetics were measured using HPLC.

This material is based upon work supported by grant EB-000246 from the National Institutes of Health and is supported under a National Science Foundation Graduate Research Fellowship to DAC.