This study was to design a mucoadhesive based on the biological and physicochemical properties of the buccal mucosa to achieve optimal mucoadhesion in the aqueous buccal environment. Since the buccal surface is negatively charged, a series of novel mucoadhesive poly-[acrylic acid-co-poly(ethylene glycol) monomethylether monomethacrylate-co-dimethylaminoethyl methacrylate] [poly (AA-PEGMM-DMEMA)] were synthesized by incorporating the cationic monomer DMEMA into poly(AA-PEGMM) to enhance the interactions between the mucohadhesive polymer and the buccal mucosa. The compositions of poly(AA-PEGMM-DMEMA) were varied by changing the content of DMEMA from 0 to 4.8 mol % while keeping the mole ratio of AA to PEGMM at a constant 9:1. It was found that the force of mucoadhesion of poly(AA-PEGMM-DMEMA) increased initially, as DMEMA content increased, and reached the maximum at 1% of DMEMA. Further increasing the content of DMEMA decreased the mucoadhesion. The polymers with 0.5 to 2.9% DMEMA appeared to have maximum mucoadhesion after prehydration for 5 min. An ATR-FTIR spectroscopy study revealed that intrapolymer interactions and intersurface interactions played opposite roles in the mucoadhesion performance of the polymers. Optimal mucoadhesion can be achieved by balancing these two interactions. (C) 2004 Wiley Periodicals, Inc.