The potential of the buccal mucosa as an alternative route for the systemic delivery of donepezil (DPZ) hydrochloride, and the impact of various skin penetration enhancers on DPZ buccal permeability, was assessed using an in vitro model. DPZ was applied to porcine buccal mucosa in modified Ussing chambers either alone (20 ?g/mL) or with different treatment protocols of various enhancers including Azone? (AZ), deoxycholic acid (DA), polyethylene glycol (PEG) 400, and oleic acid (OA)-PEG 400. DPZ permeated the buccal mucosa very rapidly with a permeability coefficient of 35.6 ? 4.9 ? 10 -6 cm/s, which was not significantly affected by AZ pretreatment. Coapplication of DA 0.6 (w/w), but not DA 0.01 (w/w), reduced the buccal permeation of DPZ (3.5-fold), and PEG 400 reduced the absorption of DPZ in a dose-dependent manner (1.6- and 18.0-fold reduction at 5 and 50 , w/w, PEG 400, respectively). Coapplication of a combination of OA 1 (v/w) and PEG 400 5 (w/w) further reduced DPZ permeability (5.5-fold), which was demonstrated to result from excipient-induced DPZ precipitation as assessed by light microscopy analysis. These results confirm the feasibility of a novel buccal delivery system for Alzheimer s disease, and suggest various approaches that may be exploited for controlled buccal delivery of DPZ.