Abstract: Diltiazem hydrochloride (DTZ HCl) buccoadhesive discs were developed to control the drug release and enhance its bioavailability by evading the first pass metabolism. Buccoadhesive discs were prepared by direct compression of mucoadhesive polymers, namely; polyvinylpyrrolidone (PVP K-30), Sodium Carboxymethyl Cellulose (SCMC) and Carbopol 934 (CP934) in combination with Eudragit L100-55, or Sodium Alginate (SA), as matrix polymers to control the drug release. In vitro characterization showed that drug release, swelling capacity, surface pH and mucoadhesion depended on the type of polymers used and their ratios. In vivo testing in human volunteers showed that most of the formulae had suitable mucoadhesion and controlled drug release, however those containing SA and SCMC mixtures showed optimum drug release and greater mucoadhesion values. Relative bioavailability of a selected DTZ HCl buccoadhesive formulation (SA/SCMC, 3:1) was determined and compared with that of a commercial sustained release oral tablet (Altiazem® SR) as a reference in rabbits. The percentage relative bioavailability of DTZ HCl from the selected buccoadhesive disc was found to be 197.7%. The estimated tmax and AUC0-∞ values were also significantly higher after buccal administration (p<0.05). The proposed buccoadhesive formulation of DTZ HCl could be an alternative for the currently available oral therapy.