Hydroxypropyl methylcellulose (HPMC-4000cps, fixed amount), various contents of calcium hydroxide, stearyl alcohol, magnesium stearate, different drug: PVP ratios and altered tablet hardness were used to design floating tablet formulation capable to deliver glibenclamide in a sustained manner. Both full factorial and Box-Wilson designs, in consecutive manner, were used to investigate for the influences of these formulation variables on the developed dosage form performance and drug release.Tablet hardness has revealed an influential effect on tablet onset of floating, and drug release was shown to be more evident in the initial phase (p<0.05). Loading level of calcium hydroxide, stearyl alcohol and tablet swellability all have showed profound enhancing effects on duration of tablet buoyancy and drug release.Glibenclamide release from tablets of the invention was shown to follow the anomalous type (n=0.8212-1.0244). Application of statistical and mathematical modeling has enabled the optimization of the developed tablet formulation to meet selective constraints for floating, hardness and drug release.The optimized buoyant tablet formulation with highest CI revealed hardness of 50 N, immediate onset of floating and floating duration >6 hours. Concerning drug release, the formula showed evidence of 25 and 84% drug release after 1 and 6 hours, respectively, with T50% of 3 hours. Moreover, release kinetics of the drug from the optimized formula was shown to be near the desired zero order type of release (n=0.8897 or 0.0132; r2=0.9993). The in vivo dosage form residence time study in six human subjects demonstrated that the developed tablet formulation retained in the stomach for more than four hours under fasting conditions.Comparative bioavailability study revealed that floating tablets showed 2-2.5 times increase in AUC (p≤ 0.1) indicating the sustained release tendency of the drug from the floating tablet formulation.The three months based stability study indicated that the drug and the dosage form retained their initial physical characters in both accelerated and normal conditions for the test duration as far as blister pack is considered.