Background: Due to short-lasting action, fast clearance and enzymatic instability of anti-diabetic drugs result in low bioavailability as they are mainly absorbed from the stomach and the lower part of the gastrointestinal tract. The bioavailability of antidiabetic drugs can be significantly increased by enhancing the gastric residence time using gastroretentive drug delivery systems such as floating microspheres.
 Objectives: The present investigation deals with the development and optimization of floating microspheres for gastroretentive delivery containing repaglinide using Box-Behnken design and also investigates the effect of different process variables on the formation of the microsphere. Thereby, increasing the bioavailability and reducing the mentioned side effects of repaglinide.
 Materials and methods: Floating microspheres of repaglinide formulated by ionic gelation method and optimized using Box-Behnken design. The independent variables were the concentration of Hydroxy methylcellulose (HPMC) (A), Sodium alginate (B), and calcium chloride (C) while entrapment efficiency (R1), swelling index (R2), and in vitro drug release (R3) were considered as dependent variables. The optimized formulation of floating microspheres was characterized by various physicochemical properties, surface morphology, drug excipient interaction, in vitro release, and buoyancy studies.
 Results: Based on obtained 3D response surface plot factors A, B, and C were found to give a synergistic effect on R1, while factor A has a negative effect on R2. Interaction of AC was negative on R1 and R2 but positive on R3. The interaction of AC and BC was negative in all the responses. Scanning electron microscopy (SEM) revealed that microspheres were spherical with nearly smooth surface morphology. Good entrapment and buoyancy were observed for 12 h. The in vitro drug release was found to be controlled for more than 12 hours and followed the Higuchi model. The validations of response surface methodology (RSM) for three dependent variables were 100.09%, 99.68%, and 97.02%.
 Conclusion: Repaglinide floating microspheres were prepared and optimized by use of Box – Behnken process optimization software. The quantitative responses of particle size, entrapment efficiency, and in vitro drug release for different combinations of independent variables, sodium alginate as release retarding polymer, HPMC K100M as floating polymer, and calcium chloride as a cross-linking agent were obtained experimentally, and the results were found to fit the design model. The quantitative effect of these factors at different levels on the responses could be predicted using polynomial equations, and high linearity was observed between predicted and actual values of response variables. The results of the present study showed that the responses i.e, particle size, entrapment efficiency, and in vitro release are significantly affected by the concentration of polymer and a cross-linking agent. The formulation OF1 was found to be the optimum formulation predicted by the point prediction of the design expert software. The in vitro drug release was found to be controlled for more than 12 h and followed the Higuchi model. The validations of RSM for three dependent variables were 100.09%, 99.68%, and 97.02%. Therefore, it can be concluded that a floating microsphere for repaglinide was developed and optimized using a three-factor, three-level Box – Behnken design.