In this research work, nateglinide, ezetimibe were selected as model drugs. Nateglinide is an amino acid derivative that induces an early insulin response to meals decreasing postprandial blood glucose levels which act by binding to β cells of the pancreas to stimulate insulin release. Ezetimibe is a lipid-lowering compound that inhibits intestinal cholesterol and phytosterol absorption. Formulation of sustained release floating bilayer tablets of ezetimibe-nateglinide with Polyox WSR 303, Carbopol 934P, HPMC K4M, Na CMC. The compatibility of nateglinide and excipients used in study was determined using DSC and this study revealed that no interaction between drug and excipients used in the formulation. The optimized nateglinide-ezetimibe floating formulations (NGT3, NGT10) showed satisfactory results with respect to in vitro buoyancy and sustained drug release, and was physically stable during 3 months period. The in vivo radiographic studies showed that the BaSO4-loaded floating tablets were retained in the stomach for 4.16 ± 1.57 h (n=3).