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Objectives: Atorvastatin calcium (ATC) is widely used to treat hyperlipidemia but its effectiveness is limited by its low oral bioavailability. The aim of this study was to formulate and evaluate mucoadhesive buccal films containing ATC-loaded nanoemulsion (NE) in an attempt to enhance ATC hypolipidemic effectiveness. Methods: Based on various parameters, including ATC saturation solubility, NE mean droplet size, clarity, thermodynamic stability, and flowability, the optimum NE components were selected which included 10% oleic acid as oil phase, 50% tween 20: ethanol at different ratios as surfactant co-surfactant mixture (SCmix) and 40% water. ATC mucoadhesive buccal films were prepared using hydroxypropyl methylcellulose mixed with the selected optimum ATC-loaded NE by solvent casting technique. Prepared films were subjected to various evaluations including physicochemical characteristics, mucoadhesive properties, ex vivo drug release and finally subjected to in vivo study to evaluate the effectiveness in treating rabbits with diet-induced hyperlipidemia. Results: NE-based film and control film showed acceptable physical characteristics without significant difference in the mucoadhesive properties. NE-based film was more effective in enhancing the penetration of ATC than the control film through chicken pouch membrane by non Fickian mechanism. The in vivo study revealed that both blood analysis and histopathological examination proved the superior effectiveness of NE-based film in reduction of cholesterol level in rabbits with hyperlipidemia over the control film. Conclusion:The formulated NE-based mucoadhesive buccal films were successful in enhancement of hypolipidemic benefits of ATC, in tested rabbits, in comparison to the control film through improving the solubility and bioavailability of ATC.