In the contemporary medical model world, the proniosomal system has been serving as a new drug delivery system that is considered to significantly enhance the bioavailability of drugs with low water solubility. In this work, Cilnidipine, a promising 4th generation Ca2+ channel blocker with a rational pharmacological profile i.e. dual L/N-type Ca2+channel-blocking action is used in the treatment of hypertension. Cilnidipine loaded Proniosomes (CIL-PRO) were developed to improve the oral bioavailability. Cilnidipine-Proniosomes were prepared by film hydration followed by rotary flask evaporator applying the concepts of Design of Experiments. Box-behnken designwas applied to optimize the formulation variables;Cholesterol (A), Span-60 (B), Sorbitol (C). The particle sizes were in the nanometer range and spherical shaped for all prepared formulations and the zeta potential(-11.2mV) absolute values were high, predicting good long-