Solid lipid nanoparticle (SLN) is a very well tolerated carrier systems for dermal application due to the employment physiological and/or biodegradable lipids. The effects of five factors, two categorical and three quantitative factors, were studied on the mean diameter and entrapment efficiency of the produced SLNs using response surface method (RSM), D-optimal design. Two methods of microemulsion and solvent diffusion and two types of lipid, cetyl palmitate and stearic acid, were examined comparatively. The quantitative variables were studied in three levels; amount of original Paromomycin (60, 90 and 120 mg), fraction of surfactant (0.5, 0.75 and 1 w/v %) and drug to lipid ratio (2, 4 and 6). Mean particle size and entrapment efficiency of the loaded Paromomycin were modeled statistically and the optimal condition was determined to approach to the maximum entrapment efficiency. The drug release profile of the optimal formulated material was examined in aqueous media and 64% of the Paromomycin loaded in SLNs was gradually released during 24 h, which reveals efficient prolonged release of the drug.