The oral cavity displays one potentially attractive route that is not associated with gastric transit and hepatic first pass metabolism. However, poorly soluble active candidates require a drug delivery system to facilitate their transport through oral biological membranes. To this end, nanostructured lipid carriers (NLC) were loaded with Domperidone and produced with high pressure homogenization. NLC were characterized regarding particle size, particle size distribution, zeta potential, entrapment efficiency and crystallinity. Moreover, permeability studies through the buccal mucosa were performed using in-vitro and ex-vivo models. Palmitic acid (solid lipid) and oleic acid (liquid lipid) in the ratio 9:1 were able to dissolve the highest amount of Domperidone. Particle diameters of about 280 nm and monomodal size distribution were obtained. A zeta potential higher than −30 mV was observed over a period of 28 days indicating good physical stability. NLC dispersed in saliva did not agglomerate and were actively internalized by buccal TR 146 cells without causing adverse side effects. Ex-vivo studies confirmed that Domperidone permeated the entire tissue. This leads to the conclusion that NLC are appropriate carrier systems that facilitate the transport of poorly soluble drugs across buccal and sublingual tissue.