This study focuses on the properties of topical vehicles based on alkylpolyglucoside natural surfactant-mixed emulsifier, cetearyl glucoside and cetearyl alcohol, in order to propose their use as "ready to use" pharmaceutical bases for a number of model drugs. We were interested to investigate how the alternative use of three lipophilic excipients (Ph. Eur. 6.0), differing in their polarity indexes (medium chain triglycerides (MG), decyl oleate (DO), and isopropyl myristate (IPM), respectively), affects the colloidal structure of the alkylpolyglucoside-based vehicles and in vitro permeation profiles of two model drugs: diclofenac sodium (DC) and caffeine (CF), both sparingly soluble in water. Finally, we aimed to evaluate the safety profile of such vehicles in vitro (acute skin irritation test using a cytotoxicity assay), comparing it with in vivo data obtained by the methods of skin bioengineering. The results have shown that the emulsion vehicles consisted of a complex colloidal structure of lamellar liquid crystalline and lamellar gel crystalline type. Varying of lipophilic excipient influenced noteworthy variations in the colloidal structure demonstrated as different rheological profiles accompanied to the certain degree by different water distribution modes, but notably provoked by drug nature (an amphiphilic electrolyte drug vs. nonelectrolyte). In vitro permeation data obtained using ASC membranes in an infinite dose-type of experiment stressed the importance of the vehicle/solute interactions in case of small variation in formulation composition, asserting the drug properties in the first hours of permeation and rheological profile of the vehicles in the later phase of experiment as decisive factors. In vitro skin irritation test demonstrated a mild nature of the emulsifying wax and the absence of negative effects of used oil phases on cell viability in formulation concentrations correspondent to the therapeutic need. This result alongside with data obtained from in vivo study, could additionally promote investigated topical vehicles as prospective "ready to use" pharmaceutical bases.