Transepidermal delivery of beta-blocking agents: Evaluation of enhancer effects using stratum corneum lipid liposomes

The effect of the penetration enhancers Atone, 1-dodecanol, and dodecyl-2-(N,N-dimethylamino)propionate (DDAIP) on the structural integrity of liposomes composed of stratum corneum (SC) lipids was studied. With increasing enhancer concentration (0-1.5 mM) in the incubation medium (30% w/w aqueous ethanol), the lipid bilayer structure was found to become more disordered, as demonstrated by a decrease in 1,6-diphenyl-1,3,5-hexatriene (DPH) fluorescence anisotropy, and the efflux of the entrapped hydrophilic fluorescent marker, calcein, was found to increase. The lipid fluidizing effects of Atone and DDAIP were stronger than that of 1-dodecanol. In addition, transport of propranolol hydrochloride and sotalol hydrochloride, administered as solutions in 45% w/w aqueous ethanol containing 0-10 mM enhancer, was investigated across human epidermis in vitro. The flux enhancements of Atone and DDAIP were more pronounced with the hydrophilic sotalol and increased with increasing enhancer concentration, whereas 1-dodecanol was found to have a negligible effect. The flux of the lipophilic propranolol, on the other hand, was only slightly augmented by the enhancers. The lipid disordering effects and flux enhancement (especially that of the hydrophilic drug) followed a similar trend demonstrating the importance of SC lipid interactions as a mode of action of the enhancers studied.